Idiopathic inflammatory myopathies: diagnosis, treatment and outcome van de Vlekkert, Janneke

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1 UvA-DARE (Digital Academic Repository) Idiopathic inflammatory myopathies: diagnosis, treatment and outcome van de Vlekkert, Janneke Link to publication Citation for published version (APA): van de Vlekkert, J. (2015). Idiopathic inflammatory myopathies: diagnosis, treatment and outcome General rights It is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons). Disclaimer/Complaints regulations If you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible. UvA-DARE is a service provided by the library of the University of Amsterdam ( Download date: 28 Dec 2018

2 Idiopathic inflammatory myopathies: diagnosis, treatment and outcome Janneke van de Vlekkert Idiopathic inflammatory myopathies: diagnosis, treatment and outcome Janneke van de Vlekkert

3 Idiopathic inflammatory myopathies: diagnosis, treatment and outcome Janneke van de Vlekkert

4 J. van de Vlekkert, Amsterdam, The Netherlands 2015 All rights reserved. No parts of this publication may be reported or transmitted, in any form or by any means, without permission of the author. Cover: gomori trichrome stain in a patient with IBM. Lay out: J. van de Vlekkert Printed by: Proefschriftmaken.nl ll Uitgeverij BOXPress ISBN: Funding: the research in this thesis was supported by a grant of the Prinses Beatrix Fonds. Publication of this thesis was made possible by financial support of: Biogen idec, UCB Pharma BV and Ipsen Farmaceutica BV.

5 Idiopathic inflammatory myopathies: diagnosis, treatment and outcome ACADEMISCH PROEFSCHRIFT ter verkrijging van de graad van doctor aan de Universiteit van Amsterdam op gezag van de Rector Magnificus prof. dr. D.C. van den Boom ten overstaan van een door het College voor Promoties ingestelde commissie, in het openbaar te verdedigen in de Agnietenkapel op 13 mei 2015, te uur door Janneke van de Vlekkert geboren te Zaandam

6 Promotiecommissie: Promotores: Prof. dr. M. de Visser, Universiteit van Amsterdam Prof. dr. R.J. de Haan, Universiteit van Amsterdam Co-promotor: Dr. J.E. Hoogendijk, Universiteit Utrecht Overige leden: Prof. dr. E.M.A. Aronica, Universiteit van Amsterdam Dr. U.A. Badrising, Universiteit Leiden Prof. dr. L.H. van den Berg, Universiteit Utrecht Prof. dr. J.W.J. Bijlsma, Universiteit van Amsterdam Dr. A.J. van der Kooi, Universiteit van Amsterdam Faculteit der Geneeskunde

7 Contents Chapter 1 General introduction 7 Diagnosis Chapter 2 Chapter 3 Combining MRI and muscle biopsy improves diagnostic accuracy in subacute-onset idiopathic inflammatory myopathy Muscle & Nerve 2015;51: Myositis with endomysial cell invasion indicates inclusion body myositis, even if other IBM criteria are not fulfilled Accepted for publication in Neuromuscular Disorders in revised version Treatment Chapter 4 Quality of case reports in myositis open to improvement. A systematic review Arthritis Care & Research 2004;51: Chapter 5 Oral dexamethasone pulse therapy versus daily prednisolone in sub-acute onset myositis, a randomised clinical trial Neuromuscular Disorders 2010;20: Outcome Chapter 6 Long-term follow up of 62 patients with myositis Journal of Neurology 2014;261: Chapter 7 Spontaneous recovery of dermatomyositis and unspecified myositis in three adult patients JNNP 2008;79: Chapter 8 General discussion Summary Samenvatting Dankwoord List of publications Curriculum vitae

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9 Chapter 1 General Introduction

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11 General introduction The idiopathic inflammatory myopathies (IIM) in adults are a heterogenic group of disorders characterized by muscle inflammation and progressive muscle weakness. This group consists of five subacute-onset disorders: polymyositis (PM) which is extremely rare, (clinically amyopathic) dermatomyositis (DM), nonspecific or overlap myositis (NSM), necrotizing autoimmune myopathy (NAM), and sporadic inclusion body myositis (IBM)(Table 1). 1 The number of entities is still expanding with increasing immunological developments. An autoimmune pathogenesis is presumed but the target antigens and the triggering factors in these diseases remain unknown as to date. Approximately 12-20% of patients 2-7 have an established concomitant autoimmune disease, mainly connective tissue diseases (like scleroderma, systemic lupus erythematosus, Sjögrenꞌs syndrome, rheumatoid arthritis, mixed connective tissue disease), and these are found mostly in patients with NSM (40%). 2 However, with the growing number of autoantibodies, nowadays most cases (up to 67%) of IIM occur in the setting of overlap syndromes. These are based on overlap features (like polyarthritis, Raynaudꞌs phenomenon) and overlap autoantibodies (like anti-synthestase, anti-signal recognition particle) but in the absence of an established connective tissue disease. 8 These overlap syndromes occur in over 50% of patients with DM, NSM and NAM. 9,10 There is also an increased frequency of malignancy in myositis. This association is strongest in DM patients (25%), but has also been described in PM (10-15%). 11,12 NAM can also be found as a paraneoplastic phenomenon. Malignancy may occur before, at the same time or within the first few years following the diagnosis of myositis. 1 9

12 Chapter 1 Table 1. Characteristics of the idiopathic inflammatory myopathies. PM DM OM/NSM NAM IBM Age Any age Any age Any age Any age >45 years Female:male :1 2-5:1 2-5:1 2-5:1 0.7:1 Disease course Subacute Subacute Subacute Subacute Slowly progressive Muscle Symmetrical proximal weakness Symmetrical proximal weakness Symmetrical proximal weakness Symmetrical proximal weakness Asymmetrical distal (fingerflexors) proximal (quadriceps) Skin None Periorbital heliotrope edema, Gottron papules, nailfold lesions None None None Myalgia Myalgia Myalgia Myalgia No myalgia No myalgia Serum CK Often elevated (to 50-fold) Often elevated (to 50-fold) Often elevated (to 50-fold) Always elevated IU/L Normal or slightly elevated Auto-antibodies Anti-Mi-2 Anti-MDA-5 Anti-TIF1- gamma Anti-NXP2 Anti-SAE Anti-synthetase (Jo1, PL-7, PL- 12, OJ, EJ, KS, Ha, Zo), anti- SS-A, anti-ss- B, anti-rnp, anti-pm-scl, anti-scl70 Anti-SRP Anti-HMGCR Anti-cytosolic5 PM=polymyositis, DM=dermatomyositis, OM=overlap myositis, NSM=nonspecific myositis, NAM=necrotizing autoimmune myopathy, IBM=inclusion body myositis. IBM is a completely different disease entity as compared to the other IIMs, with different epidemiological features, pattern of muscle weakness, and muscle biopsy findings and without a sustained response to treatment. Besides inflammation, there are also signs of muscle degeneration. 13 Because IBM does not improve with prednisone or immunosuppression in contrast to the other IIMs, the distinction is extremely important. 10

13 General introduction From 1975 onwards patients with PM and DM were classified based on the Bohan and Peter criteria in which the distinction between DM and PM was solely based on the presence or absence of typical skin abnormalities. 14,15 Currently subgroups of patients with a subacute myositis are found to have different clinical, histopathological and immunological findings and diagnostic criteria have changed accordingly. 1 Epidemiology The annual incidence of all IIM is around 8 per million population ( ) and the prevalence is 1400/ ( ). 16 In The Netherlands, about 120 patients each year will be diagnosed with an IIM. Most of them have IBM. The individual incidence of PM, DM, NSM and NAM is unknown. PM, DM, NSM and NAM are found more often in women than in men as is the case in many autoimmune disorders. IBM is diagnosed more frequently in men compared to women. The cause of this gender difference is unexplained as yet. Clinical features of IIMs In subacute-onset IIM (PM, DM, NSM and NAM) muscle weakness develops within weeks to months in a symmetrical and proximal distribution in the arms and legs, starting in de hip flexors and/or shoulder abductors, and extending to the neck flexors and distal muscles. 1 Myalgia, dysphagia, and extramuscular manifestations such as arthralgia, Raynaud s phenomenon and interstitial lung disease can occur. The heart can be involved in NAM associated with anti-srp antibodies. In DM, the typical rash may manifest as periorbital heliotrope edema, and can be present in the face, on the chest (V sign) and neck (shawl sign) and over extensor surfaces of the hands, fingers, elbows and knees (Gottron papules or Gottron sign), and nail fold lesions are also a frequent sign. 17 Calcinosis is found in 40% of patients with juvenile DM but rarely in adults. 18 In IBM muscle weakness and wasting develop slowly (over years), mostly in patients over 45 years old and is usually predominant in distal musculature. Asymmetrical weakness of deep finger flexors, quadriceps/iliopsoas muscles, and dysphagia are important clinical clues to the diagnosis

14 Chapter 1 Diagnosis The diagnosis is based on clinical, laboratory, and pathological examinations. Laboratory examination can support the diagnosis. Serum creatine kinase (CK) activity is often elevated. CK can be markedly high in NAM, but can be normal or mildly elevated in DM and IBM. Positive antinuclear antibodies (ANA) and antibodies to the extractable nuclear antigens (ENA) e.g., myositis associated antibodies (MAAs) such as anti-ss-a, anti-ss-b, anti-ribonucleoprotein (anti- RNP), anti-pm-scl, anti-scl 70 and anti-centromere antibodies can suggest a concomitant connective tissue disease. Myositis specific antigens (MSAs), are sometimes associated with specific syndromes, e.g., anti-jo1 antibodies (antisynthetase syndrome), anti-signal recognition particle (anti-srp; often severe, treatment resistant NAM), anti-mi-2 (DM), anti-melanoma differentiationassociated gene 5 (anti-mda-5; amyopathic DM with progressive interstitial lung disease), anti-transcriptional intermediary factor 1 gamma (anti-tif1-gamma; cancer associated DM), anti-nuclear matrix protein 2 (anti-nxp2; cancer associated DM), anti-small ubiquitin-like modifier activating enzyme (anti-sae; DM), anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (anti-hmgcr; NAM), and cytosolic 5'-nucleotidase 1A (IBM). 8,19-26 Except for patients with characteristic DM skin abnormalities or with a myositis in association with a known connective tissue disease, a muscle biopsy is necessary to confirm the diagnosis. In 10-20% the muscle biopsy is not conclusive. This may be due to sampling error caused by the scattered distribution of cell infiltrates even if a clinically affected muscle is chosen for biopsy. Muscle imaging, like muscle MRI could be helpful to select the most suitable biopsy site in order to decrease sampling error and thus reduce false negative findings. The histopathology in DM shows a complement-mediated microangiopathy with perifascicular atrophy (usually in later stages and more so in children than adults) and inflammatory cell infiltrates composed of macrophages, B-cells, plasmacytoid dendritic, and CD4 positive T-helper cells, located predominantly at perivascular sites in the perimysium In NAM, necrotic, atrophic and regenerating fibers surrounded by macrophages are found. There are only sparse or no inflammatory infiltrates. Pathogenesis is probably also immune mediated 12

15 General introduction because of the association with anti-srp and anti-hmgcr antibodies and the response to immunosuppressive treatment. 24,33-35 The histopathological findings described as diagnostic for PM consist of muscle fibre necrosis, regeneration, and endomysial mononuclear cell infiltrates surrounding and invading non-necrotic muscle fibres expressing major histocompatibility complex (MHC) class 1 antigens, consisting of CD8 positive cytotoxic T-cells, myeloid dendritic cells, plasma cells and macrophages This type of polymyositis is extremely rare. 39,40 Muscle biopsy specimens in IBM show the same type of endomysial inflammation as in PM. In addition, a histopathological diagnosis of IBM requires degenerative changes such as basophilic rimmed vacuoles, eosinophilic inclusions, and amyloid deposits. Degenerative changes, however, are not always present early in the disease and it has now been shown that many patients previously diagnosed with 'treatment resistant PM' turn out to have IBM based on repeat biopsies and the clinical picture. It has been suggested that it should be possible to diagnose IBM on the typical clinical features if for instance rimmed vacuoles are absent in the muscle biopsy, but not all IBM patients show all typical clinical features at onset. 1 Treatment Since the 1950s, oral high dose (1-1.5 mg/kg) corticosteroids have been the first line therapy in (sub)acute idiopathic inflammatory myopathies. After 4-6 weeks this is followed by slow tapering over a period of year. This treatment is generally accepted, on empirical grounds, but it causes considerable adverse effects with long-term use, and often relapses occur during tapering. Therefore, there is an urgent need for alternative first-line treatments. Immunosuppressive agents, such as azathioprine or methotrexate are often used in case of relapse, as steroid-sparing agent, or in case of rapidly progressive disease However no trials have shown the superiority of one of these agents over the others. In patients with refractory or severe disease intravenous immunoglobulin (IVIG) 45, intravenous methylprednisolone 46, rituximab 47 or enteracept 48 can be considered, albeit the evidence is not very solid. Interstitial lung disease is treated with high dose corticosteroids. In severe interstitial lung disease ciclophosphamide 49-52, azathioprine 49-52, methotrexate 49-52, ciclosporine 53,54 and tacrolimus 55 can be used. 13

16 Chapter 1 Because of the low incidence of subacute IIM it is difficult to enroll sufficient numbers of patients in randomised controlled trials (RCTs). RCTs give the best evidence about treatment effectivity, but when these types of trials are not available, case series and case reports can be taken into consideration. However, whereas there are clear criteria to guarantee the quality of RCTs, such criteria are not commonly applied in case reports, hampering their interpretation. Outcome It is generally assumed that subacute IIMs worsen if left untreated. However, there are no firm data to corroborate this notion, and the natural course of these disorders is largely unknown because patients are usually treated as soon as the diagnosis has been established. Spontaneous clinical improvement has been described before corticosteroid treatment was generally accepted as first line treatment Outcome of patients after treatment is mainly reported in retrospective studies. On the long term, myositis has a chronic continuous or polyphasic disease course in the majority of patients with major effects on perceived disability and quality of life. However, by using different classification criteria, definitions and outcome measures, the results from these studies vary widely. Therefore, prospectively obtained data on outcome would improve our knowledge of patients perspectives. 14

17 General introduction Aims and outline of this thesis To clarify some of the issues raised above we performed the following studies: 1 Diagnosis Chapter 2 describes the diagnostic value of the combination of MRI of the skeletal muscles and muscle biopsy in patients suspected of having a (sub)acute IIM. In chapter 3 we assessed the disease course in patients with endomysial inflammation with invasion of non-necrotic muscle fibers in the muscle biopsy which also showed rimmed vacuoles, or typical clinical IBM features but no rimmed vacuoles, or neither, hypothesizing that all these patients show a disease course consistent with IBM. Treatment In chapter 4 the quality of case reports on the treatment of myositis is assessed. In chapter 5 the results of the Dexa Myositis Trial are presented. In this RCT treatment with monthly pulsed oral dexamethasone was compared with daily oral prednisolone in newly-diagnosed patients with subacute myositis. Outcome Patients who participated in the Dexa Myositis Trial were followed and their disease course is described in Chapter 6. Chapter 7 reports the natural disease course of three patients with a proven subacute myositis who recovered spontaneously. 15

18 Chapter 1 References 1. Hoogendijk JE, Amato AA, Lecky BR, et al. 119th ENMC international workshop: trial design in adult idiopathic inflammatory myopathies, with the exception of inclusion body myositis, October 2003, Naarden, The Netherlands. Neuromuscul Disord. 2004;14: Bronner IM, van der Meulen MF, de Visser M, Kalmijn S, van Venrooij WJ, Voskuyl AE, et al. Long-term outcome in polymyositis and dermatomyositis. Ann Rheum Dis 2006;65(11): Shu XM, Lu X, Xie Y, Wang GC. Clinical characteristics and favorable long-term outcomes for patients with idiopathic inflammatory myopathies: a retrospective single center study in China. BMC Neurol 2011;11: Yu KH, Wu YJ, Kuo CF, See LC, Shen YM, Chang HC, et al. Survival analysis of patients with dermatomyositis and polymyositis: analysis of 192 Chinese cases. Clin Rheumatol 2011;30(12): Dankó K, Ponyi A, Constantin T, Borgulya G, Szegedi G. Long-term survival of patients with idiopathic inflammatory myopathies according to clinical features: a longitudinal study of 162 cases. Medicine 2004;83(1): Sultan SM, Ioannou Y, Moss K, Isenberg DA. Outcome in patients with idiopathic inflammatory myositis: morbidity and mortality. Rheumatology 2002;41(1): Ponyi A, Borgulya G, Constantin T, Váncsa A, Gergely L, Dankó K. Functional outcome and quality of life in adult patients with idiopathic inflammatory myositis. Rheumatology 2005;44(1): Troyanov Y, Targoff IN, Tremblay JL, et al. Novel classification of idiopathic inflammatory myopathies based on overlap syndrome features and autoantibodies: analysis of 100 French Canadian patients. Medicine 2005;84(4): Fernandez C, Bardin N, De Paula AM, et al. Correlation of clinicoserologic and pathologic classifications of inflammatory myopathies: study of 178 cases and guidelines for diagnosis. Medicine 2013 Jan;92(1): Troyanov Y, Targoff IN, Payette MP, et al. Redefining dermatomyositis: a description of new diagnostic criteria that differentiate pure dermatomyositis from overlap myositis with dermatomyositis features. Medicine 2014;93(24): Hill CL, Zhang Y, Sigurgeirsson B, et al. Frequency of specific cancer types in dermatomyositis and polymyositis: a population-based study. The Lancet 2001;357(9250): Zampieri S, Valente M, Adami N, et al. Polymyositis, dermatomyositis and malignancy: a further intriguing link. Autoimmun Rev. 2010;9(6): Griggs RC, Askanas V, DiMauro S, et al. Inclusion body myositis and myopathies. Ann Neurol 1995;38(5): Bohan A, Peter JB. Polymyositis and dermatomyositis (first of two parts). N Engl J Med Feb 13;292(7): Bohan A, Peter JB. Polymyositis and dermatomyositis (second of two parts). N Engl J Med Feb 20;292(8):

19 General introduction 16. Meyer A, Meyer N, Schaeffer M, Gottenberg JE, Geny B, Sibilia J. Incidence and prevalence of inflammatory myopathies: a systematic review. Rheumatology (Oxford) Jul 26. pii: keu Tanimoto K, Nakano K, Kano S et al. Classification criteria for polymyositis and dermatomyositis. J Rheumatol 1995;22(4): Wienel S, Callen JP. Calcinosis cutis complicating adult-onset dermatomyositis. Arch Dermatol 2004;140: Troyanov Y, Targoff IN, Tremblay JL, Goulet JR, Raymond Y, Senécal JL. Novel classification of idiopathic inflammatory myopathies based on overlap syndrome features and autoantibodies: analysis of 100 French Canadian patients. Medicine 2005;84(4): Marie I, Hatron PY, Dominique S, Cherin P, Mouthon L, Menard JF, et al. Short-term and long-term outcome of anti-jo1-positive patients with anti-ro52 antibody. Semin Arthritis Rheum 2012;41(6): Marie I, Lahaxe L, Benveniste O, Delavigne K, Adoue D, Mouthon L, et al. Long-term outcome of patients with polymyositis/dermatomyositis and anti-pm-scl antibody. Br J Dermatol 2010;162(2): Hoshino K, Muro Y, Sugiura K, Tomita Y, Nakashima R, Mimori T. Anti-MDA5 and anti- TIF1-gamma antibodies have clinical significance for patients with dermatomyositis. Rheumatology 2010;49(9): Bodoki L, Nagy-Vincze M, Griger Z, et al. Four dermatomyositis-specific autoantibodiesanti-tif1γ, anti-nxp2, anti-sae and anti-mda5-in adult and juvenile patients with idiopathic inflammatory myopathies in a Hungarian cohort. Autoimmun Rev Dec;13(12): Allenbach Y, Drouot L, Rigolet A, Charuel JL, Jouen F, Romero NB, et al. Anti- HMGCR autoantibodies in European patients with autoimmune necrotizing myopathies: inconstant exposure to statin. Medicine 2014;93(3): Pluk H, van Hoeve BJ, van Dooren SH, et al. Autoantibodies to cytosolic 5'-nucleotidase 1A in inclusion body myositis. Ann Neurol Mar;73(3): Larman HB, Salajegheh M, Nazareno R, et al. Cytosolic 5'-nucleotidase 1A autoimmunity in sporadic inclusion body myositis. Ann Neurol Mar;73(3): De Visser M, Emslie-Smith AM, Engel AG. Early ultrastructural alterations in adult dermatomyositis. Capillary abnormalities precede other structural changes in muscle. J Neurol Sci Dec;94(1-3): Emslie-Smith AM, Engel AG. Microvascular changes in early and advanced dermatomyositis: a quantitative study. Ann Neurol Apr;27(4): Griggs RC, Karpati G. The pathogenesis of dermatomyositis. Arch Neurol Jan;48(1): Dalakas MC. Polymyositis, dermatomyositis and inclusion-body myositis. N Engl J Med Nov 21;325(21): Carpenter S, Karpati G. The pathological diagnosis of specific inflammatory myopathies. Brain Pathol Jan;2(1): Dalakas MC. Immunopathogenesis of inflammatory myopathies. Ann Neurol May;37 Suppl 1:S

20 Chapter Bronner IM, Hoogendijk JE, Wintzen AR, van der Meulen MF, Linssen WH, Wokke JH, et al. M. Necrotising myopathy, an unusual presentation of a steroid-responsive myopathy. J Neurol 2003 Apr;250(4): Liang C, Needham M. Necrotizing autoimmune myopathy. Curr Opin Rheumatol 2011;23(6): Stenzel W, Goebel HH, Aronica E. Review: immune-mediated necrotizing myopathies--a heterogeneous group of diseases with specific myopathological features. Neuropathol Appl Neurobiol. 2012;38(7): Engel AG, Arahata K. Monoclonal antibody analysis of mononuclear cells in myopathies. II: Phenotypes of autoinvasive cells in polymyositis and inclusion body myositis. Ann Neurol Aug;16(2): Arahata K, Engel AG. Monoclonal antibody analysis of mononuclear cells in myopathies. I: Quantitation of subsets according to diagnosis and sites of accumulation and demonstration and counts of muscle fibers invaded by T cells. Ann Neurol Aug;16(2): Arahata K, Engel AG. Monoclonal antibody analysis of mononuclear cells in myopathies. III: Immunoelectron microscopy aspects of cell-mediated muscle fiber injury. Ann Neurol Feb;19(2): van der Meulen MF, Bronner IM, Hoogendijk JE, et al. Polymyositis: an overdiagnosed entity. Neurology 2003;61(3): Vilela VS, Prieto-González S, Milisenda JC, et al. Polymyositis, a very uncommon isolated disease: clinical and histological re-evaluation after long-term follow-up. Rheumatol Int Dec Bunch TW, Worthington JW, Combs JJ, Ilstrup DM, Engel AG. Azathioprine with prednisone for polymyositis. A controlled, clinical trial. Ann Intern Med 1980;92: Bunch TW. Azathioprine with prednisone for polymyositis: a long-term follow up. Arthritis Rheum 1981;24: Villalba L, Hicks JE, Adams EM, Sherman JB, Gourley MF, Leff RL, et al. Treatment of refractory myositis: a randomised crossover study of two new cytotoxic regimens. Arthritis Rheum 1998;41: Vencovsky J, Jarosova K, Machacek S, Studynkova J, Kafkova J, Bartunkova J, et al. Ciclosporine A versus methotrexate in the treatment of polymyositis and dermatomyositis. Scand J Rheumatol 2000;29: Dalakas MC, Illa I, Dambrosia JM, Soueidan SA, Stein DP, Otero C, et al. A controlled trial of high-dose intravenous immune globulin infusion as treatment for dermatomyositis. N Engl J Med 1993;329: Bolosiu HD, Man L, Rednic S. The effect of methylprednisolone pulse therapy in polymyositis/dermatomyositis. Adv Exp Med Biol. 1999;455: Oddis CV, Reed AM, Aggarwal R, Rider LG, Ascherman DP, Levesque MC, et al. Rituximab in the treatment of refractory adult and juvenile dermatomyositis and adult polymyositis: a randomized, placebo-phase trial. Arthritis Rheum. 2013;65(2): Muscle study group. A randomized, pilot trial of etanercept in dermatomyositis. Ann Neurol Sep;70(3):

21 General introduction 49. Schnabel A, Reuter M, Gross WL. Intravenous pulse ciclophosphamide in the treatment of interstitial lung disease due to collagen vascular diseases. Arthritis Rheum 1998;41: Marie I, Hachulla E, Chérin P, Dominique S, Hatron PY, Hellot MF, et al. Interstitial lung disease in polymyositis and dermatomyositis. Arthritis Rheum Dec 15;47(6): Schnabel A, Reuter M, Biederer J, Richter C, Gross WL. Interstitial lung disease in polymyositis and dermatomyositis: clinical course and response to treatment. Semin Arthritis Rheum Apr;32(5): Douglas WW, Tazelaar HD, Hartman TE, Hartman RP, Decker PA, Schroeder DR, Ryu JH. Polymyositis-dermatomyositis-associated interstitial lung disease. Am J Respir Crit Care Med Oct 1;164(7): Nawata Y, Kurasawa K, Takabayashi K, Miike S, Watanabe N, Hiraguri M, et al. Corticosteroid resistant interstitial pneumonitis in dermatomyositis/polymyositis: prediction and treatment with ciclosporine. J Rheumatol 1999;26: Gruhn WB, Diaz-Buxo JA. Ciclosporine treatment of steroid resistant interstitial pneumonitis associated with dermatomyositis/polymyositis. J Rheumatol 1987;14: Gordon P, Gooptu B. Tacrolimus in idiopathic inflammatory myopathyassociated interstitial lung disease: defining roles and responders. Rheumatology 2015;54(1): O'Leary PA, Waisman M. Dermatomyositis. A study of forty cases. Arch Derm Syphilol. 1940;41: Winkelmann RK, Mulder DW, Lambert EH, Howard FM, Jr., Diessner GR. Course of dermatomyositis-polymyositis: comparison of untreated and cortisone-treated patients. Mayo Clin.Proc. 1968;43: Jordan JR, Paruthi S, Pichardo RO, Challa VR, Donofrio PD, Jorizzo JL. Spontaneously remitting dermatomyositis. J Eur Acad Dermatol Venereol. 2004;18:

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23 Chapter 2 Combining MRI and muscle biopsy improves diagnostic accuracy in subacute-onset idiopathic inflammatory myopathy Janneke van de Vlekkert, Mario Maas, Jessica Hoogendijk, Marianne de Visser, Ivo van Schaik Muscle & Nerve 2015;51:

24 Chapter 2 Abstract Background: In 10-20% of patients with subacute-onset idiopathic inflammatory myopathy (IIM), muscle biopsy is normal or shows non-specific findings. MRI can be used as a triage test prior to muscle biopsy and as an add-on test if the biopsy is non-diagnostic. Methods: MRI scans of skeletal muscles and muscle biopsies were evaluated prospectively in 48 patients suspected to have IIM. The interpretations of MRI and muscle biopsy were compared with the definite diagnosis (based on ENMC criteria and response to corticosteroids). Results: The false negative rate (FNR) of all muscle biopsies was Biopsies of a muscle showing hyperintensity on MRI (as triage test) had an FNR of The result of MRI as an add-on test in patients with a non-diagnostic muscle biopsy decreased the FNR from 0.23 to Conclusion: We recommend both MRI and muscle biopsy in patients suspected of having IIM. 22

25 Combining MRI and muscle biopsy Introduction Adult subacute-onset idiopathic inflammatory myopathies (IIM) are subclassified into polymyositis (PM), dermatomyositis (DM), non-specific myositis (NSM), and necrotizing autoimmune myopathy (NAM). 1-4 Diagnosis is based on a combination of signs and symptoms, including symmetrical proximal muscle weakness and abnormalities on muscle biopsy. Estimation of serum creatine kinase (sck) activity, assessment of myositis-specific antibodies, and electromyography can be helpful, but these diagnostic tools lack sensitivity and, to a greater degree, specificity. A definite diagnosis requires signs of muscle fiber degeneration and regeneration. Inflammation usually is present in PM, DM, and NSM, but absent in NAM and sometimes also in the early stages of DM. Muscle biopsy is normal or shows non-specific findings in approximately 10-20% of patients, even in those with clinically active disease. 5,6 False negative findings may be due to sampling error caused by the scattered distribution of cell infiltrates, even if clinically affected muscles are chosen for biopsy. 7,8 Muscle imaging may be a promising diagnostic tool in IIM. Many imaging techniques, e.g., (contrast-enhanced) ultrasonography, MRI, MR spectroscopy, scintigraphy, and positron emission tomography have been evaluated for diagnostic purposes MRI can demonstrate muscle edema by showing areas of high signal intensity on STIR (short tau inversion recovery) and fat-suppressed T2-weighted sequences, even in clinically asymptomatic muscles. 13 Hyperintensity on MRI can also be found in patients with rhabdomyolysis, ischemia, and denervation. 14,15 MRI can be used as a triage or add-on test for evaluation of subacute-onset IIM. 16 In triage, MRI is used prior to the muscle biopsy to select the most suitable site in order to decrease sampling error and thus reduce false negative findings. Recommendations to perform MRI as a guide for muscle biopsy are based on 4 relatively small studies 17-20, and on studies including only patients with an established diagnosis of IIM. 15,21-28 MRI can also be helpful as an add-on test in patients with a negative muscle biopsy who have a clinical presentation consistent with subacute-onset IIM. Data to support this role have not been found in the literature. 2 23

26 Chapter 2 We assessed the diagnostic accuracy of skeletal muscle MRI as a triage test prior to muscle biopsy and as an add-on test in patients with a presumed diagnosis of subacute-onset IIM. Patients and Methods Patients Between January 2000 and January 2008, all adult patients seen consecutively in our outpatient neuromuscular clinic with a suspicion of subacute-onset IIM based on signs and symptoms and in whom a diagnostic muscle biopsy was considered underwent MR imaging. Signs and symptoms included symmetrical proximal muscle weakness without sensory abnormalities for less than a year. Patients were excluded if they met 1 of the following criteria:1) a high suspicion for sporadic inclusion body myositis (sibm) 29 ; 2) muscle biopsy performed elsewhere before referral; 3) other causes for the muscle complaints, i.e., the use of myotoxic medication (e.g., statins), viral diseases, or a positive family history for neuromuscular disease; 4) immunosuppressive treatment already started; 5) previous history of myositis; 6) contraindications for MRI; or 7) conditions which may hinder interpretation of MRI, such as hip implants. The length of follow up was defined as the time between MRI and time of data collection. Study interventions MRI at 1.5 Tesla of the upper arms or the thighs was performed, based on the distribution of muscle weakness, 2 weeks or less prior to biopsy. Sequences included axial T1 [TR (repetition time) 420msec, TE (echo time) 14msec, slice thickness 5 mm], axial fast spin echo T2-weighted sequences within fat suppression [TR 4000, TE 75, ETL (echo train length) 5, slice thickness 5] and coronal STIR [TR 4000, TE 69, TI (inversion time) 170 msec, ETL (echo train length) 12, slice thickness 5 mm]. An experienced radiologist (MM) assessed all MR images. He was aware that there was a clinical suspicion for subacute-onset IIM but did not have any other clinical details. He recommended the most suitable site for a muscle biopsy. The quadriceps muscle was the preferred site, 24

27 Combining MRI and muscle biopsy but another muscle was chosen if MRI showed a high signal elsewhere. The surgeon performed the open muscle biopsies under local anaesthesia. Needle electromyography was not done in any of the patients. The protocol for this study was reviewed with the Ethics committee who judged that their approval was not needed, because all investigations were part of standard diagnostic workup. 2 Study measures After the inclusion period the same radiologist reviewed all MRI scans blinded and in random order. The presence of high signal intensity on T2 weighted and STIR images in muscle, skin, subcutaneous fat, and fascia was assessed semiquantatively and scored according to the degree of muscle involvement (0 = less than 25%, 1 = 25-75%, 2 = more than 75%). In addition, on T1 weighted images the occurrence of fatty infiltration in skeletal muscle was assessed. A final judgement was made indicating whether: 1) the findings were in accordance with an inflammatory myopathy (high T2/STIR signal intensity), or 2) whether the MRI was normal or showed non-specific changes. These data were compared to the muscle biopsy findings. The muscle tissue was processed and stained routinely and read by a neurologist with extensive experience (MdV) who was unaware of clinical information and MRI findings. Immunohistochemical staining for subtypes of the inflammatory infiltrate and for MHC class I antigen, electron microscopy, and analysis of myositis-specific antibodies were not done routinely. Biopsies were labeled as: 1) PM, DM, NSM or NAM; 2) sibm or a different neuromuscular disease; or 3) normal/non-specific findings. The results from MR imaging, muscle pathology, and final diagnosis were compared. The final diagnosis (reference standard) was based on established expert criteria (ENMC workshop held in 2003) and a positive response to corticosteroids during follow up. 1 These criteria include clinical features (symmetrical subacute progressive proximal muscle weakness, rash in DM), and ancillary investigations such as laboratory and muscle biopsy analysis. A positive effect of corticosteroids was defined by improvement of symptoms and muscle strength as measured with manual muscle strength testing. Muscle biopsy findings were included in the final diagnosis, but normal muscle biopsy findings were allowed if clinical symptoms and response to treatment 25

28 Chapter 2 were compatible with the diagnosis, e.g., in early-onset DM, and if other diagnoses were excluded. Depending on the clinical signs and the results of the muscle biopsy, patients were diagnosed with DM (with or without malignancy), PM, NAM (with or without connective tissue disorder (CTD) or malignancy), and NSM (characterized by perimysial/perivascular mononuclear cell infiltrates) with or without a CTD. Statistical analysis Two-by-two tables were used to calculate sensitivity and specificity with 95% confidence limits and the false negative rate (FNR). To calculate negative and positive predictive value, an estimate of the a priori chance in addition to values of sensitivity and specificity is required. With these 3 parameters, we applied Bayesian analysis to obtain predictive values. Results Patient enrollment and patient characteristics Eighty-two patients with suspected subacute-onset IIM underwent MR imaging. Nineteen did not meet the inclusion criteria because they did not have muscle weakness on examination and therefore the suspicion of IIM was too low to consider a muscle biopsy. At follow up none of these 19 patients were eventually diagnosed as having IIM or turned out to have any other neuromuscular disorder. Fifteen patients met the exclusion criteria, leaving 48 patients for evaluation (31women and 17 men with a mean age (SD) of 50 (14) years]. Median followup was 2.2 years (range years). In 1 patient muscle biopsy was cancelled because of spontaneous complete recovery of muscle strength after MRI was done. sck value and MRI were normal. In the remaining 47 patients both MRI and muscle biopsy were done. Thirty-five of 48 patients (73%) had a final diagnosis of nonspecific myositis (NSM), NAM, or DM according to the reference standard defined in the methods section (7DM of whom 2 had an associated malignancy, 27 NSM of whom 13 had an associated CTD, and 1 NAM without malignancy or CTD). All 35 responded favorably to steroids with significant improvement or resolution of muscle 26

29 Combining MRI and muscle biopsy strength and normalization of sck. Endomysial inflammatory cell infiltrates surrounding (and invading) non necrotic muscle fibres were not found in any of the muscle biopsy specimens, thus not a single patient fulfilled the ENMC criteria for probable or definite PM. The remaining 13 patients were diagnosed as follows: no neuromuscular disease (6 patients with near-normal muscle biopsies, who did not develop a neuromuscular disorder during a median follow up of 2.2 years and whose weakness resolved spontaneously); non-specific myopathy (5 patients with mild non-specific abnormalities in the muscle biopsy, who did not develop a neuromuscular disorder during follow up); mitochondrial myopathy (1); and vasculitis (1). Twenty-eight of 35 patients (80%) with a final diagnosis of subacute-onset IIM had increased (more than twice the upper limit of normal) sck [mean 4367 (SD 5296); range IU/L] prior to diagnosis. 2 MRI findings MRI of the upper legs or arms was carried out as a triage test (prior to muscle biopsy) in 43 and 5 patients, respectively. T2-weighted and STIR images showed hyperintensity in skeletal muscles (MRI+) in 36 (75%), and results were normal or showed minimal hyperintensity (MRI-) in 12 (25%). Most patients with myositis (n=27, 93%) had a symmetrical distribution of high signal intensity, most frequently in the quadriceps muscles (n=22), but also commonly in the adductor (n=19) and hamstring muscles (n=16) (Figure 1). 27

30 Chapter 2 Figure 1 Example of axial fast spin echo T2-weighted sequences with fat suppression of the upper legs in a patient with myositis showing that signal intensity varies between muscles. In this patient the quadriceps muscles (long arrow) are predominantly affected while the hamstring muscles (short arrow) are relatively spared. MRI of the upper arms showed a high signal intensity in the triceps brachii (n=3) and deltoid muscles (n=2), sometimes in combination with high signal intensity in the supraspinatus (n=2) and pectoral muscles (n=1). In 48% of patients with myositis, the affected muscles were involved partially (between 25 and 75%). Usually the vastus lateralis muscle and to a lesser extent the vastus medialis or rectus femoris muscles were chosen for biopsy. Five patients with myositis had some signs of diffuse fatty infiltration, and 1 elderly patient had pronounced fatty infiltration of the muscle (4 had a concomitant connective tissue disease, and 2 had DM associated with malignancy). MRI findings in these 48 patients were compared with the final diagnosis (reference standard). MRI yielded a sensitivity of 0.91 (95% CI 0.78, 0.97) and specificity of 0.69 (95% CI 0.42, 0.87) (Table 1). 28

31 Combining MRI and muscle biopsy Table 1. Test parameters of MRI and muscle biopsy in patients suspected of subacute-onset idiopathic inflammatory myopathy. Sensitivity (95% CI) Specificity (95% CI) FNR 2 MRI (n=48) 0.91 (0.77, 0.98) 0.69 (0.39, 0.91) 0.09 Muscle biopsy (n=47) a 0.77 (0.60, 0.90) 1.0 (0.74, 1.0) 0.23 Muscle biopsy after MRI as triage 0.81 (0.64, 0.93) 1.0 (0.40, 1.0) 0.19 test (n=36) b MRI as add-on test to muscle biopsy 0.94 (0.81, 0.99) 0.67 (0.35, 0.90) 0.06 (n=47) c a All muscle biopsies; b Muscle biopsies guided by an abnormal MRI; c Results if one or both tests are positive; FNR = false negative rate In 32 of 36 patients with an MRI compatible with myositis, the diagnosis was confirmed by clinical and histological features. There were 4 false positive patients who eventually were considered to have a non-specific myopathy (3) or no neuromuscular disease (1). A muscle biopsy was performed in 47 patients (Table 2). In 36 of 47, the biopsy was taken from a weak muscle which showed hyperintensity on T2-weighted and STIR images; in the remaining 11 patients, MRI was normal, and a clinically weak muscle was chosen as biopsy site. The results of all 47 muscle biopsies showed a sensitivity of 0.77 (95% CI 0.61, 0.88) [FNR of 0.23 (n = 8), Table 1]. Biopsies from an MRI-positive muscle (n=36) had an FNR of Biopsies from an MRI-negative muscle (n=11) had a false negative rate of In 4 patients the suspected diagnosis could not be confirmed (Table 2). 29

32 Chapter 2 Table 2. Test results of MRI and muscle biopsy in 47 patients suspected of subacute-onset idiopathic inflammatory myopathy compared to final diagnosis (reference standard). IIM No IIM Total MRI + Biopsy MRI + Biopsy MRI Biopsy MRI Biopsy Total MRI + indicates that MRI results were compatible with a diagnosis of IIM; biopsy + indicates that the results of biopsy were compatible with a diagnosis of IIM. Analysis of the results of the MRI as an add-on test to the muscle biopsy in all 47 patients yielded a sensitivity of 0.94 (95% CI 0.81, 0.98) and specificity of 0.67 (95% CI 0.39, 0.86) (Table 1). MRI as an add-on test in all 20 patients with a negative muscle biopsy decreased the FNR from 0.23 for muscle biopsy alone to 0.06 at the expense of an increase in the false positive rate from 0.0 for muscle biopsy alone to Eight patients with a final diagnosis of subacute-onset IIM had a false negative muscle biopsy, and six of them had MRI hyperintensities (Table 2). Electron microscopy was done in 3 of the false negative biopsies and showed no microtubular inclusions indicative of DM or NSM. 30 In these 8 patients the final diagnosis [NSM with CTD (n=6), DM (n=2)] was based on the presence of subacute-onset progressive proximal muscle weakness and an increased sck (n=8; mean 3400, range IU/L), or skin abnormalities typical for DM (n=2). 31 All 8 responded favorably to immunosuppressive treatment with marked improvement in muscle strength and skin abnormalities and normalization of sck. 30

33 Combining MRI and muscle biopsy Applying the reference standard, the prevalence of subacute-onset IIM was 73% in our total patient sample (n=48). Table 3 summarizes the positive and negative predictive values for the 4 diagnostic strategies for the a priori chance of having a subacute-onset IIM. 2 Table 3. Positive and negative predictive values for prevalence in our patient sample PPV NPV Prevalence (%) MRI (n=48) Muscle biopsy (n=47) a Muscle biopsy after MRI as triage test (n=36) b MRI as add-on test to muscle biopsy (n=47) c a All muscle biopsies; b Muscle biopsies guided by an abnormal MRI; c Results if one or both tests are positive. PPV = positive predictive value, NPV = negative predictive value. 31

34 Chapter 2 Figure 2. The positive (A) and negative (B) predictive values, in percentages, plotted against the prior probability for IIM for 4 different diagnostic strategies. The dotted line represents the 80% positive and negative predictive values. Muscle biopsy and MRI-guided-muscle biopsy are equally good in avoiding false positives over a wide range of a priori chances of having IIM (Figure 2). MRI as an add-on test yields the lowest FNR over a wide range of a priori chances of not having IIM, especially between 30 and 70%. 32

35 Combining MRI and muscle biopsy Discussion This prospective study on the diagnostic accuracy of MRI as a triage test prior to muscle biopsy and as an add-on test in the diagnostic evaluation of 48 adult patients with possible subacute-onset IIM shows that MRI is a useful tool. MRI alone has a high sensitivity of 0.91 in diagnosing myositis, and MRI as an add-on test in patients with a negative muscle biopsy increases this sensitivity to The combination of the 2 tests with MRI as an add-on tool yields a false negative rate (FNR) of 0.06 in our study and the highest negative predictive value of all test strategies over a wide range of a priori chances of not having subacuteonset IIM. A muscle biopsy, even if it is normal or shows non-specific findings followed by an MRI showing hyperintensity of muscles, has a high positive predictive value (>80%) only if the a priori chance of having IIM is larger than 60%. If the a priori chance is between 50 and 70% (i.e., a priori chance of not having IIM between 30% and 50%), MRI as an add-on test reduces false negatives very efficiently (negative predictive value 92 to 96%) with very good positive predictive values of 74 to 87%. For a treatable disease like DM, NSM, or NAM, a low FNR is important, even if it is at the expense of a higher false positive rate. MRI can be false negative if disease activity is low, since there must be a certain level of inflammation to cause edema that can be visualized on MRI. 13,21 2 This study corroborates the results of previous studies in which MRI was found to be useful in diagnosing IIM. However, those studies were found to have methodological shortcomings. A prospective study of MRI-guided biopsies in 35 patients with possible myositis found 100% sensitivity of MRI in 11 with biopsyproven PM or DM. 10 It is of note that 11 out of 24 patients who were not diagnosed to have myositis had an autoimmune disease and elevated sck. Whether these patients received immunosuppressive treatment was not mentioned. Another relatively small study showed that MRI-guided biopsies in IIM are cost-effective. In this study 1 false-negative biopsy in 14 patients with myositis randomized for MRI-guided biopsy was found compared to 5 falsenegative biopsies in the 11 controls in whom no MRI was made. Four of the 5 required re-biopsy. The authors concluded that MRI prior to muscle biopsy is cost 33

36 Chapter 2 saving by reducing the need for repeat biopsies. 17 This group was different from ours because only patients with PM were included. Other studies compared MRI and biopsy data in those with an established diagnosis. They were limited by the small sample size, or biopsies and MRI were not performed from the same limb. MRI as an add-on test to muscle biopsy has not been investigated previously. A limitation of this study is the fact that muscle biopsies were guided by a high MRI signal in those with abnormal MRI. Ideally, muscle biopsies and MRI should have been investigated independently to appreciate the merits of the MRI as add-on or triage-tests. The usefulness of MRI can be improved by more precise targeting of the muscle biopsy. In conclusion, MRI has a high diagnostic accuracy in diagnosing a subacute-onset IIM, in particular as an add-on test to the muscle biopsy in patients with a negative muscle biopsy but an otherwise typical clinical presentation consistent with myositis. Furthermore, our results suggest that MRI may be useful as a triage test in reducing false negative muscle biopsies. Therefore, in patients presumed to have a subacute-onset idiopathic inflammatory myopathy we recommend both MRI and muscle biopsy. 34

37 Combining MRI and muscle biopsy References 1. Hoogendijk JE, Amato AA, Lecky BR, Choy EH, Lundberg IE, Rose MR et al. 119th ENMC international workshop: trial design in adult idiopathic inflammatory myopathies, with the exception of inclusion body myositis, October 2003, Naarden, The Netherlands. Neuromuscul Disord. 2004;14: Bronner IM, Hoogendijk JE, Wintzen AR, van der Meulen MF, Linssen WH, Wokke JH, et al. Necrotising myopathy, an unusual presentation of a steroid-responsive myopathy. J Neurol. 2003;250(4): Lian C, Needham M. Necrotizing autoimmune myopathy. Curr Opin Rheumatol. 2011;23(6): Amato AA, Barohn RJ. Evaluation and treatment of inflammatory myopathies. J Neurol Neurosurg Psychiatry. 2009;80: Bohan A, Peter JB, Bowman RL, Pearson CM. Computer-assisted analysis of 153 patients with polymyositis and dermatomyositis. Medicine (Baltimore). 1977;56: Bunch TW. Polymyositis: a case history approach to the differential diagnosis and treatment. Mayo Clin Proc. 1990;65: Plotz PH, Dalakas M, Leff RL, Love LA, Miller FW, Cronin ME. Current concepts in the idiopathic inflammatory myopathies: polymyositis, dermatomyositis, and related disorders. Ann Intern Med. 1989;111: Munsat T, Cancilla P. Polymyositis without inflammation. Bull Los Angeles Neurol Soc. 1974;39: von Kempis J, Kalden P, Gutfleisch J, Grimbacher B, Krause T, Uhl M et al. Diagnosis of idiopathic myositis: value of 99mtechnetium pyrophosphate muscle scintigraphy and magnetic resonance imaging in targeted muscle biopsy. Rheumatol Int. 1998;17: Weber MA, Jappe U, Essig M, Krix M, Ittrich C, Hagen Huttner B,et al. Contrast-enhanced ultrasound in dermatomyositis and polymyositis. J. Neurol. 2006;253: Garcia J. MRI in inflammatory myopathies. Skeletal Radiol. 2000;29: Kuo GP, Carrino JA. Skeletal muscle imaging and inflammatory myopathies. Curr Opin Rheumatol. 2007;19: Tomasova SJ, Charvat F, Jarosova K, Vencovsky J. The role of MRI in the assessment of polymyositis and dermatomyositis. Rheumatology (Oxford). 2007;46: Adams EM, Chow CK, Premkumar A, Plotz PH. The idiopathic inflammatory myopathies: spectrum of MR imaging findings. Radiographics. 1995;15: Schedel H, Reimers CD, Vogl T, Witt TN. Muscle edema in MR imaging of neuromuscular diseases. Acta Radiologica. 1995;3: Bossuyt PM, Irwig L, Glasziou P. Comparative accuracy: assessing new tests against existing diagnostic pathways. BMJ. 2006;332: Schweitzer ME, Fort J. Cost-effectiveness of MR imaging in evaluating polymyositis. AJR. 1995;165: O'Connell MJ, Powell T, Brennan D, Lynch T, McCarthy CJ, Eustace SJ. Whole-body MR imaging in the diagnosis of polymyositis. AJR. 2002;179:

38 Chapter Cantwell C, Ryan M, O'Connell M, Cunningham P, Brennan D, Costigan D, et al. A comparison of inflammatory myopathies at whole-body STIR MRI. Clin Radiol. 2005;60: Pitt AM, Fleckenstein JL, Greenlee RG, Burns DK, Wilson W, Haller R. MRI-guided biopsy in inflammatory myopathy: initial results. Magnetic Resonance Imaging. 1993;11: Fraser DD, Frank JA, Dalakas M, Miller FW, Hicks JE, Plotz P. Magnetic resonance imaging in the idiopathic inflammatory myopathies. J Rheumatol. 1991;18: Kaufman LD, Gruber BL, Gerstman DP, Kaell AT. Preliminary observations on the role of magnetic resonance imaging for polymyositis and dermatomyositis. Ann Rheum Dis. 1987;46: Dorph C, Englund P, Nennesmo I, Lundberg IE. Signs of inflammation in both symptomatic and asymptomatic muscles from patients with polymyositis and dermatomyositis. Ann Rheum Dis. 2006;65: Bartlett ML, Ginn L, Beitz L, Villalba ML, Plotz P, Bacharach SL. Quantitative assessment of myositis in thigh muscles using magnetic resonance imaging. Magn Res Imag. 1999;17: Fujino H, Kobayashi T, Goto I, Onitsuka H. Magnetic resonance imaging of the muscles in patients with polymyositis and dermatomyositis. Muscle Nerve. 1991;14: Reimers CD, Schedel H, Fleckenstein JL, et al. Magnetic resonance imaging of skeletal muscles in idiopathic inflammatory myopathies of adults. J. Neurol 1994;241: Löfberg M, Liewendahl K, Lamminen A, Korhola O, Somer H. Antimyosin scintigraphy compared with magnetic resonance imaging in inflammatory myopathies. Arch Neurol. 1998;55: Fujitake J, Ishikawa Y, Fuji H, Nishimura K, Hayakawa K, Tatsuoka Y. Magnetic resonance imaging of skeletal muscles in the polymyositis. Muscle Nerve. 1997;20: Needham M, Mastaglia FL. Inclusion body myositis: current pathogenetic concepts and diagnostic and therapeutic approaches. Lancet Neurol. 2007;6: Bronner IM, Hoogendijk JE, Veldman H, Ramkema M, van den Bergh Weerman MA, Rozemuller AJ, et al.tubuloreticular structures in different types of myositis: implications for pathogenesis. Ultrastruct Pathol. 2008;32: Tanimoto K, Nakano K, Kano S, et al. Classification criteria for polymyositis and dermatomyositis. J Rheumatol 1995;22:

39 Chapter 3 Myositis with endomysial cell invasion indicates inclusion body myositis, even if other IBM criteria are not fulfilled Janneke van de Vlekkert, Jessica Hoogendijk, Marianne de Visser Accepted for publication in Neuromuscular Disorders in revised version

40 Chapter 3 Abstract Objective: To investigate if patients with endomysial mononuclear cell infiltrates invading non-necrotic fibres have a disease course consistent with inclusion body myositis (IBM), irrespective of other histopathological and clinical characteristics. Methods: All patients with a muscle biopsy showing endomysial inflammation with invasion of non-necrotic muscle fibres during the period in two tertiary neuromuscular referral centers were classified into three groups: 1) patients whose biopsies also showed rimmed vacuoles; 2) patients whose biopsies showed no vacuoles but fulfilled clinical criteria for IBM, and 3) patients whose biopsies showed no vacuoles, and also did not fulfil clinical criteria for IBM (unclassified patients). These groups were compared with regard to age, gender, clinical features, and disease course including response to immunosuppressive treatment. Results: Eighty-one individuals (41 men) were included. Rimmed vacuoles were found in 49 patients (60.5%). Fourteen patients (17.3%) fulfilled clinical criteria for IBM and 18 patients (22.2%) were unclassified at presentation. At follow up (mean duration 9 years) three women remained unclassified (4%). There were no differences in disease course or effect of treatment between the three groups. Men had more often rimmed vacuoles than women (73% vs 48%; p= 0.018), and women more often than men were unclassified. Women tended to show more often temporary improvement if treated (p=0.07), but none had sustained improvement. Conclusions: Patients with a muscle biopsy showing endomysial cell infiltration with invasion of non-necrotic muscle fibers most probably have IBM, regardless of clinical and other pathological features. Women lack typical features more often than men. 38

41 Endomysial cell invasion indicates IBM Introduction Idiopathic inflammatory myopathies (IIMs) include polymyositis (PM), dermatomyositis (DM), nonspecific myositis, necrotizing autoimmune myopathy (NAM), and sporadic inclusion body myositis (IBM). 1 The diagnostic criteria for these IIMs have been going through different stages. The first set of criteria for PM and DM was developed by Bohan and Peter in ,3 Only skin abnormalities distinguish DM from PM. In 1984, Engel and Arahata described distinct histopathological differences between PM and DM. Pathologically, PM was defined by endomysial mononuclear cell infiltrates surrounding and invading nonnecrotic muscle fibres, muscle fibre necrosis and regeneration. 4-6 In 1973, Yunis and Samaha had introduced the term inclusion body myositis for a condition which was histopathologically characterized by eosinophilic intracellular inclusions, basophilic rimmed vacuoles, and tubulofilaments on electron microscopy. 7 The inflammation found in muscle biopsies of these patients was undistinguishable from that found in PM. 4,5 Gradually, clinical differences between IBM and PM became more important 1,8-10 and some patients diagnosed with PM turned out to have IBM at follow up raising doubt about the validity of endomysial localization of inflammation with invasion of nonnecrotic fibres as a diagnostic criterion for PM. 10,16,17 We investigated the disease course in patients with endomysial mononuclear cell infiltrates with invasion of non-necrotic fibres, hypothesizing that their disease course is in keeping with IBM and not PM, even if they did not fulfil histopathological or clinical criteria for IBM at onset. In addition we further characterized the patients who showed endomysial mononuclear inflammatory infiltrates with invasion of non-necrotic fibers but did not fulfil present criteria for IBM. 3 Methods Patients Medical records and biopsy slides from all adult patients diagnosed with an inflammatory myopathy during the years in two tertiary neuromuscular referral centers in The Netherlands were reviewed. Those patients meeting the following inclusion criteria were included in the study cohort: 1) 39

42 Chapter 3 frozen, hematoxylin and eosin stained sections of a muscle biopsy were available for re-evaluation; 2) endomysial mononuclear cell infiltrate invading non-necrotic muscle fibers was present; 3) sufficient clinical data at baseline and follow up were available. All muscle biopsies were read by the three authors who were unaware of the demographic, clinical and biochemical data and of the diagnosis made at the time of presentation. Presence of endomysial infiltrates, invasion by endomysially located mononuclear inflammatory cells of non-necrotic fibres, and presence of rimmed vacuoles had to be agreed upon by all investigators (see figure for illustrations). Figure. Infiltrates and vacuoles in muscle biopsies. A, B, and D: Invasion of non-necrotic muscle fibers by endomysially located mononuclear cells (arrows). C: perimysial, perivascular mononuclear cell infiltrate, spreading into the endomysium, no invasion. E: basophilic rimmed vacuoles. F: non-rimmed vacuoles in a degenerating muscle fiber. Hematoxylin and eosin stain. Patient characteristics used in analysis Muscle biopsy specimens of eligible patients were re-evaluated for the presence of rimmed vacuoles. Assessment of muscle biopsy findings and of the clinical data was done separately. All patients were examined by one of the three authors at first presentation. Data were extracted from clinical records of all 40

43 Endomysial cell invasion indicates IBM patients and additional information was obtained by personal contact or by questionnaires that were sent to patients who were no longer in our regular care. Of all eligible patients the following characteristics at onset of the disease were collected: gender; age of symptoms at onset; time until muscle biopsy; serum creatine kinase activity (sck); presence of myalgia and distribution of muscle weakness. The following data on the disease course were obtained through examination by the investigators or from the questionnaires, or extracted from the clinical records without knowledge of the muscle biopsy findings: myalgia, distribution of muscle weakness, the use of immunosuppressants and its effect (none, temporary improvement, sustained improvement of muscle signs and symptoms), course of the disease (improvement, stable over a period of years, variable but not progressive, slowly progressive (over years), rapidly progressive (over months)), and the presence of concomitant disease. In patients treated with corticosteroids special attention was paid to dose and duration. 3 Classification All patients were classified into one of three groups: 1) Patients with a histopathological diagnosis of IBM based on the presence of rimmed vacuoles; 2) Patients whose muscle biopsies showed no rimmed vacuoles but who fulfilled clinical criteria for IBM; 3) Patients whose muscle biopsies did not show rimmed vacuoles and did also not fulfil clinical criteria for IBM. The latter group was designated as unclassified. Clinical criteria for IBM included duration of weakness > 12 months at the time of diagnosis, age at onset >45 years, weakness of finger flexion muscles more than shoulder abduction muscles and knee extension muscles as weak as or weaker than hip flexor muscles. 9 Statistical analysis Analyses were performed with SPSS 17.0 for Windows. Continuous data were reported as median (range) or mean (SD) and analyzed with one-way Anova. Differences between categorized data were analyzed with Pearson Chi-Square or the Fisher s exact test. P values < 0.05 were considered significant. 41

44 Chapter 3 Results Patient classification Eighty-one patients were identified (41 men) with a mean age at presentation of 60 years (SD 11). Mean duration of follow up was 9 years (SD 5). Rimmed vacuoles were found in the muscle biopsy specimens of 49 patients (60%) of whom 30 out of 41 men and 19 out of 40 women (p=0.018). At onset, 14 patients (7 men, 7 women) out of the 32 without rimmed vacuoles fulfilled the clinical criteria for IBM, and 18 patients (4 men, 14 women, p=0.007) did not (Table 1). At follow up, 29 out of the 32 patients without rimmed vacuoles fulfilled the clinical criteria for IBM, and 3 did not, as described in more detail below. Table 1. Classification at baseline and at follow up in 81 patients with endomysial mononuclear cell infiltrates with invasion of non-necrotic muscle fibres RVs present Clinical IBM Unclassified At presentation N (%) 49 (60,5) 14 (17,3) 18 (22,2) At follow up N (%) ND 29 (36) 3 (4) RV: rimmed vacuoles; clinical IBM: rimmed vacuoles absent, but fulfilling clinical criteria for IBM; unclassified: fulfilling neither pathological nor clinical criteria for IBM; ND: not determined. Patients in the three groups did not differ with respect to age at first symptoms, time to first muscle biopsy, sck, duration of follow-up, and mode of data collection (Table 2). At onset but not at follow up, myalgia and symmetrical weakness were significantly more frequent in unclassified patients (p=0.038 and p=0.025, respectively). In the three patient groups (with rimmed vacuoles, patients with clinical IBM, unclassified patients) a concomitant autoimmune disease was found in 14, 29 and 33%, respectively (p=0.17) including systemic sclerosis, thyroid disease, sarcoidosis, rheumatoid arthritis, ulcerative colitis, coeliac disease, SLE and psoriasis. 42

45 Endomysial cell invasion indicates IBM Table 2. Characteristics at presentation and at follow up RVs present Clinical IBM Unclassified P value N=49 N=14 N=18 Age at presentation in yrs median (range) 64 (40-79) 54 (34-76) 60 (33-73) Time until biopsy in yrs 3 median (range) 3 (1-16) 4.5 (1-13) 2 (1-14) Duration of follow up, yrs median (range) 9 (1-28) 9.5 (2-15) 8 (1-14) Myalgia Presentation 2 (4%) 2 (15%) 5 (28%) Follow up 4 (8) 0 1(6%) Dysphagia Presentation 14 (29%) 2 (15%) 5 (28%) Follow up 29 (60%) 8 (62%) 10 (59%) Asymmetrical weakness Presentation 28 (60%) 6 (43%) 3 (18%) Follow up 36 (73%) 8 (62%) 9 (50%) 0.09 Concomitant auto-immune disease Presentation 7(15%) 1 (7%) 6 (33%) Follow up 7 (14%) 4 (29%) 6 (33%) sck at presentation < 12x upper limit of normal 37 (86%) 13 (93%) 17 (94%)

46 Chapter 3 Treatment and disease course Immunosuppressive or immunomodulating treatment was started in 21 out of 49 patients with rimmed vacuoles (43%), in 9 out of 14 patients without rimmed vacuoles but clinical IBM (64%), and in 12 out of 18 unclassified patients (67%), and included prednisolone (1-1.5 mg/kg for at least four weeks followed by slow tapering), methotrexate, intravenous immunoglobulins (IVIG), and different combinations mostly after failure of treatment with prednisolone. None of the treated patient showed sustained improvement. All patients stopped their treatment because of lack of sustained response and not because of side effects. There were no differences in response to treatment between the three groups. All three patients who remained unclassified at follow up were treated, and all three did not show any improvement. There were no differences in disease course between treated and untreated patients (Table 3). Table 3. Disease course Diagnosis at presentation RVs present Clinical IBM Unclassified P value N=49 N=14 N=18 Disease course Improvement No change Slow progression 49 (100%) 12 (88%) 16 (89%) Fluctuating course Rapid progression Treated 21 (43%) 9 (64%) 12 (67%) Effect of treatment Sustained improvement Temporary improvement 5 (24%) 3 (33%) 4 (33%) None 15 (71%) 6 (67%) 8 (67%) Unknown 1 (5%)

47 Endomysial cell invasion indicates IBM Slow progression was observed in all patients with histologically defined IBM. Slow progression was also found in 12 out of 14 patients with clinically defined IBM and 16 out of 18 unclassified patients. One patient with clinically defined IBM and one unclassified patient had not experienced any change in severity. One 70-year-old woman with clinically defined IBM had a fluctuating disease course without treatment during six years of follow up. One 33-year-old woman with unclassified disease deteriorated rapidly. In weeks, she developed progressive symmetrical weakness of proximal arm and leg muscles, abdominal and facial muscles and tongue. She experienced regurgitation of food through her nose and she had swollen fingers and eyelids without skin abnormalities. SCK was 2700 IU/L, anti-ana antibodies were positive and anti-jo1 antibodies were negative. MRI of her upper legs showed signs of edema in all quadriceps and adductor muscles. There were no signs of an infectious disease. Her muscle biopsy showed extensive degeneration and regeneration, many CD68 positive cells and CD4 positive T lymphocytes with endomysial localization and only little invasion of non-necrotic muscle fibers, and no COX negative fibers. She did not respond to high-dose corticosteroids and IVIG and was lost to follow up because she left the country and died abroad within one year after presentation. Besides this patient, there were two other patients who remained unclassified at follow up. One 66-year-old woman presented with slowly progressive symmetrical weakness of shoulder abductors and deep finger flexors and weakness of knee flexors and hip flexors with normal knee extensors strength. sck activity was 4 times elevated and she showed no response to corticosteroids during two years of treatment. MRI showed asymmetrical atrophy of knee extensors. She eventually died of a pneumonia and in cardiac failure. One 73-year-old patient had slowly progressive generalized symmetrical weakness and dysphagia. SCK activity was 2 times elevated. She showed no improvement after one year of corticosteroids and eventually needed a percutaneous endoscopic gastronomy tube and died of pneumonia. Six unclassified patients were not treated because they had a very slowly progressive disease course. This group consisted of 2 men and 4 women with a mean age of 58 years (SD 10), median duration of symptoms before muscle biopsy was 2 years, four patients presented with symmetrical weakness without myalgia, 1 patient had weakness of finger flexors. None had a raised sck. 3 45

48 Chapter 3 Gender differences Comparisons between men and women are shown in table 4. Table 4. Gender comparisons At presentation, N (%) Rimmed vacuoles present Clinical IBM Unclassified At follow-up, N (%) Clinical IBM Unclassified Myalgia Presentation Follow up Men N=41 30 (73%) 7 (17%) 4 (10%) 11 (27%) 0 5 (13%) * Women N=40 19 (48%) 7 (18%) 14 (35%) 18 (45%) 3 (8%) 4 (11%) 4 (10%) * 1 (3%) ** P value P=0.018 P=0.96 P=0.007 P=0.09 P=0.076 P=1.0 P=0.51 Dysphagia Presentation Follow up 7 (18%) * 20 (50%) * 27 (71%) ** P= (36%) P=0.12 * Asymmetrical weakness Presentation Follow up 22 (55%) * 27 (66%) 15 (39%) ** P= (65%) * P=1.0 Auto-immune disease at follow up (%) 4 (10%) 13 (33%) P=0.012 Treatment started 16 (39%) 26 (65%) P=0.019 Treatment effect Temporary improvement (% of treated 2 (13%) 10 (38%) P=0.073 patients) No improvement 14 (87%) 16 (62%) P=

49 Endomysial cell invasion indicates IBM Men Women P value N=41 N=40 Disease course Stable 0 2 (5%) Slowly progressive course 41 (100%) 36 (90%) P=0.24 Fluctuating 0 1 (2.5%) Rapidly progressive * = 1 missing value, ** = 2 missing values. 0 1 (2.5%) 3 Men had more often rimmed vacuoles in their muscle biopsy than women (73% vs 48%; p= 0.018). The proportion of men and women who were diagnosed with clinically defined IBM at presentation was not different (17% vs 18%; p=0.96), but women were more likely than men diagnosed as unclassified at presentation (35% vs 10%; p=0.007). Significantly more women than men had concomitant autoimmune diseases in the course of their disease (33% vs 10% p=0.012). No other clinical differences were found between men and women, including age at onset, time until biopsy and duration of follow up. Treatment was started more often in women than in men (65% vs 39%; p=0.02). If treatment was started, a temporary improvement was experienced by ten out of 26 women (38%) and two out of the 16 men (13%; p=0.07). Stable or slowly progressive disease was found in all men and in 38 of the 40 women (95%, p=0.24). One woman had a fluctuating disease course and another woman had rapidly progressive disease, as described in detail above. Discussion Inflammation and signs of myodegeneration are the histopathological hallmarks of sporadic IBM. The inflammation is located endomysially and shows invasion of non-necrotic muscle fibres. The degenerative signs include rimmed vacuoles, eosinophillic inclusions, amyloid deposits and tubulofilaments in the vicinity of the rimmed vacuoles at the ultrastructural level. Of these, rimmed vacuoles are the easiest to assess and therefore mostly used in daily clinical practice. However, they may be absent in patients who otherwise have all the typical clinical IBM features. A recent study has shown that there is no difference in disease course and response to treatment between patients who fulfil 47

50 Chapter 3 histopathological criteria and patients who fulfil clinical, but not all histopathological criteria. 18 It was postulated that typical clinical features should allow for a diagnosis of IBM, because typical pathological features such as rimmed vacuoles may develop later in the course of the disease. In clinical practice, however, patients whose muscle biopsy shows a mononuclear endomysial infiltrate with invasion of non-necrotic fibres, but no rimmed vacuoles, may present with a myopathy which does also not fulfil all clinical criteria for IBM. In the present study we demonstrate that the disease course in these patients did not differ from the disease course of patients who fulfil either histopathological or clinical criteria for IBM. None of these patients showed a sustained response to adequate corticosteroid treatment. In addition, most of these patients were found to have the clinical characteristics of IBM at follow up years after presentation. Apparently, not only the histopathological, but also the characteristic clinical features of IBM can develop over time. Our findings have implications for daily clinical practice and for therapeutic and diagnostic studies: since a patient with endomysial mononuclear cell infiltrates and invasion has a poor prognosis with respect to response to treatment, such a patient is at risk of being treated unjustly with long-term, harmful drugs. Inclusion of these patients in therapeutic trials in PM/DM may lead to an underestimation of treatment efficacy. Furthermore, inclusion of these patients as PM controls in diagnostic studies for IBM could lead to an underestimation of diagnostic specificity. In this respect, it is of note that in recent studies describing high specificity for IBM of auto-antibodies against cytosolic 5'- nucleotidase 1A, PM was not defined on the basis of endomysial infiltrates with invasion of non-necrotic fibres, but on the basis of other criteria, not including specific muscle biopsy abnormalities, 19,20 or on the basis of the presence of an endomysial infiltrate but not requiring invasion. 21,22 Our findings differ from those of other investigators. Firstly, among 146 patients diagnosed as either PM or IBM on the basis of their muscle biopsy, Chahin and Engel identified 27 patients who were diagnosed as PM based on subacute onset of predominant proximal weakness, an endomysial infiltrate and absence of clinical or pathological signs of IBM. 11 Among these 27 patients, 17 showed invasion of non-necrotic muscle fibres. Twenty-two patients showed improvement with treatment. Among the PM patients responsiveness to immunotherapy was not significantly different according to presence or absence 48

51 Endomysial cell invasion indicates IBM of invaded fibers in their biopsy specimens. Brady et al., in a study into the diagnostic value of pathological features for the diagnosis IBM, found invasion of non-necrotic fibres in two out of 11 patients with PM or DM, defined as a subacute limb girdle weakness, significantly raised CK, inflammation in a muscle biopsy and a sustained unequivocal clinical and biochemical response to steroid immunosuppression, with or without DM skin changes. 23 We cannot explain the disparity between these and our results, but it is of note that the follow up time in Chahin and Engel s study was about one-third on average of our follow up. Conspicuously, women with an endomysial mononuclear cell infiltrate with invasion of non-necrotic fibres more often than men lacked rimmed vacuoles, and far more often than men did also not fulfil clinical criteria for IBM at presentation, while duration of symptoms until presentation and the histopathological picture was comparable. Yet their disease course and response to treatment was not different from those in men and none of them showed a sustained improvement if treated. Almost all women without the clinical features of IBM at presentation were found to have these at follow up. There were three female patients who remained unclassified at follow up. In two, their older age, slowly progressive disease course and unresponsiveness to treatment made them otherwise indistinguishable from IBM. It should also be noted that these women, albeit not fulfilling all clinical criteria, both showed a clinical feature suggestive of IBM (deep finger flexor weakness and pronounced dysphagia, respectively), allowing for a diagnosis of probable IBM according to the 2011 ENMC criteria. 9 There was one remarkable patient showing a very rapid deterioration and unresponsiveness to adequate treatment, whose clinical and histopathological features did not match IBM but also not any other type of myositis. Our findings suggest that women may be underdiagnosed with IBM as compared to men. This is in line with the reported male predominance in IBM and the reported longer mean doctor s delay until diagnosis in women (3.5 versus 1.5 years) Also, in earlier studies patients without rimmed vacuoles ( possible IBM or PM/IBM or PM with COX negative fibres) were predominantly female, and case studies describing the presence of rimmed vacuoles only at repeated muscle biopsies mostly concerned women. 11,15,27,28 Thus, it seems that women develop typical pathological and clinical IBM features in the course of their disease. We cannot readily explain this gender difference. In IBM, both 3 49

52 Chapter 3 autoimmune and degenerative processes seem to play a role in the pathogenesis. It is conceivable that in women, autoimmune processes initially dominate, resulting in a 'PM-like' phenotype at presentation. This is suggested by the non-significant tendency in our female patients to show temporary improvement if treated. In conclusion, our data imply that 1) if immunosuppressive treatment is started in a patient with endomysial inflammation with invasion, this patient should be carefully monitored for treatment failure in order to prevent undue prolongation of ineffective, potential harmful treatment; 2) a muscle biopsy showing endomysial infiltrates with invasion should be an exclusion criterion in therapeutic studies on PM patients since these patients have a high a priori chance of being a non-responder; 3) women with IBM may be underdiagnosed. Acknowledgments: We thank Dr. WGM Spliet for providing the pictures shown in the figure. 50

53 Endomysial cell invasion indicates IBM References 1. Hoogendijk JE, Amato AA, Lecky BR, Choy EH, Lundberg IE, Rose MR et al. 119th ENMC international workshop: trial design in adult idiopathic inflammatory myopathies, with the exception of inclusion body myositis, October 2003, Naarden, The Netherlands. Neuromuscul Disord. 2004;14: Bohan A, Peter JB. Polymyositis and dermatomyositis (first of two parts). N Engl J Med Feb 13;292(7): Bohan A, Peter JB. Polymyositis and dermatomyositis (second of two parts). N Engl J Med Feb 20;292(8): Engel AG, Arahata K. Monoclonal antibody analysis of mononuclear cells in myopathies. II: Phenotypes of autoinvasive cells in polymyositis and inclusion body myositis. Ann Neurol Aug;16(2): Arahata K, Engel AG. Monoclonal antibody analysis of mononuclear cells in myopathies. I: Quantitation of subsets according to diagnosis and sites of accumulation and demonstration and counts of muscle fibers invaded by T cells. Ann Neurol Aug;16(2): Arahata K, Engel AG. Monoclonal antibody analysis of mononuclear cells in myopathies. III: Immunoelectron microscopy aspects of cell-mediated muscle fiber injury. Ann Neurol Feb;19(2): Yunis EJ, Samaha FJ. Inclusion body myositis. Lab Invest Sep;25(3): Benveniste O, Hilton-Jones D. International Workshop on Inclusion Body Myositis held at the Institute of Myology, Paris, on 29 May Neuromuscul Disord Jun;20(6): Rose MR; ENMC IBM Working Group. 188th ENMC International Workshop: Inclusion Body Myositis, 2-4 December 2011, Naarden, The Netherlands. Neuromuscul Disord Dec;23(12): Amato AA, Barohn RJ. Evaluation and treatment of inflammatory myopathies. J Neurol Neurosurg Psychiatry Oct;80(10): Chahin N, Engel AG. Correlation of muscle biopsy, clinical course, and outcome in PM and sporadic IBM. Neurology 2008 Feb 5;70(6): Dalakas MC, Hohlfeld R. Polymyositis and dermatomyositis. The Lancet 2003;362: Dalakas MC. Sporadic inclusion body myositis diagnosis, pathogenesis and therapeutic strategies. Nat Clin Pract Neurol. 2006;Aug;2(8): van der Meulen MF, Bronner IM, Hoogendijk JE, et al. Polymyositis: an overdiagnosed entity. Neurology 2003 Aug 12;61(3): van der Meulen MF, Hoogendijk JE, Jansen GH, et al. Absence of characteristic features in two patients with inclusion body myositis. J Neurol Neurosurg Psychiatry 1998 Mar;64(3): Hengstman GJ, van Engelen BG. Polymyositis, invasion of non-necrotic muscle fibres, and the art of repetition. BMJ Dec 18;329(7480): Bradley WG. Polymyositis: an overdiagnosed entity. Neurology 2004 Jul 27;63(2):

54 Chapter Brady S, Squier W, Hilton-Jones D. Clinical assessment determines the diagnosis of inclusion body myositis independently of pathological features. J Neurol Neurosurg Psychiatry 2013 Nov;84(11): Pluk H, van Hoeve BJ, van Dooren SH, et al. Autoantibodies to cytosolic 5'-nucleotidase 1A in inclusion body myositis. Ann Neurol Mar;73(3): Tanimoto K1, Nakano K, Kano S, et al. Classification criteria for polymyositis and dermatomyositis. J Rheumatol Apr;22(4): Larman HB, Salajegheh M, Nazareno R, et al. Cytosolic 5'-nucleotidase 1A autoimmunity in sporadic inclusion body myositis. Ann Neurol Mar;73(3): Greenberg SA. Cytoplasmic 5'-Nucleotidase Autoantibodies in Inclusion Body Myositis: Isotypes and Diagnostic Utility. Muscle Nerve 2014 Oct;50(4): Brady S, Squier W, Sewry C, et al. A retrospective cohort study identifying the principal pathological features useful in the diagnosis of inclusion body myositis. BMJ Open Apr 28;4(4):e Badrising UA, Maat-Schieman MLC, van Duinen SG, et al. Epidemiology of Inclusion Body Myositis in the Netherlands: a nationwide study. Neurology 2000;55: Nakanishi H, Koike H, Matsuo K, et al. Demographic features of Japanese patients with sporadic inclusion body myositis: a single-center referral experience. Intern Med. 2013;52(3): Lotz BP, Engel AG, Nishino H, et al. Inclusion body myositis. Observations in 40 patients. Brain 1989 Jun;112 (Pt 3): Blume G, Pestronk A, Frank B, et al. Polymyositis with cytochrome oxidase negative muscle fibres. Early quadriceps weakness and poor response to immunosuppressive therapy. Brain 1997 Jan;120: Calabrese LH, Mitsumoto H, Chou SM. Inclusion body myositis presenting as treatmentresistant polymyositis. Arthritis Rheum Apr;30(4):

55 Chapter 4 Quality of case reports in myositis open to improvement. A systematic review Janneke van de Vlekkert Manuel Tjin-A-Ton Jessica Hoogendijk Arthritis Care & Research 2004;51:

56 Chapter 4 To the Editor: Polymyositis (PM) and dermatomyositis (DM) are idiopathic inflammatory myopathies with a presumed autoimmune pathogenesis. 1,2 The generally accepted first choice therapy is high-dose prednisone. 2 When this treatment fails, because of insufficient improvement, frequent relapses during tapering of the dose, or unacceptable side effects, a second line therapy is started. Many different treatments are being used for the second line treatments in PM and DM, and there is no consensus on best choice. 2 Efficacy of therapies can only be assessed appropriately with randomized controlled trials (RCTs). When RCTs are not available, other types of controlled studies can be useful, although they provide a lower level of evidence because of their obvious potential of biases. If there are not sufficient controlled studies to make a treatment decision, as is often the case in rare diseases, the clinician is confined to reports of uncontrolled observations and the opinion of experts. 3 For RCTs, criteria for good quality have been well established 4, and are applied widely. Criteria for a clear and adequate description of single cases and case series have also been formulated 5, but the methodological quality of this type of evidence in published reports has never been evaluated. 6 This hampers the appreciation of their validity and practical value. Controlled studies in PM and DM are extremely rare, but, in contrast, there is a large body of reported single cases and uncontrolled case series. We undertook a study to assess the quality of reported descriptions of uncontrolled observations on the second line treatment of polymyositis (PM) and dermatomyositis (DM). Single case reports and case series reports on second line therapy in adult DM, PM, myositis associated with a connective tissue disease or with malignancy were found by electronic searching Medline and Embase for publications in English, French or German between 1966 through 2001 using the terms dermatomyositis, polymyositis, inflammatory myopathy, treatment and therapy. We hand-searched all reference lists of identified publications and of relevant review papers for additional publications. Excluded were controlled studies, abstracts and publications on inclusion body myositis, juvenile DM, and aspects other than weakness (e.g. pulmonary involvement). 54

57 Quality of case reports in myositis Two investigators systematically and independently examined all eligible studies. A third investigator was involved to resolve differences by discussion. All articles were examined against ten criteria for a clear and adequate case description, which were chosen with the intention that a clinician should be able to recognise his or her own patient as the patient described in the study, copy the described treatment, and get a fair impression of the treatment effects. 5 On the basis of these requirements we arbitrarily pre-designed the following ten criteria: 1) sex and age; 2) credible diagnosis; clear description of 3) disease duration, 4) previous therapies, and 5) severity of the disease at start of second line treatment; 6) reason for failure of previous treatments; 7) dose, mode of administration and duration of the second line therapy; 8) clear description of effect of the therapy on muscle strength or function; 9) description of side effects; 10) follow up at least six months (because of the chronicity of these diseases). For a credible diagnosis of DM reference to Bohan and Peters criteria sufficed 1, but a mere reference to these diagnostic criteria was accepted for PM only if it was clear from the text that the symptoms had evolved over weeks to months. This criterion was chosen as a feasible attempt to rule out inclusion body myositis and muscular dystrophies (obviously, nowadays specific investigations of muscle biopsy material are considered to be required for an accurate diagnosis of PM). By applying this criterion we may have judge the diagnosis as uncredible in some patients with slowly evolving PM. Severity of disease before and after second line treatment was preferably described in terms of MRC scores, dynamometry or accepted scales of disability or handicap, but we also accepted any ad hoc scales, and mere descriptions of functional abilities as long as this gave a fair impression of muscle strength or function. A clear description of the reason for failure of previous treatments was considered mandatory, because the therapeutic prospects are probably quite different for a patient who had improved on prednisone, but did not tolerate it, than for a patient who did not benefit from previous therapies. We separately analysed articles published before and after 1985 (when evidence-based medicine became into general use), and we made a distinction between single case reports (in which the patient or patients are described individually) and case series reports (in which patients are described as a group). 4 55

58 Chapter 4 We identified 148 publications of which 92 were eligible for the study (references available from the authors). These 92 publications described a total of 915 patients (median 2 per publication; 75th centile 7). Ninety-two patients were described twice or more in different articles. There were 74 single case reports and 18 case series reports. Seventy-seven percent of the studies was retrospective, 14% was prospective, and in 9% this was equivocal. 40 percentage of patients number of fulfilled criteria The number of fulfilled criteria per publication is shown in the figure. All 10 criteria were fulfilled in nine publications (10%), describing 2.6% of all patients. All these 9 articles were single case reports (references available from the authors). The number of publications fulfilling each criterion is shown in the table. Four criteria (previous treatment, reason for start second line treatment, and disease severity before and after treatment) were met in less than 50% of described patients. For example, treatment results were often indicated merely in terms of e.g. remarkable improvement of strength, better than ever, doing well and muscle condition satisfactory. Nine criteria were fulfilled in single case reports more often than in case series reports. Reports published after 1985 did not do better than earlier publications (figure). 56

59 Quality of case reports in myositis Table. Number of publications and patients fulfilling criteria for good quality Criteria Single case Case series Patients reports 1 (%) reports 1 (%) (%) Sex and age 73 (99) 15 (83) 692 (76) 4 2. Credible diagnosis 58 (78) 13 (72) 473 (52) 3. Duration of disease prior to 2nd line treatment 68 (92) 10 (56) 598 (65) 4. Previous treatment 36 (49) 4 (22) 311 (34) 5. Disease severity prior to 2nd line treatment 43 (58) 3 (17) 265 (29) 6. Reason for starting 2nd line treatment 66 (89) 7 (39) 357 (39) 7. Dose and scheme 2nd line treatment 74 (100) 15 (83) 716 (78) 8. Disease severity after 2nd treatment 51 (69) 6 (33) 434 (47) 9. Side effects 51 (69) 15 (83) 738 (81) 10. Follow up at least 6 months 56 (76) 10 (56) 593 (65) 1 : Articles were considered fulfilling a specific criterion if at least one patient described in this article fulfilled that criterion. In conclusion, we found the methodology of patient descriptions (the evidence) in single case reports and case series reports on second-line treatments in PM and DM unsatisfactory. Therefore, the added value of these reports for making treatment decisions in clinical practice, or for identifying new treatments of interest is dubious. Also, any attempts at doing a systematic review of treatment results reported in these articles should be considered unrealistic 6. It is noted that readers have a better change to find relevant and complete information in 57

60 Chapter 4 single case reports than in reports of large series of patients (see table). Our results further show that introduction of the principles of evidence-based medicine in recent years has not lead to more adequate data presentation in these types of studies as yet. We conclude that reports of uncontrolled observations can improve considerably if criteria for good quality are taken into account. References 1. Bohan A, Peter JB. Polymyositis and dermatomyositis. N Engl J Med 1975;292: Dalakas M.C. Polymyositis, dermatomyositis and inclusion-body myositis. N Engl J Med 1991; 325; Barton S. Which clinical studies provide the best evidence? BMJ 2000;321: Moher D, Schulz K, Altman D. The CONSORT statement: revised recommendations for improving the quality of reports of parallel-group randomised trials. Lancet 2001;357: Huston P, Squires BP. Case reports: information for authors and peer reviewers. Can Med Assoc J 1996;154: Jenicek M. Clinical case reporting in evidence-based medicine. 2nd ed. Holder Headline Group, London and Oxford University Press Inc., New York

61 Chapter 5 Oral dexamethasone pulse therapy versus daily prednisolone in sub-acute onset myositis, a randomised clinical trial Janneke van de Vlekkert, Jessica Hoogendijk, Rob de Haan, Ale Algra, Ingeborg van der Tweel, Ludo van der Pol, Esther Uijtendaal, Marianne de Visser Neuromuscular Disorders 2010;20:

62 Chapter 5 Abstract Objective: To determine if high-dose pulsed dexamethasone is more effective and safer than daily high-dose prednisolone in treatment-naive adult patients with inflammatory myopathies (sporadic inclusion body myositis excluded) we performed a multicenter, double-blind randomised controlled clinical trial with 18 months follow up. Methods: Sixty-two patients were randomised into 28-day cycles of oral highdose dexamethasone or daily high-dose prednisolone. Primary outcome measures included 1) seven point composite score of six clinically relevant outcomes and 2) (time-to) remission and (time-to) relapse. Results: No difference between both treatment groups on the composite score was found. Side effects occurred significantly less frequently in the dexamethasone group. Median time to relapse was 60 (2.9) weeks in the prednisolone and 44 (4.7) weeks in the dexamethasone group (log-rank test p=0.03). Conclusion: Pulsed high-dose oral dexamethasone is not superior to daily prednisolone as first-line treatment of idiopathic inflammatory myopathies, but is a good alternative by causing substantially fewer side effects. 60

63 Dexamethasone pulse therapy Introduction Dermatomyositis, polymyositis, and non-specific myositis are immune-mediated myopathies and have an estimated prevalence of one per 100,000 population. These disorders are characterised by subacute-onset, progressive muscle weakness and inflammation in the skeletal muscle. They often cause severe chronic disability, and may be complicated by life-threatening impairment of swallowing and lung function. 1 First-line treatment consists of a four week course of high-dose daily oral prednisone (1-1.5 mg/kg/day), followed by slow tapering to prevent relapses, although this has never been investigated in a placebo-controlled trial. 2 This long-term treatment with corticosteroids is often complicated by debilitating side effects such as diabetes mellitus, hypertension, mood changes, weight gain, gastric symptoms and osteoporosis. To perform a placebo-controlled trial would nowadays be considered unethical. Other immunosuppressive drugs can be used as add-on medication but are usually not as effective, stressing the need for alternative first-line treatment strategies with fewer side effects. 3 Oral dexamethasone is seven times more potent than prednisone and pulsed schemes have been successfully used in other autoimmune diseases as an alternative to prednisone.4-11 Dexamethasone was well tolerated with fewer side effects than prednisone. Previously, we performed a small open-label study with pulsed dexamethasone as initial first-line treatment on patients with idiopathic inflammatory myopathies, sporadic inclusion body myositis (sibm) excluded, who showed a quick improvement without severe side effects. 12 Based on these promising results we initiated a clinical trial to investigate whether high-dose pulsed oral dexamethasone is more effective and safer than daily high-dose prednisolone as first-line treatment in newly diagnosed adult patients with myositis. 5 Methods We performed a multicentre, double-blind, randomised trial with 18 months follow-up. Patients consent was obtained according to the Declaration of Helsinki. The study protocol was approved by the medical ethics committees of 61

64 Chapter 5 all participating hospitals. Written informed consent was obtained from all patients before study entry. The Data Safety Monitoring Board comprised an independent neurologist, a biostatistician and a clinical epidemiologist who monitored possibly unfavourable events and the progress during the study period, and who performed interim analyses. The International Standard Randomized Controlled Trials number, ISRCTN is Patients Patients were recruited from Neurological and Rheumatologic Departments from all major hospitals in the Netherlands. Inclusion criteria were as follows: 1) less than one year duration of symmetrical proximal muscle weakness, and 2) one of the following sets of criteria a) increase in serum creatine kinase (sck) activity (more than two times the upper limit of normal) and endomysial mononuclear cell infiltrates surrounding and invading non-necrotic muscle fibers (this category was designated polymyositis) 13 ; b) characteristic skin abnormalities (i.e., Gottron s sign or papules, heliotrope perorbital oedema) 14 or perifascicular atrophy in combination with a perimysial/perivascular mononuclear cell infiltrate (designated as dermatomyositis) 15 ; c) increase in sck activity and perimysial/perivascular mononuclear cell infiltrate without signs compatible with a diagnosis of polymyositis or dermatomyositis (designated as non-specific myositis). 15 This last definition was established during an international expert consensus meeting and includes patients with clinical PM with muscle weakness on physical examination combined with inflammation in the muscle biopsy who do not fulfil the biopsy criteria for PM. Immunophenotyping of lymphocytes, MHC-I staining and myositis specific antigens were not routinely done when we started the trial and were as such not part of the definitions established at the consensus meeting. Patients were stratified according to the diagnosis: polymyositis, dermatomyositis, non-specific myositis, myositis with a co-existing connective tissue disease or with cancer within two years before onset of myositis. Exclusion criteria were the following: 1) age less than 18 years, 2) positive family history for proximal muscle weakness, 3) three rimmed vacuoles per 1000 muscle fibers, 4) rapid increase and spontaneous decrease in sck activity, 5) contra-indication to use corticosteroids, 6) (planned) pregnancy, 7) use of 62

65 Dexamethasone pulse therapy more than 20 mg prednisone/day or other immunosuppressant or immunomodulatory treatment. Study interventions Patients were randomised to oral prednisolone or oral dexamethasone. Prednisolone was started at a dose of 70 mg/day (body weight < 70 kg) or 90 mg/day ( 70 kg body weight) for 28 days, followed by a slow tapering scheme during 44 or 52 weeks, depending on the initial dose. The dosage decreased every week with 5 mg every other day (e.g., day /85 mg every other day; day /80 mg every other day). Dexamethasone was given as six cycles of 40 mg/day for 4 consecutive days at 28-day intervals. Randomisation was performed by the pharmacist of one of the organising hospitals (University Medical Center Utrecht) with a computer-generated randomisation list, applying stratification by diagnosis. Patients, investigator and treating physicians were blinded for the treatment until the study was completed. All patients took an equal number of identical-looking capsules for a period of 52 weeks, regardless of their treatment assignment. On drug-free days and after six months of pulsed dexamethasone therapy, placebo capsules were administered to all patients. Patients were asked at each visit if they had continued taking all medication and week numbers were checked. No other immunosuppressive drugs were allowed. All patients received osteoporosis prophylaxis consisting of alendronate (70 mg/week), calcium (1000 mg/day) and vitamin D (400 IE/day). The prescription of physiotherapy or drugs to prevent or treat adverse effects was at the discretion of the treating physician. 5 Assessment of outcome All patients were evaluated by one experienced investigator (JV). Patient characteristics were collected at baseline. Follow-up visits were planned at one and three months, and subsequently every three months for 18 months (seven follow-up visits). This length of follow up was chosen because of the expected slow improvement and long duration of treatment. There were two primary outcome measures: 1) a composite score of measures for favorable outcome at 18 months of follow up or at the time point of discontinuation of the trial; 2) (time to) remission and relapse. 63

66 Chapter 5 A maximum of seven points on the composite score could be gained on the following six items: 1) score on modified Rankin scale of 0 (no symptoms) or 1 (no significant disability despite symptoms) 16 (2 points); 2) remission within three months (1 point) ; 3) no relapse (1 point); 4) a Medical Research Council (MRC) manual muscle strength testing scale (0-5) sum score of at least 138 out of 140 in 15 muscle groups (1 point); 5) a score of 0-2 out of 10 on the VAS for muscle pain (1 point); and 6) no cushingoid appearance (1 point). The MRC sum score was composed from strength-testing in the following 15 muscle groups: neck flexors, neck extensors, m. deltoideus, m. biceps brachii, m. triceps brachii, wrist flexors, wrist extensors, finger flexors, finger extensors, hip abductors, m. iliopsoas, m. quadriceps femoris, hamstrings, ankle flexors, ankle extensors. The maximum score for each muscle is 5 points (normal strength). With the exception of the neck muscles, all muscles were tested on both sides. Remission was defined as a Rankin score of 0-1 out of a maximum score of 5. Relapse was defined as deterioration of muscle weakness and daily functioning perceived by the patient (in association with 1) a decrease in MRC sum score of four points or 2) reduction in Rankin score of one point, or 3) a more than two times increase in sck activity. An asymptomatic increase in sck activity was not considered a relapse. Measurements were repeated when an increased sck activity was not combined with a decrease in strength or function. Time until remission and relapse was defined as the period between baseline and the moment the patient fulfilled the definition of remission or relapse. The presence of a cushingoid appearance was assessed by three investigators (JV, JH, MdV) independently comparing photographs at baseline and at follow up. In case of different scores, consensus was reached after discussion. Secondary outcome measures included treatment failures, adverse effects, sck activity, Rankin score (0-5), MRC sum score, presence and VAS for pain (0-10), dysphagia and skin changes (in dermatomyositis), presence of arthralgia or Raynaud s phenomenon, Neuromuscular Symptom Score (20 items in daily functioning with a maximum score of 60) 17, and the Short Form-36 (SF-36) as a measure for quality of life. 18 Patients were not systematically screened for lung or cardiac involvement. Treatment was considered a failure leading to discontinuation of study medication and determination of endpoints in case of 1) no improvement or 64

67 Dexamethasone pulse therapy further deterioration of muscle weakness after three months of receiving study medication; 2) MRC sum score < 120 or Rankin score 4-5 or serious dermatomyositis skin abnormalities or serious lung complications requiring additional treatment after three months of receiving study medication; 3) relapse within six months after onset of trial medication. In these circumstances further treatment was at the discretion of the treating physicians. When a relapse occurred after six months following significant improvement, patients double-blindly restarted their initial trial medication (dexamethasone three extra cycles and prednisone in starting dose). At each visit the investigator systematically documented the outcome parameters, adverse events, serum glucose level, body weight and blood pressure. Ophthalmological examination for glaucoma or cataract and dual energy X-ray absorptiometry (DXA) of the lumbar spine was performed at baseline and at follow up. Osteoporosis was defined as a significantly reduced bone mineral density according to the WHO classification (T score -2.5 SD). After the last visit, the patients and the investigator were asked to guess drugassignment. 5 Statistical analyses Based on data collected during the pilot study, a sample size calculation showed that 80 patients (40 patients in each arm) were needed to detect an effect size δ=0.65 on the composite outcome score (1.3 points difference in favour of the dexamethasone group, assuming that the common standard deviation is 2), with a 0.05 two-sided significance level and a power of 80%. Inclusion rate was estimated at 20 patients per year resulting in a total study period of 5.5 years. A safety analysis was scheduled after two years and after 40 patients had completed the trial, and an effectiveness analysis was planned to commence after 40 patients. However, recruitment of trial patients exceeded the period of time available for the study, prompting a group sequential analysis. This analysis was designed with the same characteristics (δ, two-sided significance level, power) as used in the original sample size calculation. The cumulative data of the composite score, with groups of 5 patients each, were analysed with PEST4 software, using a double triangular test. 19,20 An estimate for the standardised difference together with a 95%-confidence interval was calculated, adjusted for 65

68 Chapter 5 the cumulative inspections of the data. This method is an efficient way to monitor the results of an RCT, leading, on average, to an earlier decision than a corresponding fixed sample size analysis. All other statistical analyses were performed using SPSS, version 12 and STATA, version 10. Baseline characteristics were summarised with descriptive statistics. Differences in primary and secondary outcome parameters between the two groups were analysed with an unpaired t-test, Mann-Whitney test or Fisher s exact test, when appropriate. Kaplan-Meier survival curves and the log-rank test were used for comparing time to remission and relapse. Analyses were based on the intention-to-treat principle. In case of incomplete follow-up, we used the last observation carried forward approach. Since a substantial number of patients did not complete the total study period of 18 months, the composite outcome scores (one of the two primary outcome measures) were additionally analysed using a linear mixed model, including all available patients composite scores as measured at all the seven follow-up visits. In this mixed model (adjusted for Rankin scores, MRC sum scores and VAS pain scores at baseline) we estimated difference in the composite scores between the treatment groups (treatment effect), change in the composite scores over time (time effect), and the interaction between time and treatment group (time by treatment effect). We also explored whether the composite scale results were consistent in a per-protocol analysis. Two-sided P-values were set at Differences were also accompanied by their 95% confidence intervals. 66

69 Dexamethasone pulse therapy Assessed for eligibility (n=162) Excluded (n=100) No myositis (45) Refusal by patient (14) Corticosteroids already started (13) Duration of symptoms > 1 year (11) Contraindication to treatment (6) Spontaneous recovery (4) Logistic problems (3) Requiring other immunosuppressive treatment (2) Pregnancy (1) Death (1) Randomised (n=62) Allocated to dexamethasone (n=30) Allocated to prednisolone (n=32) 5 Early discontinuation of treatment (n=21) Relapse < 6 mo (6) * No improvement (7) * Serious side effects (3) Discontinuation by patient (2) Co-morbidity required medication change (2) Sudden death (1) Early discontinuation of treatment (n=17) Relapse < 6 mo (1) * No improvement (5) * Serious side effects (5) Discontinuation by patient (2) Co-morbidity required medication change (3) Spontaneous recovery (1) Completed follow-up period (n=9) Completed follow-up period (n=15) Analysed (n=30) No composite score assessed (n=2) 1 early deterioration 1 died shortly after baseline visit Analysed (n=32) No composite score assessed (n=2) 1 early deterioration 1 bowel perforation after colonoscopy Figure 1. Enrolment and number of patients studied. Footnote: * indicates treatment failure (see Methods section) 67

70 Chapter 5 Results Characteristics of the patients Of the 162 patients screened between July 2001 and February 2007, 62 were randomised (Figure 1): 32 in the prednisolone group and 30 in the dexamethasone group. None of the patients met the criteria for polymyositis. 15 All patients diagnosed with dermatomyositis had one or more characteristic skin abnormalities. Baseline characteristics of the study population are described in Table 1. The two groups were comparable regarding their demographic and clinical features. A total of 38 (61%) patients discontinued trial medication within 18 months (17 in the prednisolone and 21 in the dexamethasone group). Nineteen (31%) fulfilled the definition of treatment failure (6 treated with prednisolone and 13 treated with dexamethasone; Fisher Exact test p=0.054, Figure 1), 13% had serious side-effects and in 17% there were various other reasons (see Figure 1). No significant differences in baseline demographic features were found between patients who did and did not discontinue the study. The average time until discontinuation was not significantly different between treatment groups (22 weeks in prednisolone versus 19 weeks in dexamethasone, unpaired t-test p=0.56). One patient showed recovery before medication was started. All others received their assigned treatment. There was one unintended allocation revelation. Patients and first author guessed the correct treatment in 69% and 68% of cases respectively. 68

71 Dexamethasone pulse therapy Table 1: Baseline characteristics of 62 included patients with inflammatory myopathies, sporadic inclusion body myositis excluded. Characteristic Dexamethasone (n = 30) Prednisolone (n = 32) Age, years, mean (SD) 49 (14.6) 48 (13.4) Female sex 20 (67%) 19 (59%) Weight, kg, median 70 (47-118) 74 (49-111) Diagnosis Polymyositis Dermatomyositis 11 (37%) 12 (38%) Non-specific myositis 12 (40%) 14 (44%) Myositis with connective tissue disease 6 (20%) 6 (19%) Myositis with malignancy 1 (3%) 0 Disease duration, months, median 4 5 (1-11) 3 5 (1-11) sck, IU/L, median 2749 ( ) 4074 ( ) Rankin score (0-5), median * 3 0 (1-4) 3 0 (1-4) MRC sum score (maximum 140), mean (SD) * 127 (7 1) 128 (8 4) Hypertension treatment 5 (17%) 3 (9%) Blood pressure, mm Hg, median Systolic Diastolic 130 (90-190) 80 (60-100) 130 (90-170) 80 (50-90) Diabetes Mellitus treatment 2 (7%) 0 Serum glucose, mmol/l, mean (SD) 5 6 (1 6) 5 9 (1 6) Presence of pain VAS pain (0-10), median * Presence of dysphagia 24 (80%) 6 0 (3-10) 15 (50%) 26 (81%) 6 5 (2-9) 15 (47%) VAS dysphagia (0-10), median 5 0 (1-8) 5 0 (2-7) Arthralgia 20 (67%) 17 (53%) Raynaud s phenomenon 13 (43%) 8 (25%) 69

72 Chapter 5 Characteristic Dexamethasone (n = 30) Prednisolone (n = 32) Neuromuscular Symptom Score (maximum 60), mean (SD) 32 (10) 36 (15) SF-36 (0-100), median Physical functioning Role functioning physical Bodily pain Social functioning Mental health Role functioning emotional Vitality General health perceptions Standardised physical component scale Standardised mental component 33 (0-80) 0 (0-100) 32 (0-100) 75 (0-100) 60 (8-100) 100 (0-100) 35 (5-90) 40 (0-62) 25 (8-40) 51 (26-71) 25 (0-95) 0 (0-100) 32 (0-100) 100 (0-100) 72 (20-100) 100 (0-100) 25 (0-100) 40 (0-77) 24 (9-42) 54 (28-69) Results are shown as mean (SD) for normally distributed continuous variables, median (min-max) for skewed continuous variables and numbers (%) for categorical variables. * denotes characteristics which are part of the composite score. sck = serum creatine kinase activity (normal < 170 IU/L), MRC = Medical Research Council, VAS = Visual analogue scale (0-10). Primary and secondary outcomes Six years after the first randomisation, the data-monitoring committee recommended a group sequential analysis because the enrollment rate faltered. At that time, 62 patients were included. The sequential analysis indicated no difference on the composite score between treatment groups. Inclusion of all 80 planned patients would not lead to a statistically significant superiority of one treatment over the other. Therefore, enrollment was terminated after the inclusion and follow-up of 62 patients. The composite score of four patients could not be determined because only baseline data were available (two in each treatment group; Figure 1). 70

73 Dexamethasone pulse therapy The (median unbiased) estimate of the standardised treatment difference based on data of 58 patients was 0.08 (95% CI to 0.66). The mean composite score in both groups was 2.8 (95% CI 2.1 to 3.5 in dexamethasone and 95% CI 2.0 to 3.6 in prednisolone). The mean composite score between the different diagnoses did not differ significantly. Table 2 shows the further results of the primary outcome. The individual items of the composite score did not systematically differ between both treatment groups. An additional per-protocol analysis on fifteen patients treated with prednisolone and nine patients treated with dexamethasone who completed the total study period of 18 months showed no difference in their median composite scores (3.0 (0-6) and 4.0 (1-7), respectively (Mann-Whitney test, p=0.56)). Linear mixed modeling (adjusted for baseline Rankin score, MRC sum score and VAS pain), including all available patients composite scores as measured at all follow-up visits, also confirmed that there was no significant treatment effect (p = 0.55). Neither did we observe a time effect (p = 0.58) or a time-treatment interaction effect (p = 0.27). Estimated difference in mean composite scores of the treatment groups was 0.15 (95% CI to 0.90). The proportion of patients with remission (risk difference -12% (-32 to 9)) and relapse (risk difference 9% (-15 to 34)), and time to remission (log-rank p=0.73) were not statistically different between treatment groups (Table 2). Median (SE) time to relapse was 60 (2.9) weeks in the prednisolone and 44 (4.7) weeks in the dexamethasone group (log-rank test p=0.03). In the dexamethasone group 58% of relapses occurred after a medication-free period of on average 20 weeks. In the prednisolone group, all but one relapses occurred during the end-phase of tapering or shortly thereafter. The initial dose of prednisolone (70 or 90 mg) was not associated with significant differences in relapse, remission or discontinuation of the study in all prednisolone-treated patients (data not presented). Amongst the secondary outcome measures, side effects showed a significant difference in favour of dexamethasone-treated patients. Twenty-nine of 30 patients treated with prednisolone (97%) and 22 of 28 patients treated with dexamethasone (79%) experienced one or more adverse effects (risk difference 18%; 95% CI of the risk difference -35 to -2%, Fisher s Exact Test p=0.048; Table 2). A broad range of side-effects occurred systematically more often in 5 71

74 Chapter 5 prednisolone treated patients (Table 3). Ten patients (33%) treated with prednisolone and one patient (4%) treated with dexamethasone developed diabetes mellitus (risk difference 29%; 95% CI of the risk difference -48 to - 12%). Mood changes occurred in 20 patients (67%) and 8 (29%), respectively (risk difference 38%; 95% CI of the difference -62 to -14%). Treatment adjustments for co-morbid conditions (hypertension, diabetes mellitus) were needed in one patient in the dexamethasone group, compared with 15 patients in the prednisolone group. In eight patients (13%) serious side effects necessitated discontinuation of the study (see also Figure 1). Reasons for discontinuation in the five prednisolone-treated patients included bowel perforation after colonoscopy; imminent manic psychosis; agitation in combination with hypertension and gastric discomfort; ill-controlled diabetes mellitus; and imminent adrenal insufficiency. Two dexamethasone-treated patients with scleroderma discontinued the study because of renal crisis, and one dexamethasone-treated patient had a sigmoid perforation due to diverticulitis. With regard to the other secondary outcome measures (Table 2) no significant differences between both treatment groups could be demonstrated. 72

75 Dexamethasone pulse therapy Table 2. Primary and secondary outcome measures. Primary outcome measures 1. Composite score, mean (SD) (0-7) * 95% C.I. Median (range) Dexamethasone (n=30) 2 8 (1 8) (1-7) Prednisolone (n=32) 2 8 (2 2) (0-7) Remission (Rankin 0-1) 5 (17%) 9 (28%) Remission <3 months 2 (7%) 3 (9%) No relapse 16 (53%) 20 (63%) MRC sum score at least 138 * 16 (57%) 16 (53%) 5 VAS pain 0-2 * 18 (64%) 13 (43%) No Cushing * 18 (64%) 13 (43%) 2. Remission Mean # time until remission, weeks (SE) Relapse Median time until relapse, weeks (SE) 5 (17%) 58 8 (5 1) 14 (47%) 44 (4 7) 9 (28%) 58 0 (4 6) 12 (38%) 60 (2 9) Secondary outcome measures * sck, IU/L, median 197 ( ) 100 ( ) Rankin, median 2.0 (0-4) 2.0 (0-3) MRC sum score (maximum 140), mean (SD) 136 (5) 135 (6) Pain present VAS pain, median Dysphagia present VAS dysphagia, median 15 (54%) 4.0 (1-10) 8 (29%) 3 0 (1-7) 16 (53%) 5.5 (3-8) 6 (20%) 5 0 (3-6) VAS skin changes in dermatomyositis, median 1 0 (0-8) 5 0 (0-9) Arthralgia 16 (57%) 16 (53%) Raynaud s phenomenon 6 (21%) 5 (17%) 73

76 Chapter 5 Dexamethasone (n=28) Prednisolone (n=30) Neuromuscular Symptom Score (maximum 60), mean (SD) 41 (13) 46 (13) SF-36 (minimum 0; maximum 100), median Physical functioning Role functioning physical Bodily pain Social functioning Mental health Role functioning emotional Vitality General health perceptions Standardised physical component scale Standardised mental component 72 (5-100) 13 (0-100) 72 (12-100) 100 (13-100) 88 (32-100) 100 (0-100) 60 (10-100) 45 (5-72) 39 (21-56) 56 (32-63) 75 (5-100) 0 (0-100) 72 (0-100) 100 (25-100) 88 (44-100) 100 (0-100) 55 (20-100) 45 (5-72) 40 (9-55) 56 (36-69) Any side-effect 22 (79%) 29 (97%) * = assessment of 58 patients (only baseline information available in 4 patients). # = median time until remission could not be calculated. Mean survival time is restricted to the longest follow up time. As the largest observed analysis time in both groups was censored, means are underestimated. sck = serum creatine kinase activity (normal < 170 IU/L), MRC = Medical Research Council, VAS = visual analogue scale (0-10). 74

77 Dexamethasone pulse therapy Table 3. Side-effects at any time during the study period Variable Dexamethasone (n=28) Prednisolone (n=30) Any side-effect 22 (79%) 29 (97%) Mood changes 8 (29%) 20 (67%) Diabetes mellitus 1 (4%) 10 (33%) Mean weight gain >5 kg 5 (18%) 10 (33%) Cushingoid appearance 10 (36%) 17 (57%) Skin thinning or ecchymoses 7 (25%) 14 (47%) Gastric symptoms 7 (25%) 13 (43%) 5 Impaired wound healing 6 (21%) 12 (40%) Hair loss 9 (32%) 11 (37%) Infections 5 (18%) 7 (23%) Acne 6 (21%) 8 (27%) Hirsutism 4 (14%) 8 (27%) Hypertension 1 (4%) 5 (17%) Cataract 0 4 (13%) Striae 1 (4%) 2 (7%) Renal crisis 2 (7%) 0 Bowel perforation 1 (4%) 1 (3%) Imminent adrenal insufficiency 0 1 (3%) Glaucoma 0 0 Discussion This is the first long-term RCT comparing first-line treatment of idiopathic inflammatory myopathies, sporadic inclusion body myositis excluded. No statistically significant difference in the primary composite outcome scores of dexamethasone-treated or prednisolone-treated patients was found. However, a 75

78 Chapter 5 more favourable side-effect profile was observed in dexamethasone-treated patients, probably by the intermittent administration. This was most conspicuous with regard to the occurrence of diabetes mellitus and mood changes, albeit that all side-effects were significantly less frequent in the dexamethasone as compared to the prednisone-treated patients. The study did show that a relapse occurred somewhat later if patients were treated with prednisolone. In the latter group almost all relapses occurred towards the end of tapering whereas the dexamethasone-treated patients who relapsed did so after a medication-free period of on average 20 weeks. One could argue that this might be explained by the higher cumulative dosage of corticosteroids in the prednisolone-group, and in particular in the patients (n = 20 out of 32) who started on a dosis of 90 mg/day (total dose mg) as compared to the dexamethasone-treated patients (total dose 960 mg; 6720 mg if converted to prednisolone). However, no differences were found between patients with an initial dose of 70 or 90 mg of prednisolone (data not presented). In clinical practice, like in other immune-mediated neuromuscular diseases such as myasthenia gravis, maintenance treatment with prednisolone is often needed to prevent or treat relapses at the risk of developing adverse effects after prolonged use over many years. 21 With dexamethasone treatment almost half of the relapses occurred during the treatment period of six months necessitating a switch to conventional prednisolone treatment according to the protocol. Since the other half of the relapses in dexamethasone-treated patients occurred after a medication-free period the patients were treated with repeat pulses, also according to protocol. In clinical practice, frequency and dosage of these pulses can be tailored according to the needs of the individual patient and are to be preferred to maintenance treatment of oral prednisolone given the more favourable profile of the side-effects in the dexamethasone-treated patients. No differences in outcome were found between the different groups of diagnoses. Remarkably, we found no patients with PM as defined by strict histopathological criteria. 15 We previously reported that PM is extremely rare in the Dutch myositis population. 22 This pragmatically designed study has a number of limitations. First, 61% of the patients had to discontinue study medication, either dexamethasone or prednisolone, before the 18 months follow up was completed. Treatment failure was reason for discontinuation in 31%, whereas in 13% serious side effects and 76

79 Dexamethasone pulse therapy in 17% various other conditions were the reason to stop. These patients were all included in the analysis according to the intention-to-treat principle and the last observation carried forward approach. As this approach in combination with the substantial number of incomplete follow-ups may introduce methodological flaws, we additionally investigated the composite outcome score (primary endpoint) within the framework of a linear mixed regression technique, including all followup time points, and also performed a per-protocol analysis in a subgroups of completers. Again these additional analyses did not demonstrate significant differences between the treatment groups. Second, to make this trial feasible, we have chosen for a continuous scale score to reach sufficient power with a minimal number of patients. Therefore, we designed a composite score in which all constituent items are relevant for a favourable clinical outcome. The use of a composite score may theoretically have a disadvantage as a decrease or increase might be the result of changes in the individual items. 23 However, the individual item scores did not systematically differ between both treatment groups. We did not investigate the psychometric properties of this outcome measure for myositis. However, MRC-sumscore and the modified Rankin score have been proven reliable and valid outcome measures in other neuromuscular disorders that manifest with progressive muscle weakness and are amenable to treatment. 24,25 In addition, several international rheumatological initiatives to establish consensus guidelines for outcome measures in trials of therapies in the idiopathic inflammatory myopathies were undertaken after our study had already started. 26,27 In the power analysis and related sequential analysis we regarded the composite outcome score as a continuous measure. In the psychometric literature considerable debate surrounded the way summated ordinal (Likerttype) items should be treated. The arguments range from the extreme position that the numbers themselves are interval and can be manipulated as such to the opposite view that that the numbers must be demonstrated to have a linear relationship with the underlying property. The debate shows no sign of resolution. 28 In our study we have followed the pragmatic approach of the psychometrician Jum Nunnaly who demonstrated that under most circumstances one can analyse data from a summated rating scale in a parametric way without introducing severe bias. 29 Notwithstanding the above-mentioned limitations, the strength of our study is the magnitude of the study cohort and the long follow-up period. We performed 5 77

80 Chapter 5 the largest randomised controlled trial in idiopathic inflammatory myopathies so far and evaluated the patients 18 months after onset of the trial medication. Until now, only a few, short-term and relatively small RCTs evaluating immunosuppressive treatment in polymyositis and dermatomyositis have been published, underscoring the difficulty in obtaining evidence-based data in these rare diseases. 17,30-34 Most of these studies examined add-on therapy in refractory myositis. The only double-blind RCT in newly-diagnosed patients so far was done thirty years ago. That short-term study was small with a 30% drop-out rate and showed no difference in muscle strength after three months treatment with prednisone alone or in combination with azathioprine. 35 Another small study in treatment-naive patients, showed less side effects on methotrexate as compared to azathioprine as add-on treatment to daily prednisone. 36 We have experienced difficulties performing this trial. The low incidence of myositis makes recruitment time-consuming. The high drop-out rate shows that steroids alone are often not sufficient to reach a (sustained) improvement in myositis. Future trials should thus preferably be conducted in international settings and include add-on treatments. Although the prime aim of our study was to compare two regimes of corticosteroids and not the efficacy of steroids per se, our results indicate that we are in dire need of novel therapeutic interventions. The high rate of patients relapsing after prednisolone tapering shows that prednisolone is indeed effective, but the need for maintenance treatment to prevent relapses carries a high risk of side effects, indicating that corticosteroids alone are not an adequate therapy in a substantial portion of patients. Other immunosuppressive treatments are often combined with daily prednisolone. Whether these add-on drugs are effective in combination with dexamethasone pulse therapy has as yet not been examined. Furthermore, our results show that pulsed oral dexamethasone is not superior to prednisolone but causes substantially less adverse events, providing a justified alternative in the first-line treatment of idiopathic inflammatory myopathies, especially in patients with a high risk of developing side effects on daily corticosteroids. 78

81 Dexamethasone pulse therapy Acknowledgment section We thank: all patients for participating in the study; Data and Safety Monitoring Board: P.A. van Doorn (Erasmus Medical Center, Rotterdam), A. Algra (University Medical Center, Utrecht), I. van der Tweel (University Medical Center, Utrecht); Steering Committee: J.W.J. Bijlsma (University Medical Center, Utrecht), J.H.J. Wokke (University Medical Center, Utrecht), B.G.M. van Engelen (University Medical Center St. Radboud, Nijmegen), F.H.J. van den Hoogen (University Medical Center St. Radboud, Nijmegen), A.F.A.M. Schobben (University Medical Center, Utrecht), A.R. Wintzen (Leids University Medical Center, Leiden); All referring clinicians: J.W.M. Brans (Medical Center Alkmaar), C.M. Verhoef (Flevoziekenhuis, Almere), R.J.M. ten Berge, K. Vos, M.A. de Rie (Academic Medical Center, Amsterdam), H.L. Hamburger, D. van Schaardenburg (Jan van Breemen Instituut, Amsterdam), I.N. van Schaik (OLVG, Amsterdam), P.M. Elte (Medical Center Boerhaave, Amsterdam), W.H.J.P. Linssen, H.C. Weinstein, E.J. Wouda, M.M. Geenen (St Lucas Andreas Hospital, Amsterdam), A.E. Voskuijl (VU Medical Center, Amsterdam), F.B.J. Scholtes (Gemini Hospital, Den Helder), H.Th.J. Niekus (Reinier de Graaf groep, Delft), G.P.H. Lucker (Deventer Hospital), A.A.A. Westgeest (Maxima Medisch Centrum, Eindhoven), M.A.F.J. van de Laar, M.W.M. Kruijsen (Medisch Spectrum Twente, Enschede), H.K. Rondaij (Leyenburg hospital, The Hague), M.J. van der Veen (Sint Jansdal, Harderwijk), E.S. Louwerse, M.A.W. Geurts (Jeroen Bosch Hospital, s- Hertogenbosch), J.J. Claus (Tergooiziekenhuizen, Hilversum), J.O. Mispelblom Beyer, A.M. Lagaaij (Spaarne Hospital, Hoofddorp), D. Broere, G.J. Lambrechts, (Westfriesgasthuis, Hoorn), J.J.G.M. Verschuuren, J.M. van Laar (Leids University Medical Center, Leiden), H.C.M. Haanen (Sint Antonius Hospital, Nieuwegein), P.A. van Doorn (Erasmus Medical Center, Rotterdam), H.C. van Paassen (Sint Fransiscus Gasthuis, Rotterdam), P.J. de Jong (Rivierenland Hospital, Tiel), R.H.W.M. Derksen, C.J.M. Frijns, A.M. Huisman (University Medical Center, Utrecht), M.F.G. van der Meulen, J.C. Ehrlich (MESOS, Utrecht), G.J.M. van Veen (Isala klinieken, Zwolle). We are grateful for the useful discussions on the protocol or manuscript with M. Vermeulen, D. van de Beek (Academic Medical Center, Amsterdam), K. Kuitwaard (Erasmus Medical Center, Rotterdam), and J.H.P. Winter. 5 79

82 Chapter 5 References 1. Bronner IM, van der Meulen MF, de Visser M et al. Long-term outcome in polymyositis and dermatomyositis. Ann Rheum Dis 2006;65(11): Dalakas MC. Therapeutic targets in patients with inflammatory myopathies: present approaches and a look to the future. Neuromuscul Disord 2006;16(4): Choy EH, Hoogendijk JE, Lecky B, Winer JB. Immunosuppressant and immunomodulatory treatment for dermatomyositis and polymyositis. Cochrane Database Syst Rev 2005;(3):CD Andersen JC. Response of resistant idiopathic thrombocytopenic purpura to pulsed highdose dexamethasone therapy. N Engl J Med 1994;330(22): Bromberg MB, Carter O. Corticosteroid use in the treatment of neuromuscular disorders: empirical and evidence-based data. Muscle Nerve 2004;30(1): Cheng Y, Wong RS, Soo YO et al. Initial treatment of immune thrombocytopenic purpura with high-dose dexamethasone. N Engl J Med 2003;349(9): Molenaar DS, van Doorn PA, Vermeulen M. Pulsed high dose dexamethasone treatment in chronic inflammatory demyelinating polyneuropathy: a pilot study. J Neurol Neurosurg Psychiatry 1997;62(4): Sood A, Midha V, Sood N, Awasthi G. A prospective, open-label trial assessing dexamethasone pulse therapy in moderate to severe ulcerative colitis. J Clin Gastroenterol 2002;35(4): Toth GG, van de Meer JB, Jonkman MF. Dexamethasone pulse therapy in pemphigus. J Eur Acad Dermatol Venereol 2002;16(6): Toth GG, Westerlaken BO, Eilders M, Laseur M, Jonkman MF, Uges DR. Dexamethasone pharmacokinetics after high-dose oral therapy for pemphigus. Ann Pharmacother 2002;36(6): Westerlaken BO, de Kleine E, van der Laan B, Albers F. The treatment of idiopathic sudden sensorineural hearing loss using pulse therapy: a prospective, randomized, double-blind clinical trial. Laryngoscope 2007;117(4): van der Meulen MF, Hoogendijk JE, Wokke JH, de Visser M. Oral pulsed high-dose dexamethasone for myositis. J Neurol 2000;247(2): Dalakas MC, Hohlfeld R. Polymyositis and dermatomyositis. Lancet 2003;362(9388): Tanimoto K, Nakano K, Kano S et al. Classification criteria for polymyositis and dermatomyositis. J Rheumatol 1995;22(4): Hoogendijk JE, Amato AA, Lecky BR et al. 119th ENMC international workshop: trial design in adult idiopathic inflammatory myopathies, with the exception of inclusion body myositis October 2003, Naarden, The Netherlands. Neuromuscul Disord 2004;14: van Swieten JC, Koudstaal PJ, Visser MC, Schouten HJ, van Gijn J. Interobserver agreement for the assessment of handicap in stroke patients. Stroke 1988;19(5):

83 Dexamethasone pulse therapy 17. Dalakas MC, Illa I, Dambrosia JM et al. A controlled trial of high-dose intravenous immune globulin infusions as treatment for dermatomyositis. N Engl J Med 1993; 329(27): Sultan SM, Ioannou Y, Moss K, Isenberg DA. Outcome in patients with idiopathic inflammatory myositis: morbidity and mortality. Rheumatology (Oxford) 2002;41(1): PEST 4. Operating manual. MPS Research Unit. Reading: The University of Readin. MPS Research Unit ed. The University of Reading (UK); Whitehead J. The design and analysis of sequential clinical trials. Revised 2nd ed. Chichester: Wiley; Arahata K, Engel AG. Monoclonal antibody analysis of mononuclear cells in myopathies. I: Quantitation of subsets according to diagnosis and sites of accumulation and demonstration and counts of muscle fibers invaded by T cells. Ann Neurol 1984;16(2): Van der Meulen MFG, Bronner IM, Hoogendijk JE, Burger H, Van Venrooij WJ, Voskuyl AE, Dinant HJ, Linssen WHJP, Wokke JHJ, De Visser M. Polymyositis. An overdiagnosed entity. Neurology 2003;61: Ferreira-Gonzalez I, Brusse JW, Heels-Ansdell D et al. Problems with use of composite end points in cardiovascular trials: systematic review of randomised controlled trials. BMJ 2007;334: Kleyweg RP, van der Meché FG, Schmitz PI. Interobserver agreement in the assessment of muscle strength and functional abilities in Guillain-Barré syndrome. Muscle Nerve 1991;14: Merkies IS, Schmitz PI, van der Meché FG et al. Inflammatory Neuropathy Cause and Treatment (INCAT) Group. Connecting impairment, disability, and handicap in immune mediated polyneuropathies. J Neurol Neurosurg Psychiatry 2003;74: Isenberg DA, Allen E, Farewell V et al. International consensus outcome measures for patients with idiopathic inflammatory myopathies. Development and initial validation of myositis activity and damage indices in patients with adult onset disease. Rheumatology (Oxford) 2004;43(1): Lachenbruch PA, Miller FW, Rider LG. Developing international consensus on measures of improvement for patients with myositis. Stat Methods Med Res 2007;16(1): Streiner DL, Norman GR. Health measurement scales; a practical guide to their development and use. Oxford University Press, 2008, page Nunally JC. Psychometric Theory. New York: McGraw-Hill, 1978, page Behera M, Kumar A, Soares HP, Sokol L, Djulbegovic B. Evidence-based medicine for rare diseases: implications for data interpretation and clinical trial design. Cancer Control 2007;14(2): Miller FW, Leitman SF, Cronin ME et al. Controlled trial of plasma exchange and leukapheresis in polymyositis and dermatomyositis. N Engl J Med 1992;326(21): Vencovsky J, Jarosova K, Machacek S et al. Cyclosporine A versus methotrexate in the treatment of polymyositis and dermatomyositis. Scand J Rheumatol 2000;29(2):

84 Chapter Villalba L, Hicks JE, Adams EM et al. Treatment of refractory myositis: a randomized crossover study of two new cytotoxic regimens. Arthritis Rheum 1998;41(3): Chung YL, Alexanderson H, Pipitone N et al. Creatine supplements in patients with idiopathic inflammatory myopathies who are clinically weak after conventional pharmacologic treatment: Six-month, double-blind, randomized, placebo-controlled trial. Arthritis Rheum 2007;57(4): Bunch TW, Worthington JW, Combs JJ, Ilstrup DM, Engel AG. Azathioprine with prednisone for polymyositis. A controlled, clinical trial. Ann Intern Med 1980;92(3): Miller J, Walsh Y, Saminaden S, Lecky BRF, Winer JB. Randomised double blind controlled trial of methotrexate and steroids compared with azathioprine and steroids in the treatment of idiopathic inflammatory myopathy. Journal of the Neurological Sciences Ref Type: Abstract. 82

85 Chapter 6 Long-term follow up of 62 patients with myositis Janneke van de Vlekkert, Jessica Hoogendijk, Marianne de Visser Journal of Neurology 2014;261:

86 Chapter 6 Abstract Objectives: To evaluate disease related mortality and the course of the disease including functional outcome and quality of life. Methods: We did a follow up study on a large prospective cohort of 62 patients with subacute-onset idiopathic inflammatory myopathy (IIM) (dermatomyositis (n=24), nonspecific myositis (n=34), necrotizing autoimmune myopathy (n=4)) after treatment with corticosteroids only (randomized controlled trial comparing daily high-dosage prednisone with pulse therapy of dexamethasone). Development of connective tissue disease (CTD) or malignancy, disease course and mortality, functional outcome and quality of life were evaluated. Results: After a mean follow up of 3 years (SD 1.5) 22% had developed a CTD and 17% a malignancy. Disease-related mortality was 15%. A monophasic disease course was found in 27%. Most patients had a chronic (35%) or polyphasic disease (35%) course and experienced single or multiple relapses. Sixteen patients (33%) were off medication after a mean of one year of treatment. Disability scores improved particularly in the first 18 months. At follow up 68% still perceived disabilities. Quality of life scores as measured by the short-form (SF)-36 improved in the first 18 months. After 18 months, scores remained stable during the next years of follow up and remained low compared to a normal population. Conclusions: 1. Two-thirds of the patients with an IIM have a polyphasic or chronic disease course and need maintenance treatment. 2. The impact on functional outcome and quality of life is considerable and does not improve further after 18 months. 84

87 Long term follow up Introduction Idiopathic inflammatory myopathies (IIM) consist of a heterogenic group of autoimmune muscle diseases characterized by mononuclear cell infiltrates in skeletal muscle. 1 Polymyositis (PM) and dermatomyositis (DM) occur in isolation or combined with a connective tissue disease (CTD) or malignancy. Sporadic inclusion body myositis (sibm) is also classified as part of the IIM but has different clinical features without sustained improvement on immunosuppressive treatment. Recently, other immune-mediated disease entities have been recognized including nonspecific or overlap myositis (NSM) 2,3 and necrotizing autoimmune myopathy (NAM) 4-6, both associated with a connective tissue disorder, and the latter also with malignancy and statin use. Muscle biopsy in NAM shows signs of muscle fiber degeneration, but virtually no cell infiltration. 6 High dose of corticosteroids is the mainstay of treatment although never properly investigated in a randomized controlled trial. Long-term outcome varies widely. Favourable long-term outcome ranges from 18-90%. 7 Predictors of poor outcome are higher age 7-17, male sex 7,8,13,15, presence of cancer 7,9,10,11,13,15-17, pulmonary disease (especially interstitial lung disease, ILD) and cardiac involvement 10,11,13,14,16-18, longer duration of symptoms 11,14,15, non-caucasian race 8,9, dysphagia 11,13,14, skin-ulcers 17, autoantibodies, i.e., anti-synthetase 3,19, anti-srp 3, anti-pm-scl 20, anti-mda5 and anti-tifγ1 21 ). Disease-related mortality rates in PM and DM are at least 11% 7-9,11,13,17,22 and mostly related to cancer, especially during the first years after onset of treatment. A monophasic disease course was seen in 15-20% of patients. 7,9,11,23 On the long term, myositis has a chronic continuous or polyphasic disease course in 55-85% 7,9,11,23 with major effects on perceived disability and quality of life, despite regained muscle strength. 7,24 Others report that after a median of 7.5 years of follow-up most patients (86%) had no disease activity, and 83% no disability. 9 One prospective study showed complete remission in 50% and two-third had a favorable outcome (improvement from baseline or asymptomatic) after a median follow up of 4.6 years. 22 It is of note that all these outcome studies were performed using the conventional classification criteria for PM and DM 25 and are 85

88 Chapter 6 mainly of retrospective nature which carries the risk for selection bias and missing data. In addition, comparison of these data is complicated by other factors such as heterogeneity, small group sizes, not well-defined outcome measures, various first line treatment modalities, and variability in duration of the disease before initiation of treatment. Here we present the follow-up results of a large prospective cohort of patients with subacute-onset myositis after treatment with corticosteroids only. Our research questions were the following: how many patients develop a concomitant CTD or malignancy? What is the disease related mortality? What is the course of the disease including functional outcome and quality of life? Methods Inclusion and exclusion criteria, specification of treatment, and results were described in detail previously. 26 In summary, 62 newly diagnosed adult patients, classified according to the ENMC 27 criteria as polymyositis, dermatomyositis, nonspecific myositis, myositis associated with CTD or malignancy were randomized and treated with high dose daily oral prednisolone or six 4-week cycles of oral pulsed dexamethasone (Dexa myositis trial). At time of inclusion, the median disease duration was four months. Patients with sibm were not included. Written informed consent was obtained from all patients before study entry. Since there was no difference in treatment effect between the two treatment groups, all patients were analyzed together as one group in this follow up study. Patients with NAM were at the time of the previous study not recognized as a separate entity but were included in the group with nonspecific myositis. These patients are separately classified as NAM in the present study on the basis of a histopathological picture of a necrotizing myopathy without inflammatory infiltrates. During and after the study period, follow up information was collected. All patients, including patients who discontinued the study before the planned endpoint at 18 months, were contacted and seen at 18 months. Thereafter questionnaires were sent, or follow up information was retrieved from the 86

89 Long term follow up treating physicians. When no follow up data could be obtained, data from the 18 months visit were used. The following data were collected: current symptoms, functional outcome, perceived disability and quality of life, number of remissions and relapses (from the beginning of the trial period), treatment modalities, development of concomitant CTD or malignancy, course of the disease, and mortality. The modified Rankin score classifies disability in patients between 0 (no symptoms) to 6 (death). 28 With the Neuromuscular Symptom Score (NMSS) 20 items in daily activities are scored with a maximum (best) score of 60 points. 29 Quality of life was measured with the Short Form (SF)-36 questionnaire. This multi-item scale assesses eight health domains. 23,30 The questionnaires encompassed items of the Rankin score, SF-36, information about current and used treatment, and if and for how long treatment was discontinued and if and how many times treatment was changed because of flares of the disease. All patients were familiar with the Rankin and SF-36 questions since these were also used during the RCT. 6 Relapse was defined as a deterioration of muscle complaints that required restart of treatment or increasing treatment dose. Remission was defined as stable muscle strength without signs of progression of the disease after discontinuation of treatment. The disease course was defined as monophasic if the patient was in remission and off all medications at 24 months after diagnosis, polyphasic if the patient had recurrence of active disease after a remission, and chronic continuous if there was persistent disease or continuation of medications beyond 24 months after diagnosis. 31 CTD and cancer were diagnosed by rheumatologists and oncologists, respectively. Patients were not routinely screened for interstitial lung disease (ILD). The study protocol was approved by the medical ethics committee. Statistical analysis Analyses were performed using SPSS for Windows 17.0 statistics software. Medians were used rather than means when non-gaussian distribution occurred. The chi-square test and Fisher s exact test were used in the SF36 analysis. P values less than 0.05 were considered statistically significant. 87

90 Chapter 6 Results Sixty-two patients (63% women) were studied. Mean age was 49 years (SD 14). Diagnosis at baseline of the 62 patients is shown in Table 1. DM was found in 24 (39%), NSM in 34 (55%) and NAM in 4 patients (6%). None of the patients had PM as defined by the ENMC criteria [27]. Median sck was 3257 IU/L ( ). Mean duration of follow up was 3 years (SD 1.5) after time of diagnosis. In two patients only baseline data were available because they discontinued the trial prematurely and refrained from participating in this study (1 DM, 1 NSM). At the end of follow up 11 patients had died. Four patients could not be traced and the information at the 18 months visit was used. Follow up data regarding symptoms, disease course, Rankin score, and SF-36 scores were available in 49, 49, 58 and 45 patients, respectively. Diagnosis, disease course and outcome at follow up are presented in Table 1. Diagnosis at follow up Connective tissue disease At baseline, concomitant CTD was found in 11 out of 34 patients with NSM including systemic scleroderma (n=5), systemic lupus erythematosus (n=4), Sjögren s syndrome (n=1), and one patient was suspected of having mixed connective tissue disease (MCTD), and one out of four patients with NAM had MCTD. During follow-up systemic scleroderma occurred in one DM patient, amounting to a total of 13 (22%) patients with concomitant CTD at the end of the follow-up period. All but one were female. The median sck level was 140 IU/L (40-902). One patient with NSM developed interstitial lung disease (ILD). Autoantibodies were examined in 53 patients. Antinuclear antibodies (ANAs) were found in 62%. Of the extractable nuclear antigen antibodies (ENAs), which were seen in 43%, anti-ssa was found most frequent (25% of all 52 patients), followed by anti Jo-1 antibodies (15%), anti-rnp (9%), anti-scl70 (2%) and anti-smb antibodies (2%). Eight patients, of whom four males, had anti Jo-1 antibodies (6 NSM, 1 DM, 1 NAM). One had a CTD (Sjögren s syndrome). Two patients (NSM) with anti-jo1 antibodies developed an anti-synthetase syndrome manifesting with ILD and arthralgia. Anti Jo-1 antibodies were found together 88

91 Long term follow up with anti-ssa antibodies in 75%. Five patients, of whom four women, had anti- RNP antibodies (2 NSM, 2 NSM with SLE, 1 NAM with MCTD). Malignancy One DM patient had a lung carcinoma diagnosed nine months prior to inclusion in the trial. Two DM patients were found to have a malignancy during the screening at baseline and 7 patients (12%) were diagnosed with a malignancy during follow up, amounting to a total of 10 (17%) malignancies in 60 patients (6 out of 23 DM patients, 3 out of 33 NSM patients and 1 out of 4 NAM patients; mean age 65 year (53-80); 6 women). The types of malignancies were the following: 4 lung, 1 ovarian, 2 breast, 2 unknown carcinoma, 1 cholangiocarcinoma). Median time between a diagnosis of myositis and diagnosis of malignancy was 18 months (range 0-60). The malignancies in DM occurred within two years of follow up. In NSM, the malignancies occurred after 22, 29 and 60 months of follow up, respectively, and the malignancy in the NAM patient occurred after 60 months of follow up. No malignancy was found in the eight patients with anti Jo-1 antibodies. 6 Mortality Of all 62 patients, 11 died (18%; 6 women, 5 men) after a median of 0.6 years after inclusion (range 0.1 to 5.2). Median age at death was 64 years (range 34-76). Diagnoses at follow up in these patients are shown in Table 1. Disease-related mortality was 15%. Cause of death was malignancy-related in six patients (5 DM, 1 NSM). Other causes of death included pneumonia after three months of treatment (1 DM), systemic scleroderma related kidney failure (1 NSM, 67 years), myositis-related in one (34 years) and unknown in two (55 and 76 years). None of the anti-jo1 positive patients died. Outcome in surviving patients Treatment and disease course Of all 62 patients, 32 were initially treated with prednisolone and 30 were treated with dexamethasone. After the total study period of 18 months 47 patients were still using medication. Thereafter, patients were treated by their own physicians with the following treatment modalities: prednisolone, dexamethasone, 89

92 Chapter 6 intravenous methylprednisolone, azathioprine (AZA), methotrexate (MTX), intravenous immunoglobulines (IVIG), mycophenolate mofetil and combinations of these. Of the 49 patients alive at follow up a monophasic disease course was found in 13 (27%; Table 1). Three additional patients were in remission without treatment at 18 months but could not be classified as monophasic because this definition required a 24 months period. These 16 patients (33%) had stopped treatment after a mean of 12 months. Of these patients, 13 had used only corticosteroids (7 prednisolone, 6 dexamethasone), one had used prednisolone and AZA, one dexamethasone and AZA and one patient had been treated with prednisolone, IVIG and MTX. A polyphasic disease course was found in 16 patients (33%). Five patients were treated with prednisolone, six in combination with AZA, three in combination with MTX, one with AZA and MTX and one with AZA with mycophenolate mofetil. A chronic disease course was found in 17 patients (35%). Six patients were treated with corticosteroids (1 dexamethasone, 5 prednisolone), three prednisolone in combination with AZA, one prednisolone with MTX, four prednisolone with AZA and IVIG, two AZA and MTX and one patient with AZA, MTX and IVIG. Maintenance treatment was needed in 33 patients (68%) of whom six (out of eight) had anti-jo1 antibodies. No significant differences in disease course between the different diagnoses were found (Table 1). Table 1: Diagnosis, disease course and outcome 90

93 Long term follow up 6 91

94 Chapter 6 Symptoms and disability Symptoms, Neuromuscular symptom score (NMSS), sck at baseline and follow up are shown in Table 2. A proportion of patients had difficulty with walking stairs (24%), rising from a chair (15%), lifting the arms (10%) and moderate exertion (like exercise; 56%). Table 2. Symptoms, NMSS and sck at baseline and follow up. Characteristic Baseline N = 62 Follow up N = 52 Muscle weakness, N (%) 62 (100%) 37 (71%) Muscle pain, N (%) 50 (81%) 26 (50%) Dysphagia, N (%) 30 (48%) 10 (19%) Arthralgia, N (%) 37 (60%) 25 (48%) NMSS, median (range) 33 (11-55) 52 (19-60)* Elevated sck, N (%) 54 (87%) 14 (33%)** sck, IU/L, median (range) 3257 ( ) 147 (40-902)** NMSS = neuromuscular symptom score (0-60). sck = serum creatine kinase *N=45, **N=43 Almost all patients (95%) experienced problems in daily functioning at the time of diagnosis, measured by the modified Rankin score. Thirty-four (55%) were dependent on help from others for their activities of daily living (Rankin 3-5). Improvement occurred in the first 18 months. After that, the Rankin score remained stable. After a mean follow up of 3 years, a Rankin score of 3-5 was found in 38% of patients. No significant difference in independency between the different diagnoses was found (Table 1). At follow up patients with a monophasic and those with a polyphasic disease course, with or without therapy had a median Rankin score of 2. In patients with a monophasic disease course who were able to taper all medication, 20% experienced no symptoms, 20% experienced symptoms but no disability and 60% experienced disabilities. 92

95 Long term follow up Quality of life The Short Form 36 (SF-36) questionnaire scores at baseline, 18 months and follow up are presented in Figure 1. Except for the domains mental health and role-emotional, scores in all domains were lower at baseline compared to the normal population. Quality of life improved in all these domains during the first 18 months. No significant further improvement was found at follow up. The scores in most domains, especially general health perceptions, physical functioning and role-physical, remained lower at follow up compared to the normal population. Comparing presence or absence of a CTD, malignancy or continuous treatment showed no statistically significant different SF-36 scores (except for vitality in CTD). Figure 1. SF-36 at baseline, 18 months and long term follow up. 6 Figure 2. SF-36 and Rankin score at follow up. 93

96 Chapter 6 Figure 2 shows a trend in patients with higher Rankin scores (more disability) at follow up with lower SF-36 scores (in 44 patients in whom both scores were available). Differences between patients with Rankin 0 and Rankin 3 were significant except for social functioning, mental health and role-emotional. Patients with 2 or more relapses had significant lower SF-36 scores in the role physical domain (p=0.001), vitality (p=0.021), and general health perceptions (p=0.034) compared to patients with a monophasic disease. SF-36 scores showed no significant differences between the different subtypes of myositis. Discussion This prospective study shows the disease course of a large cohort of patients after a mean follow up of three years. A concomitant CTD was found in 12 patients at the time of diagnosis of the myositis, and in one patient during follow up, amounting to 22% in total. A CTD occurred mostly in patients with NSM which is in concordance with previous retrospective studies in which a CTD was found in 12-19%. 7,9,10,13,17,23,24 Overall mortality was 18% and 15% was disease-specific. Malignancy was the major cause of death. Three patients had a malignancy at baseline and seven patients developed a malignancy during follow up (together 17%), mostly in DM. In all patients with malignancy and DM, the malignancy had occurred within the first two years following the diagnosis of myositis. Since malignancy in NSM and NAM was found only in four out of 37 patients (11%, 95% CI 3-25), and after a mean of 43 months (range 22-60) this could be a chance association, albeit that paraneoplastic NAM has been described. 5 The incidence of malignancy in a Dutch population of the same mean age is about 2-6% (statistics Netherlands; Our results underline the need for malignancy screening in DM. 32 We suggest that screening should be performed at the time of diagnosis and annually for two years, including a meticulous history, physical examination including rectal examination, routine laboratory tests, CT of chest and abdomen, mammography and gynecological examination in women, testicular examination in men and colonoscopy in patients older than 50 years. Our study does not allow for making recommendations concerning screening for cancer in NSM and 94

97 Long term follow up NAM. Firstly, an association between NAM and cancer has been suggested from reported case series 4-6, but in the present study the relation of NAM and cancer remains unclear because both diseases occurred five years apart. The malignancy occurring within two years in two out of 33 NSM patients does not differ significantly from the incidence of cancer in the Dutch population of the same age (data not shown). Secondly, the number of patients with malignancy in our study is too small to rule out a significant relation. The results of this prospective study clearly show the different disease courses that may occur in myositis. A monophasic disease course was found in 27% and a polyphasic or chronic disease course was found in 68%, resembling the results from four retrospective studies. 7,9,11,23 Most patients (68%) experienced single or multiple relapses and needed different kinds of maintenance immunosuppressive treatment to prevent relapses, and this is also in line with previous studies. 7,9,11,24 In only 33% treatment could be stopped after a median time of treatment of one year. Disability scores improved during follow up and in particularly in the first 18 months as measured by the Rankin score and the NMSS. At follow up 68% still perceived disabilities. Patients with more disabilities scored lower on quality of life scores, measured by the SF-36. As far as we know no prospective longitudinal data have been published. Our data show an improvement of SF-36 scores in the first 18 months which is in line with the improvement of function. After that, scores remained stable during the next years of follow up and were lower compared to the normal population values. 33 As was also found in previous retrospective studies by our group and others, even in patients who could taper all medication and were considered to be in remission disability and quality of life scores rarely completely returned to normal. 7,24 This possibly reflects the disease damage occurring in the first 18 months of active disease. Other measurements of disease damage, i.e. the Myositis Damage Index and the physician global damage assessment which are recommended by the IMACS, an international collaborative group, were not done since these were published after our study had already started. 30,34 Prognosis was worse in patients with a malignancy, but no other significant differences between the different myositis subtypes or sex were found considering disease course, need for continuous treatment, mortality, Rankin score and SF

98 Chapter 6 The strength of this study lies in the prospective design and the inclusion of newly diagnosed patients with various subtypes in which diagnosis was confirmed by biopsy. We did not routinely perform imaging of the lungs to detect interstitial lung disease, neither did we investigate the cardiac status and that can be considered a weakness of the study. 35 Other limitations of this study include the lack of MRC scores and information on DM skin changes after 18 months of follow up. Furthermore, other myositis specific antibodies (except for anti Jo-1) which were assessed at the start of the study, were not systematically searched for. How can we further improve outcome? A lag-time between the start of the disease and initiation of treatment is a known prognostic unfavorable factor. 11,14,15 However, in our study patients were treated as soon as possible (median 4 months after onset of symptoms, range 1-11) and probably it is not realistic to assume that treatment can start much earlier. All our patients were initially treated with high dosages of corticosteroids (dexamethasone or prednisolone). It is possible that this treatment is not effective enough to suppress inflammation adequately and to prevent irreversible disease damage. Properly designed randomized controlled trials with biologicals or immunomodulating medication e.g., CD-20 antibodies, immunoglobulins or early co-administration of classic immunosuppressants as first line treatment are urgently warranted. In conclusion, although myositis is a treatable disease, most patients develop a polyphasic or chronic continuous disease course and need maintenance treatment as is also often the case in other immune-mediated disorders such as myasthenia gravis. The negative effects on function and quality of life are considerable and the lack of further improvement after a period of 18 months is disappointing. New treatment modalities in the future will hopefully not only vigorously suppress inflammation but also decrease the amount of disease damage and improve quality of life and function. 96

99 Long term follow up References 1. M.C. Dalakas. Polymyositis, dermatomyositis and inclusion-body myositis. N Engl J Med 1991;325(21): van der Meulen MF, Bronner IM, Hoogendijk JE, Burger H, van Venrooij WJ, Voskuyl AE, et al. Polymyositis: an overdiagnosed entity. Neurology 2003;61(3): Troyanov Y, Targoff IN, Tremblay JL, Goulet JR, Raymond Y, Senécal JL. Novel classification of idiopathic inflammatory myopathies based on overlap syndrome features and autoantibodies: analysis of 100 French Canadian patients. Medicine 2005;84(4): Bronner IM, Hoogendijk JE, Wintzen AR, van der Meulen MF, Linssen WH, Wokke JH, et al. M. Necrotising myopathy, an unusual presentation of a steroid-responsive myopathy. J Neurol 2003 Apr;250(4): Liang C, Needham M. Necrotizing autoimmune myopathy. Curr Opin Rheumatol 2011;23(6): Grable-Esposito P, Katzberg HD, Greenberg SA, Srinivasan J, Katz J, Amato AA. Immunemediated necrotizing myopathy associated with statins. Muscle Nerve 2010;41(2): Bronner IM, van der Meulen MF, de Visser M, Kalmijn S, van Venrooij WJ, Voskuyl AE, et al. Long-term outcome in polymyositis and dermatomyositis. Ann Rheum Dis 2006;65(11): Schiopu E, Phillips K, MacDonald PM, Crofford LJ, Somers EC. Predictors of survival in a cohort of patients with polymyositis and dermatomyositis: effect of corticosteroids, methotrexate and azathioprine. Arthritis Res Ther 2012;14(1):R Shu XM, Lu X, Xie Y, Wang GC. Clinical characteristics and favorable long-term outcomes for patients with idiopathic inflammatory myopathies: a retrospective single center study in China. BMC Neurol 2011;11: Yu KH, Wu YJ, Kuo CF, See LC, Shen YM, Chang HC, et al. Survival analysis of patients with dermatomyositis and polymyositis: analysis of 192 Chinese cases. Clin Rheumatol 2011;30(12): Marie I, Hachulla E, Hatron PY, Hellot MF, Levesque H, Devulder B, et al. Polymyositis and dermatomyositis: short term and longterm outcome, and predictive factors of prognosis. J Rheumatol 2001;28(10): Marie I, Hatron PY, Levesque H, Hachulla E, Hellot MF, Michon-Pasturel U, et al. Influence of age on characteristics of polymyositis and dermatomyositis in adults. Medicine 1999;78(3): Dankó K, Ponyi A, Constantin T, Borgulya G, Szegedi G. Long-term survival of patients with idiopathic inflammatory myopathies according to clinical features: a longitudinal study of 162 cases. Medicine 2004;83(1): Koh ET, Seow A, Ong B, Ratnagopal P, Tjia H, Chng HH. Adult onset polymyositis/dermatomyositis: clinical and laboratory features and treatment response in 75 patients. Ann Rheum Dis 1993;52(12): Airio A, Kautiainen H, Hakala M. Prognosis and mortality of polymyositis and dermatomyositis patients. Clin Rheumatol 2006;25(2):

100 Chapter Torres C, Belmonte R, Carmona L, Gómez-Reino FJ, Galindo M, Ramos B, et al. Survival, mortality and causes of death in inflammatory myopathies. Autoimmunity 2006;39(3): Yamasaki Y, Yamada H, Ohkubo M, Yamasaki M, Azuma K, Ogawa H, et al. Longterm survival and associated risk factors in patients with adult-onset idiopathic inflammatory myopathies and amyopathic dermatomyositis: experience in a single institute in Japan. J Rheumatol 2011;38(8): Marie I, Hatron PY, Hachulla E, Wallaert B, Michon-Pasturel U, Devulder B. Pulmonary involvement in polymyositis and in dermatomyositis. J Rheumatol 1998;25(7): Marie I, Hatron PY, Dominique S, Cherin P, Mouthon L, Menard JF, et al. Short-term and long-term outcome of anti-jo1-positive patients with anti-ro52 antibody. Semin Arthritis Rheum 2012;41(6): Marie I, Lahaxe L, Benveniste O, Delavigne K, Adoue D, Mouthon L, et al. Long-term outcome of patients with polymyositis/dermatomyositis and anti-pm-scl antibody. Br J Dermatol 2010;162(2): Hoshino K, Muro Y, Sugiura K, Tomita Y, Nakashima R, Mimori T. Anti-MDA5 and anti- TIF1-gamma antibodies have clinical significance for patients with dermatomyositis. Rheumatology 2010;49(9): Ramesha KN, Kuruvilla A, Sarma PS, Radhakrishnan VV. Clinical, electrophysiologic, and histopathologic profile, and outcome in idiopathic inflammatory myositis: An analysis of 68 cases. Ann Indian Acad Neurol 2010;13(4): Sultan SM, Ioannou Y, Moss K, Isenberg DA. Outcome in patients with idiopathic inflammatory myositis: morbidity and mortality. Rheumatology 2002;41(1): Ponyi A, Borgulya G, Constantin T, Váncsa A, Gergely L, Dankó K. Functional outcome and quality of life in adult patients with idiopathic inflammatory myositis. Rheumatology 2005;44(1): Bohan A, Peter BJ. Polymyositis and dermatomyositis. Parts 1 and 2. New Engl J Med 1975;292:344-47, van de Vlekkert J, Hoogendijk JE, de Haan RJ, Algra A, van der Tweel I, van der Pol WL, et al. Oral dexamethasone pulse therapy versus daily prednisolone in sub-acute onset myositis, a randomised clinical trial. Neuromuscul Disord 2010;20(6): Hoogendijk JE, Amato AA, Lecky BR, Choy EH, Lundberg IE, Rose MR, et al. 119th ENMC international workshop: trial design in adult idiopathic inflammatory myopathies, with the exception of inclusion body myositis, October 2003, Naarden, The Netherlands. Neuromuscul Disord 2004;14: van Swieten JC, Koudstaal PJ, Visser MC, Schouten HJ, van Gijn J. Interobserver agreement for the assessment of handicap in stroke patients. Stroke 1988;19(5): Dalakas MC, Illa I, Dambrosia JM, Soueidan SA, Stein DP, Otero C, et al. A controlled trial of high-dose intravenous immune globulin infusions as treatment for dermatomyositis. N Engl J Med 1993; 329(27):

101 Long term follow up 30. Miller FW, Rider LG, Chung YL, Cooper R, Danko K, Farewell V, et al. Proposed preliminary core set measures for disease outcome assessment in adult and juvenile idiopathic inflammatory myopathies. Rheumatology 2001;40(11): Huber AM, Lang B, LeBlanc CM, Birdi N, Bolaria RK, Malleson P, et al. Medium- and longterm functional outcomes in a multicenter cohort of children with juvenile dermatomyositis. Arthritis Rheum 2000;43(3): Zahr ZA, Baer AN. Malignancy in myositis. Curr Rheumatol Rep 2011;13(3): Nationaal Kompas Volksgezondheid, RIVM, 13 dec Rider LG, Lachenbruch PA, Monroe JB, Ravelli A, Cabalar I, Feldman BM, et al. Damage extent and predictors in adult and juvenile dermatomyositis and polymyositis as determined with the myositis damage index. Arthritis Rheum 2009;60(11): Lundberg IE. The heart in dermatomyositis and polymyositis. Rheumatology 2006;45 Suppl 4:iv

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103 Chapter 7 Spontaneous recovery of dermatomyositis and unspecified myositis in three adult patients Janneke van de Vlekkert Jessica Hoogendijk Rinie Frijns Marianne de Visser JNNP 2008;79:

104 Chapter 7 Abstract Dermatomyositis (DM), polymyositis and unspecified myositis are idiopathic inflammatory myopathies in which prednisone is usually started as soon as the diagnosis has been established. Therefore, little is known about the natural history of these diseases and spontaneous recovery may escape attention. Here, we present three patients who achieved remission without administration of immunosuppressants. In these three patients treatment was not started because of spontaneously improving symptoms and signs during the diagnostic process. After 3-5 years all patients are still free of muscle weakness. These case reports demonstrate that spontaneous long-lasting remission can occur in a small proportion of patients with subacute-onset idiopathic inflammatory myopathies. In some patients an immunosuppressive treatment with a risk of serious side effects can perhaps be omitted. Of course, close and frequent monitoring is required in these instances. 102

105 Spontaneous recovery Idiopathic inflammatory myopathies (sporadic inclusion body myositis excluded) are characterised by subacute-onset proximal and symmetrical muscle weakness, typical skin abnormalities (in dermatomyositis), and mononuclear cell infiltrates in a skeletal muscle biopsy specimen. Since the 1960 s patients with these disorders have been treated with corticosteroids. Usually this treatment is started as soon as the diagnosis is made, as studies have shown that outcome may be better when treatment is started early. 1-6 Therefore, little is known about the natural history of these types of inflammatory myopathy. Here, we present three patients who achieved remission without immunosuppressants. Case Reports Patient 1. A 65-year-old man noticed muscle pain, stiffness and weakness in upper arm and leg muscles, progressing over weeks. He had not been ill, did not have fever and had not been taking any drugs. He lost weight because of loss of appetite and swallowing difficulty. In the ensuing two weeks he felt gradually stronger and generally better. On examination at that point we found moderate wasting and symmetric weakness (Medical Research Council (MRC) grade 4- to 4+) of upper arm and leg muscles. 7 There were no skin abnormalities, and no clinical or radiological signs of pulmonary involvement. There were no laboratory signs of infection. Serum creatine kinase activity (sck) was increased to 5244 IU/L (upper limit of normal 200), TSH was normal and anti-jo-1 antibodies were present on immunoblot analysis. MRI-STIR images of the upper arms revealed high signal intensity in the deltoid muscles. A muscle biopsy showed small perivascular mononuclear cell infiltrates, mostly CD8 positive cells, predominantly in muscle and fascia and with some spreading into the subcutaneous fat. In addition, scattered atrophic muscle fibers and signs of muscle fiber degeneration were found. No frozen muscle tissue was available to perform MHC-I staining. A diagnosis of non-specific myositis was made. Treatment with prednisone was withheld because of spontaneous improvement. One month later (three months after onset of symptoms) dysphagia had resolved, muscle weakness had improved to MRC grade 4 to 5-, and sck had steadily decreased to 2025 IU/L. There was gradual further improvement. One 7 103

106 Chapter 7 year after onset of symptoms, the patient had fully resumed his former activities, muscle strength was completely normal, sck normalized and a repeat MRI-STIR showed no abnormalities. Now, 3 years later, he is still symptom-free. Patient 2. A 27 year-old woman was referred to the rheumatologist because of periods of arthralgia which had been present for many years. She subsequently developed slowly progressive muscle weakness over a period of one year. On examination weakness of the proximal muscles of the arms and legs (MRC 4 to 4+) was found. Laboratory investigations showed an increased sck activity (1369 IU/L) and normal TSH, and EMG revealed myopathic abnormalities consistent with a diagnosis of myositis. In the mean time she became pregnant. Gradually myalgia subsided, weakness improved and sck decreased to 382 U/L. Therefore, muscle biopsy was not performed at that time and treatment withheld. After a miscarriage at 30 weeks of pregnancy, pain and stiffness in the joints returned, sck rose again (5729 U/L) over a period of a few months and she developed weakness in the proximal limb muscles (MRC 4+ to 5-). A muscle biopsy showed some degenerating and regenerating fibers, and cell infiltrates consisting of macrophages, B-lymphocytes, and T-lymphocytes located in the perimysium and at perivascular sites with some spreading into the endomysium (figure 1). Some MHC-I positive, non-necrotic muscle fibers were present. At that time she was again pregnant and therefore treatment was withheld. Gradually, weakness improved during pregnancy. She had a second miscarriage at 12 weeks. A cause for her recurrent miscarriages has never been found. Currently, 4 years after the first muscle symptoms, no muscle weakness is found and she resumed all her former activities. Her sck decreased considerably but remained slightly elevated (four times the upper limit of normal). 104

107 Spontaneous recovery 7 Figure 1. Perivascular inflammatory cells at perimysial sites. H&E stain (x 100; patient 2). Patient 3. A 54-year-old woman developed progressive weakness of arm and leg muscles in combination with a rash of the face, chest and fingers over a period of three months. She complained about difficulty with swallowing. On examination, there were characteristic signs of dermatomyositis (heliotropic rash and oedema of the eyelids, Gottron s papules over the proximal and distal interphalangeal joints, erythema on the chest, and periungual teleangiectasia). Weakness (MRC 4 to 4+) was present in muscles of upper arms, upper legs and neck. Serum CK and TSH were not raised. A diagnosis of probable dermatomyositis was made. An abnormal chest X-ray urged us to wait for the further results of all oncologic examinations before starting treatment. She was found to have stadium IIIB non-small cell lung cancer that was not amenable to treatment. During these two weeks, the patient had noticed spontaneous improvement of her muscle symptoms and subsequently her skin, so we decided to postpone steroid 105

108 Chapter 7 treatment. All symptoms and signs resolved completely within 2 months. Currently, 3 years later, all symptoms and signs of the dermatomyositis have resolved completely without treatment. The cancer is slowly progressive, despite treatment with a tyrosinekinase-inhibitor. Discussion We present three patients with a subacute-onset idiopathic inflammatory myopathy. The diagnoses were based on the clinical presentation, presence of anti-jo-1 antibodies, muscle MRI features and muscle biopsy findings. 8 Other diagnoses, including reversible myopathies induced by febrile (viral) illness, medication or metabolic disturbances were ruled out. Patient 1 had positive anti- Jo-1 autoantibodies but signs of a complete antisynthetase syndrome were absent. In patient 3 the characteristic skin changes in combination with the muscle weakness were sufficient to establish a diagnosis of probable DM associated with malignancy, without the necessity of a muscle biopsy 8. All three patients recovered completely clinically and have been without signs of myositis over the past 3 5 years. Although the serum CK activity in patient 2 remains slightly elevated, the absence of any muscle symptoms and signs justifies a waitand-see policy. Spontaneous clinical improvement has been described before corticosteroid treatment was generally accepted as first line treatment. In 1940, 4 out of 40 untreated patients with dermatomyositis who made a complete recovery were identified. 9 In none of these weakness had been severe, but no details of individual patients were provided. In six other cases a brief remission lasting a few months was described. 9 In 1968, a group of 279 patients with PM or DM was reported, 96 of whom reached remission. However, criteria applied for diagnosis and remission were not specified. Fifty percent of the patients in remission had not received any treatment, but steroid-induced remissions were reached earlier and were associated with earlier comfort and recovery of function. 10 In 2004, spontaneous remission in a patient with biopsy-proven DM was reported. 11 During the one-year follow-up the skin changes and weakness recovered completely without systemic steroid treatment. 106

109 Spontaneous recovery We observed spontaneous remission in well-documented patients with subacuteonset idiopathic inflammatory myopathy. This observation, although probably rare, is of utmost importance for daily clinical practice and also for clinical research: if patients report stabilisation or amelioration of symptoms, a waitand- see policy with close monitoring can sometimes be justified avoiding serious side effects of long-term immunosuppressive treatment. If patients are included in clinical trials early in their disease, it should be kept in mind that differences in natural course between patients will hamper the interpretation of results. Acknowledgments The authors thank Prof. Dr. E. Aronica and Prof. Dr. D. Troost for their help with the muscle biopsies

110 Chapter 7 References 1. Benbassat J, Gefel D, Larholt K, Sukenik S, Morgenstern V, Zlotnick A. Prognostic factors in polymyositis/dermatomyositis. A computer-assisted analysis of ninety-two cases. Arthritis Rheum. 1985;28: Bohan A, Peter JB, Bowman RL, Pearson CM. Computer-assisted analysis of 153 patients with polymyositis and dermatomyositis. Medicine (Baltimore) 1977;56: Fafalak RG, Peterson MG, Kagen LJ. Strength in polymyositis and dermatomyositis: best outcome in patients treated early. J Rheumatol. 1994;21: Joffe MM, Love LA, Leff RL, Fraser DD, Targoff IN, Hicks JE, Plotz PH, Miller FW. Drug therapy of the idiopathic inflammatory myopathies: predictors of response to prednisone, azathioprine, and methotrexate and a comparison of their efficacy. Am J Med. 1993;94: Marie I, Hachulla E, Hatron PY, Hellot MF, Levesque H, Devulder B, Courtois H. Polymyositis and dermatomyositis: short term and longterm outcome, and predictive factors of prognosis. J Rheumatol. 2001;28: Pearson CM. Patterns of polymyositis and their responses to treatment. Ann Intern Med. 1963;59: Aids to the examination of the peripheral nervous system. W.B. Saunders, Hoogendijk JE, Amato AA, Lecky BR, Choy EH, Lundberg IE, Rose MR, Vencovsky J, de VM, Hughes RA. 119th ENMC international workshop: trial design in adult idiopathic inflammatory myopathies, with the exception of inclusion body myositis, October 2003, Naarden, The Netherlands. Neuromuscul Disord. 2004;14: O'Leary PA, Waisman M. Dermatomyositis. A study of forty cases. Arch Derm Syphilol. 1940;41: Winkelmann RK, Mulder DW, Lambert EH, Howard FM, Jr., Diessner GR. Course of dermatomyositis-polymyositis: comparison of untreated and cortisone-treated patients. Mayo Clin Proc. 1968;43: Jordan JR, Paruthi S, Pichardo RO, Challa VR, Donofrio PD, Jorizzo JL. Spontaneously remitting dermatomyositis. J Eur Acad Dermatol Venereol. 2004;18:

111 Chapter 8 General discussion

112 Chapter 8 In this chapter, we review our most important findings and try to fit them into the current knowledge about these topics. Diagnosis Currently, idiopathic inflammatory myopathies (IIMs) in adults include polymyositis (PM), (clinically amyopathic) dermatomyositis (DM), nonspecific or overlap myositis (NSM), necrotizing autoimmune myopathy (NAM), and sporadic inclusion body myositis (IBM). 1 The number of entities is still expanding with the increasing immunological developments. With the growing number of autoantibodies and their associations with different clinical and histopathological characteristics, different subcategories emerge. 2-5 Accurate classification is important to choose the right diagnostic and treatment policy and to be informed about prognosis. Development of symptoms in weeks to months is called subacute in this thesis, which is seen in treatment-responsive IIMs (PM, DM, NSM and NAM), in contrast to the treatment resistant, chronic IBM. Muscle MRI Muscle biopsy is essential for diagnosing most patients with an IIM. International guidelines have been made for a standardized diagnostic work up of muscle biopsy. 6 Even for experts, reading a muscle biopsy and the interpretation of diagnostic criteria can be very difficult. 6 To acquire a representative biopsy, a moderately weak muscle should be chosen to reduce sampling error but even then, a false negative muscle biopsy is found in 10-20% of patients probably caused by the scattered distribution of cell infiltrates Many imaging techniques have been evaluated for diagnostic purposes. MRI can demonstrate muscle edema by showing areas of high signal intensity on STIR (short tau inversion recovery) and fat-suppressed T2-weighted sequences, even in clinically asymptomatic muscles. Hyperintensity on MRI can also be found in patients with rhabdomyolysis, ischemia, and denervation and it is not suitable to replace muscle biopsy but it can be used to guide muscle biopsy. Adding 110

113 General discussion gadolinium has no added value. Recommendations to perform MRI as a guide for muscle biopsy are based on a few relatively small studies 11-14, and on studies including only patients with an established diagnosis of IIM We aimed at investigating the added value of muscle MRI in diagnosing new patients suspected of subacute IIM. In chapter 2 muscle MRI was prospectively studied in a cross-sectional study in patients suspected of having a subacute IIM. Results of MRI and muscle biopsy were compared with the final diagnosis. The final diagnosis was based on established expert criteria 1 and a positive response to corticosteroids during follow up. These criteria include clinical features (symmetrical subacute progressive proximal muscle weakness, rash in DM), and ancillary investigations such as laboratory and muscle biopsy analysis. MRI was examined as triage (before muscle biopsy) to select the most suitable biopsy site in order to decrease sampling error and thus reduce false negative findings. The value of muscle MRI was also evaluated as add-on test in patients with a negative muscle biopsy. This study showed that MRI has a high diagnostic accuracy in diagnosing a subacute-onset IIM, in particular as an add-on test to the muscle biopsy in patients with a negative muscle biopsy but an otherwise typical clinical presentation consistent with myositis. The need for a repeat muscle biopsy can thus be avoided in these patients. Furthermore, our results suggest that MRI may be useful as a triage test, prior to the muscle biopsy, in reducing false negative muscle biopsies. Therefore, in patients suspected of having a subacuteonset idiopathic inflammatory myopathy we recommend both MRI and muscle biopsy. In most patients muscle biopsy remains necessary to further classify the IIM and to exclude other myopathies. Future studies could further explore this topic in several ways. For diagnostic purpose, the use of whole body MRI may be of value. Large volumes of muscle can be examined and the extent of inflammation, even at unsuspected sites, provides information about disease activity. MRI is also an excellent technique to show fatty infiltration, which usually occurs in late stages of myositis or can be helpful in diagnosing IBM. 24,25 Most research on whole body MRI was done in juvenile DM, and showed that whole body MRI provides additional information to clinical evaluation with 8 111

114 Chapter 8 inflammation in muscular, subcutaneous and myofascial locations which were undetected by clinical examination. 24,26 Because of the small number of patients in studies about MRI in adults, it was not possible to investigate whether specific patterns of muscle involvement correlate to different IIM diagnoses. In our study, 93% of patient with T2 hyperintensity had a symmetrical distribution of hyperintensities, which in 81% were seen in the quadriceps muscles, in 70% in the adductor muscles and in 59% in the hamstring muscles. A high signal on the STIR was found in the fascia in 5 patients with a diagnosis of DM and in 8 patients with PM/non-specific myositis, of whom 4 also had a connective tissue disease. This was always found at the same site as high signal intensity in the skeletal muscles. It would be interesting to investigate if specific MRI patterns are related to pathogenetic mechanisms or outcome. MRI in IBM shows specific patterns of muscle involvement, namely fatty infiltration in particularly the flexor digitorum profundus muscles and the anterior muscles of the upper leg, all muscles of the lower leg preferentially the medial compartment of the gastrocnemius muscles with relative sparing of the rectus femoris muscles compared with other quadriceps muscles. 25 Muscle biopsy: invasion of non-necrotic muscle fibers Distinction of inclusion body myositis (IBM) from the other types of myositis is important since IBM does not respond to immunosuppressive treatment. Both in IBM and PM, cellular-mediated cytotoxic mechanism plays an important role. The histopathological picture of PM is defined by muscle fibre necrosis, regeneration, and endomysial mononuclear cell infiltrates surrounding and invading nonnecrotic muscle fibres expressing major histocompatibility complex (MHC) class 1 antigens, consisting of CD8 positive cytotoxic T-cells, myeloid dendritic cells, plasma cells and macrophages The inflammation found in IBM proved to be undistinguishable from that found in PM, but in IBM degenerative features are also found, such as eosinophilic intracellular inclusions, basophilic rimmed vacuoles, amyloid deposits and tubulofilaments on electron microscopy. The current criteria for IBM include clinical signs allowing for a diagnosis if not all muscle pathology findings typical for IBM are present. Since IBM and PM share the same endomysial infiltrates 112

115 General discussion with invasion of non-necrotic muscle fibers, distinguishing these two can be difficult when rimmed vacuoles or typical clinical characteristics for IBM are not present. Furthermore, PM characterized by endomysial infiltrates with invasion of non-necrotic muscle fibers seemed to be very rare. 30,31 In chapter 3 we investigated disease course in patients with endomysial mononuclear cell infiltrates invading non-necrotic fibres but no diagnosis of IBM (unclassified patients in comparison with patients with IBM on clinical grounds or IBM on histopathological grounds). Clinical criteria for IBM included duration of weakness > 12 months at the time of diagnosis, age at onset >45 years, weakness of finger flexion muscles more than shoulder abduction muscles and knee extension muscles as weak as or weaker than hip flexor muscles. 32 At presentation, rimmed vacuoles were found in 60.5% of patients, 17.3% fulfilled clinical criteria for IBM and 22.2% were unclassified. At onset fewer women than men were found to have rimmed vacuoles and women more often than men also did not have characteristic clinical features. This indicates that women with IBM are at risk for underdiagnosis. At follow up after a mean of 9 years (SD 5), all men and almost all women fulfilled clinical criteria for IBM. All had a slow progressive disease and none experienced sustained improvement if treated. In conclusion, patients with a muscle biopsy showing endomysial cell infiltration with invasion of non-necrotic muscle fibers most probably have IBM, even if they do not fulfill defined histopathological or clinical criteria at presentation. These findings are important for future treatment studies. We postulate that a muscle biopsy showing endomysial infiltrates with invasion of non-necrotic fibers should be an exclusion criterion in therapeutic studies in PM patients since these patients have a high a priori chance of being a non-responder. 8 Table 1 shows the 2011 ENMC criteria for IBM. 32 These ENMC criteria offer great advantage since patients can be diagnosed with IBM on clinical grounds with supportive (but not all) histopathological features. Diagnosis could possibly be made earlier and more patients can be included in trials. The histopathological features of the ENMC criteria are in accordance with the pathological criteria previously proposed by Griggs

116 Chapter 8 Table ENMC criteria for inclusion body myositis Clinical features Classification Histopathological features Duration of weakness >12 months Creatine kinase 15xULN Age at onset > 45 years Finger flexion weakness > shoulder abduction weakness AND/OR Knee extension weakness hip flexor weakness Clinicopathologically defined IBM All of the following: Endomysial inflammatory infiltrate Upregulation of MHC class I Rimmed vacuoles Protein accumulation or nm filaments Duration of weakness >12 months Creatine kinase 15xULN Age at onset > 45 years Finger flexion weakness > shoulder abduction weakness AND Knee extension weakness hip flexor weakness Clinically defined IBM One or more, but not all, of: Endomysial inflammatory infiltrate Upregulation of MHC class I Rimmed vacuoles Protein accumulation or nm filaments Duration of weakness >12 months Creatine kinase 15xULN Age at onset > 45 years Finger flexion weakness > shoulder abduction weakness OR Knee extension weakness hip flexor weakness Probable IBM One or more, but not all, of: Endomysial inflammatory infiltrate Upregulation of MHC class I Rimmed vacuoles Protein accumulation or nm filaments Recently, specificity and sensitivities of 24 previously proposed IBM diagnostic categories were studied. 34 The authors found 90% sensitivity and 96% specificity with the combined next three criteria: 1) finger flexion or quadriceps weakness, 2) endomysial inflammation and 3) either invasion of non-necrotic muscle fibers 114

117 General discussion or rimmed vacuoles. The sensitivity and specificity of invasion was found to be comparable with the sensitivity and specificity of rimmed vacuoles in IBM, so the feature of invasion could be of supportive value in IBM IBM according to these authors. How can we explain that we did not find patients fulfilling the criteria for PM, while others do? The question is whether the criterion of invasion is a valid diagnostic criterion for PM and it was suggested that this notion has not been based on solid data. 35 In chapter 3 we argue that invasion should not be part of the PM criteria. It may well be possible that PM patients described by others, especially rheumatologists who tend to use the Bohan and Peter criteria 7,36,37 did not use the criterion of endomysial inflammation with invasion, and rather use the term PM for patients with treatment-responsive, subacute onset, proximal, symmetrical weakness, with or without a connective tissue disease and with inflammation in the muscle biopsy, which can be located perimysially of perivascular with or without expansion in the endomysial site. However, others did describe patients fulfilling PM criteria including invasion of non-necrotic fibers. 38,39 An alternative explanation might be that in some patients it takes many years to evolve from a PM-like presentation including invasion to a typical IBM phenotype. 30 This may hold in particular for women as we have shown in chapter 3. 8 Currently, diagnostic testing for auto-antibodies against cytosolic 5'-nucleotidase 1A are topic of investigations A specificity of 92-98% for IBM was found especially in case of high levels of antibodies. The target is a muscle specific enzyme involved in energy balance, metabolic regulation and cell replication. In the near future, these auto-antibodies could be helpful in distinguishing IBM from PM patients. It would be of interest to examine the few auto-antibody positive PM patients for the presence of invasion of non-necrotic fibers. This would support our hypothesis that these patients have IBM. Future studies on this topic will clarify the role of these auto-antibodies in diagnosing IBM. 115

118 Chapter 8 Treatment First line treatment in patients with subacute idiopathic inflammatory myopathies consists of high dose oral prednisone for 4-6 weeks followed by slow tapering during one year or more. 43 This treatment is generally accepted albeit not examined in a RCT. A major drawback of this therapy is its many and severe adverse effects with long-term use. In chapter 5 the results of the Dexa Myositis Trial are presented. In this RCT first-line treatment with daily prednisone was compared to monthly pulsed therapy with dexamethasone. This treatment was chosen after positive results in other auto-immune diseases and promising results of a small pilot study. 44 Our study showed that dexamethasone was not better than daily prednisone but patients experienced fewer side effects. The small numbers did not allow for a subgroup analysis to identify the patients who responded well to dexamethasone but the results of this trial do provide an alternative for prednisone as first-line treatment in those at risk for severe adverse effects. This study also demonstrated the difficulties performing a large trial in a rare, chronic disease. Besides slow recruitment of patients, we also experienced a high dropout rate due to failing the allotted therapy. Early discontinuation occurred in 21 patients treated with dexamethasone (13 because of treatment failure) and in 17 patients treated with prednisone (6 because of treatment failure). This underlines the urgent need for international collaboration in treatment trials. For this purpose it is essential that diagnostic criteria and outcome measures, currently being developed by IMACS international collaborative group are widely agreed on. 45,46 The Cochrane 2012 update on treatment for IIM, analyzed 10 RCTs on first and second-line treatment performed until 2011 (Table 2) The authors concluded that the small number of RCTs of immunosuppressants and immunomodulatory agents are inadequate to decide whether these agents are beneficial in DM and PM. Only two small trials in DM suggest that intravenous immunoglobulin therapy and enteracept, respectively, may be beneficial. 50,57 One study in refractory patients showed no difference between intravenous immunoglobulin therapy or placebo. 58 In the second study in refractory patients, comparing early (weeks 0 116

119 General discussion and 1) and late treatment (weeks 8 and 9) with rituximab both showed an improvement. 59 Table 2. RCTs performed in PM and DM Patients PM/DM Treatment Difference between the arms Bunch newly AZA+corticosteroids vs No diagnosed placebo+corticosteroids Miller refractory Plasma exchange, No leukapheresis or sham vs placebo Dalakas refractory IVIG vs placebo, 3 months Yes (DM) Villalba refractory MTX oral +AZA vs MTX No IV+leucovorin rescue Vencovsky new (30 MTX oral vs ciclosporine A, No newly diagnosed) add-on to corticosteroids Takada refractory Eculizumab vs placebo No Miller refractory AZA or MTX, add-on to No corticosteroids Coyle refractory Infliximab vs placebo No Vlekkert newly Prednisone vs No diagnosed dexamethasone Myositis study group DM (11 refractory) Enteracept vs placebo, addon to corticosteroids (pilot) Yes 8 Miyasaka refractory IVIG vs placebo No Oddis refractory Rituximab add-on (early versus late) No (both improved) Besides these few RCTs, there are many uncontrolled studies and case reports, as is often the case in rare diseases. In chapter 4 quality of single case reports and case series on second-line treatments in PM and DM was assessed using self-devised criteria for a clear and adequate description of patients and therapy. We found the methodology unsatisfactory and concluded that reports of uncontrolled observations can improve considerably if criteria for good quality are taken into account. 117

120 Chapter 8 Outcome Not much is known about the natural course of the disease because patients are usually treated as soon as the diagnosis has been established. In chapter 7 we report three patients with a proven subacute myositis who recovered spontaneously. These patients noticed a spontaneous improvement during the diagnostic process before treatment was started. In rare instances a wait-andsee policy with close monitoring seems to be justified, thus avoiding unnecessary and potential harmful treatment. Current knowledge about disease course and prognosis come mainly from retrospective studies. We studied prospectively disease-related mortality and the course of the disease including functional outcome and quality of life in the 62 patients who participated in the Dexa Myositis Trial (chapter 6). After a mean follow up of three years, two-thirds of the patients had a polyphasic or chronic disease course and needed maintenance treatment and had experienced single or multiple relapses. Sixteen patients (33%) were off medication after on average one year of treatment. The small numbers did not allow for a subgroup analysis to identify characteristics of these patients. Disease-related mortality was 15%, mainly caused by DM-related cancer. An associated connective tissue disease developed in 22% and 17% developed a malignancy, especially DM patients. In our study, all malignancies in DM developed within the first two years, but since it was shown that the risk of malignancy in DM remains high for many years after diagnosis, repeated malignancy screening in DM patients is recommended for at least five years. 60 The relation of NAM or PM and cancer remains unclear. At follow up 68% still perceive disabilities. Our results are in line with earlier, retrospective data 61-63, but contradict retrospective results of others showing better outcome: at a mean follow up of 8 years, 86% of 156 surviving patients had no disease activity and 83% had no disability. 64 Ours was the first study prospectively studying quality of life using the SF-36 in IIM. Quality of life improved during the first 18 months which is in line with the improvement of disability as measured with the Rankin score. After that, scores remained stable during follow up and were lower compared to the normal population values. This may be due to permanent disease damage. All our 118

121 General discussion patients were initially treated with high dosages of corticosteroids (dexamethasone or prednisone) and it may well be that this treatment is not effective enough to suppress inflammation adequately and to prevent irreversible disease damage. This is supported by our high dropout rate because of treatment failure. New treatment modalities in future will hopefully not only vigorously suppress inflammation but also decrease the amount of disease damage and improve quality of life and function. Until now, trials in IBM have shown disappointing results. Recently, a small placebo controlled study with bimagrumab in 14 patients with IBM showed an increased muscle mass on MRI and improved 6-minutes walking distance in patients treated with one dose of bimagrumab. A large international trial is currently underway

122 Chapter 8 References 1. Hoogendijk JE, Amato AA, Lecky BR, Choy EH, Lundberg IE, Rose MR et al. 119th ENMC international workshop: trial design in adult idiopathic inflammatory myopathies, with the exception of inclusion body myositis, October 2003, Naarden, The Netherlands. Neuromuscul Disord. 2004;14: Troyanov Y, Targoff IN, Tremblay JL, et al. Novel classification of idiopathic inflammatory myopathies based on overlap syndrome features and autoantibodies: analysis of 100 French Canadian patients. Medicine 2005;84(4): Fernandez C, Bardin N, De Paula AM, et al. Correlation of clinicoserologic and pathologic classifications of inflammatory myopathies: study of 178 cases and guidelines for diagnosis. Medicine 2013 Jan;92(1): Troyanov Y, Targoff IN, Payette MP, et al. Redefining dermatomyositis: a description of new diagnostic criteria that differentiate pure dermatomyositis from overlap myositis with dermatomyositis features. Medicine 2014;93(24): Stenzel W, Goebel HH, Aronica E. Review: immune-mediated necrotizing myopathies-a heterogeneous group of diseases with specific myopathological features. Neuropathol Appl Neurobiol. 2012;38(7): De Bleecker JL, De Paepe B, Aronica E, et al. 205 th ENMC International Workshop: Pathology diagnosis of idiopathic inflammatory myopathies Part II March 2014, Naarden, The Netherlands. Neuromuscul Disord Dec Bohan A, Peter JB, Bowman RL, Pearson CM. Computer-assisted analysis of 153 patients with polymyositis and dermatomyositis. Medicine (Baltimore). 1977;56: Bunch TW. Polymyositis: a case history approach to the differential diagnosis and treatment. Mayo Clin Proc. 1990;65: Plotz PH, Dalakas M, Leff RL, Love LA, Miller FW, Cronin ME. Current concepts in the idiopathic inflammatory myopathies: polymyositis, dermatomyositis, and related disorders. Ann Intern Med. 1989;111: Munsat T, Cancilla P. Polymyositis without inflammation. Bull Los Angeles Neurol Soc. 1974;39: Schweitzer ME, Fort J. Cost-effectiveness of MR imaging in evaluating polymyositis. AJR. 1995;165: O'Connell MJ, Powell T, Brennan D, Lynch T, McCarthy CJ, Eustace SJ. Whole-body MR imaging in the diagnosis of polymyositis. AJR. 2002;179: Cantwell C, Ryan M, O'Connell M, Cunningham P, Brennan D, Costigan D, et al. A comparison of inflammatory myopathies at whole-body STIR MRI. Clin Radiol. 2005;60: Pitt AM, Fleckenstein JL, Greenlee RG, Burns DK, Wilson W, Haller R. MRI-guided biopsy in inflammatory myopathy: initial results. Magnetic Resonance Imaging. 1993;11: Schedel H, Reimers CD, Vogl T, Witt TN. Muscle edema in MR imaging of neuromuscular diseases. Acta Radiologica. 1995;3: Fraser DD, Frank JA, Dalakas M, Miller FW, Hicks JE, Plotz P. Magnetic resonance imaging in the idiopathic inflammatory myopathies. J Rheumatol. 1991;18:

123 General discussion 17. Kaufman LD, Gruber BL, Gerstman DP, Kaell AT. Preliminary observations on the role of magnetic resonance imaging for polymyositis and dermatomyositis. Ann Rheum Dis. 1987;46: Dorph C, Englund P, Nennesmo I, Lundberg IE. Signs of inflammation in both symptomatic and asymptomatic muscles from patients with polymyositis and dermatomyositis. Ann Rheum Dis. 2006;65: Bartlett ML, Ginn L, Beitz L, Villalba ML, Plotz P, Bacharach SL. Quantitative assessment of myositis in thigh muscles using magnetic resonance imaging. Magn Res Imag. 1999;17: Fujino H, Kobayashi T, Goto I, Onitsuka H. Magnetic resonance imaging of the muscles in patients with polymyositis and dermatomyositis. Muscle Nerve. 1991;14: Reimers CD, Schedel H, Fleckenstein JL, et al. Magnetic resonance imaging of skeletal muscles in idiopathic inflammatory myopathies of adults. J. Neurol 1994;241: Löfberg M, Liewendahl K, Lamminen A, Korhola O, Somer H. Antimyosin scintigraphy compared with magnetic resonance imaging in inflammatory myopathies. Arch Neurol. 1998;55: Fujitake J, Ishikawa Y, Fuji H, Nishimura K, Hayakawa K, Tatsuoka Y. Magnetic resonance imaging of skeletal muscles in the polymyositis. Muscle Nerve. 1997;20: Curiel RV, Jones R, Brindle K. Magnetic resonance imaging of the idiopathic inflammatory myopathies: structural and clinical aspects. Ann N Y Acad Sci. 2009;1154: Cox FM, Reijnierse M, van Rijswijk CSP, et al. Magnetic resonance imaging of skeletal muscles in sporadic inclusion body myositis. Rheumatology 2011;50: Castro TC, Lederman H, Terreri MT, et al. Whole-body magnetic resonance imaging in the assessment of muscular involvement in juvenile dermatomyositis/polymyositis patients. Scand J Rheumatol. 2014;43(4): Engel AG, Arahata K. Monoclonal antibody analysis of mononuclear cells in myopathies. II: Phenotypes of autoinvasive cells in polymyositis and inclusion body myositis. Ann Neurol Aug;16(2): Arahata K, Engel AG. Monoclonal antibody analysis of mononuclear cells in myopathies. I: Quantitation of subsets according to diagnosis and sites of accumulation and demonstration and counts of muscle fibers invaded by T cells. Ann Neurol Aug;16(2): Arahata K, Engel AG. Monoclonal antibody analysis of mononuclear cells in myopathies. III: Immunoelectron microscopy aspects of cell-mediated muscle fiber injury. Ann Neurol Feb;19(2): van der Meulen MF, Bronner IM, Hoogendijk JE, et al. Polymyositis: an overdiagnosed entity. Neurology 2003;61(3): Vilela VS, Prieto-González S, Milisenda JC, et al. Polymyositis, a very uncommon isolated disease: clinical and histological re-evaluation after long-term follow-up. Rheumatol Int Dec Rose MR; ENMC IBM Working Group. 188th ENMC International Workshop: Inclusion Body Myositis, 2-4 December 2011, Naarden, The Netherlands. Neuromuscul Disord Dec;23(12):

124 Chapter Griggs RC, Askanas V, DiMauro S, et al. Inclusion body myositis and myopathies. Ann Neurol 1995;38: Lloyd TE, Mammen AL, Amato AA, Weiss MD, Needham M, Greenberg SA. Evaluation and construction of diagnostic criteria for inclusion body myositis. Neurology Jul 29;83(5): Hengstman GJ, van Engelen BG. Polymyositis, invasion of non-necrotic muscle fibres, and the art of repetition. BMJ Dec 18;329(7480): Bohan A, Peter JB. Polymyositis and dermatomyositis (first of two parts). N Engl J Med Feb 13;292(7): Bohan A, Peter JB. Polymyositis and dermatomyositis (second of two parts). N Engl J Med Feb 20;292(8): Chahin N, Engel AG. Correlation of muscle biopsy, clinical course, and outcome in PM and sporadic IBM. Neurology 2008 Feb 5;70(6): Brady S, Squier W, Sewry C, et al. A retrospective cohort study identifying the principal pathological features useful in the diagnosis of inclusion body myositis. BMJ Open Apr 28;4(4):e Greenberg SA. Cytoplasmic 5'-Nucleotidase Autoantibodies in Inclusion Body Myositis: Isotypes and Diagnostic Utility. Muscle Nerve 2014 Oct;50(4): Pluk H, van Hoeve BJ, van Dooren SH, et al. Autoantibodies to cytosolic 5'-nucleotidase 1A in inclusion body myositis. Ann Neurol Mar;73(3): Larman HB, Salajegheh M, Nazareno R, et al. Cytosolic 5'-nucleotidase 1A autoimmunity in sporadic inclusion body myositis. Ann Neurol Mar;73(3): Dalakas MC. Therapeutic targets in patients with inflammatory myopathies: present approaches and a look to the future. Neuromuscul Disord 2006;16(4): van der Meulen MF, Hoogendijk JE, Wokke JH, de Visser M. Oral pulsed high-dose dexamethasone for myositis. J Neurol 2000;247(2): Miller FW, Rider LG, Chung YL, et al. Proposed preliminary core set measures for disease outcome assessment in adult and juvenile idiopathic inflammatory myopathies. Rheumatology 2001;40(11): Rider LG, Lachenbruch PA, Monroe JB, et al. Damage extent and predictors in adult and juvenile dermatomyositis and polymyositis as determined with the myositis damage index. Arthritis Rheum 2009;60(11): Gordon PA, Winer JB, Hoogendijk JE, Choy EH. Immunosuppressant and immunomodulatory treatment for dermatomyositis and polymyositis. Cochrane Database Syst Rev Aug 15;8:CD Bunch TW, Worthington JW, Combs JJ, et al. Azathioprine with prednisone for polymyositis. A controlled, clinical trial. Ann Intern Med Mar;92(3): Miller FW, Leitman SF, Cronin ME, et al. Controlled trial of plasma exchange and leukapheresis in polymyositis anddermatomyositis. N Engl J Med May 21;326(21): Dalakas MC, Illa I, Dambrosia JM, et al. A controlled trial of high-dose intravenous immune globulin infusions as treatment for dermatomyositis. N Engl J Med Dec 30;329(27):

125 General discussion 51. Villalba L, Hicks JE, Adams EM, et al. Treatment of refractory myositis: a randomized crossover study of two new cytotoxic regimens. Arthritis Rheum Mar;41(3): Vencovský J, Jarosová K, Machácek S, et al. Cyclosporine A versus methotrexate in the treatment of polymyositis and dermatomyositis. Scand J Rheumatol. 2000;29(2): Takada K, Bookbinder S, Furie R, et al. A pilot study of eculizumab in patients with dermatomyositis. Arthritis and Rheumatism 2002;46(Suppl):S Miller J, Walsh Y, Saminaden S, Lecky BRF, Winer JB. Randomised double blind controlled trial of methotrexate and steroids compared with azathioprine and steroids in the treatment of idiopathic inflammatory myopathy. Journal of the Neurological Sciences 2002;199(Suppl 1):S Coyle K, Pokrovnichka A, French K, et al. A randomized, double-blind, placebocontrolled trial of infliximab in patients with polymyositis and dermatomyositis. Arthritis and Rheumatism 2008;58(Suppl):Abstract No: Van de Vlekkert J, Hoogendijk JE, De Haan RJ, et al. Oral dexamethasone pulse therapy versus daily prednisolone in sub-acute onset myositis, a randomised clinical trial. Neuromuscular Disorders 2010;20(6): Muscle Study Group. A randomized, pilot trial of etanercept in dermatomyositis. Ann Neurol Sep;70(3): Miyasaka N, Hara M, Koike T, et al. Effects of intravenous immunoglobulin therapy in Japanese patients with polymyositis and dermatomyositis resistant to corticosteroids: a randomized double-blind placebo-controlled trial. Mod Rheumatol Jun;22(3): Oddis CV, Reed AM, Aggarwal R, et al. Rituximab in the treatment of refractory adult and juvenile dermatomyositis and adultpolymyositis: a randomized, placebo-phase trial. Arthritis Rheum Feb;65(2): Hill CL, Zhang Y, Sigurgeirsson B, et al. Frequency of specific cancer types in dermatomyositis and polymyositis: a population-based study. The Lancet 2001;357(9250): Bronner IM, van der Meulen MF, de Visser M, Kalmijn S, van Venrooij WJ, Voskuyl AE, et al. Long-term outcome in polymyositis and dermatomyositis. Ann Rheum Dis 2006;65(11): Marie I, Hachulla E, Hatron PY, Hellot MF, Levesque H, Devulder B, et al. Polymyositis and dermatomyositis: short term and longterm outcome, and predictive factors of prognosis. J Rheumatol 2001;28(10): Ponyi A, Borgulya G, Constantin T, Váncsa A, Gergely L, Dankó K. Functional outcome and quality of life in adult patients with idiopathic inflammatory myositis. Rheumatology 2005;44(1): Shu XM, Lu X, Xie Y, Wang GC. Clinical characteristics and favorable long-term outcomes for patients with idiopathic inflammatory myopathies: a retrospective single center study in China. BMC Neurol 2011;11: Amato AA, Sivakumar K, Goyal N, et al. Treatment of sporadic inclusion body myositis with bimagrumab. Neurology 2014;83(24):

126

127 Idiopathic inflammatory myopathies: diagnosis, treatment and outcome Summary

128 The idiopathic inflammatory myopathies (IIM) are disorders characterized by muscle inflammation and progressive muscle weakness. This group consists of polymyositis (PM), dermatomyositis (DM), nonspecific myositis (NSM), necrotizing autoimmune myopathy (NAM) and sporadic inclusion body myositis (IBM) and the number of entities is still expanding due to novel auto-antibodies. Distinction between IBM, a hitherto treatment-resistant disease, and PM, a treatable disease, can sometimes be difficult. First-line treatment of DM, PM, NSM and NAM consists of high dose corticosteroids. This causes considerable adverse effects, and therefore alternative first-line treatments are urgently needed. Long-term outcome is mainly reported retrospectively (chapter 1). The investigations described in this thesis focus on diagnosis, treatment and outcome in adult patients with idiopathic inflammatory myopathies. Diagnosis A muscle biopsy is needed for diagnosing patients with an IIM, except for DM patients with characteristic skin changes and patients with a known connective tissue disease who develop a myositis. In some patients the muscle biopsy is not conclusive. This may be due to sampling error caused by the scattered distribution of cell infiltrates. In myositis, muscle MRI can demonstrate muscle edema by showing high signal intensity on STIR (short tau inversion recovery) and on fat-suppressed T2-weighted sequences, even in clinically asymptomatic muscles. Chapter 2 describes the diagnostic value of the combination of MRI of the muscles and muscle biopsy in 48 patients suspected of having a (sub)acute IIM. MRI was used as triage (before muscle biopsy) to select the most suitable site in order to decrease sampling error and thus reduce false negative findings. The value of muscle MRI was also assessed as add-on test in patients with a negative muscle biopsy. We found that muscle biopsies taken from a muscle with a high signal intensity on MRI (as triage test) had a decreased false negative rate. The false negative rate was also decreased by using MRI as add-on test. This is important because a repeat muscle biopsy can be avoided and thus treatment can be initiated as soon as possible. We conclude that MRI is strongly recommended in diagnosing patients with a subacute idiopathic inflammatory myopathy. 126

129 Summary Endomysial inflammation with invasion of non-necrotic muscle fibers is a required diagnostic feature in patients with inclusion body myositis (IBM) and also in patients with polymyositis (PM). However, distinctive pathological features in IBM, i.e. rimmed vacuoles, are not always present in IBM and recently it was suggested that it is justified to make a diagnosis of IBM on clinical grounds only. However, patients also do not always fulfil the spectrum of clinical IBM criteria, and in these patients the distinction between IBM, a hitherto treatment-resistant disease, and PM, a treatable disease, may remain difficult. In chapter 3 we investigated the disease course of 81 patients whose biopsies showed endomysial mononuclear cell infiltrates with invasion of non-necrotic muscle fibres (auto-invasive myositis), hypothesizing that these patients show a disease course consistent with IBM (namely treatment unresponsive, chronic progression), even if they did not fulfil either typical histopathological or clinical criteria of IBM from the outset. We distinguished three groups: 1) patients muscle biopsies with rimmed vacuoles regardless of clinical features; 2) patients muscle biopsies without rimmed vacuoles but fulfilling clinical criteria for IBM and 3) patients muscle biopsies without rimmed vacuoles which also did not fulfil clinical criteria for IBM. This study shows that patients with endomysial inflammation with invasion of non-necrotic muscle fibers all had a slow progressive disease and none experienced sustained improvement after treatment. In conclusion, patients with a muscle biopsy showing endomysial cell infiltration with invasion of non-necrotic muscle fibers most probably have IBM, even if they did not did not have typical clinical and other pathological features. Our study also showed that more women than men with IBM were at risk for underdiagnosis because they less frequently showed rimmed vacuoles in their muscle biopsy as compared to men and the same holds true for typical clinical signs at presentation. Implications of these findings are the following: 1) patients with endomysial auto-invasive myositis who are treated should be carefully monitored for treatment failure, 2) this holds especially for women and 3) endomysial mononuclear invasion of non-necrotic muscle fibres should be an exclusion criterion for PM. 127

130 Therapy The incidence of the subacute IIMs is low. Therefore, it is difficult to enroll sufficient numbers of patients in randomised controlled trials (RCTs). When RCTs are not available, results of treatments described in case series or case reports can be taken into consideration. For RCTs, criteria for good quality have been well established and are applied widely. Criteria for a clear and adequate description of single cases and uncontrolled case series are not commonly used. In chapter 4 the quality of case reports of 92 publications describing 915 patients with myositis was assessed based on self-devised criteria. We found the methodology of patient descriptions (the evidence) in single case reports and case series reports on second-line treatments in PM and DM unsatisfactory. First-line treatment in patients with subacute idiopathic inflammatory myopathies consists of high dose oral prednisolone for 4-6 weeks followed by slow tapering over a period of years. This treatment is generally accepted on empirical grounds, but comes with considerable adverse effects. In chapter 5 the results of the Dexa Myositis Trial are presented. In this RCT monthly pulsed oral dexamethasone was compared with daily oral prednisolone in 62 newly diagnosed patients. After a follow up of 18 months, there was no difference in most primary outcomes, but side effects were significantly less with pulsed dexamethasone. We also found that relapses occurred somewhat earlier with dexamethasone. In Chapter 6 we evaluated the disease course in myositis. Patients who participated in the Dexa Myositis Trial were followed and their disease course was described. After a mean follow up of three years, two-thirds of the patients showed a polyphasic or chronic disease course, needed maintenance treatment and experienced single or multiple relapses. Quality of life scores improved within the first 18 months but after that, scores were stable during the next years of follow up and remained worse compared with a healthy population. The impact of the disease on functional outcome and quality of life proved to be considerable. 128

131 Summary It is generally assumed that patients with (sub)acute myositis if left untreated will experience a progressive disease course. In Chapter 7 we report three patients with a proven subacute myositis who recovered spontaneously. Therefore we recommend a wait-and-see policy with close monitoring of patients who notice a spontaneous improvement during the diagnostic process and before treatment is started, thus avoiding unnecessary and potential harmful treatment. A general discussion of our findings is presented in chapter

132

133 Idiopathic inflammatory myopathies: diagnosis, treatment and outcome Samenvatting

134 De groep van de idiopathische inflammatoire myopathieën (IIM) bestaat uit aandoeningen gekarakteriseerd door spierontsteking en progressieve spierzwakte. Deze groep bestaat uit polymyositis (PM), dermatomyositis (DM), niet-specifieke of overlap myositis (NSM), necrotiserende auto-immuun myopathie (NAM) en inclusion body myositis (IBM). In de loop van de tijd komen er steeds meer nieuwe entiteiten bij, mede op basis van nieuwe immunologische ontwikkelingen die antistoffen aan het licht brengen. Het onderscheiden van IBM, een tot dusverre onbehandelbare aandoening, van PM, een behandelbare aandoening, kan soms moeilijk zijn. Eerstelijns behandeling van DM, PM, NSM en NAM bestaat uit hoog gedoseerde corticosteroïden. Deze behandeling veroorzaakt vaak bijwerkingen en daarom is er behoefte aan alternatieve eerstelijns behandelingen. Langetermijnuitkomsten komen voornamelijk van retrospectieve studies (hoofdstuk 1). De onderzoeken in dit proefschrift richten zich op de diagnose, behandeling en uitkomsten in volwassen patiënten met idiopathische inflammatoire myopathieën. Diagnose Voor het stellen van de diagnose IIM is een spierbiopt nodig, behalve bij patiënten met DM met karakteristieke huidafwijkingen en bij patiënten met een bindweefselaandoening die een myositis ontwikkelen. In sommige patiënten is het spierbiopt niet bewijzend. Dit kan komen doordat de ontsteking niet gelijk over de spier verdeeld hoeft te zijn. Een MRI van de spieren kan bij myositis tekenen van oedeem laten zien in de vorm van een verhoogd signaal op de STIR (short tau inversion recovery) en T2 gewogen afbeeldingen met vetsuppressie, zelfs in klinisch niet aangedane spieren. In hoofdstuk 2 wordt de diagnostische waarde beschreven van de combinatie van MRI van de spieren en het spierbiopt van 48 patiënten verdacht voor het hebben van een IIM. De waarde van MRI was onderzocht als triage test (voor het spierbiopt) om de meest geschikte plaats voor het spierbiopt uit te zoeken om vals negatieve uitkomsten te reduceren. De waarde van spier-mri werd ook onderzocht als addon test (na het spierbiopt) in patiënten met een negatief spierbiopt. We vonden dat spierbiopten afgenomen van spieren met een verhoogd signaal op de MRI (als triage test) een lagere vals negatieve waarde hadden. De vals negatieve waarde werd verder verminderd bij het gebruik van de MRI als add-on test. Dit is van belang omdat zo een tweede spierbiopt voorkomen kan worden en therapie zo vroeg mogelijk kan worden gestart. We concluderen dat MRI zinvol is in het diagnosticeren van IIM. 132

135 Samenvatting Endomysiale ontsteking met invasie van niet-necrotische spiervezels is een van de diagnostische criteria van zowel inclusion body myositis (IBM) als van polymyositis (PM). Andere histopathologische kenmerken van IBM, zoals gerande vacuolen (rimmed vacuoles) zijn niet altijd aanwezig in het spierbiopt en recent werd vastgesteld dat de diagnose IBM ook op klinische kenmerken gesteld kan worden wanneer niet aan alle histopathologische criteria wordt voldaan. Sommige patiënten voldoen niet aan de klinische criteria voor IBM en bij hen kan het onderscheid tussen IBM, een tot dusverre onbehandelbare aandoening, en PM, een behandelbare aandoening moeilijk zijn. In hoofdstuk 3 werd het ziektebeloop onderzocht van 81 patiënten met endomysiale mononucleaire infiltraten met invasie van niet-necrotische spiervezels, met als hypothese dat deze patiënten een ziektebeloop vergelijkbaar met IBM zouden hebben (namelijk therapieresistent, chronisch progressief), ook als zij niet voldeden aan de histopathologische of de klinische criteria voor IBM. Patiënten werden ingedeeld in drie groepen: 1) patiënten met in het spierbiopt rimmed vacuoles ongeacht de klinische kenmerken; 2) patiënten zonder rimmed vacuoles in het spierbiopt maar die wel voldeden aan de klinische kenmerken voor IBM en 3) patiënten zonder rimmed vacuoles en die niet voldeden aan de klinische kenmerken voor IBM. Deze studie laat zien dat alle patiënten met endomysiale infiltraten met invasie van niet-necrotische spiervezels een langzaam progressief ziektebeloop hadden zonder aanhoudende verbetering op therapie. We concludeerden dat patiënten met endomysiale infiltraten met invasie van niet-necrotische spiervezels in het spierbiopt waarschijnlijk IBM hebben, ongeacht de klinische of andere histopathologische bevindingen. Deze studie liet ook zien dat vrouwen vaker dan mannen risico lopen om niet gediagnosticeerd te worden met IBM, omdat bij hen vaker rimmed vacuoles ontbraken en zij ook niet de typische klinische kenmerken bij presentatie hadden. Deze bevindingen hebben de volgende implicaties: 1) bij patiënten met endomysiale infiltraten met invasie van niet-necrotische spiervezels die behandeld worden, dient goed gelet te worden op het falen van de behandeling, 2) dit geldt in het bijzonder voor vrouwen en 3) endomysiale infiltraten met invasie van niet-necrotische spiervezels zou een exclusiecriterium moeten zijn voor PM. Therapie De incidentie van subacute IIM is laag. Hierdoor is het moeilijk om voldoende grote groepen patiënten te includeren in gerandomiseerde gecontroleerde studies (RCT s). Wanneer dit type studie weinig of niet aanwezig is, kan gekeken worden naar therapieën die beschreven worden in losse case reports of case series. Voor 133

136 RCT s zijn duidelijke kwaliteitscriteria beschikbaar en deze worden bijna altijd toegepast. Criteria voor duidelijke beschrijvingen van losse case reports en ongecontroleerde case series worden niet vaak gebruikt. In hoofdstuk 4 wordt de kwaliteit van case reports in 92 publicaties, waarin tweedelijns behandeling van 915 patiënten met PM of DM worden beschreven, beoordeeld op basis van zelf gemaakte criteria. We vonden de methodologie van de beschrijvingen (de bewijskracht) in losse case reports en case series ontoereikend. Eerstelijnsbehandeling van patiënten met subacute idiopathische inflammatoire myopathieën bestaat uit hoge dosering prednison gedurende 4-6 weken, gevolgd door een langzaam afbouwschema gedurende een jaar of langer. Deze behandeling is algemeen geaccepteerd maar veroorzaakt aanzienlijke bijwerkingen. In hoofdstuk 5 worden de resultaten van de Dexa Myositis Trial beschreven. In deze gerandomiseerde gecontroleerde studie werden maandelijkse orale dexamethason stootkuren vergeleken met dagelijks orale prednison in 62 nieuw gediagnosticeerde patiënten. Na een follow up van 18 maanden vonden we geen verschillen in de meeste primaire uitkomstmaten, behalve significant minder bijwerkingen bij dexamethason stootkuren. Ook vonden we dat als relapsen optraden, dit iets vroeger ontstond bij dexamethason. In hoofdstuk 6 onderzochten we het ziektebeloop van myositis. Patiënten die deelnamen aan de Dexa Myositis Trial werden gevolgd en hun ziektebeloop werd beschreven. Na een gemiddelde duur van drie jaar had tweederde van de patiënten een polyfasisch of chronisch ziekte beloop, hadden onderhoudsbehandeling nodig en maakten enkele of meerdere relapsen door. Kwaliteit van leven scores verbeterden binnen de eerste 18 maanden, maar bleven daarna stabiel en lager vergeleken met die van een gezonde populatie. De invloed van de ziekte op functionele uitkomst en kwaliteit van leven was aanzienlijk. In het algemeen wordt aangenomen dat patiënten met een (sub)acute myositis zonder behandeling een progressief ziektebeloop zullen doormaken. In hoofdstuk 7 worden drie patiënten met een bewezen subacute myositis beschreven die spontaan verbeterden. Bij patiënten die een spontane verbetering bemerken tijdens het diagnostisch proces voordat behandeling is gestart, kan een afwachtend beleid met frequente controles worden gevolgd. Een onnodige en mogelijk schadelijke behandeling kan dan voorkomen worden. Tot slot worden de resultaten van dit proefschrift bediscussieerd in hoofdstuk

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141 Verschillende mensen hebben een bijdrage geleverd aan dit onderzoek. Ik wil ze hier graag bedanken. Prof. dr. M. de Visser, beste Marianne. Ik ben je ontzettend dankbaar voor alles wat je voor het onderzoek en mijn opleiding hebt gedaan. Naast je drukke agenda heb je altijd tijd gemaakt voor overleg. Wat zou ervan geworden zijn als er nog geen bestond? Je kritische blik (zelfs na honderd versies van een artikel) en besluitvaardigheid heeft het onderzoek en mij steeds een stap vooruit geholpen. Je enthousiasme voor dit onderwerp heeft mij altijd gestimuleerd om door te zetten. Ik hoop dat er in de nieuwe fase van je carrière nog ontzettend veel leuke kansen op je pad komen. Dr. J.E. Hoogendijk, beste Jessica. Ik wil je bedanken voor de ontzettend fijne samenwerking. Ik heb de tijd dat we samen patiënten voor de trial zagen en urenlang vacuolen zochten in de biopten heel leuk gevonden. Hoeveel dilemma s zijn we wel niet tegengekomen tijdens onze onderzoeken? Ik heb veel van je geleerd tijdens deze discussies en ook van je nauwkeurigheid, je geduld en je kritische blik. Prof. dr. R.J. de Haan, klinisch epidemioloog AMC. Beste Rob, je bijdrage aan de Dexa Myositis Trial is groot geweest. Heel veel dank hiervoor. De myositis patiënten die deel hebben genomen aan de Dexa Myositis Trial. Zonder jullie was er geen onderzoek. Ik wil jullie bedanken voor het vertrouwen dat jullie in mij hadden om tijdens de onzekere periode rond het stellen van de diagnose te kiezen voor een behandeling in onderzoeksverband. Alle collega s in het land die patiënten voor de Dexa Myositis Trial hebben verwezen. Bedankt voor de prettige samenwerking. Pathologen in het AMC: Prof. dr. D. Troost, Dr. A.J. Rozemuller, prof dr. E.M.A. Aronica. Bedankt voor het snel beoordelen van de spierbiopten ten tijde van de Dexa Myositis Trial. 139

142 De leden van de promotiecommissie: bedankt voor het beoordelen van het manuscript en het plaats nemen in deze commissie. Prinses Beatrix fonds. Bedankt voor de subsidie om dit onderzoek te kunnen uitvoeren. Mijn opleider Prof. dr. J. Stam. Beste Jan, ik wil je bedanken voor de kans die je mij gaf en voor alle jaren dat je mijn opleider bent geweest. Tijdens jouw klinisch lijn college s is mijn interesse voor de neurologie ontstaan. Prof. dr. M. Vermeulen. Beste Rien, bedankt dat je altijd bereid was om over het onderzoek kritisch mee te denken. Prof. dr. I.N. van Schaik. Beste Ivo, je hebt ons erg geholpen met het MRI onderzoek waarvoor veel dank. Prof. dr. M. Maas. Beste Mario, bedankt voor je medewerking aan het MRI stuk. Behalve leerzaam was het ook gezellig om samen alle scans te beoordelen. De neurologen in het AMC. Ieder heeft zijn eigen aandachtsgebied waardoor ik veel van jullie heb geleerd. Arts-assistenten van de neuromusculaire kamer (Jeldican, Camiel, Marieke, Filip, Joost en natuurlijk Steven voor het jarenlang delen van de cubicle) en alle andere assistenten. Bedankt voor de gezellige tijd en de goede sfeer. Dr. U.A. Badrising. Beste Umesh, bedankt voor het meedenken tijdens de opzet van het IBM onderzoek. Prof. dr. A. Algra, klinisch epidemioloog UMC Utrecht. Beste Ale, bedankt voor het kritisch meedenken en je adviezen tijdens de Dexa Myositis Trial. Mw. I. van der Tweel, biostatisticus, Universiteit Utrecht. Beste Ingeborg, bedankt voor je hulp bij de sequentiële analyse van de Dexa Myositis Trial. 140

143 Mw. E.V. Uijtendaal, apotheker UMC Utrecht. Beste Esther, het is een heel gepuzzel geweest om de studiemedicatie van de Dexa Myositis Trial blind te kunnen geven. Bedankt voor je bijdrage. Mijn paranimf Loes Reichman. Bedankt voor de steun tijdens deze promotieperiode en bedankt voor alle gezelligheid en geweldige reizen. Mijn paranimf Krista Kuitwaard. Bedankt dat je in jouw drukke leven ook nog eens mijn paranimf wilt zijn. Nog even en jij bent ook klaar! Irene Bronner. Bedankt voor je luisterend oor en begrip. Je hebt het allemaal meegemaakt. Nu kunnen we echt een myositis centrum starten. Collega s van de afdeling neurologie van het Flevoziekenhuis. Bedankt voor jullie interesse en steun. Ik ben ontzettend blij met zo n fijne groep collega s. Lieve pap en mam. Bedankt dat jullie het mogelijk hebben gemaakt om geneeskunde te gaan studeren. Jullie hebben me altijd gesteund en gestimuleerd. Nu zien jullie eens waar ik al die jaren op gebroed heb. Lieve Martijn. Zonder jou was dit promotietraject vast veel sneller verlopen, maar uiteindelijk is het nu toch af. Afleiding hebben en leuke dingen doen waren deze jaren ook heel belangrijk. Daar komt nu meer tijd voor. 141

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145 List of publications