Polymyalgia Rheumatica; Giant Cell Arteritis Paul Katzenstein, MD

Transcription

1 Polymyalgia Rheumatica; Giant Cell Arteritis Paul Katzenstein, MD What is it; is it not? How is this thought about, characterized, understood, treated Time honored published clinical experience Clinical presentations, lab and radiology, clinical course Classification criteria (for trials) What is the biology?

2 What is not PMR; not GCA Seronegative RA Idiopathic inflammatory myopathies ANCA associated vasculitides Non ANCA vasculitides SLE, Sjogrens, SNSA IgG4 related disease Adult Stills Celiac sprue Fibromyalgia Sarcoidosis Neoplasms and paraneoplastic syndromes Atrial myxoma Chronic infections (ie SBE, osteomyelitis, syphilis) Thyroid disease, adrenal insufficiency, hypopituitarism

3 What is PMR? Ann. Rheum. Dis. (1957), 16, 230. MYALGIC SYNDROME WITH CONSTITUTIONAL EFFECTS; POLYMYALGIA RHEUMATICA H. STUART BARBER A condition characterized by widespread muscular pains without arthritis but accompanied by a high erythrocyte sedimentation rate and occasional pyrexia is described. It is proposed to term the syndrome "polymyalgia rheumatica". Lancet. Volume 390, Issue 10103, 7 13 October Polymyalgia rheumatica. González-Gay MA, Matteson EL, Castañeda S Polymyalgia rheumatica is an inflammatory disorder characterized by severe pain and stiffness affecting the shoulders and proximal aspects of the arms bilaterally. Pain and stiffness is also common in the neck. Less frequently these symptoms affect the pelvic girdle and the proximal aspects of the thighs. Patients have morning stiffness that lasts more than min and non-specific symptoms such as fatigue and malaise. Increases in acute phase reactants (ie, erythrocyte sedimentation rate and C-reactive protein) is a characteristic feature of the disease

4 What is GCA? Temporal arteritis was first encountered at the Mayo Clinic in the spring of In the original publication it was stated that temporal arteritis is characterized by periarteritis and arteritis of the temporal vessels with painful tender areas over the scalp ; that it is accompanied by headache, general malaise, and lassitude, weakness, fever, night sweats, anorexia, loss of weight, anemia and a mild leukocytosis ; that it is apparently a focal localization of some unknown systemic disease and that it represents a definite clinical entity. That temporal arteritis is not a localized disease was first demonstrated in 1935 when biopsy on both a radial and a temporal artery in one case, that of a woman, age 68 years old, revealed essentially the same inflammatory process. Proc Annu Meet Cent Soc Clin Res U S Nov 1-2;19:78. Temporal arteritis; report of 39 cases. Bayard T. Horton, MD ( ) Received his MD degree from the University of Virginia in 1922

5 PMR and GCA tissue Arthritis and Rheumatism, Vol. 27, No. 10 (October 1984) CLINICAL AND PATHOLOGIC STUDIES OF SYNOVITIS IN POLYMYALGIA RHEUMATICA ARTHRITIS & RHEUMATISM Vol. 39, No. 7, July 1996, pp LEUKOCYTE INFILTRATION IN SYNOVIAL TISSUE FROM THE SHOULDER OF PATIENTS WITH POLYMYALGIA RHEUMATICA Ocul Oncol Pathol Jan;3(1): Studies on the Histopathology of Temporal Arteritis

6 PMR-GCA Imaging Ultrasound, FDG PET-CT, CTA, MRI, MRA Newer techniques: contrast enhanced ultrasound; 3T and 7T MRI Ultrasound GCA (at dx): halo sign Ultrasound PMR: subacromial/subdeltoid bursitis PET-CT in PMR: increased activity shoulder and hip girdle, cervical and lumbar interspinous bursae, entheses. Extracranial GCA seen in up to 30% PET-CT in GCA: large vessel activity Limited utility for disease activity monitoring

7 PET-CT findings in patients with polymyalgia rheumatica without symptoms of cranial ischaemia. Dan Med J 2017;64(10):A5410 Typical positron emission tomography-computed tomography (PET-CT) findings in a patient with treatmentnaïve polymyalgia rheumatica. A. Maximum intensity projection PET shows diffusely increased 18 F-labelled fluorodeoxyglucose (FDG) uptake in the shoulders and hips (red circles). B. Transaxial fused PET-CT images of the same patient show the increased FDG uptake to be located to juxtaarticular soft tissue and muscles (white arrows).

8 Whole-body MRI of patients with polymyalgia rheumatica identifies a distinct subset with complete patient-reported response to glucocorticoids. Ann Rheum Dis 2015;74: Results of blinded scoring of gadolinium-enhanced MRI scans.

9 18F-FDG PET/CT in polymyalgia rheumatica a pictorial review. Br J Radiol 2017; 90 : Figure 5. Fluorine-18 fludeoxyglucose (18F-FDG) positron emission tomography (PET)/CT, maximum intensity projection PET scans of the torso of patients with giant-cell arteritis (GCA) and polymyalgia rheumatica (PMR). Cases A and B are typical for GCA; Cases D and E are typical for PMR cases; and Case C represents a mixture of features. Lesser mixtures of PMR and GCA signs are also seen in Cases B and D, with predominance of only a subset of components. This demonstrates that the characteristic signs of GCA (red arrowheads) and PMR (yellow and green arrowheads) are frequently not clear or exact.

10 Biomed Res Int. 2015;2015: doi: /2015/ Epub 2015 Jan 28. Large-vessel vasculitis: interobserver agreement and diagnostic accuracy of 18F-FDG- PET/CT 18F-FDG PET/CT scans showing: (a) PMR patient (cerebral and urinary tract 18-18F-FDG uptake are physiological), (b) maximum intensity projection (MIP) image: scored as large-vessel vasculitis by all observers according to all methods

11 PMR-GCA at Diagnosis Symptoms and Signs PMR Cranial GCA Infracranial GCA Proximal myalgia shoulder and/or hip girdle Elevated acute phase reactants Fever, weight loss Headache Amaurosis fugax Jaw or tongue claudication Synovitis/tenosynovitis or remitting seroneg symmetric synovitis with pitting edema

12 PMR-GCA at Diagnosis GCA present in approx % PMR at diagnosis PMR present in approx. 50% GCA at diagnosis Temporal artery biopsy + in 40-80% at diagnosis (<60%+ in infracranial GCA) GCA has been perceived as a cranial disease. Infracranial GCA (large vessel vasculitis) develops in up to 17-80% of GCA, over time.

13 PMR-GCA Recurrences and flares: occur in 1/3-2/3; related to dose and duration of glucocorticoids. Taper too rapidly => durable response <25% Symptoms suggesting vasculitis: incomplete PMR response to steroids; fevers, sweats, weight loss, anemia, elevated alk phos; amaurosis, headache, jaw or tongue claudication, scalp necrosis, arm claudication Vasculitis complications: acute vision loss; strokes especially posterior circulation; ischemia/stenosis like Takayasu; aneurysm, dissection, rupture

14 Glucocorticoids Consensus recommendations (Lancet Jul 31. pii: S (17) doi: /S (17) ) PMR start at mg/d GCA start at mg/d Taper very slowly, often over one year Many can never completely stop steroids Pneumocystis prophylaxis Osteoporosis, dyslipidemia, atherosclerosis, hypertension, diabetes mellitus, cataracts, thin skin

15 Methotrexate May be modestly steroid sparing

16 Dejaco, C. et al. (2017) Giant cell arteritis and polymyalgia rheumatica: current challenges and opportunities Nat. Rev. Rheumatol. doi: /nrrheum

17 N Engl J Med 377(4): , 2017 Trial of Tocilizumab in Giant-Cell Arteritis 251 newly diagnosed or relapsing GCA; 86% completed 4 arms: Weekly tocilizumab + 26 week prednisone taper Every other week tocilizumab + 26 week prednisone taper Placebo + 26 week prednisone taper Placebo + 52 week prednisone taper Primary outcome: sustained remission at 52 weeks 52 wk sustained remission % flare % receiving prednisone escape Rx Cumulative prednisone Wkly Toc 56% 23% 23% 1.86 gm Qowk Toc 53% 26% 33% 1.86 gm 26 wk prednisone 52 week prednisone 14% 68% 74% 3.3 gm 18% 49% 55% 3.8 gm

18 IL-6 antagonist FDA approved subq tocilizumab for GCA in May 2017 Also effective in PMR (nonrandomized studies) What was measured=> vasculitis surrogates, not vessel wall inflammation Steroids still required initially; no rapid response w tocilizumab alone Unclear if tocilizumab will prevent aneurysms; unclear how long to treat Who should get it? People requiring persistently high doses of steroids People with multiple relapses People with no MTX response People with excess glucocorticoid risk or toxicity

19 A Randomized, Double Blind Trial of Abatacept (CTLA 4Ig) for the Treatment of Giant Cell Arteritis 49 patients Each treated with prednisone mg qd + abatacept; prednisone tapered to 20 mg qd by 12 weeks 41 patients in remission; randomized to abatacept or placebo, and prednisone tapered off by week month relapse free % was 48% in abatacept group and 31% in placebo group Arthritis & Rheumatology 69(4): ; MAR 2017

20 Ongoing Trials PMR-GCA ( Tocilizumab (interleukin 6 antagonist) Infliximab (TNF antagonist) Anakinra (interleukin 1 antagonist) Ustekinumab (interleukin 12/23 antagonist) Abatacept (T cell costimulation antagonist) Baricitinib (janus kinase inhibitor) Biomarkers 18F FDG PET/CT Ultrasound

21 PMR Summary PMR has variable presentations, a wide ddx, and variable duration of steroids/dose required. PMR can evolve into another inflammatory disorder ie RA, vasculitis PMR involves demonstrable inflammation in bursae, joints and entheses, to variable extents Musculoskeletal ultrasound, MRI, PET-CT can aid in the diagnosis Glucorticoids still primary treatment;?tocilizumab in those requiring too much prednisone for too long?

22 GCA Summary Is a systemic vasculitis with perhaps two initial presentations: (a) primarily cranial (increasing prevalence of extracranial disease over time), and (b) primarily extracranial disease May be relatively nonspecific until an untoward event occurs Can develop anytime in the life of PMR and is present in approx % of PMR patients MSK ultrasound, MRI, PET-CT can aid in the diagnosis Glucocorticoids still primary.?tocilizumab in those with high glucocorticoid risk or with relapses

23 Development of Classification and Response Criteria for Rheumatic Diseases Arthritis & Rheumatism (Arthritis Care & Research) Vol. 55, No. 3, June 15, 2006, pp Many rheumatic diseases are characterized by overlapping organ system involvement, lack of a pathognomonic diagnostic test, and widespread manifestations. These characteristics hinder easy diagnosis or recognition of changes in disease status, and also present a tremendous challenge when conducting and evaluating the results from clinical research. Criteria that classify a disease (classification criteria), define disease activity, or specify a measurement of change in disease activity in response to an intervention (response criteria) are critical for conducting most types of clinical studies with the aim of improving patient care. Criteria sets that define disease entities for clinical studies are generally not described as diagnostic criteria but rather as classification criteria. Classification criteria are often useful teaching aides for trainees and will almost always mirror the list of criteria that one uses for diagnosis, but they are not synonymous with diagnostic criteria. In a typical clinical setting, meeting prespecified criteria is not required for diagnosis.

24 Ann. Rheum. Dis. 71, (2012) PMR classification criteria scoring algorithm required criteria: age 50 years or older, bilateral shoulder aching and abnormal CRP and/or ESR Points without US (0 6) Points with US (0 8) Morning stiffness duration >45 min 2 2 Hip pain or limited range of motion 1 1 Absence of RF or ACPA 2 2 Absence of other joint involvement 1 1 At least one shoulder with subdeltoid bursitis and/or biceps tenosynovitis and/or glenohumeral synovitis (either posterior or axillary) and at least one hip with synovitis and/or trochanteric bursitis Both shoulders with subdeltoid bursitis, biceps tenosynovitis or glenohumeral synovitis Not applicable 1 Not applicable 1 A score of 4 or more is categorised as PMR in the algorithm without US and a score of 5 or more is categorised as PMR in the algorithm with US. Optional ultrasound criteria. ACPA, anticitrullinated protein antibody; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; PMR, polymyalgia rheumatica; RF, rheumatoid factor; US, ultrasound.

25 Arthritis Rheum 1990;33: CRITERIA FOR THE CLASSIFICATION OF GIANT CELL (TEMPORAL) ARTERITIS. 1. Development of symptoms or findings beginning at age 50 or older 2. New onset of or new type of localized pain in the head 3. Temporal artery tenderness to palpation or decreased pulsation, unrelated to arteriosclerosis of cervical arteries 4. Erythrocyte sedimentation rate >=50 mm/hour by the Westergren method 5. Biopsy specimen with artery showing vasculitis characterized by a predominance of mononuclear cell infiltration or granulomatous inflammation, usually with multinucleated giant cells For purposes of classification, a patient shall be said to have giant cell (temporal) arteritis if at least 3 of these 5 criteria are present. The presence of any 3 or more criteria yields a sensitivity of 93.5% and a specificity of 91.2%