Idiopathic Inflammatory Myopathies

Transcription

1 62 SUPPLIMENT TO JAPI JUNE 2006 VOL. 54 Idiopathic Inflammatory Myopathies Ashok Kumar Definition The idiopathic inflammatory myopathies (IIM) are nonsuppurative muscle disorders which are characterised by symmetrical, proximal muscle weakness, decreased muscle endurance and chronic inflammation in muscle tissue. 1 Epidemiology IIMs are rare disorders (estimated incidence: 5 to 10 per million per year). A bimodal age of onset (10-15 years and years) has been reported. Female to male ratio is 2:1 except in inclusion-body myositis where it is reversed. Prevalence of the disease is the highest in the Japanese and the lowest in blacks. HLA associations include B8, DR3 and DRW52. Pathophysiology The molecular basis of muscle weakness in myositis is not yet known. Even the degree of inflammation observed histopathologically bears no direct relation with the extent of weakness. 2,3 The significance of replacement of muscle tissue by fat is also not clear. 4 Role of factors other than inflammation is strongly suspected because of abnormalities of energy metabolism as revealed by reduced levels of phosphocreatine (PCr) and adenosine triphosphate (ATP) on magnetic resonance spectroscopy. 5-7 Diagnostic criteria The generally accepted criteria for diagnosis of IIM include: 8 1. Proximal muscle weakness 2. Elevated levels of muscle enzymes (CPK, LDH, aldolase, AST, ALT) 3. Myopathic changes demonstrated on electromyography 4. Muscle biopsy evidence of inflammation. The addition of a skin rash (Criterion 5) allows the diagnosis of dermatomyositis Differential Diagnosis Although classical presentation of dermatomyositis hardly has any differential diagnosis, a long list of conditions needs to be considered in the differential diagnosis of polymyositis. These include drug-induced myopathies, endocrinopathies, paraneoplastic myopathy, pyomyositis, parasitic myositis, muscle dystrophies, metabolic myopathies, myasthenia gravis, Lambert-Eaton syndrome, Guillaine-Barre syndrome, spinal muscular atrophies, amyotrophic lateral sclerosis, etc. Important drugs which are known to cause myopathy include Professor of Medicine & Head, Clinical Immunology and Rheumatology Service, AIIMS, New Delhi glucocorticoids, d-penicillamine, zidovudine, cholesterollowering drugs (clofibrate and statins) and chloroquine. Classification Table 1 gives the clinical classification currently favoured. Another classification, based on myositis-specific autoantibodies (MSAs) is given in Table 2. MSAs identify relatively homogeneous groups of patients with IIM. The significance of this classification is diminished by the fact that MSAs occur only in about 35% of patients. 10 Group I Group II Group III Group IV Group V Group VI Table 1 : Clinical classification of the idiopathic inflammatory myopathies Idiopathic polymyositis in adults (PM) Idiopathic dermatomyositis in adults (DM)* DM/PM associated with malignancy Childhood associated DM/PM DM/PM associated with CTD Inclusion body myositis (IBM) *Also includes amyopathic dermatomyositis Table 2 : Classification based on myositis-specific autoantibodies 10 Autoantibody Clinical features HLA Treatment response Antisynthetase Anti-SRP Anti-Mi2 PM or DM with relatively acute-onset Interstitial lung disease, Fever, Arthritis, Raynaud s phenomenon PM with very acute onset, often in fall, Severe weakness, Palpitations DM with V sign, shawl sign and cuticular overgrowth DR3, DRw- 52 DR5, DRw52 DR7, DRw53 Moderate with disease persistence Poor Good Clinical Features Typically, patients present with a recent-onset (a few weeks to months) difficulty in getting up from chair, climbing stairs, lifting objects and combing hair. The ocular muscles are never involved. The facial and distal muscles are spared in the majority. Neck-drop (weakness of neck-flexors) and dysphagia (weakness of pharyngeal muscles) are frequent features. Advanced cases may develop weakness of respiratory muscles. Myalgia and muscle tenderness is quite uncommon. In the author s series (76 cases), dermatomyositis was the commonest subset (47%), followed by CTD-associated group (29%) and idiopathic PM (17%). IBM is exceedingly rare in India. Juvenile dermatomyositis is not as rare but under-reported from India. 11,12 Table 3 gives a comparative account of demographic and clinical features. Two Indian

2 SUPPLIMENT TO JAPI JUNE 2006 VOL Parameters Table 3 : Demographic and clinical features in patients with IIM Author s series (unpublished data) Prasad et al 13 Chowdhary et al 14 Love et al 15 Hausmanowa et al 16 Number of patients Mean age at diagnosis F:M 2.8:1 1.3:1 2:1 2:1 4:1 Ethnicity North Indian North Indian North Indian While Americans Polish Arthritis 40% 37% 55% 47% 70% Raynaud s 18% NA 24% 35% 41% ILD 8% NA 8% 29% 18% Fever 28% NA 65% 37% 39% Weight loss NA NA 47% NA 42% DM rash 41% 42% 39% 27% 37% Dysphagia 38% 48% NA NA NA Dyspnoea 10% NA NA NA NA Table 4 : Comparison of dermatomyositis with polymyositis Characteristic Dermatomyositis Polymyositis Age-group All age groups Mainly adults Overlap with SLE/SSc Overlap with other autoimmune disease Infrequent Association with cancer 15% Debatable Viral aetiology Not proven HIV, HTLV-1 Drug-induced Rare Well known series are also included for comparison Clinical features of dermatomyositis and polymyositis are compared in Table 4. Table 5 gives the serological profile of IIMs, including MSAs MSA-based subsets have not been identified in Indian population. The data are grossly inadequate and more work is needed in this area. Significant HLA associations were found in the author s series, with DR3 and B8. Laboratory Investigations Despite their limitations, muscle biopsy, electromyography and muscle enzyme levels (particularly, CPK) are useful in establishing the diagnosis of an inflammatory myopathy. In order to assess the response to treatment, one needs to reliably test the activity of disease. For this purpose, numerous clinical instruments have been described but all suffer from drawbacks Laboratory plays a supplementary role in discriminating between active and chronic disease. ESR and other acute-phase reactants are not useful in the evaluation of IIM. 23 Similarly, limitations of muscle enzymes such as CPK when used alone to measure disease activity are well known Serum CPK levels are also influenced by exercise. 27 Although muscle histology can provide useful information on the disease activity, the currently used technique of open muscle biopsy can not be recommended for monitoring purposes. In the research setting this problem has been overcome with the use of a conchotome. This semi-open technique can be used with little discomfort to the patient for performing repeated biopsies. 28 Magnetic Resonance Imaging MRI provides a non-invasive but expensive modality of diagnosis and assessment of disease activity. However, it can not replace muscle biopsy for the diagnosis of IIM. In follow-up studies, a strong correlation was observed between increased T2 and STIR signal intensity and disease activity Magnetic Resonance Spectroscopy (MRS) And Ultrasound Phosphorus MRS, assesses muscle bioenergetic metabolites such as phosphocreatine (PCr) and ATP. In active dermatomyositis, levels of these metabolites are reduced, while the ratio of inorganic phosphate (Pi) to PCr (Pi/PCr) is increased relative to controls. Exercise accentuates these abnormalities further. 31,32 MRS abnormalities underscore the significance of metabolic disturbances in the pathogenesis of the muscle weakness and point to the need for therapies other than immunosuppressants. Muscle bioenergetic defects have been shown to precede other changes and even persist after resolution of inflammation. 32,34 Proton MRS determines lipid-to-water ratio in the muscle. In the active stage of dermatomyositis, the ratio was found abnormally low and it rose markedly at 3 months of treatment. 35 Urinary proton MRS metabolic profiles may also have the potential to be a non-invasive method for assessment of disease activity in IIM patients. Ultrasound does not seem to be helpful because muscle echogenicity bears no correlation with muscle strength. Management Corticosteroids are the mainstay of treatment of this disease even though their use is not based on rigorous scientific evidence. A starting dose of prednisone of 0.75 mg/kg/day (which corresponds to mg/day) is recommended. 36 There are no data to show that higher doses are associated with superior outcome. Tapering could be started when a normal or close to normal muscle function has been achieved (usually, after 4-12 weeks), irrespective of

3 64 SUPPLIMENT TO JAPI JUNE 2006 VOL. 54 Table 5 : Serological features of patients with IIM Parameters Authors series (unpublished data) [n = 76] Chowdhary et al 12 [n = 22] Love et al 13 [n = 2I2] Hausmanowa et al 14 [n = 84] Brouwer et al 15 [n = 417] ANA 50% 22% 52% NA NA UIRNP ND 4% 11% 4% 6% Sm ND 4% 3% 0% Ro ND 23% 12% 14% 25% La ND 14% 8% 0% 5% Pm-Scl ND 4% 2% 24% 6% MSA 30%+ 31% 31% 19% 38% Anti-synthetase a. Anti-Jo-1 b. Others 30% 5% 25% 18% 14% 4% 23% 17% 6% 13% 11% 2% 21% 18% 3% Anti-SRP ND 4% 3% 1% 5% Anti-Mi-2 ND 9% 5% 5% 14% ND = not done NA - not available CPK levels. Tapering of corticosteroids should be begun at the rate of 10 mg reduction/month, initially. When a dose of 20 mg/day is reached, the reduction should be more gradual. Maintenance dosage of 5-15 mg/day is often required for several years. An attempt to withdraw should be made after 2-3 years. 37 Significant clinical improvement is noted in 60-80% of the patients There are two situations in which other immunosuppressives are required: steroid-resistant cases (about 30%) and steroidresponsive patients who develop major adverse effects. 41 In both situations azathioprine (2.5 mg/kg/day) has been found to be useful. 42 A combination of oral methotrexate with azathioprine may prove beneficial in refractory cases. 43 IVIG was found beneficial in treatment-resistant dermatomyositis patients but its role in polymyositis remains controversial. 44 Plasmapheresis had no positive effect compared to corticosteroids alone in a controlled trial. 45 Open studies and case reports indicate a beneficial effect of methotrexate ( mg/week administered orally, i.m., or up to 100 mg/week i.v.) in steroid-resistant cases. 45,47 The effect of cyclophosphamide in IIM is more controversial. There are scant data on the beneficial effects of cyclosporin A in adults with refractory IIM. The effect is often seen within a few weeks of treatment. In IBM, it is still controversial whether immunosuppressive drugs have a beneficial effect. Some authorities advocate a combination of steroids and other immunosuppressants from the start of therapy. 36,48 Physical Exercise And Rehabilitation For a long time, there have been few advocates of physical exercise in the management of IIMs because of fear of causing disease flare-ups. Recent studies however, have demonstrated the safety and usefulness of active exercise in stable IIM. 49,50 Active physical exercises such as mild aerobic programme on a bicycle or in the pool can be introduced when disease activity begins to subside. 51 Prognosis The IIM are serious disorders with as many as two-thirds of patients developing residual functional impairment in the long-term. 52,53 Conclusions IIMs are a challenging group of muscle disorders both from the pathogenetic and therapeutic standpoint. Recent work from NIH, USA has shed some light on their immunopathogenesis. A new classification based on myositisspecific autoantibodies has been proposed which represents a substantial advance in this area. However, MSAs are found only in 35-40% of patients. Thus, large lacunae remain in our current understanding of these disorders. The use of MRS to assess metabolic abnormalities may throw some light in this regard and also serve as a means of disease activity assessment. On the therapeutic front, there is paucity of hard scientific evidence with regard to the best treatment. Considering the high frequency of sequelae of disease and substantial mortality, some authorities have recommended combinations of steroids and immunosuppressive drugs from the start. Active physical exercises have an important role in the management of IIM once the activity of disease is brought under reasonable control. The present treatment protocols for IIM are based on experience gained from uncontrolled clinical trials. Many patients suffer from serious side effects of steroid therapy. There is an urgent need for developing a validated disease activity measure and performing controlled trials to develop better treatment strategies. There is also a need to develop molecular approaches to the treatment of IIM similar to those developed for rheumatoid arthritis. Another important area, which needs to be explored, is the possible metabolic disturbance in IIM as a cause of the persisting muscle weakness.

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