A Bohan, J B Peter
Polymyositis and dermatomyositis (first of two parts).
N Engl J Med. 1975 Feb 13;292(7):344-7. doi: 10.1056/NEJM197502132920706.
Abstract/Text
上阪 等ほか編：多発性筋炎/皮膚筋炎に関する研究, 厚生労働科学研究費補助金難治性疾患等政策研究事業 自己免疫疾患に関する調査研究, 平成26年度総括・分担研究報告書, 2015, 26-69.
A Bohan, J B Peter, R L Bowman, C M Pearson
Computer-assisted analysis of 153 patients with polymyositis and dermatomyositis.
Medicine (Baltimore). 1977 Jul;56(4):255-86.
Abstract/Text
C D Reimers, M Finkenstaedt
Muscle imaging in inflammatory myopathies.
Curr Opin Rheumatol. 1997 Nov;9(6):475-85.
Abstract/Text
Myositides are characterized by perivascular and intrafascicular inflammatory infiltrates and often by fiber de- and regeneration. In chronic disease, muscle size decreases, and replacement of muscle parenchyma by adipose and fibrous tissue (and, in childhood myositis, calcifications of the muscles and subcutaneous fat) occurs. Muscle imaging techniques such as ultrasonography and magnetic resonance (MR) imaging facilitate the assessment of the type (edema, inflammation, fat, fibrosis, and calcifications), degree, and localization of these alterations. Both methods allow evaluation of the activity, chronicity, and severity of myositis and assist in directing the biopsy site. However, MR imaging is more sensitive in the detection of muscle edema, which is common in the early stages of inflammatory myopathies. In general, MR tomographic features provide more information regarding the differential diagnosis than do creatine kinase activity and even electromyography. Muscle imaging techniques should be considered in the diagnostic evaluation and to assist in treatment of inflammatory myopathies. This paper reviews the value and limitations of muscle imaging in inflammatory myopathies.
C Dorph, I Nennesmo, I E Lundberg
Percutaneous conchotome muscle biopsy. A useful diagnostic and assessment tool.
J Rheumatol. 2001 Jul;28(7):1591-9.
Abstract/Text
OBJECTIVE: To evaluate the diagnostic yield, performance simplicity, and safety of the percutaneous conchotome muscle biopsy technique for clinical and research purposes in an outpatient rheumatology clinic.
METHODS: Biopsies taken by rheumatologists in an outpatient clinic during 1996 and 1997 were evaluated for histopathological and clinical diagnoses.
RESULTS: A total of 149 biopsies were performed on 122 patients. Physicians learned the method easily. Samples were of adequate size and quality to allow for diagnostics. In total 106 biopsies were taken due to different diagnostic suspicions: 24 polymyositis (PM) or dermatomyositis (DM); 43 PM, DM, or vasculitis in addition to another rheumatic condition; 19 systemic vasculitis; and 20 myalgias. Criteria for definite or probable PM/DM were fulfilled in 21 patients, 18 with positive biopsies. Thirteen patients received vasculitis as clinical diagnosis, 3 with positive biopsies. No patient with myalgia had a biopsy with inflammatory changes. Fifteen of 43 rebiopsies performed to assess disease activity had signs of active inflammation. In 48% there were changes in immunosuppressive therapy after biopsy results. Four complications occurred; one was a serious subfascial hematoma.
CONCLUSION: The percutaneous conchotome muscle biopsy technique gives a good size sample that allows for diagnostic evaluation and has a high yield in patients with myositis. It is a simple procedure, easy to learn and to perform, with a low complication rate and minimum discomfort for the patient. The method can preferably be used as a diagnostic tool and to perform repeated biopsies to assess the effect of a given therapy for both clinical and research purposes.
M E Sayers, S M Chou, L H Calabrese
Inclusion body myositis: analysis of 32 cases.
J Rheumatol. 1992 Sep;19(9):1385-9.
Abstract/Text
Inclusion body myositis is characterized by an insidious onset, progressive indolent course, and is generally felt to be refractory to standard therapy for myositis. We reviewed the charts of 32 patients with muscle biopsy findings suggestive of inclusion body myositis. The average time from symptom onset to diagnosis was 37 months, but initially 40% were incorrectly diagnosed. Twenty-eight patients (88%) were classified as definite or probable inclusion body myositis and were treated with various combinations of prednisone and immunosuppressive agents. Sixty-eight percent of those treated experienced a decrement in function and muscle strength. Three patients exhibited longterm improvement while 12 patients experienced delayed progression, defined by short term improvement in strength or a stable functional class, All of these patients received therapy, 5 in the form of methotrexate and prednisone. All untreated patients deteriorated clinically. In summary, (1) inclusion body myositis is a clinically distinct entity which is frequently misdiagnosed initially. (2) While clinical improvement with therapy is rare, our observations support recent reports that therapy may be associated with a slower rate of clinical progression. (3) Optimal therapy remains uncertain, but the use of low dose methotrexate and prednisone may warrant further study.
Hajime Yoshifuji, Takao Fujii, Shio Kobayashi, Yoshitaka Imura, Yoshimasa Fujita, Daisuke Kawabata, Takashi Usui, Masao Tanaka, Sonoko Nagai, Hisanori Umehara, Tsuneyo Mimori
Anti-aminoacyl-tRNA synthetase antibodies in clinical course prediction of interstitial lung disease complicated with idiopathic inflammatory myopathies.
Autoimmunity. 2006 May;39(3):233-41. doi: 10.1080/08916930600622884.
Abstract/Text
In the treatment of polymyositis and dermatomyositis (PM/DM), the complication of interstitial lung disease (ILD) is an important prognostic factor. It has been reported that autoantibodies against aminoacyl-tRNA synthetases (ARS) are strongly associated with ILD. The aim of this study is to examine the correlation between anti-ARS and the clinical course of ILD. We investigated 41 cases of PM/DM with ILD. The response of ILD to corticosteroids (CS) was determined according to the change in respiratory symptoms, image findings, and pulmonary function between, before and 2 months after the treatment. Anti-ARS (anti-Jo-1, PL-7, PL-12, EJ, OJ and KS) antibodies were screened with the RNA immunoprecipitation assay. In the stratification into ILD-preceding, simultaneous and myopathy-preceding types, anti-ARS antibodies were significantly frequent in the ILD-preceding type (p < 0.05). In the stratification into anti-ARS-positive and negative groups, the response of ILD to CS was significantly better in the positive group (p < 0.05). However, recurrence of ILD was significantly more frequent in the positive group (p < 0.01), and 2 year prognoses of pulmonary function (%VC and %DLCO) were not different between the two groups. In conclusion, screening of anti-ARS may be useful to predict late-onset myopathy in ILD-preceding patients and to predict the clinical course of ILD in PM/DM patients.
Margaret R Wilkes, Susan M Sereika, Noreen Fertig, Mary R Lucas, Chester V Oddis
Treatment of antisynthetase-associated interstitial lung disease with tacrolimus.
Arthritis Rheum. 2005 Aug;52(8):2439-46. doi: 10.1002/art.21240.
Abstract/Text
OBJECTIVE: To assess the efficacy of tacrolimus in patients with anti-aminoacyl-transfer RNA synthetase (anti-aaRS)-associated interstitial lung disease (ILD) and idiopathic inflammatory myopathy (IIM).
METHODS: Ninety-eight patients with anti-aaRS autoantibodies were identified in our IIM cohort of 536 patients. The medical records of 15 patients with anti-aaRS-associated ILD treated with tacrolimus between 1992 and 2003 were retrospectively reviewed. Pulmonary parameters of response included forced vital capacity, forced expiratory volume in 1 second, and diffusing capacity for carbon monoxide. Manual muscle testing results, serum creatine kinase (CK) levels, and the daily corticosteroid dosage were used to assess improvement in myositis. Random coefficient modeling considering polynomials of time was used to assess the clinical response to tacrolimus.
RESULTS: All patients, except for 1, who had pure ILD, had definite or probable IIM. Two patients received tacrolimus for fewer than 3 months, and their data were not analyzed. For the remaining 13 patients, the mean age at onset of ILD was 46.9 years, and the mean duration of pulmonary disease was 14.7 months. Twelve patients had anti-histidyl-transfer RNA synthetase autoantibody (anti-Jo-1) and 1 had anti-alanyl-transfer RNA synthetase autoantibody (anti-PL-12). Patients received tacrolimus for an average of 51.2 months. A significant improvement was observed in all pulmonary parameters measured. The serum CK level declined significantly, and 10 patients had either an improvement in muscle strength or maintained normal muscle strength. A statistically significant reduction in the corticosteroid dosage was also observed.
CONCLUSION: Tacrolimus is a well-tolerated and effective therapy for managing refractory ILD and myositis in anti-aaRS-positive patients.
A Escalante, L Miller, T D Beardmore
Resistive exercise in the rehabilitation of polymyositis/dermatomyositis.
J Rheumatol. 1993 Aug;20(8):1340-4.
Abstract/Text
OBJECTIVE: To determine the effect of a resistive exercise program in the rehabilitation of patients with polymyositis/dermatomyositis (PM/DM).
METHODS: Five patients participated in a rehabilitation program that included resistive exercises. In 4 of the patients, these exercises were randomly alternated with nonresistive exercise. Each type of exercise was assigned for periods of 2 weeks, and at the end of each one, muscle strength was measured by means of manual muscle testing (MMT), an activities of daily living (ADL) score, and peak isometric torque (PIT) generated by muscle groups in the lower extremities. Creatine phosphokinase (CPK) levels were used to measure disease activity. The acute response to resistive exercise was studied in 4 of the patients by measuring serial levels of CPK following a session on an exercise bicycle.
RESULTS: Of the 4 patients who participated in both types of exercises, 3 experienced increases in strength during both resistive and nonresistive exercise periods. The patient who participated only in resistive exercises had considerable improvements in muscle strength. One patient made no improvements in strength with either type of exercise. None of the patients experienced clinically significant elevations in CPK attributable to either type of exercise. Following a session of resistive exercise, the mean CPK elevation in 4 patients was 7.7%, returning to pre-exercise levels by 8 h in all cases.
CONCLUSIONS: Patients with PM/DM may participate in a rehabilitation program which includes resistive exercises. Such programs may be accompanied by increased strength without clinically significant rises in serum levels of muscle enzymes.
Yves Troyanov, Ira N Targoff, Jean-Luc Tremblay, Jean-Richard Goulet, Yves Raymond, Jean-Luc Senécal
Novel classification of idiopathic inflammatory myopathies based on overlap syndrome features and autoantibodies: analysis of 100 French Canadian patients.
Medicine (Baltimore). 2005 Jul;84(4):231-49.
Abstract/Text
Our objective was to improve the currently imperfect classifications of idiopathic inflammatory myopathies (IIM). In clinical practice, overlap features are common in IIM. This provided a rationale for positioning overlap clinical features at the core of a new classification system. We conducted a longitudinal study of 100 consecutive adult French Canadian patients with IIM. Clinical and laboratory data were obtained by retrospective chart review. Sera were analyzed for autoantibodies (aAbs) by protein A-assisted immunoprecipitation and double immunodiffusion. Overlap aAbs encompassed aAbs to synthetases, systemic sclerosis-associated aAbs, anti-signal recognition particle (SRP) and anti-nucleoporins. Patients were classified both at IIM diagnosis, based on data at presentation, and at the end of follow-up, based on cumulative findings. Three classifications were used: 1) the Bohan and Peter original classification, 2) a new version of that classification as modified by us, and 3) a novel clinicoserologic classification. As investigators were blinded to aAb results, the modified classification is strictly a clinical classification. Its core concept is the attribution of diagnostic significance to the presence of overlap features, that is, their presence resulted in a diagnosis of overlap myositis (OM). This approach allowed direct comparison with the original Bohan and Peter classification. By integrating aAb results to the modified classification, we also defined the clinicoserologic classification, which allowed to examine the added value of aAbs to diagnostic, therapeutic and prognostic stratification. Whereas polymyositis (PM) was the most common IIM according to the original classification, accounting for 45% of the cohort at diagnosis, its frequency fell to 14% with the modified classification. Conversely, while the frequency of myositis associated with connective tissue disease was 24% according to the original classification, the frequency of OM was 60% when using the modified classification. At last follow-up, the frequency of PM fell further to only 9%, while the frequency of OM rose to 67%. Systemic sclerosis was the most common connective tissue disease associated with IIM, accounting for 42.6% of OM patients and 29% of the cohort. The frequencies of overlap aAbs in the cohort and in OM patients were 48% and 70.5% (n =48/68), respectively. The presence of overlap aAbs at IIM diagnosis identified additional OM patients unrecognized by the modified classification. The sensitivity of the modified classification for OM at diagnosis was 87%, suggesting that clinicians may rely on the modified classification for identification of most OM patients, while awaiting results of aAb assays. The new classifications predicted the response to prednisone and IIM course. Using stringent definitions, IIM was classified as responsive or refractory after an adequate initial corticosteroid therapy, and the disease course as monophasic or chronic after a single adequate trial of prednisone. PM was always chronic and was associated with the highest rate (50%) of refractoriness to initial corticosteroid treatment. Dermatomyositis was almost always chronic (92% rate); however, its responsiveness to initial corticosteroid treatment was high (87%). OM was almost always responsive to corticosteroids (89%-100% rates). When OM patients were divided according to aAb subsets, anti-synthetase, SRP, or nucleoporin aAbs were markers for chronic myositis, whereas aAbs to U1RNP, Pm-Scl, or Ku were markers for monophasic myositis. We conclude that the original Bohan and Peter classification should be abandoned as it leads to misclassification of patients. Much of IIM is composed of OM. The proposed modified and clinicoserologic classifications have diagnostic, prognostic, and therapeutic value.
Jessica E Hoogendijk, Anthony A Amato, Bryan R Lecky, Ernest H Choy, Ingrid E Lundberg, Michael R Rose, Jiri Vencovsky, Marianne de Visser, Richard A Hughes
119th ENMC international workshop: trial design in adult idiopathic inflammatory myopathies, with the exception of inclusion body myositis, 10-12 October 2003, Naarden, The Netherlands.
Neuromuscul Disord. 2004 May;14(5):337-45. doi: 10.1016/j.nmd.2004.02.006.
Abstract/Text
Andrew L Mammen
Dermatomyositis and polymyositis: Clinical presentation, autoantibodies, and pathogenesis.
Ann N Y Acad Sci. 2010 Jan;1184:134-53. doi: 10.1111/j.1749-6632.2009.05119.x.
Abstract/Text
Dermatomyositis (DM) and polymyositis (PM) are autoimmune myopathies characterized clinically by proximal muscle weakness, muscle inflammation, extramuscular manifestations, and frequently, the presence of autoantibodies. Although there is some overlap, DM and PM are separate diseases with different pathophysiological mechanisms. Furthermore, unique clinical phenotypes are associated with each of the myositis-specific autoantibodies (MSAs) associated with these disorders. This review will focus on the clinical features, pathology, and immunogenetics of PM and DM with an emphasis on the importance of autoantibodies in defining unique phenotypes and, perhaps, as clues to help elucidate the mechanisms of disease.
Hideto Kameda, Hayato Nagasawa, Hiroe Ogawa, Naoya Sekiguchi, Hirofumi Takei, Michihide Tokuhira, Koichi Amano, Tsutomu Takeuchi
Combination therapy with corticosteroids, cyclosporin A, and intravenous pulse cyclophosphamide for acute/subacute interstitial pneumonia in patients with dermatomyositis.
J Rheumatol. 2005 Sep;32(9):1719-26.
Abstract/Text
OBJECTIVE: Acute/subacute interstitial pneumonia (A/SIP) in patients with polymyositis/dermatomyositis (PM/DM) is frequently fatal within months despite high dose prednisolone (PSL) therapy. Our objective was to improve the survival rate of patients with A/SIP associated with PM/DM; and to characterize patients with PM/DM who are at high risk of developing A/SIP.
METHODS: We conducted a pilot trial of combined immunosuppressive therapy with high dose PSL, 10-30 mg/kg of intravenous pulse cyclophosphamide (IVCYC) every 3-4 weeks, and 2-4 mg/kg/day of cyclosporin A (CSA) for patients with A/SIP. A/SIP was diagnosed based on a history of rapidly worsening respiratory symptoms, progressive radiological findings or hypoxemia, and compatible findings in high resolution computed tomography images.
RESULTS: Before December 2000, 12 patients with DM among 83 PM/DM patients developed A/SIP, and 9 patients died despite treatment using high dose PSL with or without a choice of CSA, cyclophosphamide, or azathioprine. Thereafter, 10 patients with DM among 27 PM/DM patients developed A/SIP, and they were given combination therapy with PSL, CSA, and IVCYC. Five patients survived and are doing well for more than 2 years, although the remaining 5 patients died of respiratory failure within 3 months. DM patients with A/SIP showed the following characteristic features: mild myositis, palmar papule, fever, and negative or low titer of antinuclear antibody.
CONCLUSION: Immediate institution of intensified immunosuppressive therapy should be considered for patients with A/SIP complicating DM. However, even early recognition of A/SIP and immediate commencement of a regimen including CSA and IVCYC in addition to high dose PSL may not be sufficient for some of those patients.
Shinji Sato, Michito Hirakata, Masataka Kuwana, Akira Suwa, Shinichi Inada, Tsuneyo Mimori, Takeji Nishikawa, Chester V Oddis, Yasuo Ikeda
Autoantibodies to a 140-kd polypeptide, CADM-140, in Japanese patients with clinically amyopathic dermatomyositis.
Arthritis Rheum. 2005 May;52(5):1571-6. doi: 10.1002/art.21023.
Abstract/Text
OBJECTIVE: To identify novel autoantibodies specific for dermatomyositis (DM), especially those specific for clinically amyopathic DM (C-ADM).
METHODS: Autoantibodies were analyzed by immunoprecipitation in 298 serum samples from patients with various connective tissue diseases (CTDs) or idiopathic pulmonary fibrosis (IPF). Antigen specificity of the sera was further examined by immunoblotting and indirect immunofluorescence (IF). The disease specificity and clinical features associated with the antibody of interest were determined.
RESULTS: Eight sera recognized a polypeptide of approximately 140 kd (CADM-140 autoantigen) by immunoprecipitation and immunoblotting. Immunoreactivity was detected in the cytoplasm, and indirect IF revealed a granular or reticular pattern. Anti-CADM-140 antibodies were detected in 8 of 42 patients with DM, but not in patients with other CTDs or IPF. Interestingly, all 8 patients with anti-CADM-140 antibodies had C-ADM. Among 42 patients with DM, those with anti-CADM-140 autoantibodies had significantly more rapidly progressive interstitial lung disease (ILD) when compared with patients without anti-CADM-140 autoantibodies (50% versus 6%; P = 0.008).
CONCLUSION: These results indicate that the presence of anti-CADM-140 autoantibodies may be a novel marker for C-ADM. Further attention should be directed to the detection of rapidly progressive ILD in those patients with anti-CADM-140 autoantibodies.
Ira N Targoff
Myositis specific autoantibodies.
Curr Rheumatol Rep. 2006 Jun;8(3):196-203.
Abstract/Text
Recent studies have continued to examine the clinical associations of the group of autoantibodies that occurs predominantly in patients who have myositis (antibodies to aminoacyl-tRNA synthetases, to signal recognition particle [SRP], and to the nuclear helicase Mi-2). The anti-synthetase syndrome has been further studied, and the value of tacrolimus in treatment of the associated interstitial lung disease has been noted. The low frequency of myositis specific autoantibodies in non-myositis neuromuscular disorders has been more clearly demonstrated. The clinical associations of anti-Mi-2 and anti-SRP were further studied, and patients with antibodies without myositis were reported. Evidence suggested that ultraviolet light exposure may influence the expression of dermatomyositis and anti-Mi-2. A new classification for myositis using overlap clinical features and autoantibodies was proposed. A new autoantibody, anti-caDM-140, was described, associated with clinically amyopathic dermatomyositis and interstitial lung disease. The possibility was raised that increased antigen expression in regenerating muscle may help to perpetuate the disease. These antibodies continue to be the subject of active investigation.
M M Joffe, L A Love, R L Leff, D D Fraser, I N Targoff, J E Hicks, P H Plotz, F W Miller
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 Apr;94(4):379-87.
Abstract/Text
PURPOSE: To identify factors associated with responses to treatment with prednisone, methotrexate, or azathioprine in patients with idiopathic inflammatory myopathy, and to compare the efficacy of these drugs.
PATIENTS AND METHODS: Data were collected on 113 adult patients meeting criteria for definite idiopathic inflammatory myopathy in this retrospective cohort study. Patients were categorized as responding completely, partially, or not at all to each therapeutic trial based upon clinical and laboratory criteria.
RESULTS: Clinical group, presence of certain myositis-specific autoantibodies, and time from disease onset to diagnosis influenced rates of complete clinical response to these therapeutic agents. Patients with inclusion body myositis responded comparatively poorly to prednisone and the other drugs: 43% had no clinical response to prednisone and none responded completely to any medication. Patients with autoantibodies to aminoacyl-tRNA synthetases or to signal recognition particle proteins were likely to respond partially, but not completely, to prednisone. No patient with a long delay to diagnosis (greater than 18 months) responded completely, compared with 34% of those with a short delay (less than 3 months). A patient's response to the first course of prednisone predicted subsequent responses to prednisone and to azathioprine better than response to methotrexate. Men responded to methotrexate better than women. Among certain subgroups of patients, responses to methotrexate were better than to either azathioprine or retreatment with prednisone.
CONCLUSION: Determining the clinical group, autoantibody status, and time from disease onset to diagnosis of patients with myositis provides useful information in predicting clinical responses to therapy, and these factors should be considered in designing future therapeutic trials. Methotrexate therapy may be superior to either azathioprine or further steroid treatment alone in certain patients who do not respond completely to an initial adequate course of prednisone.
E D Newman, D W Scott
The Use of Low-dose Oral Methotrexate in the Treatment of Polymyositis and Dermatomyositis.
J Clin Rheumatol. 1995 Apr;1(2):99-102.
Abstract/Text
The objective of this study was to evaluate the efficacy of low-dose oral methotrexate (MTX) in improving muscle strength and reducing the corticosteroid requirement of patients with polymyositis (PM) and dermatomyositis (DM). The method used was a retrospective chart review of our clinic's PM/DM cohort, Between September 1989 and May 1993, 12 of 53 patients with PM/DM received low-dose oral MTX (mean maximum dose 14.4 +/- 1.2 mg/wk, range 7.5-20 mg/wk). A significant increase in strength coupled with a fall in prednisone requirement (42.5 +/- 5.8 mg/d to 13.0 +/- 5.4 mg/d) was seen during the mean follow-up time of 24.0 +/- 4.3 months of MTX therapy. The number of flares per year fell from 1.00 +/- 0.35 before oral MTX institution to 0.07 +/- 0.05 during oral MTX therapy. Toxicity was minimal. Three patients were able to stop corticosteroids altogether. Low-dose oral MTX therapy should be considered early in the treatment course of patients with PM/DM to improve strength and lower the required dose of corticosteroids.
Nicolino Ruperto, Angela Pistorio, Sheila Oliveira, Francesco Zulian, Ruben Cuttica, Angelo Ravelli, Michel Fischbach, Bo Magnusson, Gary Sterba, Tadej Avcin, Karine Brochard, Fabrizia Corona, Frank Dressler, Valeria Gerloni, Maria T Apaz, Claudia Bracaglia, Adriana Cespedes-Cruz, Rolando Cimaz, Gerard Couillault, Rik Joos, Pierre Quartier, Ricardo Russo, Marc Tardieu, Nico Wulffraat, Blanca Bica, Pavla Dolezalova, Virginia Ferriani, Berit Flato, Ana G Bernard-Medina, Troels Herlin, Maria Trachana, Antonella Meini, Emma Allain-Launay, Clarissa Pilkington, Veronika Vargova, Carine Wouters, Simona Angioloni, Alberto Martini, Paediatric Rheumatology International Trials Organisation (PRINTO)
Prednisone versus prednisone plus ciclosporin versus prednisone plus methotrexate in new-onset juvenile dermatomyositis: a randomised trial.
Lancet. 2016 Feb 13;387(10019):671-8. doi: 10.1016/S0140-6736(15)01021-1. Epub 2015 Nov 30.
Abstract/Text
BACKGROUND: Most data for treatment of dermatomyositis and juvenile dermatomyositis are from anecdotal, non-randomised case series. We aimed to compare, in a randomised trial, the efficacy and safety of prednisone alone with that of prednisone plus either methotrexate or ciclosporin in children with new-onset juvenile dermatomyositis.
METHODS: We did a randomised trial at 54 centres in 22 countries. We enrolled patients aged 18 years or younger with new-onset juvenile dermatomyositis who had received no previous treatment and did not have cutaneous or gastrointestinal ulceration. We randomly allocated 139 patients via a computer-based system to prednisone alone or in combination with either ciclosporin or methotrexate. We did not mask patients or investigators to treatment assignments. Our primary outcomes were the proportion of patients achieving a juvenile dermatomyositis PRINTO 20 level of improvement (20% improvement in three of six core set variables at 6 months), time to clinical remission, and time to treatment failure. We compared the three treatment groups with the Kruskal-Wallis test and Friedman's test, and we analysed survival with Kaplan-Meier curves and the log-rank test. Analysis was by intention to treat. Here, we present results after at least 2 years of treatment (induction and maintenance phases). This trial is registered with ClinicalTrials.gov, number NCT00323960.
FINDINGS: Between May 31, 2006, and Nov 12, 2010, 47 patients were randomly assigned prednisone alone, 46 were allocated prednisone plus ciclosporin, and 46 were randomised prednisone plus methotrexate. Median duration of follow-up was 35.5 months. At month 6, 24 (51%) of 47 patients assigned prednisone, 32 (70%) of 46 allocated prednisone plus ciclosporin, and 33 (72%) of 46 administered prednisone plus methotrexate achieved a juvenile dermatomyositis PRINTO 20 improvement (p=0.0228). Median time to clinical remission was 41.9 months in patients assigned prednisone plus methotrexate but was not observable in the other two treatment groups (2.45 fold [95% CI 1.2-5.0] increase with prednisone plus methotrexate; p=0.012). Median time to treatment failure was 16.7 months in patients allocated prednisone, 53.3 months in those assigned prednisone plus ciclosporin, but was not observable in patients randomised to prednisone plus methotrexate (1.95 fold [95% CI 1.20-3.15] increase with prednisone; p=0.009). Median time to prednisone discontinuation was 35.8 months with prednisone alone compared with 29.4-29.7 months in the combination groups (p=0.002). A significantly greater proportion of patients assigned prednisone plus ciclosporin had adverse events, affecting the skin and subcutaneous tissues, gastrointestinal system, and general disorders. Infections and infestations were significantly increased in patients assigned prednisone plus ciclosporin and prednisone plus methotrexate. No patients died during the study.
INTERPRETATION: Combined treatment with prednisone and either ciclosporin or methotrexate was more effective than prednisone alone. The safety profile and steroid-sparing effect favoured the combination of prednisone plus methotrexate.
FUNDING: Italian Agency of Drug Evaluation, Istituto Giannina Gaslini (Genoa, Italy), Myositis Association (USA).
Copyright © 2016 Elsevier Ltd. All rights reserved.
T W Bunch, J W Worthington, J J Combs, D M Ilstrup, A G Engel
Azathioprine with prednisone for polymyositis. A controlled, clinical trial.
Ann Intern Med. 1980 Mar;92(3):365-9.
Abstract/Text
A controlled, prospective, double-blind, therapeutic trial of azathioprine was conducted in the initial therapy of polymyositis. Sixteen patients received 60 mg prednisone per day plus either azathioprine (2 mg/kg of body weight per day) or placebo for a period of 3 months. Creatine phosphokinase (CPK) levels fell to normal slightly sooner in the placebo group, but not significantly so. The azathioprine group did not become significantly stronger (P = 0.58) and did not manifest significantly greater improvement of histopathologic features of muscle (P = 0.80) than the placebo group. Initial CPK elevations were significantly related to the degree of muscle inflammation (P = 0.037), but this was not the case at 3 months (P greater than 0.05). Normalization of the CPK could not be equated with disease control. Type II fiber atrophy, attributed to steroid therapy, was more marked in women than in men (P less than 0.03).
M C Dalakas, I Illa, J M Dambrosia, S A Soueidan, D P Stein, C Otero, S T Dinsmore, S McCrosky
A controlled trial of high-dose intravenous immune globulin infusions as treatment for dermatomyositis.
N Engl J Med. 1993 Dec 30;329(27):1993-2000. doi: 10.1056/NEJM199312303292704.
Abstract/Text
BACKGROUND: Dermatomyositis is a clinically distinct myopathy characterized by rash and a complement-mediated microangiopathy that results in the destruction of muscle fibers. In some patients the condition becomes resistant to therapy and causes severe physical disabilities.
METHODS: We conducted a double-blind, placebo-controlled study of 15 patients (age, 18 to 55 years) with biopsy-proved, treatment-resistant dermatomyositis. The patients continued to receive prednisone (mean daily dose, 25 mg) and were randomly assigned to receive one infusion of immune globulin (2 g per kilogram of body weight) or placebo per month for three months, with the option of crossing over to the alternative therapy for three more months. Clinical response was gauged by assessing muscle strength, neuromuscular symptoms, and changes in the rash. Changes in immune-mediated muscle abnormalities were determined by repeated muscle biopsies.
RESULTS: The eight patients assigned to immune globulin had a significant improvement in sores of muscle strength (P < 0.018) and neuromuscular symptoms (P < 0.035), whereas the seven patients assigned to placebo did not. With crossovers a total of 12 patients received immune globulin. Of these, nine with severe disabilities had a major improvement to nearly normal function. Their mean muscle-strength scores increased from 74.5 to 84.7, and their neuromuscular symptoms improved. Two of the other three patients had mild improvement, and one had no change in his condition. Of 11 placebo-treated patients, none had a major improvement, 3 had mild improvement, 3 had no change in their condition, and 5 had worsening of their condition. Repeated biopsies in five patients of muscles whose strength improved to almost normal showed an increase in muscle-fiber diameter (P < 0.04), an increase in the number and a decrease in the diameter of capillaries (P < 0.01), resolution of complement deposits on capillaries, and a reduction in the expression of intercellular adhesion molecule 1 and major-histocompatibility-complex class I antigens.
CONCLUSIONS: High-dose intravenous immune globulin is a safe and effective treatment for refractory dermatomyositis.
K A Qushmaq, A Chalmers, J M Esdaile
Cyclosporin A in the treatment of refractory adult polymyositis/dermatomyositis: population based experience in 6 patients and literature review.
J Rheumatol. 2000 Dec;27(12):2855-9.
Abstract/Text
OBJECTIVE: To evaluate the efficacy and toxicity of cyclosporin A (CSA) in the treatment of refractory adult polymyositis/dermatomyositis (PM/DM).
METHODS: The province-wide British Columbia database for CSA use for persons with rheumatic diseases at Mary Pack Arthritis Centre was reviewed to identify all patients with PM/DM for the period January 1991 through June 1998. Also, a Medline search of English language literature was conducted for this topic from 1976 until January 1999, using the terms dermatomyositis, polymyositis, inflammatory myopathy, and cyclosporin A, and the reference lists of all papers were screened to include articles not identified by the Medline search.
RESULTS: In British Columbia, 172 CSA users of whom 6 had PM/DM were identified (4 PM, 2 DM). Previous therapy included high dose prednisone (N = 6), methotrexate (N = 4), azathioprine (N = 4), intravenous immunoglobulin (N = 3), and cyclophosphamide (N = 3). The mean CSA dose was 3.5 mg/kg/day. All patients improved. Creatinine kinase (CK) levels declined 52% from baseline. All 6 patients continued CSA a median of 6 months (range 3-44 mo) after initiation of therapy. Toxicity included an increase in serum creatinine > 30% of baseline in 3 patients and hypertension in one patient. The literature review identified an additional 59 cases. Forty-eight (81%) had a reduction in CK levels and improved clinically, 9/59 (15%) developed nephrotoxicity, 5/59 (8%) hypertension responsive to dose reduction, and 9/59 (15%) had hypertrichosis, gingival hyperplasia, or tremor.
CONCLUSION: Our population based experience with 6 patients and the 59 published cases suggests CSA is an effective therapy for resistant PM/DM, and toxicity is possibly more than expected in other rheumatic diseases.
J Vencovský, K Jarosová, S Machácek, J Studýnková, J Kafková, J Bartůnková, D Nemcová, F Charvát
Cyclosporine A versus methotrexate in the treatment of polymyositis and dermatomyositis.
Scand J Rheumatol. 2000;29(2):95-102.
Abstract/Text
OBJECTIVE: To determine the effectiveness and tolerance of treatment with cyclosporine A (CyA) or methotrexate (MTX) added to corticosteroids in patients with severe, active polymyositis (PM) and dermatomyositis (DM).
PATIENTS AND METHODS: Thirty-six patients (20 with DM, 16 with PM) were enrolled into the study and randomized in MTX (n = 17) and CyA (n = 19) groups. Muscle endurance and functional test (MEFT), clinical assessment (CA), global patient's assessment (GPA), muscle MRI, serum CK, myoglobin, IL-1Ra, and autoantibody status were used to assess the response to therapy after 1, 3, and 6 months.
RESULTS: Significant improvement in MEFT, CA, GPA, and muscle MRI was found in both groups. Patients treated with MTX showed insignificantly better response than patients with CyA. CK levels in the MTX group decreased significantly after 1, 3, and 6 months, whereas a significant reduction in the CyA group was first observed after 6 months. IL-1Ra serum levels significantly dropped in the CyA group after two weeks, whereas in the MTX group the significant decrease was first seen after 3 months of treatment. Good correlation was found between each of the clinical parameters (MEFT, CA, and GPA), none of them showed any correlation with CK or IL-1Ra levels.
CONCLUSIONS: Administration of MTX or CyA added to corticosteroids was associated with clinical and laboratory improvement. Changes in CK and IL-1Ra levels were not associated with parameters of clinical disease severity measured in this study.
K Maeda, R Kimura, K Komuta, T Igarashi
Cyclosporine treatment for polymyositis/dermatomyositis: is it possible to rescue the deteriorating cases with interstitial pneumonitis?
Scand J Rheumatol. 1997;26(1):24-9.
Abstract/Text
Polymyositis and dermatomyositis are inflammatory muscular diseases of unknown etiology which have interstitial pneumonitis as a serious complication. From 1987 to 1994, we used cyclosporine to treat 14 polymyositis/dermatomyositis patients (8 with and 6 without interstitial pneumonitis). In combination with prednisolone, cyclosporine was either added to or substituted for conventional cytotoxic drugs (azathioprine, cyclophosphamide and methotrexate). Cyclosporine was effective against both myositis and interstitial pneumonitis when used early in the course of the disease.
C V Oddis, F C Sciurba, K A Elmagd, T E Starzl
Tacrolimus in refractory polymyositis with interstitial lung disease.
Lancet. 1999 May 22;353(9166):1762-3. doi: 10.1016/S0140-6736(99)01927-3.
Abstract/Text
Kazuki Takada, Kenji Nagasaka, Nobuyuki Miyasaka
Polymyositis/dermatomyositis and interstitial lung disease: a new therapeutic approach with T-cell-specific immunosuppressants.
Autoimmunity. 2005 Aug;38(5):383-92. doi: 10.1080/08916930500124023.
Abstract/Text
Interstitial lung disease (ILD) is a common complication of polymyositis (PM) and dermatomyositis (DM), and accounts for a significant proportion of their morbidity and mortality because of the resistance to therapeutic agents including corticosteroids. Its pathogenic mechanism is not known, but several studies have provided findings implicating that T-cells, especially activated CD8+ cells, may play essential roles, and thus could be therapeutic targets in this disease. To test this hypothesis, we began clinical investigation of the efficacy of T-cell-specific immunosuppressants, cyclosporine (CsA) and FK506, in PM/DM patients with ILD. In our retrospective nationwide multi-center study compiling a total of 53 patients, a combination of CsA and corticosteroids resulted in favorable early and long-term outcome in the majority of patients except for DM patients with acute ILD. In this subset, those who received the combination as an initial therapy had better survival than those who initially received corticosteroids alone. FK506 has a similar mode of action but is up to 100-fold more potent than CsA in vitro, and has been used in more refractory ILD cases. We next reviewed 5 PM/DM patients with ILD who failed on various immunosuppressants including CsA and were subsequently treated with FK506 in our hospital, and found that 3 improved promptly, 1 gradually and steadily, and another case responded slowly after prednisolone dose was increased. None developed adverse effects. In summary, these T-cell targeted therapies have a potential to be the cornerstone of the treatment for ILD in PM/DM patients. The combination therapy with CsA and corticosteroids may be efficacious especially when used early. FK506 may be advantageous even in refractory cases to CsA. These findings indicate that further investigation is warranted. Currently, prospective investigation of FK506 is underway.
S Ochi, T Nanki, K Takada, F Suzuki, Y Komano, T Kubota, N Miyasaka
Favorable outcomes with tacrolimus in two patients with refractory interstitial lung disease associated with polymyositis/dermatomyositis.
Clin Exp Rheumatol. 2005 Sep-Oct;23(5):707-10.
Abstract/Text
Two cases of progressive interstitial lung disease associated with polymyositis/dermatomyositis are presented. Both patients were refractory to conventional therapy with high-dose corticosteroids, cyclosporine, and intermittent pulse cyclophosphamide, and thus a therapeutic trial of tacrolimus was instituted. Tacrolimus was markedly effective in achieving subjective, laboratory and radiographic improvement in both patients.
