REVIEW URRENT C OPINION
Myopathy in scleroderma, its identification, prevalence, and treatment: lessons learned from cohort studies Julie J. Paik a, Andrew L. Mammen b, Fredrick M. Wigley a, and Allan C. Gelber a
Purpose of review This review discusses the characterization of myopathy in scleroderma with a focus on new developments in imaging, biomarkers, and therapy, and details several current reports and several seminal reports prior to 2012. Recent findings In the past year, studies have shown that MRI techniques highlight the importance of muscle edema in scleroderma, and that aldolase may be a useful biomarker to predict incident myopathy. When compared to studies preceding 2012, both the current and prior reports too often fail to account for the full spectrum of muscle disease in scleroderma. There remain no uniform classification criteria that are routinely integrated into clinical research reports. Thus, important questions remain to be answered, including risk factors for developing myopathy, optimal screening and diagnostic strategies, and efficacious therapies. But, just as important is the priority to systematically define what the true entity(ies) of myopathy is in scleroderma. Summary Scleroderma myopathy is a heterogeneous group of muscle disorders among patients with underlying scleroderma which requires robust studies to clarify the full spectrum of disease. Keywords epidemiology, myopathy, myositis, scleroderma
INTRODUCTION ‘Scleroderma myopathy’ is an umbrella term that encompasses several biological processes that occur at the intersection of both rheumatologic and neuromuscular disorders. Although there are clear cases of an inflammatory myopathy, indistinguishable from polymyositis, there is more often muscle weakness secondary to myopathy that is non-inflammatory in nature. In the past 50 years, advances in imaging and histopathology techniques have enabled a more thorough characterization of myopathy in scleroderma, yet the underlying cause(s) is still poorly understood. Recent developments in imaging, use of biomarkers and novel therapy, in the context of prior seminal reports in the area of scleroderma myopathy, are the major focus of this article.
STUDIES IN 2012–2013 Using the search terms of scleroderma, polymyositis, dermatomyositis, myopathy, and populationbased studies, our search resulted in 123 articles, www.co-rheumatology.com
with only 10 addressing myopathy in scleroderma. Out of the 10, 1 was a review article, and 5 were case reports, leaving 4 original research contributions that we review here.
Aldolase as a marker to identify incident myopathy In 2012, Toledano et al. [1] reported the value of aldolase to identify patients with scleroderma at increased risk to develop myopathy. The design was a prospective cohort assembled at Saint Antoine Hospital, in Paris, in which patients without a
Department of Medicine and bDepartment of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA Correspondence to Julie J. Paik, MD, MHS, 5200 Eastern Avenue, Mason F. Lord Building, Center Tower, Suite 4100, Baltimore, MD 21224, USA. Tel: +1 410 550 6929; fax: +1 410 550 3524; e-mail: [email protected] Curr Opin Rheumatol 2014, 26:124–130 DOI:10.1097/BOR.0000000000000024 Volume 26 Number 2 March 2014
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Characterization of myopathy in scleroderma Paik et al.
KEY POINTS Scleroderma myopathy is a heterogeneous disease. A systematic classification scheme should be defined to clarify the spectrum of myopathy in scleroderma. Robust studies need to be conducted in the future to enhance the understanding of the risk factors, diagnosis, and treatment of myopathy in scleroderma.
weakness at baseline were followed over time to detect incident myopathy. Weakness was measured using the 8-manual muscle testing (8-MMT) [2] scale which examines strength proximally and distally, in arm, leg, and truncal muscle groups, at both antigravity and gravity-eliminated positions. The endpoint of incident myopathy included weakness defined by at least 10% decline from baseline 8-MMT score. After weakness occurred, patients underwent an electromyogram (EMG), and/or thigh MRI, and/or muscle biopsy to confirm the presence of myopathy. The authors enrolled 137 of 150 total patients with scleroderma. Mean age was 55 years; mean disease duration was 12 years. One-third manifested the diffuse subtype of scleroderma. Overall, mean aldolase value was 10 7.5 U/l and mean creatine kinase was 111 142 U/l (upper limit for aldolase and creatine kinase were 7 and 160 U/l, respectively). During a mean follow-up period of 45 (17) months, nine patients developed persistent proximal weakness, which satisfied the investigators’ definition of scleroderma myopathy. Notably, among various muscle enzymes measured to detect incident myopathy, aldolase had the highest predictive power. The area under the receiver operating characteristic curve for aldolase was greater than that measured for creatine kinase and alanine aminotransferase (ALT). In contrast, aspartate aminotransferase (AST) and c-reactive protein (CRP) did not have predictive value. Specifically, within 3 years of cohort entry, an aldolase level of at least 9 U/l identified subsequent myopathy with a sensitivity of 89% and specificity of 67%. After adjustment for age, sex, disease subtype, and duration, those with an aldolase level above 9 U/l experienced a substantial increase in risk to develop myopathy [hazard ratio 10.3, 95% confidence interval (CI) 2.3–45.5]. Comment Whereas this important prospective cohort identified aldolase as a predictor of incident myopathy, there are several shortcomings. First, this study did not, seemingly, apply the full classification criteria
of the European Neuromuscular Center (ENMC) Workshop [3]. Thus, whereas scleroderma myopathy was defined as having satisfied ENMC criteria, histologic evidence of vasculitis, mitochondrial abnormalities, and neuropathy seemed to satisfy the definition of myopathy, unlike the referenced criteria. Further, at baseline, seven of the nine patients had an aldolase level above 10; one had a value above 20. We cannot conclude with confidence that none of these patients had established subclinical myopathy at entry. In addition, when an elevated aldolase was detected, the report states that treating physician’s behavior was unaffected, though patients with an elevated aldolase were informed and instructed to report the possible development of weakness. This is somewhat challenging to accept at face value. Knowledge regarding abnormal lab values is presumed to affect behavior, of the treating clinician or informed patient, via heightened scrutiny to ascertain the outcome.
Whole-body MRI In 2012, Schanz et al. [4] examined the range of MRI findings demonstrable among patients with scleroderma who presented with musculoskeletal symptoms. Notably, each participant satisfied the American College of Rheumatology (ACR) criteria for scleroderma [5]; patients with an overlap syndrome were specifically excluded. A total of 18 consecutive symptomatic patients underwent whole-body MRI at 1.5 Tesla at Eberhand Karls University in Tuebingen, Germany. The following complaints were reported: muscle weakness, myalgia, arthralgia, tendon sheath discomfort, and tendon friction rub. In turn, MRI was used to assess for subcutaneous thickening, fascial thickening and enhancement, perifascial enchancement, muscle edema and hyperemia, articular synovitis, tenosynovitis and enthesitis. Median age was 46 years; median disease duration was 14 months. Fifteen patients had diffuse disease, whereas three manifested the limited cutaneous subset of disease. Two radiologists, blinded to clinical information, separately analyzed the data. Whereas all 18 patients had, by design, at least one musculoskeletal symptom, tendon sheath discomfort was the predominant complaint, present in 16 (89%) members of the cohort. In contrast, only five patients (28%) reported weakness and three (17%) reported myalgia. Notably, creatine kinase was elevated in less than half, present in only 7 (47%) of 15 tested patients. Yet, musculoskeletal involvement was uniformly detected by MRI in the cohort. Muscle edema and hyperemia were found in the majority, among 14 (78%) patients.
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Yet, the authors noted that correlation was poor between clinical, laboratory, and MRI parameters. However, muscle weakness was correlated with perifascial enhancement and muscular edema (each P < 0.05).
ratio 0.3, 95% CI 0.1–0.7, P ¼ 0.0006). This confirms a previous case series published by Vandergheynst et al. [7] in 2006, which demonstrated that despite a high incidence of pulmonary fibrosis, patients with anti-PM-Scl have a favorable prognosis.
Comment This relatively small study of 18 patients confirms previous work showing MRI evidence of fascial enhancement and muscle edema are related to muscle weakness. Though a methodologic strength was that MRI radiologists were blinded to musculoskeletal symptoms and not influenced in radiologic interpretation by reported clinical features, a fundamental limitation in the study design relates to the lack of a scleroderma control group without musculoskeletal symptoms. Such a comparison group would enable specificity of the detected MRI findings to the condition of scleroderma myopathy. It would also have been informative to ascertain the association of histopathologic findings on biopsy and of electromyographic features of myopathy in relation to MRI findings, but this was not performed.
Comment The report of a well characterized scleroderma cohort is valuable to understanding the clinical profile and prognosis of a serologic subset of disease. Though only constituting 3% of the total cohort, this study reinforces the association of anti-PM-Scl antibody with a scleroderma–myositis overlap syndrome. These findings identify key organ systems (e.g. muscle and lung) to recognize among this subset. An overlap syndrome with polymyositis vs. dermatomyositis was not differentiated.
PM-Scl antibody identifies a serologic subset In the context of scleroderma, autoantibodies frequently characterize distinct phenotypic subsets of disease. In this context, Koschik et al. [6 ] examined disease manifestations and mortality risk among those with and without anti-PM-Scl antibody, evaluated at the University of Pittsburgh between 1980 and 2004. Out of the 2425 patients, 76 (3%) were PM-Scl antibody positive and 2349 (97%) were seronegative. Among the seropositive group, 36 (47%) patients had scleroderma in overlap with another autoimmune rheumatic disorder; for the large majority (33; 92%), this was inflammatory myositis. Compared with the seronegative group, the 76 PM-Scl antibody-positive patients were younger at symptom onset (38 18 vs. 43 15 years) and more often had limited cutaneous involvement (72 vs. 52%; P ¼ 0.001). Skeletal muscle involvement (51 vs. 14%; P < 0.0001), subcutaneous calcinosis (P < 0.003), and pulmonary fibrosis (50 vs. 37%; P ¼ 0.04) were each more frequent among the PM-Scl antibody-positive group, whereas gastrointestinal involvement was less frequent (52 vs. 79%; P ¼ 0.0001). Overall, survival was significantly higher for the PM-Scl seropositive compared with the seronegative patients (10-year cumulative survival rate of 91 vs. 65%, respectively; P ¼ 0.0002). After adjustment for age, sex, and disease subtype, patients with anti-PMScl antibody faced a reduced risk of death (hazard &&
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Abatacept treatment efficacy &
Elhai et al. [8 ] examined the efficacy of tocilizumab and abatacept among 27 patients with scleroderma and treatment-refractory polyarthritis and myopathy. However, closer scrutiny of the study reveals that only seven patients with refractory myopathy were evaluated, who uniformly received the drug, abatacept. Notably, abatacept is a co-stimulatory signal modulator, which down-regulates the cytotoxic T-lymphocyte antigen-4 (CTLA4)-mediated signal between antigen-presenting cells and T cells. Disease activity was assessed by patient and doctor alike, and included strength testing. The median age was 55 years, disease duration 7 years, and three (43%) were of the diffuse subtype. Virtually each of these seven patients was treated with low-dose prednisone (except one with high-dose steroids) and two were treated, concomitantly, with methotrexate and/or cyclophosphamide. Muscle biopsy was performed in five patients, uniformly showing inflammatory infiltrates, and necrosis in two patients. After 18 months of observation, disease activity, as assessed by both patient and doctor, each improved by more than 50% from baseline to last follow-up. These changes certainly appear to be clinically meaningful, but were not statistically significant (P ¼ 0.13 and 0.70, respectively). Moreover, whereas muscle strength seemingly did not improve with treatment, median level of creatine kinase did improve by greater than 50%, falling from a mean value of 456 to 192 (P ¼ 0.62). Comment This study is the only scleroderma report in the past year to evaluate efficacy of a biologic agent to treat refractory myopathy. However, the major weakness Volume 26 Number 2 March 2014
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Characterization of myopathy in scleroderma Paik et al.
of the study is the lack of a direct comparison group (placebo or active comparator). Moreover, only seven patients were evaluated, rendering a sample size too small and under-powered to observe statistically significant differences. In addition, the decrease in creatine kinase is non-specific and may be due to corticosteroid effect. Thus, whereas the findings are encouraging, replication in a larger sample and with a comparator treatment (or period) is warranted before movement to a large-scale randomized clinical trial is warranted.
Summary comment These four studies published in 2012–2013 focus directly on the subject of scleroderma myopathy. The importance of a prospective study design to identify incident myopathy was highlighted as was use of a diagnostic modality, for example, whole-body MRI, to detect muscle disease, and of serologic subsets to predict clinical phenotypes and outcomes. Further, novel drug therapy has an inherent appeal. Yet, fundamental limitations in study design are also recognized. These include the imperative to achieve consensus regarding classification of weak patients with scleroderma to enable comparisons between reports. Just as important is the need to have adequate sample size and comparator groups to enable appropriate inference. We reviewed key reports from the past 50 years in an effort to illuminate this area.
onset of symptoms until enrollment. Further, 38 patients underwent strength testing. Two-thirds (n ¼ 35) were tested for creatine kinase, aldolase, lactate dehydrogenase (LDH), and serum glutamic-oxaloacetic acid (SGOT) levels; for nine others, these data were found in prior records. Skeletal muscle tissue was obtained in 36 cases, consisting of 18 open biopsies (one patient had two different muscles biopsied) and 19 post mortem specimens. Notably, average weight loss after onset of scleroderma was 12% of body weight. Marked weight loss (>20%) was observed in 14 patients. Whereas severe objective muscle weakness was noted among 16 patients, only 7 of 38 (18%) reported musclerelated symptoms, typically affecting proximal muscles. Interestingly, creatine kinase levels were normal in all but three tested patients (having excluded those with overlapping myositis). In contrast, the most common abnormality was an elevated aldolase level, high in 20 patients (57%). Further, significant histologic abnormalities were noted in skeletal muscle from 14 (39%) of 36 patients. However, these alterations occurred more commonly in autopsy samples (10 of 19, 53%) than by biopsy (4 of 17, 24%) during life. The most common finding was interstitial and perivascular fibrosis; in fact, interstitial fibrosis was demonstrable in 13 (93%) of 14 patients with a muscle biopsy, followed by myofibril atrophy, necrosis, and degeneration (10 of 14, 71%), then interstitial and perivascular inflammatory infiltrates (8 of 14, 57%).
KEY STUDIES PRIOR TO 2012 A recent meta-analysis reported the prevalence of myositis in scleroderma to be 13% [9]. Yet, the frequency of scleroderma myopathy has ranged broadly among individual studies, from 14 to 96% [10–15], attributable to disparate diagnostic criteria between the various studies. Although rare, there have also been reports of dropped head syndrome due to neck extensor weakness [16–18] and myocarditis [19–21] associated with scleroderma. We next review three key studies prior to 2012 that focused on the characterization of scleroderma myopathy.
University of Pittsburgh In 1968, Medsger et al. [22] reported the largest case series to date to evaluate clinical features of scleroderma myopathy. At the University of Pittsburgh, 53 patients underwent clinical, biochemical, and pathologic evaluation. Only 33 patients were under ‘current’ observation; in contrast, 5 patients died during the 1965–1967 study period and 15 others had available autopsy muscle samples. Disease duration was broad, ranging from 1 to 31 years. Evaluation included assessment of weight loss from
Comment Whereas this survey provided one of the first insights into scleroderma myopathy, it also points toward the many gaps in our understanding of the disease. There is a striking discrepancy in prevalence of histologic abnormalities derived from living vs. deceased tissue samples. Caution at interpretative reconciliation between these markedly different sources of pathologic material is necessary. Ultimately, the authors concluded there was no primary muscle lesion in scleroderma except for fibrosis. But, this study made no use of quantitative muscle testing of distinct muscle groups; only a single overall weakness rating was assigned. There were also no electromyographic data to compare to later reports.
Royal Post-Graduate School of London In contrast to the Pittsburgh study, Thompson et al. [23] evaluated the prevalence of myopathy in an ‘unselected’ group of 15 patients with scleroderma at the Royal Post-Graduate School of London (mean age was 48 years). Notably, only three (20%) patients had evidence of muscle weakness and atrophy, including one on concurrent low-dose prednisone.
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For the EMG studies, only four patients demonstrated abnormalities, among whom only two had clinical weakness. Further, among 12 patients who underwent a muscle biopsy, the most common abnormality was an increase in centrally placed nuclei. Also identified was a slight increase in interstitial fibrous tissue. Of note, an inflammatory infiltrate sufficient to constitute myositis was observed in only two biopsies. One major goal of this study was to determine if EMG measurement of mean potential duration (MPD) could serve as an accurate method to identify scleroderma myopathy. Relatively few patients (only four) demonstrated clinical weakness. Further, only 4 of 15 patients had short MPDs, and these values were still within the normal range. Clinical weakness, however, did coincide in two of these cases. Yet, there was no correlation with disease severity or disease duration with the electromyographic findings. Comment The study is limited by the small number of patients, but suggests that scleroderma myopathy is uncommon. Whereas the authors sought to evaluate the diagnostic utility of EMG, most patients had normal tracings. There were too few weak patients and too few with muscle biopsies to correlate with electromyographic findings.
France: multicenter study In 2009, Ranque et al. [24] evaluated 35 patients to illuminate the clinical and pathologic features of scleroderma myopathy. Each had undergone a muscle biopsy between 1995 and 2005. Myopathy was defined by presence of muscle weakness, myalgia, or creatine kinase greater than 5 normal, together with electromyographic or histologic evidence of muscle involvement. Muscle specimens were examined for myofiber atrophy and necrosis/ regeneration; inflammation; fibrosis; microangiopathy; arteritis; mitochondrial abnormalities; and neuropathic changes. Favorable muscle outcome was defined as improvement in muscle grade and myalgia intensity; or, if no muscle weakness or myalgia (two cases), normalization or greater than 50% decrease in creatine kinase levels. There were 30 women and 5 men in the cohort. Median time from diagnosis of scleroderma to onset of myopathy was 5 years (range 0–23). Notably three-quarters (n ¼ 26) of the cohort manifested the diffuse cutaneous subset of scleroderma. The prevalence of autoantibodies was anti-nuclear (n ¼ 28; 82%), anti-DNA (2; 6%), anti-centromere (2; 6%), anti-topoisomerase 1 (6; 18%), anti-PM-Scl (4, 12%), anti-ribonucleoprotein(RNP) (5; 14%), and anti-Ro and anti-La (7; 20%), and anti-Ku (1; 9%). 128
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Among the studied patients, 27 (77%) had muscle weakness, uniformly in a proximal distribution, and 30 (86%) had myalgia. Serum creatine kinase and aldolase levels were elevated in 27 (82%) and 16 (76%) cases, respectively. Among 14 patients who underwent EMG testing, 13 (93%) had a myopathic pattern and 4 (29%) a combined peripheral neuropathy. In addition, 12 patients underwent muscle MRI; 8 (67%) showed a high-intensity signal of girdle muscles, with muscle atrophy and fatty infiltration in 3 (none with prior corticosteroids); the others had no detectable abnormality. On muscle biopsy, 22 (63%) of 35 displayed mononuclear inflammation, at septal/perimysial (n ¼ 7), endomysial (n ¼ 5), and/or perivascular (n ¼ 11) areas. Atrophy and irregular muscle fiber diameter occurred in 22 (63%) cases, fiber necrosis in 22 (63%), fiber regeneration in 15 (44%), central nuclei in 8 (24%), as well as endomysial and perimysial fibrosis in 8 (24%). There were 10 (29%) tissue specimens with microangiopathy, 3 (9%) with vasculitis of small arteries, and 1 (3%) with a mitochondrial abnormality. No neuropathic change was observed. Class I Human Leukocyte Antigen (HLA)-heightened expression on myofibers was seen in 11 (65%) of 17 cases. In three of four inflammatory myopathies with available immunostaining, the infiltrate was mostly composed of CD4þ T Cells, B cells and complement deposits on vascular walls, and in one, macrophages and CD8þ T cells predominated. After a median follow-up of 4.5 years, 24 (69%) patients showed complete (n ¼ 14) or partial muscle remission. Histological muscle inflammation was associated with good muscle prognosis in multivariate analysis [odds ratio (OR) 45, 95% CI 3–705]. Necrosis was also associated with a favorable outcome (OR 16.5, 95% CI 1.3–208). Of note, patients without muscle inflammation had a poor outcome after corticosteroid therapy (38% favorable response vs. 90% in patients with inflammation). Comment The study was particularly informative at defining a strong association between histologic evidence of muscle inflammation and necrosis with response to therapy. Notably, 100% of patients with both features on biopsy had a favorable outcome vs. only 14% in patients with neither inflammation nor necrosis. Consequently, this study underscores the need to restrict steroid treatment to those with histological evidence of an inflammatory myopathy.
CONCLUSION Common to the ‘current’ and ‘older’ studies is the imperative to define what constitutes scleroderma Volume 26 Number 2 March 2014
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Pittsburgh
Schanz [4]
Koschik [6 ]
Medsger [22]
Thompson [23]
Ranque [24]
3
4
5
6
7
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France
Royal Postgrad School of London
Pittsburgh
35
15
53
2425
18
137
7
No. of pts
Muscle weakness, myalgia, or CK >5 ULN and EMG or abnormal muscle biopsy
Proximal weakness on exam, EMG and/or biopsy
Single overall rating of muscle weakness, CK or aldolase elevation, abnormal muscle biopsy
Whole-body MRI and patient’s reported musculoskeletal complaints Proximal muscle weakness on physical exam þ elevated CK, myopathic changes on EMG, or abnormal muscle biopsy compatible with myopathy
ENMC criteria (note: full criteria were not utilized)
Refractory myopathy patients
Definition of myopathy
CK: 27/35 (82%); aldolase: 16/35 (76%)
N/A
13/14
4/15
Not done
N/A
N/A
CK: 3/53 (6%) Aldolase: 20/35 (57%)
Not done
8/9
N/A
EMG: myopathic
CK: 7/15 (47%)
9/137 (6.5%) developed incident myopathy; CK: 6/9 (67%); aldolase: 9/9 (100%)
CK: mean 546 IU/l reported in 7 patients
CK elevation and/or aldolase elevation
CK, creatine kinase; EMG, electromyography; ENMC, European Neuromuscular Center; N/A, not available; No., number; Postgrad, postgraduate; pts, patients.
&&
Germany
Toledano [1]
2
France
EULAR Scleroderma Trials and Research Group
Elhai [8 ]
1
&
Setting
First author
No.
Table 1. Summary of key articles between 2012 and 2013 and the past 50 years
35 had muscle biopsies: 22/35 (63%) had inflammation; 22/35 (63%) atrophy, centralized nuclei in 8/35 (23%), fibrosis in 8/35 (23%)
12/15 patients had muscle biopsies; out of the 12: 2/12 (17%) had inflammatory infiltrates; 11/12 (92%) had central nuclei; 7/12 (58%) interstitial fibrosis
36 had muscle biopsies (19 were autopsy samples); 14/36 (39%) had abnormal biopsies; out of the 14: 13/ 14 (93%) had interstitial fibrosis; 10/ 14 (71%) myofibril atrophy, necrosis, degeneration; 8/14 (57%) had interstitial and perivascular infiltrates
N/A
Not done
Out of the 9 who developed incident myopathy, 7/9 had muscle biopsies; unfortunately histopathologic changes were not reported
5 had muscle biopsies: 5/5 (100%) had inflammatory infiltrates; 2/5 (40%) had necrosis
Muscle biopsy characteristics
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myopathy (Table 1, article summary). Thus, whereas the Pittsburgh study was relatively large, constituting 53 patients with myopathy, this investigation purposefully excluded an overlap syndrome. Consequently, the yield of muscle enzyme and histologic appearance was low for features of an inflammatory myopathy. The English and French studies, in contrast, examined an unselected scleroderma group with myopathy. This discrepancy in study composition engenders two take-home messages. First, the importance to recognize that ‘scleroderma myopathy’ is a heterogeneous entity, including those with primarily inflammatory vs. fibrotic features. Only by being inclusive of the full spectrum of affected patients, in observational cohorts and clinical trials, can the sensitivity of diagnostic techniques (e.g. biomarkers, autoantibodies, imaging, electromyographic, and histologic parameters) to detect distinct subsets, and the impact of therapy in subgroup analysis, be fully appreciated. Second, uniform measurement of the aforementioned diagnostic modalities, at cohort entry (or trial enrollment), followed by prospective ascertainment of incident myopathy (and related outcomes), using classification criteria developed by expert consensus (e.g. the ENMC), can enhance our understanding of what constitutes scleroderma myopathy, and how best to diagnosis and treat it. The timing is ripe for multicenter and large single-university referral centers to seize this opportunity. Acknowledgements None. Conflicts of interest Dr Julie J Paik was supported by the Clinical to Research Transition Award from the Arthritis Foundation.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Toledano C, Gain M, Kettaneh A, et al. Aldolase predicts subsequent myopathy occurrence in systemic sclerosis. Arthritis Res Ther 2012; 14:R152.
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2. Rider LG, Koziol D, Gianni EH, et al. Validation of manual muscle testing and a subset of eight muscles (MMT8) for adult and juvenile idiopathic inflammatory myopathies. Arthritis Care Res (Hoboken) 2010; 62:465–472. 3. 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, 10-12 October 2003, Naarden, The Netherlands. Neuromusc Disord 2004; 14:337–345. 4. Schanz S, Henes J, Ulmer A, Kotter I, et al. Magnetic resonance imaging findings in patients with systemic scleroderma and musculoskeletal symptoms. Eur Radiol 2013; 23:212–221. 5. Preliminary criteria for the classification of systemic sclerosis (scleroderma). Subcommittee for scleroderma criteria of the American Rheumatism Association Diagnostic and Therapeutic Criteria Committee. Arthritis Rheum 1980; 23 (5):581–590. 6. Koschik RW, Fertig N, Lucas MR, et al. Anti-PM-Scl antibody in patients with && systemic sclerosis. Clin Exp Rheumatol 2012; 30:S12–S16. This study describes the clinical profile of anti-PM-Scl antibody positive patients and also gives special attention to prognosis of this specific serologic subset in scleroderma. 7. Vandergheynst F, Ocmant A, Sordet C, et al. Anti-PM/Scl antibodies in connective tissue disease: clinical and biological assessment of 14 patients. Clin Exp Rheumatol 2006; 24:129–133. 8. Elhai M, Meunier M, Matucci-Cerinic M, et al. Outcomes of patients with & systemic sclerosis-associated polyarthritis and myopathy treated with tocilizumab or abatecept: a EUSTAR observational study. Ann Rheum Dis 2013; 72:1217–1220. This is the only study in the past year that evaluates the use of a biologic medication in the treatment of refractory myopathy in scleroderma. 9. Muangchan C, Baron M, Pope J, Canadian Scleroderma Research Group. The 15% rule in scleroderma: frequency of severe organ complications in systemic sclerosis: a systematic review. J Rheumatol 2013; 40:1545–1556. 10. Mammen AL. Myopathy in scleroderma. In: Scleroderma: from pathogenesis to comprehensive management. New York: Springer; 2011. pp. 525–529. 11. West SG, Killiam PJ, Lawless OJ. Association of myositis and myocarditis in progressive systemic sclerosis. Arthritis Rheum 1981; 24:662–668. 12. Russell ML, Hanna WM. Ultrastructure of muscle microvasculature in progressive systemic sclerosis: relation to clinical weakness. J Rheumatol 1983; 10:741–747. 13. Averbuch-Heller L, Steiner I, Abramsky O. Neurologic manifestations of progressive systemic sclerosis. Arch Neurol 1992; 49:1292–1295. 14. Hietaharju A, Jaaskelainen S, Kalimo H, Hietarinta M. Peripheral neuromuscular manifestations in systemic sclerosis (scleroderma). Muscle Nerve 1993; 16:1204–1212. 15. Mimura Y, Ihn H, Jinnin M, et al. Clinical and laboratory features of scleroderma patients developing skeletal myopathy. Clin Rheumatol 2005; 24:99–102. 16. Rosato E, Rossi C, Salsano F. Dropped head syndrome and systemic sclerosis. Joint Bone Spine 2009; 76:301–303. 17. Garcin B, Lenglet T, Dubourg O, et al. Dropped head syndrome as a presenting sign of scleromyositis. J Neurol Sci 2010; 292:101–103. 18. Rojana-Udomsart A, Fabian V, Hollingsworth PN, et al. Paraspinal and scapular myopathy associated with scleroderma. J Clin Neuromuscul Dis 2010; 11:213–222. 19. Follansbee WP, Zerbe TR, Medsger TA Jr. Cardiac and skeletal muscle disease in systemic sclerosis (scleroderma): a high risk association. Am Heart J 1993; 125:194–203. 20. Allanore Y, Meune C, Vonk MC, et al. Prevalence and factors associated with left ventricular dysfunction in the EULAR Scleroderma Trial and Research group (EUSTAR) database of patients with systemic sclerosis. Ann Rheum Dis 2010; 69:218–221. 21. Ranque B, Berezne A, Le-Guern V, et al. Myopathies related to systemic sclerosis: a case-control study of associated clinical and immunological features. Scand J Rheumatol 2010; 39:498–505. 22. Medsger TA, Rodnan GP, Moosy J, et al. Skeletal muscle involvement in progressive systemic sclerosis. Arthritis Rheum 1968; 11:554–568. 23. Thompson JM, Bluestone R, Bywaters GL, et al. Skeletal muscle involvement in systemic sclerosis. Ann Rheum Dis 1969; 28:281–287. 24. Ranque B, Authier F-J, Le-Guern V, et al. A descriptive and prognostic study of systemic sclerosis-associated myopathies. Ann Rheum Dis 2009; 68:1474– 1477.
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Myopathy in scleroderma, its identification, prevalence, and treatment: lessons learned from cohort studies Julie J. Paik a, Andrew L. Mammen b, Fredrick M. Wigley a, and Allan C. Gelber a
Purpose of review This review discusses the characterization of myopathy in scleroderma with a focus on new developments in imaging, biomarkers, and therapy, and details several current reports and several seminal reports prior to 2012. Recent findings In the past year, studies have shown that MRI techniques highlight the importance of muscle edema in scleroderma, and that aldolase may be a useful biomarker to predict incident myopathy. When compared to studies preceding 2012, both the current and prior reports too often fail to account for the full spectrum of muscle disease in scleroderma. There remain no uniform classification criteria that are routinely integrated into clinical research reports. Thus, important questions remain to be answered, including risk factors for developing myopathy, optimal screening and diagnostic strategies, and efficacious therapies. But, just as important is the priority to systematically define what the true entity(ies) of myopathy is in scleroderma. Summary Scleroderma myopathy is a heterogeneous group of muscle disorders among patients with underlying scleroderma which requires robust studies to clarify the full spectrum of disease. Keywords epidemiology, myopathy, myositis, scleroderma
INTRODUCTION ‘Scleroderma myopathy’ is an umbrella term that encompasses several biological processes that occur at the intersection of both rheumatologic and neuromuscular disorders. Although there are clear cases of an inflammatory myopathy, indistinguishable from polymyositis, there is more often muscle weakness secondary to myopathy that is non-inflammatory in nature. In the past 50 years, advances in imaging and histopathology techniques have enabled a more thorough characterization of myopathy in scleroderma, yet the underlying cause(s) is still poorly understood. Recent developments in imaging, use of biomarkers and novel therapy, in the context of prior seminal reports in the area of scleroderma myopathy, are the major focus of this article.
STUDIES IN 2012–2013 Using the search terms of scleroderma, polymyositis, dermatomyositis, myopathy, and populationbased studies, our search resulted in 123 articles, www.co-rheumatology.com
with only 10 addressing myopathy in scleroderma. Out of the 10, 1 was a review article, and 5 were case reports, leaving 4 original research contributions that we review here.
Aldolase as a marker to identify incident myopathy In 2012, Toledano et al. [1] reported the value of aldolase to identify patients with scleroderma at increased risk to develop myopathy. The design was a prospective cohort assembled at Saint Antoine Hospital, in Paris, in which patients without a
Department of Medicine and bDepartment of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA Correspondence to Julie J. Paik, MD, MHS, 5200 Eastern Avenue, Mason F. Lord Building, Center Tower, Suite 4100, Baltimore, MD 21224, USA. Tel: +1 410 550 6929; fax: +1 410 550 3524; e-mail: [email protected] Curr Opin Rheumatol 2014, 26:124–130 DOI:10.1097/BOR.0000000000000024 Volume 26 Number 2 March 2014
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Characterization of myopathy in scleroderma Paik et al.
KEY POINTS Scleroderma myopathy is a heterogeneous disease. A systematic classification scheme should be defined to clarify the spectrum of myopathy in scleroderma. Robust studies need to be conducted in the future to enhance the understanding of the risk factors, diagnosis, and treatment of myopathy in scleroderma.
weakness at baseline were followed over time to detect incident myopathy. Weakness was measured using the 8-manual muscle testing (8-MMT) [2] scale which examines strength proximally and distally, in arm, leg, and truncal muscle groups, at both antigravity and gravity-eliminated positions. The endpoint of incident myopathy included weakness defined by at least 10% decline from baseline 8-MMT score. After weakness occurred, patients underwent an electromyogram (EMG), and/or thigh MRI, and/or muscle biopsy to confirm the presence of myopathy. The authors enrolled 137 of 150 total patients with scleroderma. Mean age was 55 years; mean disease duration was 12 years. One-third manifested the diffuse subtype of scleroderma. Overall, mean aldolase value was 10 7.5 U/l and mean creatine kinase was 111 142 U/l (upper limit for aldolase and creatine kinase were 7 and 160 U/l, respectively). During a mean follow-up period of 45 (17) months, nine patients developed persistent proximal weakness, which satisfied the investigators’ definition of scleroderma myopathy. Notably, among various muscle enzymes measured to detect incident myopathy, aldolase had the highest predictive power. The area under the receiver operating characteristic curve for aldolase was greater than that measured for creatine kinase and alanine aminotransferase (ALT). In contrast, aspartate aminotransferase (AST) and c-reactive protein (CRP) did not have predictive value. Specifically, within 3 years of cohort entry, an aldolase level of at least 9 U/l identified subsequent myopathy with a sensitivity of 89% and specificity of 67%. After adjustment for age, sex, disease subtype, and duration, those with an aldolase level above 9 U/l experienced a substantial increase in risk to develop myopathy [hazard ratio 10.3, 95% confidence interval (CI) 2.3–45.5]. Comment Whereas this important prospective cohort identified aldolase as a predictor of incident myopathy, there are several shortcomings. First, this study did not, seemingly, apply the full classification criteria
of the European Neuromuscular Center (ENMC) Workshop [3]. Thus, whereas scleroderma myopathy was defined as having satisfied ENMC criteria, histologic evidence of vasculitis, mitochondrial abnormalities, and neuropathy seemed to satisfy the definition of myopathy, unlike the referenced criteria. Further, at baseline, seven of the nine patients had an aldolase level above 10; one had a value above 20. We cannot conclude with confidence that none of these patients had established subclinical myopathy at entry. In addition, when an elevated aldolase was detected, the report states that treating physician’s behavior was unaffected, though patients with an elevated aldolase were informed and instructed to report the possible development of weakness. This is somewhat challenging to accept at face value. Knowledge regarding abnormal lab values is presumed to affect behavior, of the treating clinician or informed patient, via heightened scrutiny to ascertain the outcome.
Whole-body MRI In 2012, Schanz et al. [4] examined the range of MRI findings demonstrable among patients with scleroderma who presented with musculoskeletal symptoms. Notably, each participant satisfied the American College of Rheumatology (ACR) criteria for scleroderma [5]; patients with an overlap syndrome were specifically excluded. A total of 18 consecutive symptomatic patients underwent whole-body MRI at 1.5 Tesla at Eberhand Karls University in Tuebingen, Germany. The following complaints were reported: muscle weakness, myalgia, arthralgia, tendon sheath discomfort, and tendon friction rub. In turn, MRI was used to assess for subcutaneous thickening, fascial thickening and enhancement, perifascial enchancement, muscle edema and hyperemia, articular synovitis, tenosynovitis and enthesitis. Median age was 46 years; median disease duration was 14 months. Fifteen patients had diffuse disease, whereas three manifested the limited cutaneous subset of disease. Two radiologists, blinded to clinical information, separately analyzed the data. Whereas all 18 patients had, by design, at least one musculoskeletal symptom, tendon sheath discomfort was the predominant complaint, present in 16 (89%) members of the cohort. In contrast, only five patients (28%) reported weakness and three (17%) reported myalgia. Notably, creatine kinase was elevated in less than half, present in only 7 (47%) of 15 tested patients. Yet, musculoskeletal involvement was uniformly detected by MRI in the cohort. Muscle edema and hyperemia were found in the majority, among 14 (78%) patients.
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Yet, the authors noted that correlation was poor between clinical, laboratory, and MRI parameters. However, muscle weakness was correlated with perifascial enhancement and muscular edema (each P < 0.05).
ratio 0.3, 95% CI 0.1–0.7, P ¼ 0.0006). This confirms a previous case series published by Vandergheynst et al. [7] in 2006, which demonstrated that despite a high incidence of pulmonary fibrosis, patients with anti-PM-Scl have a favorable prognosis.
Comment This relatively small study of 18 patients confirms previous work showing MRI evidence of fascial enhancement and muscle edema are related to muscle weakness. Though a methodologic strength was that MRI radiologists were blinded to musculoskeletal symptoms and not influenced in radiologic interpretation by reported clinical features, a fundamental limitation in the study design relates to the lack of a scleroderma control group without musculoskeletal symptoms. Such a comparison group would enable specificity of the detected MRI findings to the condition of scleroderma myopathy. It would also have been informative to ascertain the association of histopathologic findings on biopsy and of electromyographic features of myopathy in relation to MRI findings, but this was not performed.
Comment The report of a well characterized scleroderma cohort is valuable to understanding the clinical profile and prognosis of a serologic subset of disease. Though only constituting 3% of the total cohort, this study reinforces the association of anti-PM-Scl antibody with a scleroderma–myositis overlap syndrome. These findings identify key organ systems (e.g. muscle and lung) to recognize among this subset. An overlap syndrome with polymyositis vs. dermatomyositis was not differentiated.
PM-Scl antibody identifies a serologic subset In the context of scleroderma, autoantibodies frequently characterize distinct phenotypic subsets of disease. In this context, Koschik et al. [6 ] examined disease manifestations and mortality risk among those with and without anti-PM-Scl antibody, evaluated at the University of Pittsburgh between 1980 and 2004. Out of the 2425 patients, 76 (3%) were PM-Scl antibody positive and 2349 (97%) were seronegative. Among the seropositive group, 36 (47%) patients had scleroderma in overlap with another autoimmune rheumatic disorder; for the large majority (33; 92%), this was inflammatory myositis. Compared with the seronegative group, the 76 PM-Scl antibody-positive patients were younger at symptom onset (38 18 vs. 43 15 years) and more often had limited cutaneous involvement (72 vs. 52%; P ¼ 0.001). Skeletal muscle involvement (51 vs. 14%; P < 0.0001), subcutaneous calcinosis (P < 0.003), and pulmonary fibrosis (50 vs. 37%; P ¼ 0.04) were each more frequent among the PM-Scl antibody-positive group, whereas gastrointestinal involvement was less frequent (52 vs. 79%; P ¼ 0.0001). Overall, survival was significantly higher for the PM-Scl seropositive compared with the seronegative patients (10-year cumulative survival rate of 91 vs. 65%, respectively; P ¼ 0.0002). After adjustment for age, sex, and disease subtype, patients with anti-PMScl antibody faced a reduced risk of death (hazard &&
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Abatacept treatment efficacy &
Elhai et al. [8 ] examined the efficacy of tocilizumab and abatacept among 27 patients with scleroderma and treatment-refractory polyarthritis and myopathy. However, closer scrutiny of the study reveals that only seven patients with refractory myopathy were evaluated, who uniformly received the drug, abatacept. Notably, abatacept is a co-stimulatory signal modulator, which down-regulates the cytotoxic T-lymphocyte antigen-4 (CTLA4)-mediated signal between antigen-presenting cells and T cells. Disease activity was assessed by patient and doctor alike, and included strength testing. The median age was 55 years, disease duration 7 years, and three (43%) were of the diffuse subtype. Virtually each of these seven patients was treated with low-dose prednisone (except one with high-dose steroids) and two were treated, concomitantly, with methotrexate and/or cyclophosphamide. Muscle biopsy was performed in five patients, uniformly showing inflammatory infiltrates, and necrosis in two patients. After 18 months of observation, disease activity, as assessed by both patient and doctor, each improved by more than 50% from baseline to last follow-up. These changes certainly appear to be clinically meaningful, but were not statistically significant (P ¼ 0.13 and 0.70, respectively). Moreover, whereas muscle strength seemingly did not improve with treatment, median level of creatine kinase did improve by greater than 50%, falling from a mean value of 456 to 192 (P ¼ 0.62). Comment This study is the only scleroderma report in the past year to evaluate efficacy of a biologic agent to treat refractory myopathy. However, the major weakness Volume 26 Number 2 March 2014
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Characterization of myopathy in scleroderma Paik et al.
of the study is the lack of a direct comparison group (placebo or active comparator). Moreover, only seven patients were evaluated, rendering a sample size too small and under-powered to observe statistically significant differences. In addition, the decrease in creatine kinase is non-specific and may be due to corticosteroid effect. Thus, whereas the findings are encouraging, replication in a larger sample and with a comparator treatment (or period) is warranted before movement to a large-scale randomized clinical trial is warranted.
Summary comment These four studies published in 2012–2013 focus directly on the subject of scleroderma myopathy. The importance of a prospective study design to identify incident myopathy was highlighted as was use of a diagnostic modality, for example, whole-body MRI, to detect muscle disease, and of serologic subsets to predict clinical phenotypes and outcomes. Further, novel drug therapy has an inherent appeal. Yet, fundamental limitations in study design are also recognized. These include the imperative to achieve consensus regarding classification of weak patients with scleroderma to enable comparisons between reports. Just as important is the need to have adequate sample size and comparator groups to enable appropriate inference. We reviewed key reports from the past 50 years in an effort to illuminate this area.
onset of symptoms until enrollment. Further, 38 patients underwent strength testing. Two-thirds (n ¼ 35) were tested for creatine kinase, aldolase, lactate dehydrogenase (LDH), and serum glutamic-oxaloacetic acid (SGOT) levels; for nine others, these data were found in prior records. Skeletal muscle tissue was obtained in 36 cases, consisting of 18 open biopsies (one patient had two different muscles biopsied) and 19 post mortem specimens. Notably, average weight loss after onset of scleroderma was 12% of body weight. Marked weight loss (>20%) was observed in 14 patients. Whereas severe objective muscle weakness was noted among 16 patients, only 7 of 38 (18%) reported musclerelated symptoms, typically affecting proximal muscles. Interestingly, creatine kinase levels were normal in all but three tested patients (having excluded those with overlapping myositis). In contrast, the most common abnormality was an elevated aldolase level, high in 20 patients (57%). Further, significant histologic abnormalities were noted in skeletal muscle from 14 (39%) of 36 patients. However, these alterations occurred more commonly in autopsy samples (10 of 19, 53%) than by biopsy (4 of 17, 24%) during life. The most common finding was interstitial and perivascular fibrosis; in fact, interstitial fibrosis was demonstrable in 13 (93%) of 14 patients with a muscle biopsy, followed by myofibril atrophy, necrosis, and degeneration (10 of 14, 71%), then interstitial and perivascular inflammatory infiltrates (8 of 14, 57%).
KEY STUDIES PRIOR TO 2012 A recent meta-analysis reported the prevalence of myositis in scleroderma to be 13% [9]. Yet, the frequency of scleroderma myopathy has ranged broadly among individual studies, from 14 to 96% [10–15], attributable to disparate diagnostic criteria between the various studies. Although rare, there have also been reports of dropped head syndrome due to neck extensor weakness [16–18] and myocarditis [19–21] associated with scleroderma. We next review three key studies prior to 2012 that focused on the characterization of scleroderma myopathy.
University of Pittsburgh In 1968, Medsger et al. [22] reported the largest case series to date to evaluate clinical features of scleroderma myopathy. At the University of Pittsburgh, 53 patients underwent clinical, biochemical, and pathologic evaluation. Only 33 patients were under ‘current’ observation; in contrast, 5 patients died during the 1965–1967 study period and 15 others had available autopsy muscle samples. Disease duration was broad, ranging from 1 to 31 years. Evaluation included assessment of weight loss from
Comment Whereas this survey provided one of the first insights into scleroderma myopathy, it also points toward the many gaps in our understanding of the disease. There is a striking discrepancy in prevalence of histologic abnormalities derived from living vs. deceased tissue samples. Caution at interpretative reconciliation between these markedly different sources of pathologic material is necessary. Ultimately, the authors concluded there was no primary muscle lesion in scleroderma except for fibrosis. But, this study made no use of quantitative muscle testing of distinct muscle groups; only a single overall weakness rating was assigned. There were also no electromyographic data to compare to later reports.
Royal Post-Graduate School of London In contrast to the Pittsburgh study, Thompson et al. [23] evaluated the prevalence of myopathy in an ‘unselected’ group of 15 patients with scleroderma at the Royal Post-Graduate School of London (mean age was 48 years). Notably, only three (20%) patients had evidence of muscle weakness and atrophy, including one on concurrent low-dose prednisone.
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For the EMG studies, only four patients demonstrated abnormalities, among whom only two had clinical weakness. Further, among 12 patients who underwent a muscle biopsy, the most common abnormality was an increase in centrally placed nuclei. Also identified was a slight increase in interstitial fibrous tissue. Of note, an inflammatory infiltrate sufficient to constitute myositis was observed in only two biopsies. One major goal of this study was to determine if EMG measurement of mean potential duration (MPD) could serve as an accurate method to identify scleroderma myopathy. Relatively few patients (only four) demonstrated clinical weakness. Further, only 4 of 15 patients had short MPDs, and these values were still within the normal range. Clinical weakness, however, did coincide in two of these cases. Yet, there was no correlation with disease severity or disease duration with the electromyographic findings. Comment The study is limited by the small number of patients, but suggests that scleroderma myopathy is uncommon. Whereas the authors sought to evaluate the diagnostic utility of EMG, most patients had normal tracings. There were too few weak patients and too few with muscle biopsies to correlate with electromyographic findings.
France: multicenter study In 2009, Ranque et al. [24] evaluated 35 patients to illuminate the clinical and pathologic features of scleroderma myopathy. Each had undergone a muscle biopsy between 1995 and 2005. Myopathy was defined by presence of muscle weakness, myalgia, or creatine kinase greater than 5 normal, together with electromyographic or histologic evidence of muscle involvement. Muscle specimens were examined for myofiber atrophy and necrosis/ regeneration; inflammation; fibrosis; microangiopathy; arteritis; mitochondrial abnormalities; and neuropathic changes. Favorable muscle outcome was defined as improvement in muscle grade and myalgia intensity; or, if no muscle weakness or myalgia (two cases), normalization or greater than 50% decrease in creatine kinase levels. There were 30 women and 5 men in the cohort. Median time from diagnosis of scleroderma to onset of myopathy was 5 years (range 0–23). Notably three-quarters (n ¼ 26) of the cohort manifested the diffuse cutaneous subset of scleroderma. The prevalence of autoantibodies was anti-nuclear (n ¼ 28; 82%), anti-DNA (2; 6%), anti-centromere (2; 6%), anti-topoisomerase 1 (6; 18%), anti-PM-Scl (4, 12%), anti-ribonucleoprotein(RNP) (5; 14%), and anti-Ro and anti-La (7; 20%), and anti-Ku (1; 9%). 128
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Among the studied patients, 27 (77%) had muscle weakness, uniformly in a proximal distribution, and 30 (86%) had myalgia. Serum creatine kinase and aldolase levels were elevated in 27 (82%) and 16 (76%) cases, respectively. Among 14 patients who underwent EMG testing, 13 (93%) had a myopathic pattern and 4 (29%) a combined peripheral neuropathy. In addition, 12 patients underwent muscle MRI; 8 (67%) showed a high-intensity signal of girdle muscles, with muscle atrophy and fatty infiltration in 3 (none with prior corticosteroids); the others had no detectable abnormality. On muscle biopsy, 22 (63%) of 35 displayed mononuclear inflammation, at septal/perimysial (n ¼ 7), endomysial (n ¼ 5), and/or perivascular (n ¼ 11) areas. Atrophy and irregular muscle fiber diameter occurred in 22 (63%) cases, fiber necrosis in 22 (63%), fiber regeneration in 15 (44%), central nuclei in 8 (24%), as well as endomysial and perimysial fibrosis in 8 (24%). There were 10 (29%) tissue specimens with microangiopathy, 3 (9%) with vasculitis of small arteries, and 1 (3%) with a mitochondrial abnormality. No neuropathic change was observed. Class I Human Leukocyte Antigen (HLA)-heightened expression on myofibers was seen in 11 (65%) of 17 cases. In three of four inflammatory myopathies with available immunostaining, the infiltrate was mostly composed of CD4þ T Cells, B cells and complement deposits on vascular walls, and in one, macrophages and CD8þ T cells predominated. After a median follow-up of 4.5 years, 24 (69%) patients showed complete (n ¼ 14) or partial muscle remission. Histological muscle inflammation was associated with good muscle prognosis in multivariate analysis [odds ratio (OR) 45, 95% CI 3–705]. Necrosis was also associated with a favorable outcome (OR 16.5, 95% CI 1.3–208). Of note, patients without muscle inflammation had a poor outcome after corticosteroid therapy (38% favorable response vs. 90% in patients with inflammation). Comment The study was particularly informative at defining a strong association between histologic evidence of muscle inflammation and necrosis with response to therapy. Notably, 100% of patients with both features on biopsy had a favorable outcome vs. only 14% in patients with neither inflammation nor necrosis. Consequently, this study underscores the need to restrict steroid treatment to those with histological evidence of an inflammatory myopathy.
CONCLUSION Common to the ‘current’ and ‘older’ studies is the imperative to define what constitutes scleroderma Volume 26 Number 2 March 2014
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Pittsburgh
Schanz [4]
Koschik [6 ]
Medsger [22]
Thompson [23]
Ranque [24]
3
4
5
6
7
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France
Royal Postgrad School of London
Pittsburgh
35
15
53
2425
18
137
7
No. of pts
Muscle weakness, myalgia, or CK >5 ULN and EMG or abnormal muscle biopsy
Proximal weakness on exam, EMG and/or biopsy
Single overall rating of muscle weakness, CK or aldolase elevation, abnormal muscle biopsy
Whole-body MRI and patient’s reported musculoskeletal complaints Proximal muscle weakness on physical exam þ elevated CK, myopathic changes on EMG, or abnormal muscle biopsy compatible with myopathy
ENMC criteria (note: full criteria were not utilized)
Refractory myopathy patients
Definition of myopathy
CK: 27/35 (82%); aldolase: 16/35 (76%)
N/A
13/14
4/15
Not done
N/A
N/A
CK: 3/53 (6%) Aldolase: 20/35 (57%)
Not done
8/9
N/A
EMG: myopathic
CK: 7/15 (47%)
9/137 (6.5%) developed incident myopathy; CK: 6/9 (67%); aldolase: 9/9 (100%)
CK: mean 546 IU/l reported in 7 patients
CK elevation and/or aldolase elevation
CK, creatine kinase; EMG, electromyography; ENMC, European Neuromuscular Center; N/A, not available; No., number; Postgrad, postgraduate; pts, patients.
&&
Germany
Toledano [1]
2
France
EULAR Scleroderma Trials and Research Group
Elhai [8 ]
1
&
Setting
First author
No.
Table 1. Summary of key articles between 2012 and 2013 and the past 50 years
35 had muscle biopsies: 22/35 (63%) had inflammation; 22/35 (63%) atrophy, centralized nuclei in 8/35 (23%), fibrosis in 8/35 (23%)
12/15 patients had muscle biopsies; out of the 12: 2/12 (17%) had inflammatory infiltrates; 11/12 (92%) had central nuclei; 7/12 (58%) interstitial fibrosis
36 had muscle biopsies (19 were autopsy samples); 14/36 (39%) had abnormal biopsies; out of the 14: 13/ 14 (93%) had interstitial fibrosis; 10/ 14 (71%) myofibril atrophy, necrosis, degeneration; 8/14 (57%) had interstitial and perivascular infiltrates
N/A
Not done
Out of the 9 who developed incident myopathy, 7/9 had muscle biopsies; unfortunately histopathologic changes were not reported
5 had muscle biopsies: 5/5 (100%) had inflammatory infiltrates; 2/5 (40%) had necrosis
Muscle biopsy characteristics
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myopathy (Table 1, article summary). Thus, whereas the Pittsburgh study was relatively large, constituting 53 patients with myopathy, this investigation purposefully excluded an overlap syndrome. Consequently, the yield of muscle enzyme and histologic appearance was low for features of an inflammatory myopathy. The English and French studies, in contrast, examined an unselected scleroderma group with myopathy. This discrepancy in study composition engenders two take-home messages. First, the importance to recognize that ‘scleroderma myopathy’ is a heterogeneous entity, including those with primarily inflammatory vs. fibrotic features. Only by being inclusive of the full spectrum of affected patients, in observational cohorts and clinical trials, can the sensitivity of diagnostic techniques (e.g. biomarkers, autoantibodies, imaging, electromyographic, and histologic parameters) to detect distinct subsets, and the impact of therapy in subgroup analysis, be fully appreciated. Second, uniform measurement of the aforementioned diagnostic modalities, at cohort entry (or trial enrollment), followed by prospective ascertainment of incident myopathy (and related outcomes), using classification criteria developed by expert consensus (e.g. the ENMC), can enhance our understanding of what constitutes scleroderma myopathy, and how best to diagnosis and treat it. The timing is ripe for multicenter and large single-university referral centers to seize this opportunity. Acknowledgements None. Conflicts of interest Dr Julie J Paik was supported by the Clinical to Research Transition Award from the Arthritis Foundation.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Toledano C, Gain M, Kettaneh A, et al. Aldolase predicts subsequent myopathy occurrence in systemic sclerosis. Arthritis Res Ther 2012; 14:R152.
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2. Rider LG, Koziol D, Gianni EH, et al. Validation of manual muscle testing and a subset of eight muscles (MMT8) for adult and juvenile idiopathic inflammatory myopathies. Arthritis Care Res (Hoboken) 2010; 62:465–472. 3. 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, 10-12 October 2003, Naarden, The Netherlands. Neuromusc Disord 2004; 14:337–345. 4. Schanz S, Henes J, Ulmer A, Kotter I, et al. Magnetic resonance imaging findings in patients with systemic scleroderma and musculoskeletal symptoms. Eur Radiol 2013; 23:212–221. 5. Preliminary criteria for the classification of systemic sclerosis (scleroderma). Subcommittee for scleroderma criteria of the American Rheumatism Association Diagnostic and Therapeutic Criteria Committee. Arthritis Rheum 1980; 23 (5):581–590. 6. Koschik RW, Fertig N, Lucas MR, et al. Anti-PM-Scl antibody in patients with && systemic sclerosis. Clin Exp Rheumatol 2012; 30:S12–S16. This study describes the clinical profile of anti-PM-Scl antibody positive patients and also gives special attention to prognosis of this specific serologic subset in scleroderma. 7. Vandergheynst F, Ocmant A, Sordet C, et al. Anti-PM/Scl antibodies in connective tissue disease: clinical and biological assessment of 14 patients. Clin Exp Rheumatol 2006; 24:129–133. 8. Elhai M, Meunier M, Matucci-Cerinic M, et al. Outcomes of patients with & systemic sclerosis-associated polyarthritis and myopathy treated with tocilizumab or abatecept: a EUSTAR observational study. Ann Rheum Dis 2013; 72:1217–1220. This is the only study in the past year that evaluates the use of a biologic medication in the treatment of refractory myopathy in scleroderma. 9. Muangchan C, Baron M, Pope J, Canadian Scleroderma Research Group. The 15% rule in scleroderma: frequency of severe organ complications in systemic sclerosis: a systematic review. J Rheumatol 2013; 40:1545–1556. 10. Mammen AL. Myopathy in scleroderma. In: Scleroderma: from pathogenesis to comprehensive management. New York: Springer; 2011. pp. 525–529. 11. West SG, Killiam PJ, Lawless OJ. Association of myositis and myocarditis in progressive systemic sclerosis. Arthritis Rheum 1981; 24:662–668. 12. Russell ML, Hanna WM. Ultrastructure of muscle microvasculature in progressive systemic sclerosis: relation to clinical weakness. J Rheumatol 1983; 10:741–747. 13. Averbuch-Heller L, Steiner I, Abramsky O. Neurologic manifestations of progressive systemic sclerosis. Arch Neurol 1992; 49:1292–1295. 14. Hietaharju A, Jaaskelainen S, Kalimo H, Hietarinta M. Peripheral neuromuscular manifestations in systemic sclerosis (scleroderma). Muscle Nerve 1993; 16:1204–1212. 15. Mimura Y, Ihn H, Jinnin M, et al. Clinical and laboratory features of scleroderma patients developing skeletal myopathy. Clin Rheumatol 2005; 24:99–102. 16. Rosato E, Rossi C, Salsano F. Dropped head syndrome and systemic sclerosis. Joint Bone Spine 2009; 76:301–303. 17. Garcin B, Lenglet T, Dubourg O, et al. Dropped head syndrome as a presenting sign of scleromyositis. J Neurol Sci 2010; 292:101–103. 18. Rojana-Udomsart A, Fabian V, Hollingsworth PN, et al. Paraspinal and scapular myopathy associated with scleroderma. J Clin Neuromuscul Dis 2010; 11:213–222. 19. Follansbee WP, Zerbe TR, Medsger TA Jr. Cardiac and skeletal muscle disease in systemic sclerosis (scleroderma): a high risk association. Am Heart J 1993; 125:194–203. 20. Allanore Y, Meune C, Vonk MC, et al. Prevalence and factors associated with left ventricular dysfunction in the EULAR Scleroderma Trial and Research group (EUSTAR) database of patients with systemic sclerosis. Ann Rheum Dis 2010; 69:218–221. 21. Ranque B, Berezne A, Le-Guern V, et al. Myopathies related to systemic sclerosis: a case-control study of associated clinical and immunological features. Scand J Rheumatol 2010; 39:498–505. 22. Medsger TA, Rodnan GP, Moosy J, et al. Skeletal muscle involvement in progressive systemic sclerosis. Arthritis Rheum 1968; 11:554–568. 23. Thompson JM, Bluestone R, Bywaters GL, et al. Skeletal muscle involvement in systemic sclerosis. Ann Rheum Dis 1969; 28:281–287. 24. Ranque B, Authier F-J, Le-Guern V, et al. A descriptive and prognostic study of systemic sclerosis-associated myopathies. Ann Rheum Dis 2009; 68:1474– 1477.
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