Document Type : Review
1 Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Iran
2 Assistant Professor of Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Iran
Systemic sclerosis (SSc) is an autoimmune disorder which can affect nearly every body organ. Muscle involvement is one of the most serious manifestations of SSc. It can present itself in a wide range of pathologies. It can be as indolent as a subclinical myopathy which manifests simply as a mild muscle enzyme level elevation, or it can present itself in a similar manner to other SSc organ involvements in the form of fibrosing myopathy without any existing evidence of inflammation. It can also present itself aggressively as an idiopathic inflammatory myopathy, the overlap syndrome of SSc-myositis. Due to the wide range of witnessed pathologies and the different diagnostic criteria that are used, opinions vary on the estimated prevalence of myopathy in SSc with estimates ranging from 3.3% to 14%. The severity and distribution of clinical manifestations differ among SSc-myopathy and SSc patients. These manifestations have different effects on the survival rates of patients, which will be discussed in this review. This paper will also focus on the existing treatment methods for SSc patients suffering from myopathy and their challenges.
Systemic sclerosis (SSc) is a member of the family of disorders known collectively as collagen-vascular disorders. Diseases in this category are sometimes accompanied by various auto-immune disorders. Myopathies are disorders that are sometimes associated with SSc . The presentation of these disorders differs greatly in patients, with some suffering from idiopathic inflammatory myopathies (IIM), such as polymyositis (PM), and others showing signs of non-inflammatory myopathies (NIM) which share a common pathogenesis with SSc itself, such as fibrosing myopathy (FM). Comparing the severity of extra-muscular manifestations and their prevalence among SSc patients with those who have a concurrent myopathy is a top area of research in the field. A subsequent challenge that arises relates to the treatment of these patients. While high-dose corticosteroids are the main treatment method for patients with IIM, renal crisis development is observed in SSc patients on whom this same treatment is applied, creating a challenge for rheumatologists. The impact of myopathies on the survival rate of SSc patients is a highly debated issue, but it seems that it may play a role in reducing life expectancy. To date, many articles have been published in this field since the first documented case of SSc-IIM in 1969. The current study has tried to review the most recent research carried out in this area . This article reviews the epidemiology, clinical manifestation, diagnosis, therapy, and survival rate of SSc patients with concurrent muscle involvement.
Due to the differing criteria used to diagnose IIM and the varying sizes of the cohorts involved, heterogeneity is seen in reports regarding the prevalence of SSc-myopathy. Based on a study performed on the Nijmegen Systemic Sclerosis cohort with a total of 422 patients, the prevalence of SSc-PM overlap was 5.9%. All of these patients fulfilled the Bohan and Peter diagnostic criteria for IIM . In another study performed on 302 Japanese patients, the prevalence was estimated to be 14% with a total of 43 cases of SSc-IIM . Patients with proximal muscle weakness in addition to abnormal results in at least one of either enzyme levels, electromyogram (EMG), or muscle biopsies were considered to have IIM. The South Australian SSc registry, which made use of similar criteria, reported 20 patients with myositis from among 374 living and 234 deceased patients (a total of 608 cases), showing an estimated prevalence of 3.3% . The Canadian Scleroderma Research Group reported a prevalence of 5.6% of patients with creatine kinase (CK) elevation (>200 μ/L for women and >250 μ/L for men) from among 1145 patients . They also mentioned a prevalence of nearly 10% for myopathies including IIM based on physicians’ reports.
Diagnosis and Muscle histopathology______
The histopathologic difference between concurrent SSc-IIM and isolated IIM cases is a field of great interest. Based on the Nijmegen Systemic Sclerosis cohort, the prevalence of necrotic muscle fibers is the sole difference between these groups, being present in 96% of SSc-PM and 67% of PM patients . The major histopathologic characteristics observed in the muscle biopsies of 35 patients from a multicentric French study showed varying results as opposed to those obtained from the previous study . Inflammation was the most common finding, observed in 63% of patients, followed by atrophy and necrosis which were present in 60% and 59% of patients, respectively. Fibrosis was present in 24% of the samples, and angiopathy was detected in 27%. Small vessel vasculitis was seen in 3 cases (9%), and one case (3%) was reported to have mitochondrial abnormality. In a recently published investigation, Paik et al. analyzed 42 muscle biopsies obtained from SSc patients showing signs of weakness . Similar to the aforementioned study, necrosis was the most prevalent finding, seen in 66.7% of cases, followed by inflammation and acute neurogenic atrophy which were both observed in nearly half of the obtained samples. Fibrosis was detected in one third of the obtained biopsies. Overall, non-specific myositis and necrotizing myositis were diagnosed in 15 and 9 patients, respectively. Surprisingly, magnetic resonance imaging (MRI) results, EMG, and serum CK levels were normal in 30%, 10%, and 26% of patients, respectively, even though these patients showed signs of proximal muscle weakness. In their investigation, Corallo et al. compared the histopathologic features of SSc myopathy, IIM, and NIM to elucidate a possible pathognomonic histologic characteristic of SSc myopathy . They obtained muscle biopsies from 35 patients with clinical, biologic, and EMG findings suggestive of myopathy. They reported that fibrosis was significantly higher in SSc cases (81%) compared to patients with IIM (32%) and NIM (18%). Surprisingly, the pro-angiogenic factor (vascular endothelial growth factor A (VEGF-A)) was significantly downregulated in SSc cases as opposed to the anti-angiogenic factor VEGF-A165b which was significantly upregulated. Transmission electron microscopy showed endothelial cell swelling, significant collagen deposition, and thickened sub-endothelial basement membranes in the muscle biopsies of SSc patients. These findings propose that the physiopathology underlying vasculopathies in SSc (e.g., Raynaud’s phenomenon (RP)) may also provoke muscle involvement.
Clinical manifestation and Serologic features
Several studies have compared the clinical manifestations and serologic features of SSc-IIM patients with those of SSc and IIM patients. According to the Nijmegen Systemic Sclerosis cohort, SSc-PM patients had a male to female ratio of 1:1 compared to the 2:1 ratio seen in SSc cases . Lung fibrosis was more prevalent in patients with SSc-IIM (83%) compared with those patients with either SSc or PM (49% and 53%, respectively). Pulmonary arterial hypertension confirmed by right heart catheterization was significantly lower in overlap cases compared to SSc patients (0% vs. 31%). Levels of anti-topoisomerase 1 antibody were not detected in SSc-IIM patients, and levels of anti-Jo antibody were significantly lower in this group compared with PM patients (8% vs. 42%). Another finding was that 12% of SSc patients showed elevated serum CK levels, and 5% had proximal muscle weakness but failed to fulfill the Bohan and Peter diagnostic criteria. In a French multicentric study conducted on 40 SSc-IIM cases, the findings were compared with those of 80 SSc cases matched for sex, age at onset, disease duration, and subtype . Based on multivariate analysis results, reduced forced vital capacity (FVC) and heart involvement (including congestive heart failure, left ventricular ejection fraction (LVEF) <60%, arrhythmia, and conduction abnormality) had significant correlations with myopathy, and the presence of the anti-centromere antibody was negatively associated. Interestingly, among SSc-IIM patients, individuals without histologic evidence of inflammation did not have a significantly reduced FVC compared to the control group. In a Japanese study that compared 259 SSc and 43 SSc-IIM cases, it was reported that the male to female ratio, being a member of the diffuse subset, pulmonary fibrosis (diagnosed by chest x-ray (CXR) or high resolution computed tomography (HRCT)), heart involvement (including symptomatic pericarditis/left ventricular heart failure and treatment-requiring arrhythmia), and skin hyperpigmentation were significantly higher in patients with IIM . In addition, the presence of anti-centromere antibodies and mean age were significantly lower in this group. Remarkably, the erythrocyte sedimentation rate (ESR) and serum C-reactive protein (CRP) levels were similar in both groups. The association of myocardial involvement and skeletal muscle involvement in SSc patients can be screened and differentiated using cardiac troponin tests . Cardiac troponin T is also expressed in regenerative skeletal muscles, which is highly evident in IIM. Testing for troponin T is more sensitive than measuring CK levels, but cardiac troponin I is specific to myocardial cells. Therefore, skeletal muscle involvement can be differentiated from myocardial involvement, and subclinical myocarditis can be detected using these tests. A Canadian cohort of SSc with 1145 patients compared the clinical and serologic data of patients with normal and abnormal serum CK levels . Findings, compatible with those of previous studies, showed that the male to female ratio, diffuse cutaneous SSc (dcSSc), tendon friction rub, and FVC<70% were more prevalent in cases with abnormal serum CK levels. In addition, the mean age and disease duration were lower in this group. Among the various serologic markers, anti-topoisomerase and anti-ribonucleoprotein antibodies were also more prevalent in these cases. In another study carried out on 306 members of the aforementioned cohort, 4 patients produced autoantibodies against the hydroxymethylglutaryl coenzyme A reductase (HMGCR) antibody . Although this event did not occur often enough to be of use in statistical analyses, none of the reported cases had a history or evidence of myopathy, nor did they report current or past use of statins. Anti-HMGCR antibody was significantly associated with a higher percentage of pulmonary arterial hypertension and a higher cardiac severity score. Also, SSc-related nailfold capillaroscopic changes were significantly more common among patients with genetic myopathies (without RP) compared to primary RP cases .
Treating patients with SSc-IIM overlap is tremendously challenging for rheumatologists because of the beneficial effects of corticosteroids in IIM patients and their dangerous effects on SSc patients. To date, no unified accepted protocol for IIM treatment in SSc patients has been developed, and due to the rarity of these patients, there is limited data on this matter. A French multicentric study on 35 SSc-IIM patients reported a correlation between the severity of histopathologic findings and treatment outcome . According to multivariate analyses, findings suggestive of inflammation and necrosis in muscle biopsy samples were associated with a better response to treatment. In addition, abnormal MRI results also appeared to be related to a better prognosis. High doses of corticosteroids (1 mg/kg per day) were prescribed for the majority of cases, and multivariate and univariate analyses were carried out. Multivariate analysis showed that histologic inflammation was correlated with a better response to treatment, while muscle necrosis and elevated CK levels (>5 upper normal limit) showed the same association in univariate analysis. Two patients (6%) experienced renal crises after corticosteroid treatment. Allanore et al. conducted a study to elucidate the effects of high-dose corticosteroids and immunosuppressive medications for IIM in 4 naïve-to-treatment cases of SSc with myocarditis that had been confirmed by cardiac magnetic resonance (CMR) . Based on this study, all of the cases had early and delayed enhancement due to myocarditis and wall hypokinesia before treatment. Each received 1 g methylprednisolone for 3 days followed by 1 mg/kg prednisone in addition to an immunosuppressive drug (3 cases were treated with cyclophosphamide and 1 with azathioprine). After 6 months of treatment, the hypokinesia disappeared and the area of enhancement was successfully reduced. A recently published study on the EULAR scleroderma trial and research (EUSTAR) network of SSc patients evaluated the clinical outcome of abatacept on SSc cases with refractory myopathy compared to conventional disease-modifying antirheumatic drugs (DMARDs) and cyclophosphamide . In that study, 10 mg/kg/month of abatacept was administered for a mean duration of 18 months in 7 patients with SSc-related refractory myopathy. The treatment was not effective in increasing muscle force or reducing serum CK levels, and it had no visible effect on FVC or modified Rodnan skin scores (mRSSs). No clinical trials have been conducted on the efficacy of Rituximab (RTX) in treating SSc-IIM, although a case report showed the beneficial effect of RTX on SSc-related resistant IIM. However, this was accompanied by late onset neutropenia (without serious infection), which gradually resolved .
Apart from the muscular involvement of IIM, this disorder can also severely affect various internal organs, and therefore influence patient survival. With the aim of better diagnosing and treating patients, the survival rate and mortality causes of patients suffering from SSc-IIM overlap were assessed. There is much difference of opinion regarding the mortality rate of these patients and its causes, and therefore, the results of different studies will be referred to individually. According to the Nijmegen Systemic Sclerosis cohort, the mortality rate of SSc-PM patients was significantly higher than that of SSc patients . In this cohort, 24 SSc-PM and 396 SSc cases were followed for 10 years. The 10-year survival rates were 68% for SSc-PM cases and 87% for SSc cases. Multivariate survival analysis gave a hazard ratio of 2.34 for SSc-PM compared to SSc after adjusting for sex, age at diagnosis, mRSS, and SSc cutaneous subtype. Causes of mortality were not statistically compared; however, in both groups, cardiopulmonary involvement was the major culprit. In a French multicentric case-control study, the survival rate of SSc-IIM patients was similar to that of SSc cases: 7.5% and 16.3%, respectively, during a similar time span . In a Canadian SSc cohort of SSc with 1145 cases, individuals with abnormal serum CK levels and patients with a prior history of myopathy (including IIM) had significantly lower survival rates compared with other SSc patients . The major causes of death were reported to be interstitial lung disease, pulmonary hypertension, and cardiac involvement. In an abstract recently presented at the 2016 ACR/ARHP annual meeting, Paik et al. compared the survival rate and clinical features of 28 SSc patients with IIM and 8 patients with FM that had been histopathologically confirmed . Individuals with FM had a significantly higher death rate compared to patients with IIM (62.5% versus 14.3%). Patients with SSc-FM also had lower serum CK levels, higher anti-topoisomerase antibody levels, shorter disease duration, a lower FVC, and more cases in the diffuse cutaneous subtype. However, none of these differences were statistically significant.
Conclusion and Recommendation________
Muscle involvement occurs mainly in two general forms among SSc patients: inflammatory and fibrosing myopathy. Histopathology can be used as a tool to differentiate between these two diagnoses. Early treatment of inflammatory myositis with high doses of corticosteroids is highly recommended, despite the risk of renal crises occurring in scleroderma patients. Treating fibrosing myopathy, which occurs in more severe cases of the disease, in which patients present with mild muscle enzyme elevation is adjusted according to the severity of involvement of other organs. Immunosuppressive treatment with cytotoxic drugs without the use of high-dose corticosteroids may, therefore, be a better option in these cases. In conclusion, the early diagnosis of skeletal muscle involvement by serum muscle enzymes level and histopathology is recommended to better distinguish inflammatory myopathies from non-inflammatory types. It is also recommended to start cytotoxic treatment early.
Conflicts of interest
The authors declare no conflicts of interest.