Neuromuscular manifestations of systemic sclerosis (scleroderma)

INTRODUCTION — Muscle involvement in systemic sclerosis (SSc; scleroderma) was previously thought to be relatively uncommon. However, it is increasingly recognized as a major contributor to the morbidity and mortality of the disease. Other neurologic abnormalities that are less common in SSc include central, peripheral, and autonomic neuropathies.

This topic will provide an overview of the neuromuscular manifestations of SSc. The clinical manifestations, diagnosis, and overview of the management of SSc in adults are discussed separately. (See "Clinical manifestations and diagnosis of systemic sclerosis (scleroderma) in adults" and "Overview of the treatment and prognosis of systemic sclerosis (scleroderma) in adults".)

MYOPATHY

Terminology and epidemiology — There are no formal definitions or a universally accepted classification schema of systemic sclerosis (SSc; scleroderma)-associated myopathy. Descriptions of SSc-associated muscle involvement have ranged from muscle weakness and abnormal muscle enzymes to stricter definitions that include abnormal electromyography (EMG) or biopsy-based evidence of inflammation, necrosis, or fibrosis in skeletal muscle. There is also no consensus as to whether an inflammatory myopathy in patients with SSc should be considered a complication of the disease, or as a distinct SSc-myositis overlap [1,2]. In this topic, we will include patients identified as having SSc-myositis overlap within the broader category of SSc-associated myopathy. As discussed below, histologic patterns are used to identify different subsets of myopathy; these include dermatomyositis, polymyositis, fibrosing myopathy, immune-mediated necrotizing myopathy, and nonspecific myositis, as well as neurogenic causes of myopathy (figure 1). (See 'Muscle biopsy' below.)

Estimates for the prevalence of SSc-associated muscle involvement range from 5 to 96 percent, reflecting the lack of diagnostic consensus criteria [3-6]. Up to 42 percent of myositis patients with overlap connective tissue disease have been reported to have SSc [7,8]. Thus, in addition to clear cases of overlap myositis when patients meet classification criteria for both SSc and myositis, there are also other etiologies for myopathy and/or weakness in SSc such as disuse, malnutrition, or other neurologic diseases. Risk factors for SSc-associated myopathy include diffuse cutaneous SSc subtype, African American race, male sex, and shorter SSc disease duration [9,10]. Much of the progress to understand what myopathy is in SSc has relied on muscle histopathology. (See 'Muscle biopsy' below.)

Survival and outcomes such as disability as measured by the Health Assessment Questionnaire Disability Index (HAQ-DI) have also been reported to be poor in patients with SSc myopathy. However, due to the lack of consensus classification criteria as noted above, most such studies have included SSc patients with any evidence of muscle disease such as weakness or elevated creatine kinase (CK) [10,11].

Clinical features — SSc-associated myopathy is suspected in patients with SSc who present with symmetric proximal muscle weakness, with or without elevated muscle enzymes. Patients with severe myopathy can also present with dysphagia, which is also prominent in patients with SSc uncomplicated by myopathy, perhaps in relationship to autonomic neuropathy. Muscle enzyme abnormalities in the absence of muscle weakness should also raise concern for possible SSc-associated myopathy. Other clinical features of SSc are discussed separately. (See "Clinical manifestations and diagnosis of systemic sclerosis (scleroderma) in adults".)

There have also been reports of prominent neck and upper extremity weakness consistent with a brachio-cervical inflammatory myopathy. While brachio-cervical inflammatory myopathy has been reported in association with other diseases such as myasthenia gravis and rheumatoid arthritis, it has also been reported in those with SSc [12]. Of note, in one long-term follow-up study, patients treated with immunosuppression showed improvement in their upper extremity strength, but neck weakness was found to be particularly resistant to therapy [13].

Evaluation

Physical examination — The physical examination should include an assessment for muscle weakness. Patients with SSc-associated myopathy will typically have proximal muscle weakness only. The physical exam should include evaluation of both proximal (including neck) and distal muscles of arms and legs; symmetric proximal more than distal weakness is suggestive of myopathy. Different patterns of weakness suggest an alternative diagnosis. (See "Approach to the patient with muscle weakness".)

In patients with extensive dermal and articular changes, the clinician should assess whether contractures are contributing to apparent muscle weakness.

Laboratory testing — Laboratory testing for suspected myopathy should include serum levels of muscle enzymes, CK, and aldolase.

Serum CK and aldolase levels may be normal or only slightly elevated in SSc-associated myopathy despite an objective reduction in muscle strength. In the European Scleroderma Trials and Research group (EUSTAR) cohort, the frequency of elevated CK levels were discordant with the presence of muscle weakness; 4.4 percent of patients with limited cutaneous SSc had elevated CK levels while 36 percent had muscle weakness [14]. Similarly, 11.3 percent of patients with diffuse cutaneous SSc had elevated CK levels while 28 percent had muscle weakness.

In patients with overlap myositis with SSc, anti-PM-Scl, anti-U3-RNP, and anti-Ku antibodies are most prevalent. It is not known what percentage of patients with a known SSc-associated myopathy are positive for any one of these antibodies. However, data from general SSc cohorts found a prevalence of 3 to 6 percent for anti-PM-Scl antibodies, 3 percent for anti-U3-RNP antibodies, and 7 to 9 percent for anti-Ku antibodies [15]. Depending on the laboratory or institution, these tests may be ordered in SSc patients with a myopathy either individually or as a myositis panel.

The presence of specific autoantibodies in patients with SSc-associated muscle disease permits identification of the clinical phenotype. The presence of some of these autoantibodies can sometimes allow for enhanced screening of particular disease manifestations such as interstitial lung disease or gastrointestinal dysmotility.

●Anti-PM-Scl 75/100 – Patients with SSc who are anti-PM-Scl positive are more likely to have limited cutaneous involvement with overlap polymyositis or dermatomyositis [16]. These patients are also reported to have better prognosis in terms of interstitial lung disease and mortality when compared with those who are negative for anti-PM-Scl antibodies [16,17]. In at least one case series, arm abductor weakness was more severe than hip flexor weakness in patients with anti-PM-Scl positivity in contrast to patients without these autoantibodies [18]. (See "Clinical manifestations of dermatomyositis and polymyositis in adults", section on 'Laboratory findings'.)

●Anti-U3-RNP – SSc patients who are positive for U3-RNP (fibrillarin) antibodies tend to be African American and have diffuse skin disease with muscle involvement and gastrointestinal dysmotility [19]. In one case series, muscle biopsies of these patients were reported to have minimal inflammation [19]. This is consistent with another report that patients with a fibrosing myopathy tended to be positive for anti-U3-RNP [20]. These patients are also reported to develop severe, fatal isolated pulmonary arterial hypertension [21]. (See "Clinical manifestations, evaluation, and diagnosis of interstitial lung disease in systemic sclerosis (scleroderma)".)

●Anti-Ku – Patients with SSc who are anti-Ku positive are more likely to have an inflammatory myopathy in overlap with SSc or other autoimmune diseases such as systemic lupus erythematosus (SLE) or Sjögren's syndrome (SS). Muscle biopsies most commonly show necrosis and inflammation [22]. Interstitial lung disease is also more common in patients with an inflammatory myopathy [23]. (See "Clinical manifestations of dermatomyositis and polymyositis in adults", section on 'Laboratory findings'.)

●Other autoantibodies – Other autoantibodies selective for SSc-associated muscle involvement, including anti-SMN and anti-RuvBL1, have been described, but their availability and clinical utility remain to be established [24,25].

Electromyography and nerve conduction study — EMG and nerve conduction studies should be performed in patients with SSc and suspected myopathy. Nerve conduction studies should be normal, with EMG changes of early recruitment and small-amplitude and short-duration motor unit potentials supporting a diagnosis of myopathy. Evidence of increased membrane irritability (ie, increased insertional activity, fibrillations, positive sharp waves) on EMG suggests an inflammatory myopathy [6,26]. EMG can also be helpful to identify the optimal (ie, most affected) muscle group for biopsy.

Magnetic resonance imaging — Magnetic resonance imaging (MRI) of the weak muscle group is often used in conjunction with EMG to help diagnose the etiology of muscle weakness in a patient with SSc. MRI can also be used to identify the area of most intense muscle edema for biopsy. (See "Diagnosis and differential diagnosis of dermatomyositis and polymyositis in adults", section on 'Skeletal muscle imaging'.)

The most commonly reported finding on MRI in patients with SSc-associated myopathy is muscle edema [6,26]. Intramuscular edema and fascial edema have been reported to be more common in those with an SSc-associated myopathy, especially in those patients who have fewer inflammatory changes on muscle biopsy [27]. Advanced, quantitative imaging techniques such as T2 mapping have also been reported to be helpful in detecting muscle disease in SSc [28].

Muscle biopsy — A muscle biopsy is typically not required to make the diagnosis of myopathy. It may be helpful if the clinical picture is unclear or to help guide therapy. (See "Approach to the patient with muscle weakness" and 'Management' below.)

In addition to being helpful diagnostically, the histopathologic features can also have management and prognostic implications (figure 1). Muscle biopsy is typically performed by a surgeon or a neuromuscular disease specialist. If the overlying skin is very thickened and healing is thought to be poor, the risks and benefits of the biopsy should be carefully weighed. The selection of muscle to biopsy and other aspects of technique are discussed separately. (See "Diagnosis and differential diagnosis of dermatomyositis and polymyositis in adults", section on 'Muscle biopsy'.)

Muscle histopathology in SSc-associated muscle disease is heterogeneous [5,6,26,29,30]. In one study of 35 patients with SSc-associated myopathy, 63 percent of biopsies displayed inflammation, atrophy, and necrosis, while 24 percent demonstrated endomysial and perimysial fibrosis [6]. In another series of 42 patients with SSc and muscle weakness, the major histopathologic categories included nonspecific myositis (36 percent), necrotizing myopathy (21 percent), dermatomyositis (7 percent), acute denervation (7 percent), fibrosis only (7 percent), and polymyositis (5 percent) [26]. In this study, the presence of fibrosis on biopsy was strongly associated with anti-PM-Scl antibodies. Also, nearly half of the 42 patients had histologic evidence of acute motor denervation (acute neurogenic atrophy), which had not been previously reported. In contrast to these two studies, another prospective study of 35 patients with SSc-associated myopathy found that muscle fibrosis, in particular, multifocal endomysial fibrosis without necrosis or regeneration, along with microangiopathy was the predominant histologic finding in more than 80 percent of patients [31].

Our observations suggest that fibrosing myopathy, the subset of patients with fibrosis predominance, may be a distinct subset in SSc-associated myopathy, which appears to be associated with a worse prognosis. In a study of 37 weak SSc patients, eight patients had fibrosing myopathy and 29 had inflammatory myopathy on biopsy. Compared with patients with inflammatory myopathy on biopsy, patients with fibrosing myopathy were more likely to have the diffuse cutaneous SSc subtype, lower mean CK levels, more prevalent nonirritable myopathy on EMG, and higher mortality (usually cardiac related) when compared with patients with an inflammatory myopathy [20].

On electron microscopy, a specific morphologic pattern termed minimal myositis with capillary pathology may be characteristic of patients with SSc-associated myopathy [32]. In a study including 18 patients with SSc and muscle weakness who had muscle biopsies, 12 of 18 (67 percent) biopsies had this finding on large-scale electron microscopy that demonstrated characteristic capillary morphology with basement membrane thickening and reduplications, endothelial activation, and pericyte proliferation.

Diagnosis and differential diagnosis — There are no formal diagnostic criteria for SSc-associated myopathy. A presumptive diagnosis is made in a patient with SSc who has proximal muscle weakness along with objective evidence of myopathy on EMG, MRI, or (ideally) muscle biopsy. While disuse, joint contractures, and malnutrition can cause muscle weakness, in these cases the aforementioned studies typically will not show significant muscle involvement. The differential diagnosis of myopathy in SSc should also include workup for thyroid disease.

As noted, findings on the muscle biopsy allow identification of patients with features that suggest inflammation (dermatomyositis, polymyositis, nonspecific inflammation) versus those with predominant fibrosis (see 'Muscle biopsy' above). These features may help direct appropriate therapy.

Management — The management of SSc-associated myopathy will largely depend on the presence of inflammation as evidenced by muscle MRI or, ideally, muscle biopsy. If there is a significant burden of muscle inflammation or necrosis on muscle biopsy, the first step in management is typically immunosuppression. It is less clear whether patients with fibrosing myopathy on muscle biopsy will respond to immunosuppressive therapy. Regardless of the etiology of the muscle weakness, all patients with SSc and muscle involvement should be involved in physical exercise.

●Immunosuppression – Due to the limited data regarding the management of SSc-associated myopathy, the approach to therapy is largely based on clinical experience, observational data, and extrapolation from trials of immunosuppressive agents used in patients with dermatomyositis and polymyositis. For patients with SSc-associated myopathy and histologic evidence of inflammation or necrosis on muscle biopsy, we suggest initiating treatment with a glucocorticoid-sparing agent alone. The authors prefer mycophenolate because it is also used to treat SSc-associated interstitial lung disease; however, the specific choice of treatment is made in the context of the patient's other disease manifestations. If the response is inadequate, low-dose glucocorticoids (typically less than 10 to 20 mg daily of prednisone or equivalent) can be used in combination. Some SSc patients are at high risk for developing scleroderma renal crisis, and glucocorticoids are recognized as a risk factor. Accordingly, only cautious use of low-dose glucocorticoids is advised in patients with SSc, and treated patients should be closely monitored for new onset of hypertension. (See "Treatment and prognosis of interstitial lung disease in systemic sclerosis (scleroderma)", section on 'Mycophenolate mofetil' and "Overview of the treatment and prognosis of systemic sclerosis (scleroderma) in adults".)

Intravenous immune globulin (IVIG) is a reasonable alternative therapy for patients who do not respond to mycophenolate. A retrospective study of 52 patients with SSc-associated myopathy revealed that in those who received IVIG, there was a greater decrease of glucocorticoids at three months, and lower glucocorticoid dose at one year after treatment [33].

Limited data suggest that histologic muscle inflammation and necrosis is associated with a more favorable outcome and a better response to glucocorticoids [6]. The appropriate treatment of fibrosing myopathy in SSc is uncertain [20]. In our experience, early treatment with mycophenolate mofetil and intravenous immune globulin may lead to clinical improvement in some patients.

●Exercise – All patients with SSc and muscle involvement should be involved in physical exercise. This recommendation is based upon studies that have demonstrated that exercise improves function and strength in combination with medical treatment in patients with an idiopathic inflammatory myopathy. There are multiple studies demonstrating the safety of exercise even in recent-onset polymyositis/dermatomyositis [34-37]. (See "Initial treatment of dermatomyositis and polymyositis in adults", section on 'Exercise'.)

Given that concomitant sarcopenia is also prevalent in up to 22.5 percent of SSc patients and is associated with functional disability [38], a modified exercise program or physical therapy is advised for patients in conjunction with the medical treatment of SSc-associated myopathy. An eight-week exercise study in patients with SSc showed benefit in muscle endurance and aerobic capacity [37].

NEUROPATHY

Poly- and mononeuropathies — Neuropathy is a rare (1 to 6 percent) complication of systemic sclerosis (SSc; scleroderma) [39,40]. Peripheral neuropathy is much less common than myopathy in SSc. In one electrodiagnostic study of neuropathy in SSc, 60 patients were assessed for a length-dependent peripheral neuropathy; while 28 percent had evidence of a peripheral neuropathy, a potential etiology other than SSc, such as diabetes, was found in 82 percent [41].

A variety of neuropathy syndromes have been reported in patients with SSc, including [39,42-45]:

●Trigeminal sensory neuropathy

●Sensorimotor peripheral neuropathy

●Carpal tunnel syndrome

●Multiple mononeuropathy (also called mononeuritis multiplex)

●Lumbosacral radiculopathy

●Small-fiber neuropathy

Patients who report neuropathic symptoms such as burning, tingling, or numbness should undergo a thorough neurologic examination, which may include neurodiagnostic studies as well as an evaluation for a cause other than SSc. Symptoms should be clearly distinguished from Raynaud phenomenon (RP) since similar symptoms can be induced on exposure to cold or stress in SSc patients with RP. The evaluation and treatment of patients with polyneuropathy is discussed in detail separately. (See "Overview of polyneuropathy".)

Autonomic neuropathy — Autonomic nervous systemic dysfunction has been observed in SSc and is thought to play a role in altered vascular tone, esophageal contractility, gastrointestinal motility [46-49], and cardiac rhythm abnormalities [50,51] (see "Gastrointestinal manifestations of systemic sclerosis (scleroderma)"). Autonomic dysfunction also possibly contributes to impotence, which occurs frequently in SSc patients [52-55].

Laboratory evidence of sympathetic and parasympathetic dysfunction of cardiovascular reflexes is relatively common; however, this is rarely clinically significant [52,56-59]. In addition, an abnormal or absent sympathetic skin response has been demonstrated [60,61].

SUMMARY AND RECOMMENDATIONS

●Myopathy

•Terminology – There are no formal definitions or a universally accepted classification schema of SSc-associated myopathy. Descriptions of SSc-associated muscle involvement have ranged from muscle weakness and abnormal muscle enzymes to stricter definitions that include abnormal electromyography (EMG) or biopsy-based evidence of inflammation, necrosis, or fibrosis in skeletal muscle. (See 'Terminology and epidemiology' above.)

•Epidemiology – Myopathy in systemic sclerosis (SSc; scleroderma) is increasingly recognized as a major contributor to the morbidity and mortality of the disease. Other neurologic abnormalities in SSc that are less common include central, peripheral, and autonomic neuropathies. (See 'Introduction' above.)

•Evaluation – SSc-associated myopathy is suspected in patients with SSc who present with symmetric proximal muscle weakness, with or without elevated muscle enzymes. In cases of suspected overlap myositis with SSc, the most prevalent autoantibodies include anti-PM-Scl, anti-U3-RNP, and anti-Ku antibodies. (See 'Physical examination' above and 'Clinical features' above and 'Laboratory testing' above.)

EMG and nerve conduction studies should be performed in patients with SSc and suspected myopathy. MRI of the weak muscle group is often used in conjunction with EMG to support the diagnosis and identify the area of most intense muscle edema for biopsy. (See 'Electromyography and nerve conduction study' above and 'Magnetic resonance imaging' above and 'Muscle biopsy' above.)

•Diagnosis – A presumptive diagnosis of SSc-associated myopathy is made in a patient with SSc who has proximal muscle weakness along objective evidence of myopathy on EMG, MRI, or (ideally) muscle biopsy. Histologic patterns are used to identify different subsets of myopathy, which may also have management and prognostic implications. These patterns include dermatomyositis, polymyositis, fibrosing myopathy, immune-mediated necrotizing myopathy, and nonspecific myositis, as well as neurogenic causes of myopathy (figure 1). (See 'Diagnosis and differential diagnosis' above.)

•Management – The management of SSc-associated myopathy will largely depend on the presence of inflammation as evidenced by muscle MRI or muscle biopsy. For patients with SSc-associated myopathy and histologic evidence of inflammation or necrosis on muscle biopsy, we suggest initiating treatment with a glucocorticoid-sparing agent alone (Grade 2C). The authors prefer mycophenolate because it is also used to treat SSc-associated interstitial lung disease; however, the specific choice of treatment is made in the context of the patient's other disease manifestations. If response is inadequate, low-dose glucocorticoids (typically less than 10 to 20 mg daily of prednisone or equivalent) can be used in combination. SSc patients are at high risk for developing scleroderma renal crisis, and glucocorticoids are recognized as a risk factor. Accordingly, only cautious use of low-dose glucocorticoids is advised in patients with SSc, and treated patients should be closely monitored for new onset of hypertension. (See 'Management' above.)

Regardless of the etiology of the muscle weakness, all patients with SSc and muscle involvement should be involved in physical exercise. (See 'Management' above.)

●Neuropathy

•Poly- and mononeuropathies – Peripheral neuropathy is much less common than myopathy in SSc. A variety of neuropathy syndromes have been reported in patients with SSc, including trigeminal sensory neuropathy, sensorimotor peripheral neuropathy, carpal tunnel syndrome, multiple mononeuropathy (also called mononeuritis multiplex), lumbosacral radiculopathy, and small-fiber neuropathy. (See 'Poly- and mononeuropathies' above.)

•Autonomic neuropathy – Autonomic nervous system dysfunction has been observed in SSc and is thought to play a role in altered vascular tone, esophageal contractility, gastrointestinal motility, and cardiac rhythm abnormalities. (See 'Autonomic neuropathy' above.)

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Peter H Schur, MD, and Monica L Piecyk, MD, who contributed to an earlier version of this topic review.