INTRODUCTION — Sarcoidosis, a multisystem disorder of unknown etiology, commonly presents clinically with bilateral hilar adenopathy, pulmonary infiltrates, skin and/or eye lesions, or a combination of these features. Musculoskeletal and neuromuscular manifestations occur less commonly. Sarcoidosis is characterized pathologically by the presence of noncaseating granulomas in affected organs. It typically affects young adults, and any organ may be affected.
Although musculoskeletal disease, which is estimated to clinically affect 4 to 38 percent of patients, is less common than the characteristic pulmonary features, involvement of muscle, bone, joints, and other organs and tissues may also occur and be clinically significant [1,2].
Sarcoid involvement of the muscle will be reviewed here. Sarcoid arthropathy and bone disease, other extrapulmonary manifestations of sarcoidosis, pulmonary sarcoidosis, and general issues related to sarcoidosis and its pathogenesis are discussed separately. (See "Sarcoid arthropathy" and "Sarcoidosis of bone" and "Extrapulmonary manifestations of sarcoidosis" and "Clinical manifestations and diagnosis of pulmonary sarcoidosis" and "Pathology and pathogenesis of sarcoidosis".)
PATHOGENESIS — Sarcoidosis is a multisystem disorder of unknown etiology, which is characterized by the accumulation of T lymphocytes, mononuclear phagocytes, and noncaseating granulomas in involved tissues. The pathogenesis of sarcoid myopathy is unclear, but the histopathologic findings of sarcoidosis in the muscles are the same as in other tissues, and the granulomatous inflammation in muscle appears to lead to the muscle fibrosis and tissue injury. The pathology and pathogenesis of sarcoidosis are discussed in detail separately. (See "Pathology and pathogenesis of sarcoidosis".)
The steps involved in the formation of sarcoid granulomas involve a complex interplay of immune cells and their mediators. Classic sarcoid granulomas are non-necrotizing with a tightly packed central area composed of macrophages, epithelioid cells, multinucleated giant cells, and T lymphocytes that are predominantly CD4-positive. This central area is surrounded by a mixture of CD8- and CD4-positive T lymphocytes, B lymphocytes, monocytes, mast cells, and fibroblasts, which in turn are surrounded by lamellar rings of hyaline collagen. The etiology is unknown, and genetic factors may play a role. (See "Pathology and pathogenesis of sarcoidosis".)
EPIDEMIOLOGY — Skeletal muscle involvement is estimated to occur subclinically in as many as 50 to 80 percent of individuals with sarcoidosis but is very infrequently (0.5 to 2.5 percent) symptomatic [3-5]. Noncaseating granulomas can be detected in many patients with sarcoidosis who lack clinical muscle involvement.
Patients rarely present initially with myopathy, and features of other organ involvement are usually present when sarcoid myopathy is diagnosed [5,6]. Muscle disease is more common in women; acute myopathy is seen more in younger patients (<40 years), while chronic myopathy is found more in older patients (ages 50 to 70).
Granulomatous myositis on muscle biopsy was quite rare in a series including all patients at one institution who had undergone skeletal muscle biopsy for any indication over a 12-year period [7]. In a review of the microscopic sections, only 12 of the 2985 skeletal muscle biopsy specimens demonstrated granulomatous inflammation. In men, granulomatous inflammation was most often idiopathic, while in women, sarcoidosis was more likely [7,8].
CLINICAL MANIFESTATIONS
Clinical and laboratory features — Sarcoid myopathy is usually asymptomatic, proximal, and insidious. In patients with symptoms, which are more typical of acute disease, the muscle disorder is often associated with fever, myalgia, polyarthralgia, and findings of erythema nodosum. Diaphragmatic, distal, and other muscle involvement has also been observed.
Three clinical patterns of symptomatic myopathy have been described; these include a chronic myopathy, acute myositis, and nodular myopathy [5,9]:
●Chronic myopathy – The most common form of sarcoid myopathy is the insidious onset of progressive symmetric proximal muscle weakness with normal or mildly elevated serum levels of muscle enzymes. This myopathy responds poorly to glucocorticoids and is similar in presentation to the proximal myopathy that can be induced by glucocorticoid therapy (see "Glucocorticoid-induced myopathy"). The chronic myopathy can lead to early muscle atrophy, contractures, and pseudohypertrophy; thus, it can mimic chronic polymyositis or muscular dystrophy. Dysphagia can be seen as well.
●Acute myositis – An acute myositis is typically seen in younger patients (<40 years) and is more common in women. It is characterized by diffuse muscle swelling and pain in proximal (more than distal) muscles bilaterally that may progress to muscle contracture, hardening, and hypertrophy. It is associated with elevated muscle enzymes and muscle weakness. Fatigue, fever, joint symptoms, and erythema nodosum are common in these patients. This presentation typically mimics acute polymyositis, given that both may present with muscle weakness, myalgia, and fever.
●Nodular myopathy – The least frequent pattern is nodular myopathy, which can present with single or multiple, bilateral, tender nodules; these may occur in any muscle, but lower limbs are more commonly affected. Nodules are of various sizes, are usually palpable and painful, and are not associated with muscle weakness or limitation of movement. Occasionally, contracture and myalgia may be seen. Muscle enzymes, such as creatine kinase (CK), are normal. Occasionally, larger lesions can resemble a tumor [4,10].
Symptoms may also result from muscle disease involving the diaphragm, extraocular muscles, and other muscle groups, in addition to the more typical pattern of proximal muscle involvement [3,11-15]. Respiratory failure may be an early sign of sarcoid myopathy. Respiratory insufficiency and failure may be caused by weakness of the intercostal muscles, diaphragm, and pharyngeal muscles [16]. A literature review of patients with sarcoid myopathy revealed a pattern of muscle weakness that was proximal, combined proximal and distal, and distal in 62, 23, and 15 percent, respectively. Myalgia was reported in 56 percent and muscle enzyme elevation in only 38 percent of patients [17].
Sarcoidosis can also affect the heart. Up to 25 percent of cases of cardiac sarcoid (CS) are isolated, occurring without extracardiac involvement. The clinical presentation of CS ranges from an incidentally discovered condition to syncope, heart failure, and sudden death (see "Clinical manifestations and diagnosis of cardiac sarcoidosis"). There is no evidence for a higher association of cardiac and skeletal muscle involvement beyond the general association of cardiac involvement with other extrapulmonary manifestations (including musculoskeletal disease).
Several patients with distal muscle involvement and granulomatous myositis suggestive of sarcoid have been reported with disease that clinically mimics inclusion body myositis (IBM) or sarcoid neuropathies [18].
In one series of 11 patients with sarcoidosis with chronically progressive, generalized myopathy (confirmed with muscle biopsy) and diffuse involvement of all four extremities and trunk, only two patients had muscular pain and only six had elevated serum CK levels [6]. Muscle atrophy was a prominent finding, observed in 9 of the 11 patients, mostly in the lower extremities. The hip abductors, knee flexors, and ankle plantar flexors were most commonly involved on computed tomography (CT). The various imaging modalities (gallium scanning, magnetic resonance imaging [MRI], positron emission tomography [PET]) showed evidence of inflammatory muscle disease in only one-half of the patients.
Imaging — Imaging studies may help to identify and distinguish between the different types of myopathy. MRI is the most sensitive imaging technique but is normal in some patients with mild or acute disease [19]. PET scanning is also a sensitive technique; gallium scanning and CT can also be abnormal in patients with muscle involvement.
●MRI – In acute and chronic myositis, MRI studies show diffuse increased signal intensity on T2-weighted images, although imaging may be normal in patients with mild disease and in acute cases. Some cases may reveal a "tiger man" pattern of muscle edema [17]. In chronic myopathy, MRI can detect atrophy at early stages.
Nodular myopathy produces a characteristic pattern on MRI: a star-shaped area of low signal intensity centered (a central "dark star") within the nodule, which is surrounded by areas of high intensity on T1-weighted images with contrast and on T2-weighted axial images [20-22]. Notably, even after glucocorticoid therapy, the central hypointense area persisted in a patient in whom follow-up imaging was reported [23].
MRI is more sensitive than other imaging methods, as findings suggesting myopathy can be detected in patients lacking abnormalities using other techniques, including gallium scanning and CT [19].
●PET scanning – 18F-fluorodeoxyglucose PET (FDG-PET) scans can identify active sarcoid; findings include a patchy pick-up in the skeletal muscle [24], which is referred to as the "tiger man" sign, similar to the "leopard man" sign described on gallium-67 scintigraphy [25]. PET scans have also been used to identify asymptomatic sarcoid skeletal muscle disease [26,27]. Additionally, they have been used to assess treatment response. Disease activity as per maximum standardized uptake value, however, does not correlate with serum angiotensin converting enzyme or muscle enzyme levels [27].
●Gallium scanning – Gallium scans demonstrate diffuse increased uptake of radionuclide in acute or diffuse myopathy depending upon the intensity of the inflammation [22,28,29]. The pattern of uptake can be diffuse or nodular in sarcoidosis, and the nodular pattern may help differentiate sarcoid myopathy from other inflammatory myopathies, as a nodular pattern is generally absent in other inflammatory myopathies [30].
●CT scanning – Skeletal muscle CT scans can help delineate areas of muscle atrophy, which is commonly seen in chronic myopathy. Common areas of atrophy are the paraspinal, hip adductor, knee flexor, and ankle plantar flexor muscles [6].
Electrodiagnostic studies — Electromyographic (EMG) studies in patients with sarcoidosis and muscle weakness may reveal a myopathic pattern similar to that seen in inflammatory myopathies like polymyositis. Such EMG studies typically show low-amplitude, short-duration, polyphasic motor unit potential in proximal more than distal muscles with spontaneous fibrillations and positive sharp waves. However, EMG studies in patients with nodular involvement are normal. (See "Diagnosis and differential diagnosis of dermatomyositis and polymyositis in adults", section on 'Electromyography'.)
Histopathology — Biopsy of affected muscle in patients with sarcoid myopathy typically reveals multiple noncaseating granulomas in perimysial connective tissue, generally with a diffuse cellular distribution with macrophages and CD4-positive T lymphocytes [31]. In addition, CD8-positive T lymphocytes are irregularly distributed within the granulomatous cellular infiltrate in early lesions and surrounding the granulomas seen in more mature lesions [31,32]. Perifascicular atrophy is seen in one-half of the cases.
Immunohistochemistry studies reveal increased CD4 lymphocytes and a high CD4:CD8 T-lymphocyte ratio, in contrast to the low ratio seen in polymyositis and IBM [33].
DIAGNOSIS
Diagnostic features — Sarcoid myopathy should be suspected in patients with known or suspected pulmonary or extrapulmonary sarcoidosis who exhibit the insidious development of progressive proximal weakness, acute myalgia, or nodular painful abnormality of muscle.
Findings in patients with sarcoid that support a diagnosis of sarcoid myopathy include elevated muscle enzymes, which are present in a minority of reported cases and more common in patients with acute forms of myopathy than in those with chronic and nodular disease [34]; myopathic electromyographic (EMG) studies; characteristic findings on MRI in patients with nodular myopathy; diffuse inflammatory myopathic MRI findings in acute or chronic myopathy; "tiger man" appearance of muscle edema on either muscle MRI or 18F-fluorodeoxyglucose positron emission tomography (FDG-PET); and biopsy evidence of noncaseating granulomatous infiltration, especially with a high CD4:CD8 T-lymphocyte ratio. (See 'Clinical and laboratory features' above and 'Imaging' above and 'Electrodiagnostic studies' above and 'Histopathology' above and 'Diagnostic evaluation' below and 'Muscle biopsy' below.)
Other causes of similar symptoms and findings should be excluded. (See 'Evaluation to exclude mimics of sarcoid myopathy' below and 'Differential diagnosis' below.)
Diagnostic evaluation — In patients with established sarcoidosis who are presenting with muscular symptoms, we obtain muscle enzyme testing (serum creatine kinase [CK] and aldolase) and perform EMG studies. Muscle enzyme elevations and myopathic EMG findings help establish the diagnosis in patients with known sarcoidosis, especially in patients with evidence for active sarcoidosis elsewhere (see 'Clinical and laboratory features' above and 'Electrodiagnostic studies' above and "Diagnosis and differential diagnosis of dermatomyositis and polymyositis in adults", section on 'Diagnostic approach'). However, muscle enzymes can be normal in chronic and nodular forms of myopathy (see 'Diagnostic features' above). In patients with known sarcoidosis, these studies can help establish muscle pathology as the cause of the symptoms, rather than generalized fatigue or other neurologic manifestations of sarcoidosis, although further characterization of the muscle disease is required. Most patients with sarcoid myopathy have other evidence of sarcoidosis, often pulmonary involvement or lymphadenopathy. (See "Clinical manifestations and diagnosis of pulmonary sarcoidosis" and "Extrapulmonary manifestations of sarcoidosis".)
An MRI with gadolinium contrast is the most useful next step after myopathy is suspected based on symptoms, laboratory tests, and/or EMG studies. MRI can help to further confirm the diagnosis and can also serve as a guide for muscle biopsy or fine-needle aspiration, if needed. Other imaging techniques, such as CT, gallium scanning, and PET/CT, are less useful for diagnosis due to low sensitivity and nonspecificity; however, in patients unable to undergo MRI, we perform PET/CT imaging for this purpose. Although 18F-fluorodeoxyglucose PET (FDG-PET) is costly, it may still be useful when used selectively to evaluate the distribution of muscle changes, potentially reducing the need for repeat exploratory muscle biopsies in patients with biopsy-proven sarcoidosis and clinical evidence of sarcoid myopathy. It is most often useful in patients with sarcoid myopathy who are not responding to therapy and to distinguish active muscle disease from chronic but inactive muscle disease and nonmuscular causes of weakness and fatigue. (See 'Imaging' above.)
One study, for example, evaluated the relative utility of MRI, CT scanning, and gallium scanning in four patients with biopsy-proven lower-extremity myositis [19]. By comparison, gallium scanning (with increased uptake) only identified nodular lesions, and CT failed to provide any additional information.
In patients without known sarcoidosis but with unexplained muscle symptoms, particularly proximal muscle weakness in the setting of a multisystem illness, sarcoid myopathy should also be suspected in the differential diagnosis. Such patients should undergo muscle enzyme testing, EMG testing, and MRI; additional testing in these patients includes an evaluation for the primary diagnosis and other manifestations of sarcoidosis. Muscle biopsy may be needed to confirm the diagnosis in such patients. The evaluation of suspected pulmonary and extrapulmonary sarcoidosis is described in detail separately. (See "Clinical manifestations and diagnosis of pulmonary sarcoidosis" and "Extrapulmonary manifestations of sarcoidosis", section on 'Diagnostic approach'.)
In the patient with undiagnosed weakness, the evaluation is similar to that of any patient presenting with symptoms suggestive of muscle disease. (See "Approach to the patient with muscle weakness".)
Evaluation to exclude mimics of sarcoid myopathy — In addition to evaluation for features characteristic of sarcoid myopathy (see 'Diagnostic evaluation' above), we obtain additional testing as part of our initial evaluation to identify other features of sarcoidosis and to exclude conditions that can present similarly (see 'Differential diagnosis' below). Such testing may vary depending upon the data already available and the clinical presentation, but generally includes:
●A thorough medical history and physical examination
●Complete blood count and differential white blood cell count, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), and liver chemistries
●Autoantibody testing for granulomatous vasculitis, including antineutrophil cytoplasmic antibodies, and if indicated clinically, for systemic lupus erythematosus, including antinuclear, anti-double-stranded deoxyribonucleic acid (dsDNA), anti-Smith, and anti-ribonucleoprotein antibodies
●Urinalysis
●Testing for latent tuberculosis by tuberculin skin testing or an interferon-gamma release assay (see "Tuberculosis infection (latent tuberculosis) in adults: Approach to diagnosis (screening)")
●CT of the chest and abdomen to identify findings that are unexplained by sarcoidosis
●Special staining of the muscle tissue for mycobacteria and fungi
Muscle biopsy — Muscle biopsy is usually needed in patients without previously known sarcoidosis and is important in other patients in whom the diagnosis remains uncertain. Histopathologic confirmation of the diagnosis includes demonstration of noncaseating granulomas and the exclusion of other causes of granulomatous histopathology (eg, idiopathic or infectious granulomatous myositis) with special stains for mycobacteria and fungi.
A biopsy showing granulomatous myositis, observed in 95 percent of muscle biopsies, is highly suggestive of sarcoidosis but is not diagnostic. Associated signs and symptoms of sarcoidosis should, therefore, be present before a definite diagnosis is made.
Confirmation of sarcoid myopathy, like other extrapulmonary involvement in sarcoidosis, requires documentation of sarcoid involvement of at least one additional organ system in most patients and exclusion of other multisystem granulomatous diseases. (See "Extrapulmonary manifestations of sarcoidosis", section on 'Diagnostic approach' and 'Differential diagnosis' below.)
Open surgical muscle biopsies or large-bore needle biopsies have typically been used to assess muscle disease in patients with suspected sarcoid myopathy. Although fine-needle aspiration has the advantage of being minimally invasive, the sensitivity and specificity of this approach for patients with nodular myopathy are uncertain.
Cytologic evidence for granulomatous inflammation with an absence of both neoplasia and pathogenic infectious agents may allow a diagnosis of sarcoid myopathy to be made without open or needle muscle biopsy in the setting of previously diagnosed sarcoidosis and suggestive MRI features of either characteristic "dark star" or diffuse increased signal intensity on T2-weighted images, or muscle atrophy. False negatives may occur in part because of patchy muscle involvement in sarcoid myopathy. A specific region can be targeted, particularly in nodular myopathy, with the help of the MRI finding of a "dark star," which is characteristic of nodular sarcoid myopathy, increasing the yield of this technique [35,36] (see 'Imaging' above). These MRI findings are highly specific and sensitive, even for the small nodules. Notably, the central hypointense area of the "dark star" persists after glucocorticoid therapy [23].
DIFFERENTIAL DIAGNOSIS — The differential diagnosis of myopathy in patients with sarcoidosis includes conditions related and unrelated to the primary disorder. As examples, muscle weakness is a potential adverse effect of glucocorticoid therapy; generalized fatigue and neurologic manifestations causing symptoms of weakness can be features of sarcoidosis; reduced walking capacity and dyspnea may be caused by impaired inspiratory muscle strength, which can only be reliably detected by nonvolitional tests of inspiratory muscle strength [37]; and a number of different conditions can cause proximal weakness, soft tissue nodules, or a granulomatous myositis. The specific disorders that should be considered depend upon the patient's clinical and laboratory manifestations.
●Glucocorticoid- and other drug-induced myopathies – Glucocorticoid-related myopathy is common in patients being treated with moderate to high doses of glucocorticoids (>20 mg a day) for other organ manifestations of sarcoidosis. Like sarcoid myopathy, it usually affects proximal strength in the lower extremities, with relative sparing of other muscles. It is often accompanied by other side effects of glucocorticoids, including Cushingoid features, and improves rather than worsens with a reduction in the glucocorticoid dose. It can usually be distinguished from sarcoid by MRI, which, in sarcoid, shows findings consistent with inflammatory muscle disease or nodular-type sarcoid; the diagnosis of sarcoid myopathy can be confirmed by muscle biopsy. Other drug-induced myopathies should also be considered if suggested by the patient's medical history. (See "Glucocorticoid-induced myopathy" and "Drug-induced myopathies".)
●Granulomatous myopathy from nonsarcoid causes – In patients with a muscle biopsy that reveals multiple noncaseating granulomas, the most common diagnosis is sarcoidosis; however, other granulomatous diseases must also be considered depending upon the clinical context. Examples include infectious diseases, such as tuberculosis, fungal infection, syphilis, brucellosis, human T-lymphotropic virus type I (HTLV-I), and Pneumocystis jirovecii, and noninfectious disorders, such as granulomatosis with polyangiitis; inflammatory bowel diseases; and neoplastic diseases, especially lymphoma. Other causes include foreign body reaction [14,38]. Specific testing to differentiate between sarcoidosis and one of these conditions is individualized, depending upon the findings that are present in a given patient (see appropriate topic reviews).
●Polymyositis and inclusion body myositis – Polymyositis and inclusion body myositis (IBM) can both cause muscle weakness that can be similar to the symptoms and findings in sarcoidosis. Acute sarcoid myositis can mimic acute polymyositis, given that both may present with muscle weakness, myalgia, muscle enzyme elevation, and fever. A prior diagnosis of sarcoidosis or a finding consistent with other organ involvement of sarcoidosis is usually helpful. Electromyographic (EMG) studies, muscle enzymes (these could be normal in chronic and nodular forms of sarcoid myopathy), and MRI findings may not be able to distinguish the two entities, but the muscle biopsy finding of granulomatous inflammation with a high CD4:CD8 T-lymphocyte ratio, which is unlike the findings typically seen in polymyositis and dermatomyositis, can be diagnostic. However, overlapping clinical and pathologic features of IBM and sarcoid myopathy, especially biopsy evidence of granulomas, can lead to a significant diagnostic challenge [39,40]. (See "Clinical manifestations of dermatomyositis and polymyositis in adults".)
Sarcoid and IBM have also been reported to occur in the same patients. In one series of 27 patients with IBM, two (7 percent) also had sarcoid myopathy [33]. Pathologic features of IBM in addition to noncaseating granulomas on muscle biopsy predict nonresponse to immunosuppressive therapy [39,40]. (See "Clinical manifestations and diagnosis of inclusion body myositis" and "Clinical manifestations of dermatomyositis and polymyositis in adults".)
●Soft tissue tumors – Nodular soft tissue tumors, such as giant-cell tumor and sarcoma, may have a similar clinical appearance to nodular sarcoid myopathy. Patients with sarcoid myopathy are likely to have other signs of systemic sarcoidosis that would be absent in patients with soft tissue tumors, and characteristic findings of nodular sarcoid on MRI may also strongly suggest the diagnosis of sarcoid myopathy rather than malignancy. A biopsy of the lesion can confirm the diagnosis. (See "Clinical presentation, histopathology, diagnostic evaluation, and staging of soft tissue sarcoma" and "Giant cell tumor of bone".)
TREATMENT
General principles and approach — The treatment of sarcoid myopathy involves the use of glucocorticoids and sometimes other immunosuppressive or immunomodulatory agents (eg, methotrexate [MTX], azathioprine [AZA], or tumor necrosis factor [TNF] inhibitors). Choice of therapy should be coordinated with the patient's pulmonologist and other treating clinicians, given its usual association with other disease manifestations. Glucocorticoid-related myopathy should be excluded before treating sarcoid myopathy with glucocorticoids, particularly in patients whose only symptoms and abnormal findings are due to proximal muscle weakness. (See 'Diagnosis' above and 'Differential diagnosis' above.)
Our approach is based upon clinical experience and limited data as there have been no randomized trials of glucocorticoids or other agents for sarcoid myopathy. The treatment strategy is also informed and supported by the use of these medications in patients with pulmonary and other manifestations of sarcoidosis and patients with inflammatory myopathies, such as dermatomyositis and polymyositis. (See "Treatment of pulmonary sarcoidosis: Initial approach to treatment" and "Treatment of pulmonary sarcoidosis refractory to initial therapy" and "Extrapulmonary manifestations of sarcoidosis" and "Initial treatment of dermatomyositis and polymyositis in adults" and "Treatment of recurrent and resistant dermatomyositis and polymyositis in adults".)
Drug therapy is indicated for symptomatic patients with muscle weakness or myalgias due to active disease, as demonstrated by recent elevation of muscle enzymes, muscle biopsy findings, electromyographic (EMG) study abnormalities, a changing course of symptoms (eg, progressive weakness), MRI, or other imaging findings. Early institution of therapy is critical, as glucocorticoids and other immunosuppressive agents cannot reverse muscle atrophy.
Asymptomatic muscle disease does not require specific pharmacotherapy. Treatment of asymptomatic muscle involvement in sarcoidosis with active disease in other organs is usually driven by the immunosuppressive approach used for management of the disease affecting those other organs.
All patients with sarcoidosis and muscle weakness should receive a physical therapy evaluation and instruction in a regular exercise program to maintain muscle strength and endurance and to prevent muscle fatigue. Patients with sarcoidosis who lack symptomatic muscle disease should be encouraged to remain active and to participate in light exercise.
Initial pharmacotherapy
●Acute or nodular myositis – In patients with acute myositis or nodular myositis, we suggest glucocorticoids (prednisone 0.5 to 1 mg/kg daily) as initial therapy rather than nonsteroidal antiinflammatory drugs (NSAIDs) or other immunosuppressive agents. Glucocorticoids should be gradually tapered over four to eight weeks as tolerated to below 7.5 mg daily, then patients should be gradually tapered off glucocorticoids over the next four to eight weeks, such that total duration of glucocorticoid therapy is less than three months. Inability to reduce the glucocorticoid dose to these targets due to recurrent symptoms is an indication for addition of MTX or AZA. (See 'Resistant to glucocorticoids' below.)
Although most patients with nodular myositis require systemic glucocorticoids, infrequently, a patient with only one or a few painful nodular sarcoid muscle lesions may respond to combined therapy consisting of the intralesional injection of triamcinolone, rest, and an NSAID [13].
●Chronic myopathy – In patients with chronic myopathy, we suggest initiating treatment with glucocorticoids (prednisone 1 mg/kg daily to a maximum of 80 mg daily) rather than other therapies. We follow the same approach to treatment used in the management of polymyositis or dermatomyositis, with a gradual tapering of the glucocorticoids over six to twelve months. (See "Initial treatment of dermatomyositis and polymyositis in adults", section on 'Initial glucocorticoid therapy' and "Initial treatment of dermatomyositis and polymyositis in adults", section on 'Glucocorticoid tapering'.)
In selected patients we start MTX together with initiating glucocorticoids. Examples include individuals at increased risk of adverse effects from glucocorticoids (eg, due to diabetes mellitus, reduced bone mass, or with other severe adverse effects), in patients with particularly severe disease (eg, severe weakness leading to an inability to walk), and in patients who require additional therapy because of other organ involvement (eg, due to arthritis or pulmonary disease).
Patients treated for acute or nodular myositis generally require a shorter course of therapy than patients with chronic myopathy [6]. Responses to glucocorticoid therapy vary between case series, with benefit reported in 40 to 60 percent of patients [6,41]. In one study, only 7 of 26 patients (27 percent) had a complete response, while 6 (22 percent) were stabilized, and 13 (50 percent) were nonresponsive.
Resistant to glucocorticoids — In patients with an inadequate response to glucocorticoids either due to inefficacy after two to three months of therapy, an inability to taper prednisone below 10 mg after six months of therapy, or intolerance of the glucocorticoids, we suggest adding an additional immunosuppressive agent (eg, AZA [2 mg/kg orally each day] or MTX [20 to 25 mg weekly]) [42]. Earlier treatment has significantly better outcomes, therefore early diagnosis is key [6]. The use and adverse effects of MTX and AZA are the same as for rheumatoid arthritis or inflammatory myositis and are discussed in detail separately. (See "Initial treatment of rheumatoid arthritis in adults", section on 'Initial therapy with methotrexate' and "Use of methotrexate in the treatment of rheumatoid arthritis" and "Major side effects of low-dose methotrexate" and "Initial treatment of rheumatoid arthritis in adults" and "Pharmacology and side effects of azathioprine when used in rheumatic diseases" and "Initial treatment of dermatomyositis and polymyositis in adults", section on 'Glucocorticoid-sparing agents'.)
Refractory myopathy — In patients with sarcoid myopathy who exhibit an inadequate response to a three-month trial of glucocorticoids combined with MTX or AZA, we suggest adding infliximab (titrated to 3 to 5 mg/kg administered by intravenous infusion at weeks 0, 2, 6, and subsequently every eight weeks) or adalimumab (40 mg by subcutaneous injection every other week). These TNF inhibitors have been shown in case reports to be effective in such patients [43,44]. Additional evidence suggesting potential benefit comes from various series and clinical trials in which the efficacy of TNF-alpha inhibitors (infliximab and adalimumab) has been shown for the treatment of pulmonary and other extraarticular manifestations of sarcoidosis. (See "Treatment of pulmonary sarcoidosis refractory to initial therapy", section on 'Tumor necrosis factor-alpha antagonists' and "Sarcoid arthropathy", section on 'TNF inhibitors'.)
We do not use etanercept, which has failed to show benefit in patients with progressive pulmonary sarcoidosis or chronic ocular disease. Similar regimens are used as in pulmonary sarcoidosis and for other manifestations of extrapulmonary disease, such as sarcoid arthritis.
Duration of therapy — We typically taper gradually off glucocorticoids over one year, with a target at six months of less than 10 mg prednisone or equivalent daily. We continue MTX or AZA for a total of two to three years before reducing and discontinuing the immunosuppressive medication. Unfortunately, in chronic myopathy, which is the most common form, response is variable and commonly refractory to glucocorticoids. Also, relapses are common after glucocorticoids are discontinued.
Monitoring — Patients require monitoring of their response to therapy and for drug safety:
●Myopathy – Initially, patients are evaluated monthly, usually until they respond to therapy and are on a stable treatment regimen. Subsequently, patients can be seen every 8 to 12 weeks. In addition to the medical history (eg, symptoms of weakness, pain, dysphagia, aspiration, or tachypnea), testing of muscle strength should be performed, especially of the affected muscle groups. We obtain a complete blood count, liver enzymes, and creatine kinase (CK) at each visit. Monitoring of the clinical response of the muscle disease is done in a similar fashion to that in patients with dermatomyositis or polymyositis. (See "Initial treatment of dermatomyositis and polymyositis in adults", section on 'Assessing treatment response'.)
Evaluation of the response to therapy can also be performed, if needed, by repeating the original imaging done at baseline; the most sensitive and specific imaging modality is MRI. In some cases, improvement of positron emission tomography (PET)/CT findings is also seen after treatment.
●Drug safety – Glucocorticoids, MTX, AZA, and TNF inhibitors are monitored in a standard fashion, as in rheumatoid arthritis or idiopathic inflammatory myositis, depending upon the specific medication. (See "Use of methotrexate in the treatment of rheumatoid arthritis" and "Major side effects of low-dose methotrexate" and "Pharmacology and side effects of azathioprine when used in rheumatic diseases" and "General principles and overview of management of rheumatoid arthritis in adults", section on 'Drug monitoring and prevention of drug toxicity'.)
PROGNOSIS — The prognosis of the muscle disease is variable, but it generally does not affect mortality. Patients treated early in the course of their myopathy are more likely to benefit from therapy. In one case series of 11 patients with chronic, generalized sarcoid myopathy, the therapeutic response was poor in patients with chronic disease (greater than two years), while the best outcomes were seen with earlier diagnosis and treatment (from within a few months up to two years of disease) [6].
Chronic myopathy leads to atrophy of muscle, causing long-term functional decline. Mortality is likely not affected by the course of the myopathy in most patients, as survival usually depends upon the involvement of other organs and tissues (eg, lungs, kidneys, heart). (See "Treatment of pulmonary sarcoidosis: Initial approach to treatment".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Sarcoidosis".)
SUMMARY AND RECOMMENDATIONS
●Symptomatic muscle disease is a very infrequent manifestation of sarcoidosis, a multisystem disorder of unknown etiology, which is characterized by the accumulation of T lymphocytes, mononuclear phagocytes, and noncaseating granulomas in involved tissues. Three types of clinical muscle disease are recognized: insidious proximal muscle weakness; acute myopathy with weakness and elevated muscle enzymes; and nodular myopathy, which is the least commonly seen. Muscle involvement is commonly subclinical. (See 'Pathogenesis' above and 'Epidemiology' above and 'Clinical manifestations' above.)
●In a patient with sarcoidosis, the presence of muscle weakness, muscle pain, or muscle nodules is suggestive of sarcoid myopathy. MRI may help to identify and distinguish between the different types of myopathy, but is normal in some patients with mild or acute disease. Electromyography (EMG) may reveal a myopathic pattern, but EMGs are normal in patients with nodular involvement. Biopsy of affected muscle typically shows multiple characteristic noncaseating granulomas in perimysial connective tissue. (See 'Clinical and laboratory features' above and 'Imaging' above and 'Electrodiagnostic studies' above and 'Histopathology' above.)
●A diagnosis of sarcoid myopathy can generally be made in patients with sarcoid in another site; elevated muscle enzymes; myopathic EMG studies; characteristic findings on MRI in patients with nodular myopathy; diffuse inflammatory myopathic MRI findings in acute or chronic myopathy; and biopsy evidence of noncaseating granulomas, usually with a high CD4:CD8 T-lymphocyte ratio. In addition, other causes of similar symptoms and findings should be excluded. (See 'Diagnosis' above and 'Diagnostic evaluation' above and 'Evaluation to exclude mimics of sarcoid myopathy' above and 'Muscle biopsy' above.)
●The differential diagnosis of sarcoid myopathy includes glucocorticoid- and other drug-induced myopathies, and, in patients with a muscle biopsy that reveals multiple noncaseating granulomas, other granulomatous diseases, including infections and granulomatosis with polyangiitis, must also be considered. (See 'Differential diagnosis' above.)
●Early institution of therapy is critical, as glucocorticoids and other immunosuppressive agents cannot reverse muscle atrophy. Asymptomatic muscle disease does not require specific pharmacotherapy. All patients with sarcoidosis and muscle weakness should receive a physical therapy evaluation and instruction in a regular exercise program. (See 'General principles and approach' above.)
●In most patients with symptomatic acute or chronic myopathy (ie, with muscle weakness or myalgias due to active disease), we suggest initiating glucocorticoids rather than other immunosuppressive agents (Grade 2C). For acute or nodular myositis we use prednisone 0.5 to 1 mg/kg daily with a goal of gradually tapering over no more than three months. For chronic myopathy we use prednisone 1 mg/kg daily (to a maximum of 80 mg daily), then taper gradually over 6 to 12 months. Patients at increased risk of adverse effects from glucocorticoids or with severe disease may benefit from starting methotrexate (MTX) together with initiating glucocorticoids. For patients with only one or few painful nodular lesions, we suggest intralesional injection of triamcinolone, bed rest, and a nonsteroidal antiinflammatory drug (NSAID) rather than oral glucocorticoids. (See 'Initial pharmacotherapy' above.)
●In patients with an inadequate response to glucocorticoids either due to inefficacy after two to three months of therapy, an inability to taper prednisone below 10 mg after six months of therapy, or intolerance of the glucocorticoids, we suggest adding an additional immunosuppressive agent rather than higher doses of glucocorticoids (Grade 2C). We prefer either azathioprine (AZA; 2 mg/kg orally each day) or MTX (20 to 25 mg once weekly) for this purpose. (See 'Resistant to glucocorticoids' above.)
●In patients with an inadequate response to a three-month trial of glucocorticoids combined with MTX or AZA, we suggest adding a tumor necrosis factor (TNF) inhibitor rather than another immunosuppressive or biologic agent (Grade 2C). We prefer infliximab or adalimumab, but not etanercept, which has failed to show benefit in patients with progressive pulmonary sarcoidosis or chronic ocular disease. (See 'Refractory myopathy' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Winston Sequeira, MD, who contributed to an earlier version of this topic review.
