Secondary myopathy due to systemic diseases.

BACKGROUND: Some systemic diseases also affect the skeletal muscle to various degrees and with different manifestations. This review aimed at summarizing and discussing recent advances concerning the management of muscle disease in systemic diseases.
METHOD: Literature review by search of MEDLINE, and Current Contents with appropriate search terms.
RESULTS: Secondary muscle disease occurs in infectious disease, endocrine disorders, metabolic disorders, immunological disease, vascular diseases, hematological disorders, and malignancies. Muscle manifestations in these categories include pathogen-caused myositis, muscle infarction, rhabdomyolysis, myasthenia, immune-mediated myositis, necrotising myopathy, or vasculitis-associated myopathy. Muscle affection may concern only a single muscle, a group of muscles, or the entire musculature. Severity of muscle affection may be transient or permanent, may be a minor part of or may dominate the clinical picture, or may be mild or severe, requiring invasive measures including artificial ventilation if the respiratory muscles are additionally involved. Diagnostic work-up is similar to that of primary myopathies by application of non-invasive and invasive techniques. Treatment of muscle involvement in systemic diseases is based on elimination of the underlying cause and supportive measures. The prognosis is usually fair if the causative disorder is effectively treatable but can be fatal in single cases if the entire musculature including the respiratory muscles is involved, in case of infection, or in case of severe rhabdomyolysis.
CONCLUSION: Secondary muscle manifestations of systemic diseases must be addressed and appropriately managed. Prognosis of secondary muscle disease in systemic diseases is usually fair if the underlying condition is accessible to treatment.

Introduction

Systemic diseases are characterized by involvement or affection of the entire organism and contrast focal diseases, in which only a single organ or part of it is affected [1a]. Systemic diseases are also those affecting a system which is distributed all over the body, such as the nervous system (CNS), the vascular system, or the blood. Systemic diseases include for example leukemia, anemia, central nervous systemic diseases, vasculitis, diabetes, thyroid dysfunction, hemochromatosis, rheumatological disorders, psoriasis, sarcoidosis, systemic lupus erythematosus, scleroderma, or mucoviszidosis 1. Some of these disorders secondarily affect the skeletal muscle, manifesting as myositis, muscle abscess, endocrine or metabolic myopathy, rhabdomyolysis, or myasthenia. The following review aims at summarizing and discussing recent advances concerning the management of muscle disease in systemic diseases, including infectious diseases, endocrinological disorders, metabolic disorders, immunological disorders, vascular disorders, and hematological disorders.

Methods

Data for this review were identified by searches of MEDLINE, Current Contents, for references of relevant articles using the search terms ‘infection’, ‘infectious’, ‘viral’, ‘bacterial’, ‘protozoal’, ‘helminthic’, ‘leukemia’, ‘anemia’, ‘diabetes’, ‘thyroid’, ‘hemochromatosis’, ‘rheumatological’, ‘psoriasis’, ‘lupus’, ‘scleroderma’, ‘sarcoidosis’, ‘mucoviszidosis’, ‘vasculitis’, and ‘vascular’ in combination with ‘skeletal muscle’, ‘myopathy’, ‘myositis’, ‘myasthenia’, ‘neuromuscular transmission’, and ‘rhabdomyolysis’. Randomized (blinded or open label) clinical trials, longitudinal studies, case series, and case reports were considered. Abstracts and reports from meetings were not included. Only articles published in English, French, Spanish, or German between 1966 and 2015 were included. Appropriate papers were studied and discussed for their suitability to be incorporated in this review. Due to limitations of space not all systemic diseases with muscle involvement could be discussed. Only the clinically most relevant were included.

Results

Classification of muscular manifestations of systemic diseases

Muscular manifestations in systemic diseases may be classified as acute, subacute, or chronic. Acute muscle manifestations include pathogen‐caused myositis, muscle infarction, or rhabdomyolysis. Subacute or chronic muscular manifestations of systemic diseases include secondary endocrine or secondary metabolic myopathy, myasthenia, immune‐mediated myositis, muscle abscess, or vasculitis with secondary myopathy 2. They may be further classified as transient or permanent, as mild or severe, as dominating or not dominating the clinical presentation, or as affecting a single muscle, a group of muscles, or the entire musculature.

Infectious diseases

Viral infections

Systemic viral infections may manifest in the muscle as myositis, rhabdomyolysis, or myasthenia. The most frequent among the muscle manifestations is myositis with a self‐limiting course. More rarely, viral infections may manifest with rhabdomyolysis. Myasthenia due to viral infections is only reported in single cases. Only few data about the clinical manifestations, frequency of muscle manifestations, and causative agents are available.

Myositis

In a retrospective study of 35 patients with viral myositis, muscle manifestations included localized pain of the calves (80%), lower limb weakness (71%), impaired ambulation (57%), and gait disturbance (40%) lasting on the average 3.6 days 3. Symptoms were associated with elevated muscle enzymes 3. Myositis may affect all muscles, a group of muscles 4, 5, or a single muscle 6. In a study of 355 pediatric patients with laboratory‐confirmed influenza‐B, 17.9% developed myositis 7. During the influenza pandemic in 2009, children developed more frequently myositis as compared to adults 8. Infections with human T‐cell lymphotropic virus (HTLV‐1) may manifest as axial myositis 4. Some of the viral infections may also cause orbital myositis, such as infections with the chickenpox virus 5. Rarely, a single muscle like the serratus anterior may be affected during flu 6.

Concerning the causative agents, viral myositis has been reported following infections with influenza‐B 7, influenza‐A 8, parainfluenza‐1 9, parvoviruses 10, HTLV‐1 11, Epstein‐Barr virus 12, arboviruses (e.g., dengue myositis) 13, adenovirus 14, coxsackie 15, herpes 16, human immunodeficiency virus‐1 (HIV‐1) 17, or chickenpox 5. Most frequently myositis is due to infection with the influenza 7 or parainfluenza virus 9. These patients may present with acute onset calf pain, tenderness, or gait disturbance 9. Myositis in dengue infection can be fulminant and affect the respiratory muscles requiring artificial ventilation 18. Only rarely is myositis due to infection with parvovirus‐B19 10, HCV 19, or the West Nile virus 20. Chronic HCV infection may be also associated with dermatomyositis 21 or inclusion body myositis 22. Infection with the New Jersey polyomavirus NJPyV‐2013 may cause vasculitic myopathy 2. Muscle‐tropic viruses often spread to the CNS, which may dramatically increase morbidity and mortality 23. Whether patients with an underlying subclinical primary or secondary myopathy or those taking muscle‐toxic drugs are particularly prone to develop viral myositis is unknown. Infection with HIV‐1 may be associated with polymyositis, dermatomyositis, or inclusion body myositis 17. Polymyositis from HIV‐1 may be complicated by the development of muscle abscesses 24. HIV‐myositis may be even the initial manifestation of acquired immunodeficiency syndrome (AIDS) 25.

Rhabdomyolysis

Viral infections, particularly dengue and influenza‐A, have been recognized as cause of rhabdomyolysis with considerable morbidity and mortality 26. Rhabdomyolysis as a complication of a viral infection occurs particularly in children and usually has a benign course 27. The main complication of rhabdomyolysis is acute renal failure, often requiring hemofiltration or hemodialysis 28. Rhabdomyolysis occurs in 1% of the patients with dengue infections. Risk factors for developing rhabdomyolysis include myalgia, arterial hypertension, and acute renal failure 29. More rarely rhabdomyolysis may be triggered by infections with influenza‐A 30, influenza‐B 31, 32, parainfluenza 33, herpes‐6 34, varicella zoster 35, cytomegaly virus (CMV) 36, coronavirus‐NL63 37, chikungunya 38, Alkhurma hemorrhagic fever virus 39, or HIV‐1 40. Rhabdomyolysis in dengue fever infections can be life‐threatening in some cases 41, 42, 43.

Myasthenia

Whether viral infections cause myasthenia is under debate. Well‐known, however, is that infections may deteriorate myasthenia. There are, however, some reports indicating that a causal relation between a viral infection and the development of myasthenia may exist. In six Chinese patients with a West Nile virus infection, myasthenia developed 3–7 months after the infection 44. Further evidence for an association between viral infections and myasthenia are results of single‐fiber EMG investigations in patients with influenza or echovirus infection showing a neuromuscular transmission defect 45.

Bacterial infections

Systemic bacterial infections manifest in the muscle as myositis or rhabdomyolysis.

Bacterial infections associated with myositis usually manifest as bacterial polymyositis 46. Commonly, bacterial polymyositis is a purulent infection accompanied by muscle abscesses (pyomyositis) 46. The main etiologic agent of bacterial polymyositis is Staphylococcus aureus 46. Staphylococcal pyomyositis is a severe infection with high mortality being increasingly recognized in temperate climates 47. Pyomyositis may originate from a focal infection such as arthritis, sacroiliitis, a spinal abscess, or from bacteremia or sepsis. Pyomyositis may develop after trauma, may remain focal, and may resolve upon a nonsurgical approach 48. Pyomyositis may affect a single muscle, such as the rectus femoris muscle 49, or may affect all muscles resulting in quadriparesis, as described in a patient after induction of chemotherapy for lymphoblastic leukemia 50. Pyomyositis may be diagnosed with ultrasound and culture of the aspirate 51. Pyomyositis of the iliopsoas muscle may be complicated by septic pulmonary embolism 47. These patients may require abscess drainage under CT‐guidance 47. Presence of intramuscular hemangiomas seems to predispose for pyomyositis, as reported in a 4‐year‐old child with fatal meningitis 46. Sepsis from streptococcus group‐G originating from arthritis may cause diffuse polymyositis without skin lesions or toxic shock syndrome 52. A severe form of bacterial myositis is streptococcal necrotizing myositis, which is often fatal 53. Muscle abscesses may also result from infection with Klebsiella pneumoniae 49 or mycobacterium tuberculosis 54. A rare cause of systemic myositis may be infection with campylobacter jejuni 55. Predisposing factors include skin penetration or impaired host immunocompetence (HIV‐1, transplant recipient) 47.

Occasionally, rhabdomyolysis may be a manifestation of a bacterial infection. Rhabdomyolysis has been particularly reported during infections with Staphylococcus aureus 56, Salmonella 57, brucella 58, mycoplasma pneumoniae 59, tuberculosis 60, tetanus 61, Legionella 62, or bacillus cereus 63. In a 6‐year‐old girl, life‐threatening rhabdomyolysis was triggered by streptococcus bovis sepsis 27.

Protozoal infections

Muscle manifestations of protozoal infections include myositis or rhabdomyolysis.

Protozoal infections are a frequent cause of myositis. In some of these cases, myositis may be the dominant feature of the infection, such as in muscular sarcocystis 64. Causative agents include sarcocystis, plasmodium falciparum, toxoplasma gondi, neospora, microspora, borrelia, pleistophora, babesia, ehrlichia, or trypanosoma. Muscular sarcocystis is clinically characterized by myalgia with or without fever, and delayed onset of hyper‐CKemia and eosinophilia with the possibility of relapses 65. Muscular sarcocystis is particularly prevalent in Malaysia 65. Other frequent protozoal infections with muscular involvement include toxoplasmosis 66 and malaria 67. In toxoplasmosis, severe polymyositis may be even the presenting manifestation 66. In a patient with AIDS, myositis due to toxoplasmosis developed despite adequate antimicrobial treatment 68. Rarely, toxoplasmosis may be associated with dermatomyositis 69. Occasionally, falciparum malaria may manifest with myositis 67. A rare protozoic infection with muscle involvement is neosporosis 70. In immune‐compromised patients, microsporidia, obligate intracellular parasites, may manifest as focal or generalized myositis 71, 72. Focal myositis may be also a rare manifestation of Lyme disease (Lyme myositis) 73, 74. Lyme myositis may even mimic dermatomyositis 75. Infection with Borrelia burgdorferi may also cause idiopathic inflammatory myopathy 76. In immune‐compromised patients, myositis may be rarely caused by pleistophora 77. Ocular myositis may be caused by ehrlichiosis, babesiosis, or Lyme disease 78. In immune‐compromised patients, ocular myositis may be also due to Trypanosoma cruzi infection 79.

Rhabdomyolysis due to protozoal infections has been particularly reported in malaria 80. Another rare cause of rhabdomyolysis due to protozoal infection is babesiosis or ehrlichiosis 81. Rhabdomyolysis due to Borrelia burgdorferi infection has been reported only once 82.

Helminthic infections

Helminthic infestations are frequently associated with muscle disease. Helminthic infestations manifest in the muscle predominantly as myositis. Helminthes potentially affecting the muscle include Toxocara (toxocarosis) 83, Echinococcus granulosus (hydatidosis) 84, Cysticercus (cysticercosis) 85, Trichinella (trichinosis) 86, Strongyloides (strongyloidiasis) 87, Haycocknema perplexum 88, Spirometra (sparganosis) 89, Fasciola (fasciolosis) 90, or Filaria (filariasis). Toxocara infection may go along with lumbar myositis 83. In the tropics, visceral larva migrans (toxocarosis) may manifest as tropical pyomyositis requiring repeated debridement 91. Hydatid cysts from infestation with Echinococcus may rarely occur in a single muscle as the initial manifestation 84, 92. Most commonly, liver and lung are affected 92. Hydatid cysts of the muscle have been occasionally observed in patients with primary muscle disease 93. Cysticercosis may initially manifest as ptosis if the lid elevator is affected 94. Cysticercosis may also manifest as ocular myositis 95. Focal cysticercal myositis may be diagnosed with muscle ultrasound or MRI 85. Trichinosis manifests clinically in the muscle as myalgias due to dermato‐polymyositis 86, 96. Trichinella has a unique relation to the muscle as it is located intracellularly. Patients may present with myalgia and fever, and elevated muscle enzymes 97. Rarely, trichinosis may go along with muscle weakness 98. In case of focal necrosis due to trichinosis, EMG may show profuse fibrillations 99. Later in the course, fibrosis and contractures may develop 99. Strongyloides rarely affects the musculature. Occasionally, patients taking steroids or immuno‐suppressants may develop polymyositis from strongyloides infestation 87. In Australia, myositis may be due to infestation with the nematode Haycocknema perplexum 88. In single cases, sparganosis may manifest as ocular myositis 89. Rarely, cutaneous fascioliasis may cause myositis of the intercostal muscles 90. Filariasis rarely manifests as myositis with muscle swelling 100.

Endocrinological disorders

Diabetes

Diabetes is a catabolic condition which manifests in the muscle as diabetic myopathy 101. Diabetic myopathy encompasses a spectrum of abnormalities, including wasting, muscle inflammation, ischemia, infarction, hemorrhage, necrosis, fibrosis, or fatty atrophy 101. Clinical manifestations vary depending on the underlying abnormality. The most frequent muscle manifestation in diabetes is painless muscle wasting (diabetic amyotrophy), which is either due to a diabetic plexus lesion 102 or due to affection of satellite cells by the diabetes 103. A further frequent manifestation of diabetic myopathy is diabetic myonecrosis presenting as self‐limiting condition with acute onset of swelling and severe muscle pain 104. Typically, patients have no fever, normal white blood cell count, normal blood sedimentation rate, but elevated C‐reactive protein 104. Usually, myonecrosis occurs in poorly controlled diabetes 105. The diagnosis is established by muscle MRI, and the treatment of choice is bed rest and analgesics 104. An increasingly recognized manifestation of diabetic myopathy is diabetic muscle infarction, which is regarded as rare and occurs in long‐standing diabetic patients 106. Clinical manifestations of muscle infarction include acute onset local pain, together with a focal, palpable mass lesion. The diagnosis is established by muscle MRI 106. Additionally, the expression level of Pax7, MyoD, myogenin, and fatal myosin‐heavy‐chain (MHC) is significantly decreased in diabetic myopathy 102.

Thyroid dysfunction

Hypothyroidism

Hypothyroidism is a well‐known cause of muscle disease (hypothyroid myopathy) 107. In contrast to hyperthyroid myopathy, CK is usually elevated, pain is frequent, and muscles can be swollen. Additionally, hypothyroidism due to autoimmune disease may be associated with dermatomyositis 108 or polymyositis 109, 110. Rarely, hypothyroidism may also go along with rhabdomyolysis 111. In infancy or childhood, hypothyroidism may manifest as Kocher–Debré–Semelaigne syndrome, characterized by lower limb or generalized muscle hypertrophy, myxedema, short stature, and cretinism. In adults, hypothyroidism may manifest as Hoffmann's syndrome, characterized by muscle stiffness and muscle pseudo‐hypertrophy. Muscle enzymes are generally elevated in hypothyroid myopathy. The EMG may show a myopathic, neuropathic, or a mixed pattern. Clinical manifestations of hypothyroid myopathy return to normal with hormone replacement therapy.

Hyperthyroidism

Graves’ disease may manifest in the skeletal muscle as mild and usually painless proximal weakness or as idiopathic ocular myositis 112. Myositis may respond favorable to thiamazole without adding steroids 113. Thyrotoxicosis may go along with episodic muscle weakness due to polymyositis 113. Thyrotoxicosis may also manifest as acute or chronic bulbar muscle dysfunction (bulbar myopathy). If thyrotoxicosis leads to hypokalemia, generalized muscle weakness may ensue (thyrotoxic periodic paralysis). A rare manifestation of hyperthyroidism or thyreotoxicosis may be myokymia.

Hyper‐/hypoparathyroidism

Hyperparathyroidism may cause muscle weakness (dropped head syndrome), muscle pain, or ischemic, calcifying myopathy 114, 115. Hyperparathyroidism may also go along with spontaneous rupture of the Achilles tendons. Rarely, the initial manifestation of hyperparathyroidism may be dysphagia. FDG‐PET in hyperthyroidism may show tumors mimicking muscular metastases. Affection of the muscle in hypoparathyroidism may present as myopathy, neuromyotonia, or rhabdomyolysis 116.

Other endocrinopathies

Hypoadrenalism as well as hyperadrenalism may be complicated by generalized muscle weakness. In case of acromegaly, the muscles may be hypertrophic and stronger than normal, but later in the course proximal weakness may become evident.

Metabolic disorders

Various metabolic disorders secondarily affect the muscle. The most well‐known are hemochromatosis, amyloidosis, and porphyria.

Hemochromatosis

Hereditary hemochromatosis and other iron‐metabolism disorders resulting in iron overload may involve the skeletal muscle (iron‐overload myopathy) which usually manifests as myalgias and fatigue 117, 118. Figures about the prevalence of iron‐overload myopathy are highly variable. In a study of 46 patients with hereditary hemochromatosis, myopathy was diagnosed in none of them 119. In a study of 395 patients with hereditary hemochromatosis on the contrary, 43% were diagnosed with fibromyalgia 120. In a study of 88 patients with chronic fatigue syndrome, 2.6% had hereditary hemochromatosis 121. Among 10 patients under hemodialysis, muscle biopsy disclosed iron deposition in muscle fibers or macrophages in 70% of them 118. Clinically, these patients presented with proximal muscle weakness 118.

Amyloidosis

Muscle involvement is frequent in amyloidosis and manifests as amyloid myopathy 122, clinically characterized by muscle hypertrophy (muscle overgrowth), or weakness. Depending on the cause of amyloidosis, different types of amyloid (AA, AL) may be produced. Amyloidosis usually manifests systemically in all muscles but occasionally only a single muscle or a few muscles is/are affected 123. Amyloidosis is characterized by extracellular and perivascular deposition of AA or AL amyloid 122. Rarely, amyloid myopathy occurs in patients with hereditary transthyretin amyloidosis (ATTR) 124. Occasionally, systemic amyloidosis due to multiple myeloma may be exclusively detectable in the skeletal muscle as ring‐fiber‐like muscle fibers, staining positive for Congo‐red 125. Rarely, amyloidosis due to IgD multiple myeloma may manifest as myositis 126. In systemic AL, amyloidosis amyloid myopathy may manifest with joint contractures 127. Amyloidosis of the muscle may also occur in monoclonal gammopathy 128. Histologically, amyloid myopathy can mimic inclusion body myopathy 129. In such cases, noncongophilic deposition of kappa‐light chains can be seen as subsarcolemmal rings 128. Focal accumulations of amyloid may present as amyloidoma (tumoral amyloidosis) 130. Interstitial amyloid deposition in the muscle may rarely occur in patients with myopathy due to mutations in the anoctamin‐5 gene 131.

Porphyrias

Porphyrias are diseases in which porphyrins, necessary to produce heme, accumulate. Most frequently, they manifest in the skin, brain, or peripheral nerves. More rarely, they manifest in the skeletal muscle. Acute intermittent porphyria may go along with rhabdomyolysis 132. There are also reports about transient muscle weakness and muscle contractures in acute intermittent porphyria 133. Acute intermittent porphyria may also manifest as acute myalgias or muscle weakness 134.

Immunological disorders

A number of immunological disorders may involve the skeletal muscle presenting as polymyositis, dermatomyositis, rarely as inclusion body myositis, or as ocular myositis. The most important among these disorders are systemic lupus erythematosus (SLE), Sjögren syndrome, rheumatoid arthritis, systemic sclerosis, psoriasis, and the antisynthetase syndrome (ASS).

Systemic lupus erythematosus (SLE)

SLE is a chronic inflammatory, multisystem disease with a broad spectrum of clinical and serological abnormalities 135. SLE has been repeatedly reported to manifest with muscle disease. Muscle manifestations of SLE include polymyositis or rhabdomyolysis (Table 1). Some patients with SLE may even develop myositis together with rhabdomyolysis 136. Myositis is much more frequent than rhabdomyolysis. In a study of 15 SLE patients, 9% had developed clinical myositis 137. However, histopathological evidence of myositis was seen in 47% of these patients 137. Type‐2 atrophy was the predominant histopathological finding. Occasionally, myositis may be the initial manifestation of SLE 138. Rarely, SLE may manifest as ocular myositis 139. Muscle involvement in SLE may also manifest as necrotizing autoimmune myopathy with muscle weakness and rhabdomyolysis 140. Polymyositis is also a feature of mixed connective tissue disease, including clinical and laboratory manifestations of SLE, scleroderma, and polymyositis along with high titers of anti‐U1 and anti‐U2‐nRNP antibodies 141. Myositis may also occur in patients with SLE/polymyositis or SLE/dermatomyositis overlap syndrome 142. Rhabdomyolysis in SLE may be fatal in some cases 143.

Table 1

Muscle manifestations of systemic diseases

Disorder	MP	FMS	PM	DM	IBM	MG	RM
Infectious disease
Viral infections	+	+ (om)	+	+	+	+	+
Bacterial infections	−	+ (om)	+a	−	−	−	+
Protozoal infections	−	+ (om)	+	+	−	−	+
Helminthic infections	−	+ (om)	+	+	−	−	−
Endocrinological disorders
Diabetes	+	−	−	−	−	−	−
Hypothyroid dysfunction	+	−	+	+	−	−	+
Hyperthyroid dysfunction	+	+ (om)	+	+	−	−	−
Hyperparathyroidism	+	−	−	−	−	−	+
Hypoparathyroidism	+	−	−	−	−	−	−
Hypo‐/hyperadrenalism	+	−	−	−	−	−	−
Metabolic diseases
Hemochromatosis	+	−	+	−	−	−	−
Amyloidosis	+	+	+	−	−	−	−
Porphyria	+	−	−	−	−	−	+
Immunological disorder
Systemic lupus erythematosus	−	+ (om)	+	−	−	−	+
Sjögren syndrome	+	+ (om)	+	+	+	−	−
Rheumatoid arthritis	−	+	+	−	−	−	−
Systemic sclerosis	−	+	+	+	−	−	−
Psoriasis	+	+ (om)	+	+	−	−	−
Antisynthetase syndrome	−	+	+	−	−	−	−
Sarcoidosis			+		+
Vascular diseases
Behcet disease	−	+ (om)	+	−	−	−	−
Wegener	−r	+ (om)	−	−	−	−	−
Churg–Strauss syndrome	−	+ (om)	+	−	−	−	−
Hematological disease
Sickle cell anemia	+	+	−	−	−	−	+
Neoplasms
Leukemia	−	−	+	+	+	−	−
Lymphoma	−	+	+	+	−	−	−
Breast, lung, gastrointestinal	+a	−	−	−	−	−	−
Bladder tumor	+a	−	−	−	−	−	−

MP, myopathy; FMS, focal myositis; om, orbital myositis; PM, polymyositis.

Pyomyositis, abscess; IBM, inclusion body myositis; RM, rhabdomyolysis; necrotizing myopathy.

Sjögren syndrome

The skeletal muscle is frequently affected in Sjögren syndrome usually manifesting as myalgia or weakness 144. In 3% of the patients, myositis has been described 144. In a study of 573 patients with Sjögren syndrome, myositis was found in 4.9% of them 145. Occasionally, muscle affection manifests as ocular myositis 146. Rarely, dermatomyositis may occur 147. Occasionally, Sjögren syndrome may be also associated with polymyositis 148. In some patients, Sjögren syndrome was even associated with inclusion body myositis 149. The latter patients usually carried the HLA‐DRB1 allele or its equivalent HLA‐DR3 or the MHC ancestral haplotype. This is why the association of Sjögren syndrome and sporadic inclusion body myositis was assumed due to a genetic predisposition linked to MHC 150.

Rheumatoid arthritis

Affection of the skeletal muscles in rheumatoid arthritis manifests as rheumatoid myositis 151. Causes of rheumatoid arthritis are variable and include inflammation, drugs, impaired joint flexibility, or sedentarism 151. Muscle enzymes are usually highly elevated. Electromyography (EMG) may show short duration, low‐amplitude, polyphasic motor unit action potentials 151. Active inflammation can be found on both muscle ultrasound and MRI 151. Muscle biopsy may show nonspecific findings, such as changes in fiber size or internal structure, pleomorphic mitochondria, dilated sarcotubular system, multiple internal or subsarcolemmal nuclei, a trend toward type‐II‐fibers, fiber atrophy, degenerative/regenerative modifications, and inflammatory features such as patchy B‐ or T‐cell infiltrates, mainly perivascularly or endomysially, but also in the perimysial compartment 151. In rare cases, rheumatoid myositis may be complicated by compartment syndrome 152 or may affect the extraocular muscles (ocular myositis) 153, 154. Adalimumab has been reported to induce myositis in rheumatoid arthritis. Eosinophilic myositis has been reported in a patient with myotonic dystrophy‐1 and rheumatoid arthritis 155.

Systemic sclerosis

Systemic sclerosis is characterized by arthralgia, synovitis, contractures, tendon friction rubs, tenosynovitis, and muscle disease 156. Muscle involvement in systemic sclerosis is frequent 156. Muscular manifestations of systemic sclerosis include myositis with myalgia and weakness 156. Rarely, patients with systemic sclerosis may develop inclusion body myositis 157. In a study of 1145 patients with systemic sclerosis, 5.6% had elevated CK. This subset of patients had a poor prognosis impacting survival, particularly in male with early onset, topo1 and RNP autoantibodies, and interstitial lung disease 158. If muscle weakness includes the head extensor muscles, dropped head syndrome may ensue 159. Muscle MRI is an appropriate tool to support the diagnosis of muscle involvement in systemic sclerosis 160. In some patients, myositis responded favorably to immunoglobulin 161.

Psoriasis

Psoriasis is a noninfectious, inflammatory dermatological disorder, which presents as systemic disease if joints, bands, eyes, arteries, or the heart are additionally involved. Psoriasis is associated with an increased risk of diabetes and ischemic stroke. Only rarely muscle involvement has been reported. In a study of 11370 patients with psoriasis, 13 had a pathologically confirmed myopathy (0.11%) 162. Eleven had generalized inflammatory myopathy and 2 had focal muscular inflammation 162. In two‐thirds of these patients, onset of psoriasis preceded that of myopathy. Patients receiving a TNF‐alpha blocker had an increased risk of developing myositis 162. Rarely, orbital myositis has been reported 163. FDG‐PET may show an increased tracer‐uptake in affected muscles 164. In a single case, psoriasis was associated with dermatomyositis and antibodies against the glomerular basement membrane 165.

Antisynthetase syndrome (ASS)

ASS is due to auto‐antibodies directed against aminoacyl‐transfer ribonucleic acid (tRNA) synthase enzymes such as anti‐Jo1, anti‐PL7, or anti‐PL12 166. Clinical manifestations include fever, nonerosive polyarthritis, Raynaud phenomenon, mechanic's hands, myocarditis (42% of patients), interstitial lung disease, which is frequently associated with anti‐Jo1 antibodies, pulmonary hypertension, progressive multifocal leucoencephalopathy, or myositis with myalgias 166, 167. Presence of interstitial lung disease is a major prognostic factor 168. Treatment of choice is the application of corticosteroids with or without immunosuppressive agents 168.

Vascular disorders

Muscle function not only depends on appropriate innervation and energy production, but also on sufficient blood perfusion. Muscle perfusion may depend not only on cardiac function but also on muscle artery contractility. Physiologically, endothelial cells produce basal and stimulated nitric oxide (NO). During exercise, NO production is stimulated, which contributes to exercise‐induced muscle hyperemia. In patients with reduced NO production due to reduced activity of NO‐synthetase (NOS), reduced microcirculation contributes to exercise‐induced muscle fatigue. NO deficiency results in muscle hypoperfusion with decreased provision of nutrients and thus decreased protein production 169. Microvascular perfusion is particularly compromised in systemic vasculitis, which includes Behcet disease, Wegener's granulomatosis, and Churg–Strauss syndrome.

Behcet disease

Behcet disease is a form of systemic vasculitis with the classical triad of oral ulcers, genital ulcers, and uveitis 152. Involvement of the skeletal muscle is rare 152. The most common muscle manifestation is myositis. Myositis usually shows a focal distribution 170. In single cases, orbital myositis has been reported 171. Only a single extra‐ocular muscle may be affected 172. Only rarely may myositis dominate the clinical presentation 173. Development of myositis in Behcet disease may be triggered by stress such as surgery 174. Occasionally, myositis may be of the necrotizing type 175. Generalized myositis may be diagnosed by muscle ultrasound, CT, or MRI 152. Generalized myositis in Behcet disease may occasionally respond favorably to cyclosporine 176.

Wegener's granulomatosis

Wegener's granulomatosis (granulomatosis with polyangiitis) is a systemic necrotizing vasculitis which is associated with granulomatous infection of the nasopharynx, the sinuses, the oropharynx, and the lower bronchial airways. Muscle involvement is infrequent and usually manifests as myositis. The most common type of myositis in Wegener's granulomatosis is ocular myositis 177. If myositis predominantly affects the lower limb muscles, it may go along with muscle weakness and gait disturbance 178.

Churg–Strauss syndrome

Churg–Strauss syndrome, also known as eosinophilic granulomatosis with polyangiitis, is a granulomatous vasculitis of the small arteries accompanied by infiltrates of eosinophils. It manifests clinically in three stages, initially as allergic cold and asthma, followed by eosinophilic infiltration of the lung and intestines and systemic vasculitis. Myositis is a rare muscle manifestation of the disease and presents with myalgia, fever, and muscle weakness 179. Myositis in Churg–Strauss syndrome may not only concern all muscles resulting in polymyositis 180 but may occur focally as orbital myositis 181.

Hematological disorders

Hematological disorders are rarely associated with muscle disease. Muscle involvement has been particularly reported in sickle cell anemia 182. Muscle affection in sickle cell anemia includes myalgia, focal myopathy, focal myositis, pyomyositis, myonecrosis, fibrosis, fasciitis, or rhabdomyolysis. Muscle involvement is more frequent in hematological neoplasms, but they are described in more detail below.

Neoplasms

Muscle disease in neoplasms is a paraneoplastic phenomenon and includes focal or generalized myositis, polymyositis, dermatomyositis, or necrotizing myopathy. Neoplasms associated with muscle disease include leukemia, lymphomas, or other solid tumors.

Leukemia

Polymyositis/dermatomyositis are symmetric, proximal, paraneoplastic, inflammatory myopathies with or without distinct cutaneous eruptions 183. They have been long recognized in association with cancer 183. Only rarely may polymyositis/dermatomyositis be associated with acute myelocytic leukemia 183. In single cases, chronic lymphatic leukemia may go along with inclusion body myositis 184, 185. Pyomyositis may be the initial presentation not only of chronic myeloid leukemia 186 but also of acute lymphocytic leukemia 187. In a girl with secondary acute myelogenous leukemia following chemotherapy, tuberculous myositis developed 188. Chemotherapy for leukemia may occasionally induce pyomyositis 189.

Lymphoma

Lymphoma is frequently associated with muscle disease, particularly with polymyositis or dermatomyositis 190. B‐cell lymphoma, T‐cell‐lymphoma, and Hodgkin's lymphoma have been reported in association with dermatomyositis or polymyositis 191. In a study of 32 patients with polymyositis/dermatomyositis, 20 had B‐cell lymphoma, four had T‐cell lymphoma, and two had Hodgkin's lymphoma 191. In single cases, B‐cell lymphoma manifested with isolated myositis of a single extra‐ocular muscle 192. Non‐Hodgkin lymphoma may directly develop inside the muscle.

Other malignancies

Paraneoplastic myopathy has been reported also in a number of other neoplasms. Lung, gastrointestinal, and breast carcinomas are frequently associated with necrotizing myopathy. The bladder transitional cell tumor may cause necrotizing myopathy with pipestem capillaries. Waldenström's macroglobulinemia may go along with antidecorin (BJ) myopathy. Patients with thymoma may develop rippling muscle syndrome. Patients with paraproteinemia (M‐protein, κ > λ light chains, IgG) or carcinoids may present with scleromyxedema.

Diagnosis

Methods to diagnose muscle manifestations of systemic disease are the same as those applied for diagnosing primary muscle disease. The basis is a thorough individual and family history and a thorough clinical exam. Determination of muscle enzymes, EMG, muscle imaging, and a muscle biopsy may be of additional help. FDG‐PET may show increased muscular tracer‐uptake in myositis 164 or tumors. Viral infections causing myositis may be diagnosed by detection of serum antibodies against viruses or by PCR. CK values may be higher during the acute stage of an influenza infection than during the convalescence stage 193. Determination of various muscle‐specific antibodies or auto‐antibodies, such as anti‐Jo1, anti‐PL7, anti‐PL12 (ASS) 166, anti‐EJ, anti‐OJ, anti‐SRP, anti‐Mi‐2, anti‐PM‐Scl75, anti‐PM‐Scl100, and anti‐Ku (overlap syndromes) may be necessary to establish the diagnosis of muscle disease in immunological disorders. U1‐nRNP antibodies may be determined when suspecting SLE, scleroderma, or polymyositis overlap syndrome. Topo1 and RNP antibodies may be positive in myopathy from systemic sclerosis 158. Antidecorin antibodies (BJ antigen) may indicate Waldenström's macroglobulinemia. Determination of ryanodine‐receptor antibodies may be helpful for diagnosing myasthenia gravis or myositis, and determination of monoclonal antibodies (M‐proteins) may suggest scleromyxedema. Single‐fiber EMG may show a disturbed neuromuscular transmission during the acute stage of influenza or echovirus infections 45. Disturbed neuromuscular transmission may explain muscle weakness and fatigue during a viral infection 45. If muscle imaging reveals an enhancing lesion with a fluid density and needle aspiration shows pus, Staphylococcus aureus is growing in 85% of the cases 194. Before diagnosing a secondary myopathy, a primary myopathy needs to be excluded 195.

Treatment

Treatment of muscle involvement in systemic diseases is mainly based on the treatment of the underlying disorder. Additionally, symptomatic measures for pain, muscle cramps, muscle stiffness, can be applied. Symptomatic measures for myositis may also include nonsteroidal analgesic drugs, steroids, immunoglobulin, or immunosuppressants. Diabetic myonecrosis responds favorably to bed rest and analgesics. In case of immune‐mediated myasthenia, cholinergic drugs, steroids, or immuno‐suppressants may be necessary. In case of vasculitis‐related myopathy, immuno‐suppression may be beneficial. Infectious myositis may respond to adequate antibiotic treatment. Helminthic infections may respond to antihelmintics with or without steroids. In case of abscess formation, puncture and drainage or resection may be indicated. In severe pyomyositis due to toxocarosis, repeated debridement may be inevitable 91. In a rare case of myopathy associated with Whipple disease antibiotics exhibited a beneficial effect on muscle manifestations 196. In case of severe rhabdomyolysis with renal insufficiency diuretics, hemofiltration or hemodialysis may beneficially influence the muscle pathology. Most cases of muscle involvement in systemic disease profit from physiotherapy.

Limitations

Systemic disease is not addressed in this review because of limited space, to few reports in the literature, or low frequency of muscle involvement, include aspergillosis, celiac disease 197, Henoch‐Schoenlein purpura, Crohn's disease, mucoviscidosis, sarcoidosis, AMPA‐associated immune encephalitis 198, renal myopathy, and vitamin‐D deficiency 199.

Clinical implications and summary

For treating physician, it is essential to know about muscular involvement in infectious, endocrine, metabolic, immunogenic, vascular, hematological diseases, or neoplasms. As soon as muscle involvement is suspected, referral to the neurologist is inevitable, and appropriate diagnostic measures as outlined above need to be initiated. In emergency cases due to renal or respiratory compromise, the treating neurologist must instantly manage and supervise the diagnostic procedures to initiate appropriate treatment in due time. In case of chronic muscle involvement, diagnostic steps may be taken more slowly but may be more invasive including abscess puncture or muscle biopsy. Particularly in infectious diseases, it is important to precisely determine the causative agent to apply the most specific antimicrobial agents with the highest effect. Muscle involvement in systemic diseases needs to be recognized and thoroughly investigated, as some cases may take a rapid or fulminant course with a high probability of an unfavorable or even fatal outcome.

Conflict of interest

The authors have nothing to declare.