Inflammatory Myopathies

Rebecca Traub

Christina M. Ulane

Kurenai Tanji

INTRODUCTION

Myopathies, or disorders of skeletal muscle, are due to a variety of hereditary and acquired causes. Myopathies with genetic underpinnings are discussed in Chapters 93 and 95 and throughout Section 19. Acquired myopathies due to systemic disorders and toxins is the subject of Chapter 92. This chapter focuses on acquired myopathies due to inflammation. The focus is on prototypical, noninfectious immune-mediated inflammatory myopathies: dermatomyositis, polymyositis, inclusion body myositis, and necrotizing myopathy. Distinguishing these disorders from hereditary or toxic myopathies is essential for appropriate management of patients with muscle diseases which may have similar clinical presentations.

DERMATOMYOSITIS

EPIDEMIOLOGY

Dermatomyositis (DM) is rare and exact epidemiologic data is lacking. A recent systematic review and meta-analysis estimates an incidence of approximately 7.98 cases per million per year and a prevalence of 14 per 100,000 (range 2.4 to 33.8 per 100,000) for all inflammatory myopathies.

DM occurs in all decades of life, with peaks of incidence before puberty and at about age 40 years. In young adults, women are more likely to be affected. Familial cases are rare. Adult cases are associated with an increased risk of malignant neoplasms; most often ovarian, lung, or breast cancer, although others such as nasopharyngeal carcinoma have been reported. Most studies report 15% to 25% of adult DM is associated with malignancy.

Juvenile DM is extremely rare, with estimated incidence of 2 to 5 per 1 million children per year younger than 16 years of age. It much more common in girls than boys (5:1) and essentially never associated with malignancy.

PATHOBIOLOGY

DM is thought to be an autoimmune disease with vasculopathy of muscle and skin. The antigenic target appears to be the endothelium of intramuscular microvessels, activating complement pathways to cause vascular injury. The loss of capillaries is thought to cause muscle ischemia resulting in myofiber injury and loss. Lymphocytic infiltrates are composed of both B and T cells, as contrasted to the T-cell-predominant inflammatory process of polymyositis and inclusion body myositis.

CLINICAL MANIFESTATIONS

The typical clinical presentation of DM is a combination of myopathy with characteristic skin findings. The rash may precede weakness by several weeks, but weakness alone is almost never the first symptom. Sometimes, the rash is so typical that the diagnosis can be made even without evidence of myopathy (amyopathic DM). In other cases, weakness may not be evident but there is electrophysiologic, pathologic, or serum creatine kinase (CK) evidence of myopathy.

Weakness in DM primarily affects the proximal muscles in the arms and legs and may be accompanied by discomfort (myalgias) and tenderness. Patients often describe difficulty going up stairs, standing from a seated position, and lifting their arms above the head. Cranial muscles may be involved, causing facial weakness, dysphagia, and esophageal involvement. Neck weakness may occur, causing head drop. Sensation is preserved and reflexes are lost only when the myopathy is severe.

The typical rash is on the face, often on the upper eyelids as a purplish discoloration with edema (heliotrope rash). An erythematous macular rash may be found on the face, neck and chest (V-sign), and upper back (shawl sign). The initial redness may be replaced later by brownish pigmentation. Gottron sign is denoted by red-purple scaly macules on the extensor surfaces of finger joints. Dusky discoloration of the knuckles has been called mechanic’s hands and is associated with the antisynthetase syndrome of arthritis, Raynaud phenomenon, and interstitial lung disease.

Subcutaneous calcifications can occur, more often in chronic cases and in pediatric DM. These calcifications may erode through the skin and cause ulceration and secondary infection.

Interstitial lung disease may accompany DM and is more common in the setting of anti-Jo-1 antibodies or antisynthetase syndrome, and patients should be questioned about respiratory symptoms and referred for pulmonary evaluation when appropriate. Cardiac involvement can occur, so clinical history should include questions of chest pain, palpitations, and syncope, and cardiac screening is advised.

Juvenile DM presents with a similar rash and proximal weakness.

DIAGNOSIS

DM is a clinical diagnosis (Table 90.1) aided by muscle biopsy (see the “Muscle Pathology” section later in this chapter). There should be elevations in muscle enzymes, including CK and aldolase. Other lab testing should include antinuclear antibodies (ANA), antibodies for other nuclear antigens, and myositis-specific antibodies (Table 90.2). Anti-Jo-1, which is the most common antisynthetase antibody, is associated with interstitial lung disease, arthritis, and Raynaud phenomenon. Nonsynthetase antibodies to Mi-2 are associated with a more acute onset and better response to therapy and prognosis. The presence of anti-Ro, anti-La, anti-Sm, RNP, anti-PM/Scl, and anti-Ku antibodies, among others, may suggest an overlap syndrome of a systemic rheumatologic disorder with associated myopathy.

Electrodiagnostic testing typically demonstrates normal nerve conduction studies with myopathic findings on electromyogram (EMG) with fibrillations, positive sharp waves, complex repetitive discharges, and sometimes myotonia, suggesting an inflammatory process. Magnetic resonance imaging (MRI) of the muscles can be used to look for evidence of inflammation and direct a target for muscle biopsy.

TABLE 90.1 Bohan and Peter Criteria for Myositis

Criterion	Description
Symmetric proximal weakness (over weeks to months)	Neck flexors, limb-girdle musculature
Consistent muscle biopsy findings	Necrosis, regeneration, phagocytosis, atrophy, mononuclear cell infiltrates
Elevated muscle enzymes	Creatine kinase, aldolase, transaminases, lactate dehydrogenase
Electromyographic evidence for myopathy	Muscle fiber irritability (positive sharp waves, fibrillations), short duration, small amplitude, polyphasic motor unit potentials, with spontaneous bizarre high-frequency discharges
Characteristic skin rash	Gottron sign, Gottron papules, heliotrope
Definite PM: four criteria. Definite DM: three or four criteria plus rash. Possible PM: two criteria. Possible DM: one criterion plus rash.
PM, polymyositis; DM, dermatomyositis.

The differential diagnosis for DM includes the other inflammatory myopathies, hereditary muscular dystrophies, and toxic myopathies. Clinical features, electrodiagnostic findings, muscle pathology, and genetic testing can help distinguish these entities (Tables 90.3 and 90.4).

Once the diagnosis of DM is suspected, testing should include evaluation for underlying malignancy and associated pulmonary fibrosis. Computed tomography (CT) of the chest, abdomen, and pelvis is usually sufficient, with the addition of pelvic ultrasound in woman, although positron emission tomography (PET) may be indicated in some cases.

Cancer screening is recommended in all patients diagnosed with DM, including routine mammography and colonoscopy. CT of the chest, abdomen, and pelvis, and sometimes PET scan are indicated depending on the clinical scenario.

TREATMENT

The initial treatment for both DM and polymyositis is prednisone, typically starting with high dose (60 mg daily or higher) and then tapering slowly over months in conjunction with the addition of steroid-sparing therapies.

The usual first-line steroid-sparing agent used in DM and polymyositis is azathioprine [Level 1].1,2 Azathioprine is started at a low dose (50 mg daily) and slowly increased (goal of 2 to 3 mg/kg/day), with monitoring of cell counts and hepatic function. Methotrexate is another first-line alternative, given orally (start 7.5 mg/wk, titrate up by 2.5 mg weekly to goal of 10 to 20 mg weekly; given with folic acid 1 mg daily) with close monitoring of cell counts, hepatic function, and renal function. In patients with myositis refractory to these agents or with intolerable side effects, second-line options include rituximab (1,000 mg IV on days 1 and 15 may be repeated every 24 weeks) and intravenous immunoglobulin (IVIG) (doses vary, typically 1 to 2 g/kg IV every 2 to 4 weeks). Rituximab, a monoclonal anti-CD20 antibody, when studied for treatment of DM and polymyositis in a randomized controlled trial, failed to meet the primary outcome measure, but clinical improvement and a significant reduction in steroid dose was seen in all patients receiving the treatment [Level 1].3 A randomized controlled trial of IVIG in treatment-resistant cases of DM showed it to be effective in 9 of 12 cases [Level 1].4 The American Academy of Neurology 2012 guidelines recommend IVIG as a possibly effective therapy for refractory DM. Other medications occasionally used for refractory cases include cyclosporine (starting 2.5 mg/kg daily divided b.i.d.), tacrolimus (0.075 mg/kg/day divided b.i.d.), mycophenolate mofetil (starting 500 to 1,000 mg daily), and cyclophosphamide (doses starting at 300 mg/m2 every 4 weeks). Many of these second- and third-line immunosuppressive medications have significant toxicities and side effects and should be prescribed by specialists familiar with their use.

TABLE 90.2 Myositis-Specific Antibodies

Antibody	Clinical Features
Antisynthetase Antibodies
Anti-Jo-1 Anti-PL-7 Anti-PL-12 Anti-EJ Anti-OJ Anti-KS Anti-Zo Anti-Ha	Seen in polymyositis, dermatomyositis, and interstitial lung disease
Dermatomyositis-Specific Antibodies
Anti-Mi-2	Treatment responsive
Anti-MDA5 (CADM-140)	Minimal myopathy; ILD
Anti-155/140	Cancer associated
Anti-140	Juvenile dermatomyositis, calcinosis
Anti-SAE	Amyopathic DM
Antibodies in Immune-mediated Necrotizing Myopathy
Anti-SRP	Severe, acute presentation, resistant to treatment
Anti-HMGCR	Related to statin use
ILD, interstitial lung disease; DM, dermatomyositis.
Adapted from Albayda J, Mammen AL. Is statin-induced myositis part of the polymyositis disease spectrum? Curr Rheumatol Rep. 2014;16:433.

Treatment must include management of associated systemic manifestations, with close coordination of rheumatology, neurology, pulmonology, cardiology, and oncology when appropriate.

Physical therapy, occupational therapy, and low-intensity exercise are generally recommended for all patients with inflammatory myopathies to prevent deconditioning, help with gait training, and improve muscle strength.

Treatment of juvenile DM is similar and high-dose daily oral prednisone or pulsed intravenous methylprednisolone is considered the gold standard and must be initiated promptly to prevent significant morbidity and mortality. Other steroid-sparing immunosuppressives in those who do not respond to or cannot tolerate steroids including methotrexate and cyclosporine may be used.

TABLE 90.3 Key Features of Inflammatory and Necrotizing Autoimmune Myopathies

	Dermatomyositis	Polymyositis	Inclusion Body Myositis	Necrotizing Autoimmune Myopathy
Autoantibodies	Antisynthetase antibodies (anti-Jo-1 and others) Dermatomyositis-specific antibodies (anti-Mi-2 and others)	Antisynthetase antibodies (anti-Jo-1 and others) Antibodies of systemic rheumatologic disease	Possibly anti-cytosolic 5′-nucleotidase 1A (cN1A)	Anti-SRP Anti-HMGCR
Muscle enzymes	Up to 50× ULN	Up to 50× ULN	Up to 15× ULN	Often >10× ULN
Associated disorders	Interstitial lung disease (antisynthetase) Malignancy (ovarian, lung, others)	Interstitial lung disease (antisynthetase) Systemic rheumatologic disorders	None	HMGCR—statin use
Treatment (see dermatomyositis treatment for typical doses)	Prednisone Azathioprine Methotrexate Rituximab IVIG Others	Prednisone Azathioprine Methotrexate Rituximab IVIG Others	None	Prednisone Rituximab
SRP, signal recognition particle; HMGCR, 3-hydroxy-3-methylglutaryl-coenzyme A reductase; ULN, upper limit of normal; IVIG, intravenous immunoglobulin.

POLYMYOSITIS

Polymyositis (PM), as a clinical syndrome of myopathic weakness, is similar in presentation and treatment to DM, absent the typical dermatologic findings of the latter. Pathologically, however, it is a distinct entity and associates more closely with systemic autoimmune disorders. Although treated similarly with regard to immunosuppression, distinguishing PM and DM is important to establish risk of underlying malignancy or rheumatologic disease (see Tables 90.3 and 90.4).

EPIDEMIOLOGY

Idiopathic inflammatory myopathies as a whole are reported with a prevalence of approximately 14 in 100,000. The percentage of inflammatory myopathies identified as PM vary widely from 2% to over 50% in different series.

TABLE 90.4 Features Differentiating Dermatomyositis from Polymyositis

Dermatomyositis	Polymyositis
Typical dermatologic manifestations	No rash unless lupus associated
May be associated with malignancy	Not typically associated with malignancy
Not generally associated with systemic rheumatologic disease, except sometimes scleroderma	Often associated with a systemic rheumatologic disease, including lupus, systemic sclerosis, vasculitis
Childhood form exists	Adult disease
Muscle biopsy findings (perimysial and perivascular inflammation)	Muscle biopsy findings (endomysial inflammation)

PATHOBIOLOGY

PM is considered an autoimmune disease of disordered cellular immunity (in contrast to the presumed humoral abnormalities of DM). The antigenic target is not known, however, and the nature of the immunologic aberration is not known. The association with collagen-vascular disease increases the likelihood of autoimmune disorder. Although there is some increased risk of malignancy in association with PM, the association is not as high as that seen in DM.

CLINICAL MANIFESTATIONS

The symptoms of PM are those of a myopathy that primarily affects proximal limb muscles, similar in distribution to DM: difficulty climbing stairs or rising from low seats, lifting packages or dishes, or working with the arms overhead. Weakness of neck muscles may result in head drop. Typically, cranial muscles are spared, although dysphagia can occur when the disease is severe. Respiratory muscles are only rarely affected. Pain, or myalgias, may be present, but sensory symptoms are otherwise absent.

Symptoms of systemic disease may occur in the setting of PM related to a systemic rheumatologic disorder, including arthralgia or Raynaud symptoms. The typical rash of DM is absent, but there may be a rash of lupus in association with PM.

Interstitial lung disease can occur in PM but is more commonly associated with DM and anti-Jo-1 antibodies.

There is a mild increase in cancer risk in PM compared to the general population, but the association is not nearly as strong as that seen in DM.

Cardiac involvement can occur with PM with myocarditis, arrhythmia, and rarely, congestive heart failure. Cardiology evaluation in all patients with inflammatory myopathy is advised.

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