rheumatology1.2

Question 1

Vasculitis

Answer 1

The vasculitides are a heterogeneous group of clinical disorders characterized by inflammation of blood vessels. Inflammation may involve arteries of any size: therefore, different vasculitic syndromes may have a spectrum of clinical and pathologic features. All of them mentioned here are type III.

Question 2

Terminology/Classification of vasculitis

Answer 2

Vasculitis classification can be based on the size of the vessel involved, the type of pathologic change in the vessel wall, and/or the clinical presentation. Vasculitides can be primary occurring separately from any known underlying disease or secondary to infectious disorders such as hepatitis B or C and endocarditis, drug hypersensitivity, connective tissue diseases (RA, SLE, Sjögren’s), cryoglobulins, and malignancies.

Question 3

Large-vessel vasculitis

Answer 3

includes giant cell and takayasu’s arteritis. More of t cell mediation

Question 4

Giant cell arteritis

Answer 4

temporal arteries, vessels originating from the aortic arch, other arteries less common; temporal headache, jaw claudication, scalp tenderness, visual loss; giant cell arteritis with disruption of the internal elastic lamina

Question 5

Takayasu’s arteritis

Answer 5

aortic arch and its branches, can involve any part of the aorta; claudication of upper > lower extremities, CNS events; granulomatous panarteritis. This leads to low blood flow and ischemia

Question 6

Medium-vessel vasculitis

Answer 6

includes polyarteritis nodosa and kawasaki’s disease

Question 7

Polyarteritis nodosa

Answer 7

small and medium-sized arteries; may affect any organ, but skin, joints, peripheral nerves, gut, and kidney are most commonly involved; focal but panmural necrotizing arteritis with a predilection for involvement at the vessel bifurcation. Often presents with abdominal pain

Question 8

Kawasaki’s disease

Answer 8

small and medium-sized arteries; acute febrile illness primarily affecting infants and young children; fever, prominent mucocutaneous changes, cervical lymphadenopathy, polymorphous rash, erythema and edema of hands and feet, desquamation, myocarditis, coronary vasculitis; probable infectious vector resulting in cytokine-mediated endothelial damage

Question 9

Small-vessel vasculitis

Answer 9

includes antineutrophil cytoplasmic antibody (ANCA) positive vasculitides and ANCA negative vasulitides

Question 10

Antineutrophil cytoplasmic antibody (ANCA) positive vasculitides

Answer 10

includes granulomatosis with polyangiitis (wegener’s), eosinophilic granulomatosis with polyangiitis (churg-strauss), and microscopic polyangiitis (MPA).

Question 11

Granulomatosis with polyangiitis (Wegener’s) (GPA)

Answer 11

small and medium-sized arteries; upper respiratory tract (sinuses), lungs, and kidneys, may affect other organs; pauci-immune, necrotizing, granulomatous arteritis usually associated with serum cytoplasmic-ANCA (c-ANCA to the PR-3). Noses collapses and patients often presents throws up blood with high creatinine.

Question 12

Eosinophilic granulomatosis with polyangiitis (Churg-Strauss):

Answer 12

ANCA positive. small arteries and venules; asthma, eosinophilia, multiorgan involvement – lungs, skin, peripheral nerves, gut, heart, renal (rare); necrotizing extravascular granulomas and vasculitis of small arteries and venules, eosinophils present in early stage

Question 13

Microscopic polyangiitis (MPA)

Answer 13

arterioles, capillaries, and venules; pulmonary hemorrhage, glomerulonephritis, palpable purpura, peripheral neuropathy, joint and abdominal pain; pauci-immune, necrotizing vasculitis, serum perinuclear-ANCA (p-ANCA binds to MPO) common.

Question 14

Antineutrophil cytoplasmic antibody (ANCA) negative vasculitides

Answer 14

includes Henoch-Schonlein Purpura (HSP), essential cryoglobulinemic vasculitis, and cutaneous leukocytoclastic angiitis.

Question 15

Henoch-Schönlein Purpura (HSP)

Answer 15

arterioles and venules; palpable purpuric skin lesions lower extremities, arthritis, abdominal pain, hematuria; leukocytoclastic (neutrophilic perivascular/transmural infiltrate) or necrotizing vasculitis often with IgA deposition (the only one with IgA). ANCA negative.

Question 16

Essential cryoglobulinemic vasculitis

Answer 16

cryoglobulins are immunoglobulins that are reversibly precipitated by reduced temperatures; cryoglobulins are deposited in small vessels including glomerulocapillaries; purpura, arthralgias, weakness, peripheral neuropathy, Raynaud’s phenomenon, glomerulonephritis, pulmonary hemorrhage possible; often rheumatoid factor and hepatitis C antibody positive; cryoglobulins deposited on the vascular wall stimulate complement activation and a cellular inflammatory response. ANCA negative

Question 17

Cutaneous leukocytoclastic angiitis

Answer 17

arterioles and venules; palpable purpuric skin lesions, arthralgias, systemic symptoms may be present, usually secondary to an immune response [drugs, bugs (infections), connective tissue disease, malignancy]; leukocytoclastic vasculitis. ANCA negative

Question 18

Signs/Symptoms of vasculitis

Answer 18

Common clinical features, including skin lesions, constitutional symptoms (fever, anorexia, weight loss, weakness, fatigue) and musculoskeletal symptoms (arthralgias, arthritis, myalgias, peripheral neuropathy) are found, to some extent, in all systemic vasculitides.

Question 19

Laboratory features of vasculitis

Answer 19

reflect systemic inflammation – anemia of inflammatory disease, thrombocytosis, low albumin, elevated sedimentation rate and C-reactive protein, polyclonal gammopathy; possibly elevated liver enzyme tests, low complement levels, cryoglobulins

Question 20

Diagnosis of vasculitis

Answer 20

history and physical exam to determine extent of organ involvement, detection of serum autoantibodies (RF, ANA, ANCA), biopsy of affected organ; if biopsy inaccessible, angiogram to show segments of smooth arterial stenosis alternating with areas of normal or dilated artery; tapered occlusions; thrombosis

Question 21

Incidence of vasculitis

Answer 21

rare group of disorders with mean age of onset in the fifth decade of life, although can occur at extremes of age; approximately equal sex distribution except for a female predominance in Takayasu’s and giant cell arteritis

Question 22

Ethnic associations of vasculitis

Answer 22

Although these disorders can occur in any population, there is a higher incidence of Takayasu’s arteritis in Japanese and Asian populations, and giant cell arteritis in populations of Northern European background, as well as in the northern latitudes.

Question 23

Pathology of vasculitis

Answer 23

Considerable overlap exists in the patterns of pathologic involvement in the vasculitic syndromes. Vasculitic lesions tend to be both focal and segmental. The entire circumference of the vessel may not be involved.

Question 24

Pathology of large and medium vessel vasculitis

Answer 24

typically panarteritis with infiltration to a varying degree of lymphocytes, monocytes, histiocytes, eosinophils, and polymorphonuclear leukocytes (PMNs) through the vessel wall; can be associated with granuloma or giant cell formation in some disorders (see Section I); disruption of the elastic lamina: intimal thickening results in narrowing or obliteration of the vessel lumen

Question 25

Pathology of small vessel vasculitis

Answer 25

typically fibrinoid necrosis of the vessel wall with a transmural inflammatory reaction; often referred to as “leukocytoclastic” vasculitis – a pathologic term used to describe necrotizing vasculitis with PMN-derived nuclear debris that often accompanies the neutrophilic perivascular infiltrate of the vessel wall; immunoglobulin (IgM, IgA in HSP) and complement (C3) vascular deposition are often noted in the vasculitic lesions

Question 26

Pathophysiology of vasculitis

Answer 26

No single pathophysiologic process accounts for the spectrum of pathology noted in the systemic vasculitides. Suspected mechanisms of vascular damage include immune complexes, antineutrophil cytoplasmic antibodies, antiendothelial antibodies, T cell dependent mediated endothelial cell injury, and infection of endothelial cells.

Question 27

Immune complexes (IC) and vaculitis

Answer 27

Animal models of serum sickness, human serum sickness induced by horse immunoglobulins (anti-venoms), and the demonstration of hepatitis B surface antigen and IgM in an arterial wall of a patient with polyarteritis nodosa suggest that IC can mediate inflammatory vessel disease. In animal models, platelet activating factors and other vasoactive mediators released as part of the inflammatory and cytokine response probably induce vascular permeability. This is followed by deposition of circulating IC at the vascular endothelium, the activation of complement, and the attraction of PMNs. Indirect evidence suggests the IC-induced vasculitis may be involved in hypersensitivity vasculitis, HSP, cryoglobulinemia, and hepatitis B–associated vasculitis.

Question 28

Antineutrophil Cytoplasmic Antibodies (ANCA)

Answer 28

ANCA are antibodies to antigens found in the cytoplasm of neutrophils. The cytoplasmic staining or c-ANCA (granulomatosis with polyangiitis) binds to proteinase 3 (PR3) found in the primary granules of the PMN. The perinuclear staining or p-ANCA (microscopic polyangiitis) binds to myeloperoxidase (MPO), another primary granule constituent which migrates to the perinuclear area with alcohol fixation of PMNs. Potentially, inflammatory cytokines induced by infections or other insults activate PMNs to release and express PR3 and MPO on the cell surface. The binding of ANCA to the neutrophil cell surface leads to further neutrophil activation and possibly enhanced binding to vascular endothelial cells with resultant vascular damage. PR3 and MPO have also been found on the surface of activated endothelial cells. Although ANCA may not be essential for the initiation of the vasculitis, they may play a role in amplifying the inflammatory vascular response.

Question 29

Antiendothelial antibodies

Answer 29

These antibodies have been demonstrated in a number of autoimmune and vasculitic diseases. In vitro, antiendothelial antibodies can damage endothelial cells by both antibody-dependent cellular cytotoxicity (ADCC) and complement activation mechanisms. Unfortunately, these antibodies directed toward structures on the surface of endothelial cells are not found in all vasculitic syndromes.

Question 30

T Cell Dependent Mediated Endothelial Cell Injury

Answer 30

T-cell responses in the initiation and perpetuation of vascular injury have been suggested in Takayasu’s, granulomatosis with polyangiitis, and giant cell arteritis. In patients with giant cell arteritis, there is an over-representation of the HLA-DR4 haplotype. This association has been mapped to a sequence polymorphism within the hypervariable region 2 of the HLA-DRB1 gene (a probable antigen-binding element of the HLA-DR molecule). This suggests antigen-driven vascular inflammation. This polymorphism is not shared by patients with rheumatoid arthritis.

Question 31

Infection of Endothelial Cells

Answer 31

A wide variety of infectious agents can infect endothelial cells. Infected endothelial cells promote binding of IC and PMNs to the endothelium, express MHC class II genes, enhance local lymphocyte proliferation, and release stimulatory and proliferative cytokines. These changes may promote the vascular inflammatory response and initiate a T cell proliferative response.

Question 32

Treatment of Vasculitis as Relates to Pathophysiology

Answer 32

Treat or remove the inciting agent or antigen: drugs, infections – endocarditis, hepatitis B and C. In general, the pathogenic process, the extent of inflammation and vascular involvement, and the rate of progression of the disease determine the management of vasculitis. Glucocorticoids generally control the inflammatory features of vasculitis. Rapidly progressive disease with significant major organ involvement (lung, kidney, and gut) may require high-dose glucocorticoids and a cytotoxic drug such as cyclophosphamide. Plasmapheresis may be beneficial in hepatitis C-induced cryoglobulinemia and ANCA-positive vasculitides. Rituximab, an anti-CD20 B cell monoclonal antibody, has been shown to be efficacious as a treatment for severe ANCA-associated vasculitis.

Question 33

Key Points of Vasculitis

Answer 33

The vasculitides are a rare group of disorders defined by the size of the vessel involved, the pathologic change in the vessel wall, and the clinical presentation. In primary vasculitis, the inciting agent is unknown. The vasculitic response may be due to IC deposition, autoantibodies (anti-endothelial, ANCAs), antigen-driven inflammation, and/or infection of endothelial cells.

Question 34

Polymyositis (PM) and dermatomyositis (DM)

Answer 34

the most common of the rare autoimmune inflammatory muscle diseases. Both are characterized by chronic muscle weakness and infiltration of muscle tissue by chronic inflammatory cells. In DM, the inflammatory muscle disease is accompanied by typical skin rashes. Although usually idiopathic, these disorders may occur in association with neoplastic disease or in “overlap” with other autoimmune diseases such as scleroderma, mixed connective tissue disease (MCTD), Sjögren’s syndrome, and SLE.

Question 35

Group I of PM/DM

Answer 35

Primary idiopathic polymyositis

Question 36

Group II of PM/DM

Answer 36

Primary idiopathic dermatomyositis

Question 37

Group III of PM/DM

Answer 37

PM/DM associated with neoplasia (in DM, incidence 4%-40%)

Question 38

Group IV of PM/DM

Answer 38

Childhood DM (more rarely PM)

Question 39

Group V of PM/DM

Answer 39

PM/DM associated with another rheumatic/connective tissue disease

Question 40

Other of PM/DM

Answer 40

Inclusion body myositis (IBM): Men > women; age > 50 years; insidious onset of muscle weakness predominantly involving finger flexors and thigh muscles; negative autoantibodies; classic histopathologic changes of rimmed vacuoles and inclusion; resistant to treatment with immunosuppressive drugs

Question 41

Clinical Features of Muscle Disease

Answer 41

Muscle weakness and low endurance are typically the main complaints in patients with PM/DM. Proximal extremity muscles are affected earliest and most severely leading to early complaints of difficulty with standing, rising from chairs, climbing stairs, and with brushing/washing their hair. Only half experience any muscle pain or tenderness. With untreated disease, severe weakness develops affecting the musculature of the proximal extremities, the striated muscle of the upper third of the esophagus, and possibly the muscles of respiration.

Question 42

Gottron’s papules

Answer 42

Erythematous papular rash over the metacarpal or interphalangeal joints; can also occur over the elbows and knees (Gottron’s sign).

Question 43

Heliotrope rash

Answer 43

Blue-purple discoloration of the upper eyelid.

Question 44

V-sign and shawl-sign rash

Answer 44

Erythematous V-shape rash over the anterior chest; shawl-sign is an erythematous rash over the shoulders and upper back

Question 45

Mechanic’s hands

Answer 45

Cracked, dry-appearing skin over the finger pads, particularly on the radial side of the index fingers (usually associated with anti-synthetase autoantibodies).

Question 46

Calcinosis cutis

Answer 46

Subcutaneous calcification; occurs primarily in juvenile dermatomyositis.

Question 47

Periungual erythema, nail-fold telangiectasias, and cuticular overgrowth

Answer 47

more common in DM.

Question 48

Holster sign

Answer 48

poikiloderma (atrophic mottled skin) on the lateral aspects of the thighs

Question 49

Clinical extra-muscular features of PM/DM

Answer 49

Constitutional symptoms: Unintentional weight-loss, fever, fatigue. Gastrointestinal: Dysphagia; intestinal perforation (caused by mesenteric vasculitis in juvenile DM). Pulmonary: Interstitial lung disease (pulmonary fibrosis)—50 to 60% in those with the anti-Jo-1 antibody; aspiration pneumonia. Cardiac: Myocarditis; conduction defects; arrhythmias. Musculoskeletal: Nonerosive inflammatory arthritis. Vascular: Raynaud’s phenomenon; vasculitis (in juvenile DM). Anti-synthetase Syndrome: Constellation associated with antisynthetase antibodies (e.g. anti-Jo-1 antibody): PM or DM presenting with fever (20%), arthritis (50%), mechanic’s hands (30%), Raynaud’s phenomenon (40%), and interstitial lung disease (ILD, 60%).

Question 50

Epidemiology of PM/DM

Answer 50

Incidence: 10 per 1 million persons per year. Sex: Females affected slightly more often than males; ratio ~2-3:1. Age of onset: Two peaks of incidence—childhood and 5th decade. Race: In the United States, incidence in African-Americans is 2-3 fold that in whites.

Question 51

Laboratory, Electromyography (EMG), and MRI Findings with DM/PM

Answer 51

Muscle enzymes: CPK elevated in the vast majority of patients with active disease. Other indicators of muscle injury may be elevated: aldolase, myoglobinemia, LDH, AST, ALT.

Question 52

Autoantibodies with PM/DM

Answer 52

includes myositis-specific antibodies and myositis- associated antibodies

Question 53

Myositis-specific antibodies (MSAs)

Answer 53

includes anti-synthetase, anti-Mi-2, and anti-SRP antibodies.

Question 54

Anti-synthetase antibodies

Answer 54

Directed against aminoacyl-tRNA synthetases (a family of enzymes whose role is to catalyze the attachment of a particular amino acid to its transfer RNA). Anti-Jo-1 = anti-histidyl-tRNA synthetase (present in 20% of myositis patients). Antibodies against several other aminoacyl-tRNA synthetases have been discovered and occur less frequently (1-3%). Clinical association: anti-synthetase syndrome (see above).

Question 55

Anti-Mi-2 antibody

Answer 55

Directed against a nuclear helicase. Seen in ~7% of patients with classic DM; erythroderma and the shawl-sign. Associated with a good prognosis.

Question 56

Anti-signal recognition particle (SRP) antibodies

Answer 56

SRP is involved in the translocation of newly synthesized proteins into the endoplasmic reticulum. Anti-SRP antibodies occur only in PM and are associated with severe myopathy and cardiac disease; myopathy is often refractory to corticosteroids and immunosuppressive agents.

Question 57

Myositis-associated antibodies (MAAs)

Answer 57

Antinuclear antibody (+ANA) seen in >70% of patients with PM/DM.

Question 58

EMG findings with PM/DM

Answer 58

a myopathic pattern - increased insertional activity (abnormally increased activity when the EMG needle is inserted) and spontaneous fibrillations, decreased amplitude of motor unit action potentials, and complex repetitive discharges. Always obtain EMG on one side and obtain the muscle biopsy on the contralateral side as not to complicate the interpretation of the biopsy.

Question 59

MRI findings with PM/DM

Answer 59

can demonstrate areas of muscle inflammation, edema with active myositis, fibrosis, and calcinosis; can be used to guide the optimal site for biopsy and define the response to therapy.

Question 60

Biopsy Findings with PM/DM

Answer 60

Common to both PM and DM is the finding of a chronic inflammatory infiltrate in the muscle tissue accompanied by muscle fiber necrosis and regeneration. There are histological differences between PM and DM that are important to note:

Question 61

Polymyositis

Answer 61

Endomysial distribution with mononuclear inflammatory cells surrounding and invading non-necrotic muscle fibers throughout the fascicle. The inflammatory cell infiltrates are primarily CD8+ T cells and macrophages with rare CD4+ T cells and dendritic cells. CD8+ cytotoxic T lymphocytes (CTLs) recognize MHC class I on muscle fibers and mediate muscle fiber damage. Normal (non-necrotic) skeletal muscle cells do not constitutively express MHC class I molecules although expression can be induced by proinflammatory cytokines such as interferon-γ and TNF-α. PM appears to be a direct CD8+ T cell-mediated muscle injury.

Question 62

Dermatomyositis

Answer 62

The inflammatory infiltrate (CD4+ T cells, B cells, macrophages, and dendritic cells) is concentrated in the perivascular, septal regions, and around the periphery rather than throughout the fascicle. These cells are most highly concentrated in the perivascular regions of the muscle. Vascular deposition of immunoglobulin and membrane attack complex of complement is frequently seen. Atrophy of muscle fibers in a perifascicular pattern (perifascicular atrophy) is highly characteristic of DM. Dermatomyositis is considered in part to be a complement-mediated vasculopathy.

Question 63

Cellular Immune Abnormalities with PM/DM

Answer 63

The following support cellular immune response against muscle: Muscle tissue infiltration by activated CD8+ (cytotoxic) T-lymphocytes. Increased numbers of activated T-lymphocytes in the peripheral blood of PM/DM patients. Proliferative response of peripheral blood mononuclear cells when exposed to autologous muscle (demonstrating lymphocyte recognition of muscle tissue). Lymphocytes from patients with PM have shown cytotoxicity to muscle tissue. Cytokine production: IL-1, TNF-α, and INF-α can be over expressed in muscle tissue. In DM, many of the CD4+ cells are plamacytoid dendritic cells that are proficient at producing type I interferons. High levels of type I interferon-inducible gene products are present in DM.

Question 64

Humoral Immune Abnormalities with PM/DM

Answer 64

Increased CD4+ (helper) T cells and B cells in muscle tissue of DM patients. Evidence suggesting immune complex-mediated damage:Vascular immunoglobulin and complement deposition in DM. Vasculitis in DM causing: skin ulcers; nail-fold changes; intestinal perforation (primarily in juvenile DM). Decreased density of muscle capillaries and evidence for ischemic muscle injury in DM, suggesting possible immune complex vascular injury in muscle tissue. Production of myositis-specific antibodies (MSAs) and myositis-associated antibodies (MAAs): No current evidence to support that these antibodies are pathogenic.

Question 65

Nonimmune mechanisms with Polymyositis

Answer 65

MHC class I is over expressed in myocytes; MHC class I assembly occurs in the endoplasmic reticulum (ER). It is likely that ER stress response plays a role in muscle fiber damage and destruction. The ER stress or overload response initiates upregulation of nuclear factor κB (NFκB) resulting in the induction of inflammatory cytokines such as IL-1 and TNF-α; cell death occurs if the ER’s functions are severely impaired.

Question 66

Nonimmune mechanisms with DM

Answer 66

Tissue hypoxemia from capillary loss (DM) and local tissue inflammation.

Question 67

Genetic Susceptibility with DM/PM

Answer 67

Relatively strong association with HLA-DRB1, HLA-DQA1, and HLA-DQB1 in those with anti-synthetase antibodies in PM.

Question 68

Viral Infections with DM/PM

Answer 68

Viruses might initially trigger the disease process before being eliminated by the host’s immune response. Evidence suggesting viral infections as a cause or triggering factor in PM and DM: Certain viral infections have been described to cause a form of inflammatory myositis (influenza, coxsackievirus, echoviruses). Viral particles (detected by electron microscopy) and RNA sequences (detected by virus-specific gene probes) have been detected in the muscle tissue of patients with DM and PM. HIV infection can be associated with PM. Higher prevalence of antibodies to coxsackie B virus in juvenile DM compared to controls. Isolation of enterovirus from a few patients with PM/DM. Seasonal (spring) pattern of onset in patients with anti-Jo-1 antibodies. Microarray mRNA profiling in DM: predominance of interferon-responsive pathways suggesting an antiviral response.

Question 69

Treatment with DM/PM

Answer 69

Since muscle damage and other manifestations of PM/DM are caused by an autoimmune inflammatory response, treatment is directed at suppressing this process though immunosuppressive therapy. Corticosteroids (prednisone): Used as first-line therapy in PM/DM. Immunosuppressive/Immunomodulatory Drugs: Used in conjunction with corticosteroids in those patients who do not respond well to corticosteroid therapy alone, in those patients in whom a steroid taper cannot be achieved, or those in whom steroid therapy results in significant adverse effects (e.g. exacerbation of diabetes). Such agents include: Methotrexate, Azathioprine, Cyclophosphamide, Mycophenolate, Cyclosporine or Tacrolimus, Intravenous immunoglobulin (IVIG), and Rituximab (monoclonal antibody against CD20 on B cells): case series suggest a beneficial effect in patients with refractory PM/DM. Physical therapy for muscle strengthening.

Question 70

Key Points Regarding PM/DM

Answer 70

Rare autoimmune muscle diseases characterized by symmetric proximal muscle weakness; other organs may be involved. May be accompanied by other autoimmune features: inflammatory arthritis, rash, Raynaud’s phenomenon, interstitial lung disease; myositis-specific antibodies in the anti-synthetase syndrome. Elevated levels of serum muscle enzymes (CPK) are present and EMGs reveal myopathic findings. Muscle histology reveals varying degrees of inflammation and fiber degeneration: PM: endomysial distribution; appears to be a direct CD8+ T cell-mediated muscle injury. DM: perivascular distribution; CD4+ T cells; perifascicular atrophy; considered in part to be a complement-mediated vasculopathy. There may also be a central role for type I interferons. Treatment is directed at suppressing the autoimmune inflammatory response.

Question 71

Anti-synthetase syndrome

Answer 71

a rare medical syndrome associated with Interstitial lung disease, dermatomyositis, and polymyositis and other autoimmune diseases.As a syndrome, this condition is poorly defined. Diagnostic criteria require one or more antisynthetase antibodies (which target tRNA synthetase enzymes), and one or more of the following three clinical features: interstitial lung disease, inflammatory myopathy, and inflammatory polyarthritis affecting small joints symmetrically. Other supporting features may include fever, Raynaud's phenomenon and "mechanics hands"-thick, cracked skin usually on the palms and radial surfaces of the digits. The disease, rare as it is, is more prevalent in women than in men. Early diagnosis is difficult, and milder cases may not be detected. Also, interstitial lung disease may be the only manifestation of the disease. Severe disease may develop over time, with intermittent relapses.It is postulated that autoantigens are formed against aminoacyl-tRNA synthetases. The synthethases may be involved in recruiting antigen-presenting and inflammatory cells to the site of muscle or lung injury. The specific molecular pathway of the process awaits elucidation.