Dermatomyositis
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Transcript of Dermatomyositis
DERMATOMYOSITIS
CASE7
A 52-year-old woman presents with the chief complaint of a 6-month history of progressive muscle weakness and a skin rash. In particular, she has noticed increased difficulty in climbing stairs and getting out of a chair. She has also had more difficulty raising items to high shelves, and lately she has even had problems keeping her arms raised while combing her hair. Symptoms have not been accompanied by myalgias. In addition, she has noted a 10-lb weight loss.
Physical examination is remarkable for a diffuse purple/red discoloration of the skin over her cheeks, nose, and eyelids, and extending to her chest. Examination also confirms the proximal muscle weakness.
Laboratory findings show an increase in the following: creatine kinase (CK, 10X normal), aspartate aminotransferase (AST), and alanine aminotransferase (ALT). Myoglobin is positive in the urine. Serology shows no anti-DNA antibodies but is positive for anti-Jo-1 antibodies.
SALIENT FEATURES
PRIMARY DIAGNOSIS
PATHOPHYSIOLOGY
In most cases, the cause of an inflammatory myopathy is unclear. For some reason, the body’s immune system turns against its own muscles and damages muscle tissue in an autoimmune process.
The exact cause of Dermatomyositis is still not clear. However, researchers have found similarities between this disease and autoimmune disorders. Autoimmune diseases occurs when the body’s disease fighting cells or antibodies attack healthy body cells which leads to compromise immune system. In DM, these cells attack the small blood vessels that supply muscles and skin. Viral infections are also believed to contribute to this disease.
The disease starts when putative antibodies or other factors activate C3. Activated C3 leads to formation of C3b, C3bNEO and membrane attack complex (MAC), which are deposited in and around endothelial cell wall of the endomysial capillaries. Deposition of MAC leads to destruction of capillaries, ischemia, or microinfarcts, most prominent in the fascicles, and perifascicular atrophy. B cells, plasmacytoid dendritic cells, CD4 T cells, and MACROPHAGES traffic from the circulation to the muscle. Endothelial expression of vascular cell adhesion molecule (VCAM) and intercellular adhesion molecule (ICAM) is induced by cytokines released by mononuclear cells. Integrins, specifically very late activation antigen (VLA)-4 and lymphocyte function-associated antigen (LFA)-1, bind VCAM and ICAM and promote T cell and macrophage infiltration of muscle through endothelial cell wall.
MANAGEMENT
Therapy for dermatomyositis involves both general measures and specific measures to control the muscle disease and the skin disease. In addition, some patients with dermatomyositis need treatment for other systemic manifestations or complications.
The muscle component is treated by administering corticosteroids, typically with an immunosuppressive agent. The skin disease is treated by avoiding sun exposure and by using sunscreens and photoprotective clothing, as well as with topical corticosteroids, antimalarial agents, and immunomodulatory medications such as methotrexate, mycophenolatemofetil, or intravenous immunoglobulin.
Surgical care is usually unnecessary in the management of dermatomyositis. Some patients may benefit from surgical removal of focal areas of calcinosis, particularly those that are painful. Inpatient care is needed for patients with fulminant dermatomyositis with muscle and/or internal organ involvement.
Children and adolescents are much more prone to the development of calcinosis. Aggressive and early treatment may prevent this complication.
TREATMENT AND PROGNOSIS
The prognosis for patients with dermatomyositis and polymyositiswas poor before the use of corticosteroids, with mortality rates as high as 50% or more. Corticosteroids remain the first-line of treatment for polymyositis and dermatomyositis. Immunosuppressive drugs are used in steroid-resistant disease or as steroid-sparing agents and include azathioprine and methotrexate. Intravenous immunoglobulin (IVIG), cyclophosphamide, cyclosporine, and rituximab (an antibody that targets B cells) are third-linetherapies. Inclusion body myositis usually responds poorly to steroids or
immunosuppressive therapies, another feature that argues against an inflammatory or immune origin for this disorder.
Now there are numerous treatments and immunomodulatory drugs. According to published data in 2012 (based on a study of random adult dermatomyositis and polymyositis patients seen at the University of Michigan from 1997 to 2003) the survival rates for dermatomyositis were 70% at 5 years and 57% at 10 years.Thus, it is important that treatment begin as soon as possible. The cutaneous manifestations of dermatomyositis may or may not improve with therapy in parallel with the improvement of the myositis. In some patients the weakness and rash resolve together. In others, the two are not linked, with one or the other being more challenging to control. Often, cutaneous disease persists after adequate control of the muscle disease.
LEARNING OBJECTIVES
1. Genetic, nongenetic and immunologic factors in the Etiology of SLE
Genetic Factors
Family members of patients have an increased risk of developing SLE. As many as 20% of clinically unaffected first-degree relatives of SLE patients reveal autoantibodies and other immunoregulatory abnormalities.
There is a higher rate of concordance (>20%) in monozygotic twins when compared with dizygotic twins (1% to 3%).
Studies of HLA associations support the concept that MHC genes regulate production of particular autoantibodies. Specific alleles of the HLA-DQ locus have been linked to the production of anti–double stranded DNA, anti-Sm, and antiphospholipid antibodies, although the relative risk is small.
Some lupus patients have inherited deficiencies of early complement components, such as C2, C4, or C1q. Lack of complement may impair removal of circulating immune complexes by the mononuclear phagocyte system, thus favoring tissue deposition. Knockout mice lacking C4 or certain complement receptors are also prone to develop lupus-like autoimmunity. Various mechanisms have been invoked, including failure to clear immune complexes and loss of B-cell self-tolerance. It has also been proposed that deficiency of C1q results in defective phagocytic clearance of apoptotic cells. Many cells normally undergo apoptosis, and if they are not cleared their nuclear components may elicit immune responses.
Genome-wide association studies have identified several genetic loci that may be associated with the disease. Many of these loci encode proteins involved in lymphocyte signaling and interferon responses, both of which may play a role in lupus pathogenesis, as discussed later. The relative risk for each locus is small, and even taken together these loci account for 20% or less of the genetic predisposition, suggesting an important role for environmental factors.
Immunologic Factors
Failure of self-tolerance in B cells results from defective elimination of self-reactive B cells in the bone marrow or defects in peripheral tolerance mechanisms.
CD4+ helper T cells specific for nucleosomal antigens also escape tolerance and contribute to the production of high-affinity pathogenic autoantibodies. The autoantibodies in SLE show characteristics of T cell-dependent antibodies produced in germinal centers, and increased numbers of follicular helper T cells have been detected in the blood of SLE patients.
Type I interferons play a role in lymphocyte activation in SLE. High levels of circulating type I interferons and a molecular signature in blood cells suggesting exposure to these cytokines has been reported in SLE patients and correlates with disease severity. Type I interferons are antiviral cytokines that are normally produced during innate immune responses to viruses. It may be that nucleic acids engage TLRs on dendritic cells and stimulate the production of interferons. In other words, self nucleic acids mimic their microbial counterparts. How interferons contribute to the development of SLE is unclear; these cytokines may activate dendritic cells and B cells and promote TH1 responses, all of which may stimulate the production of pathogenic autoantibodies.
TLR engagement by nuclear DNA and RNA contained in immune complexes may activate B lymphocytes. These TLRs function normally to sense microbial products, including nucleic acids. Thus, B cells specific for nuclear antigens may get second signals from TLRs and may be activated, resulting in increased production of antinuclear autoantibodies.
Other cytokines that may play a role in unregulated B-cell activation include the TNF family member BAFF, which promotes survival of B cells. In some patients and animal models, increased production of BAFF has been reported, prompting attempts to block the cytokine or its receptor as therapy for SLE.
Environmental Factors
Exposure to ultraviolet (UV) light exacerbates the disease in many individuals. UV irradiation may induce apoptosis in cells and may alter the DNA in such a way that it becomes immunogenic, perhaps because of enhanced recognition by TLRs. In addition, UV light may modulate the immune response, for example, by stimulating keratinocytes to produce IL-1, a cytokine known to promote inflammation.
The gender bias of SLE is partly attributable to actions of sex hormones and partly related to genes on the X chromosome, independent of hormone effects.
Drugssuch as hydralazine, procainamide, and D-penicillamine can induce an SLE-like response in humans.
2. Criteria for the Diagnosis of SLE
3. Common manifestations of lupus
4. Role of ANA and Immune complexes in the pathogenesis of renal disease in SLE
5. What is lupus anticoagulant and what clinical and laboratory features noted in patients who have this antibody?
SLE patients may have coagulation disorders that are often features of an anti-phospholipid antibody syndrome. Antibodies found in this syndrome may lead to prolongation of activated partial thromboplastin time ( aPTT). Lupus anticoagulant can be demonstrated in the blood of these patients.
6. Briefly describe the pathology in the joints, CNS, serosal surface, Heart, and Lung.
Joint symptoms, including arthralgia and arthritis
Serosalsurface , inflammation especially pericarditis and pleuritis
Heart, endocarditis of the characteristic atypical nonbacterial verrucous( Libman-Sacks) form, in which vegetations are seen on both sides of the mitral valve leaflet, the tricuspid valve is less frequently involved.
Lungs. Diffuse interstitial pulmonary fibrosis, manifest as interstitial pneumonitis or diffuse fibrosingalveolitis.
7. What is the long term prognosis of LE?
Renal failure and infections are the most common cause of death in patients with SLE
8. Describe chronic discoid LE, subacute cutaneous LE, and drug-induced LE
Discoid lupus is a chronic skin disease characterized by well-demarcated, erythematous discoid plaques, typically on the face and scalp but without systemic (extracutaneous ) symptoms.
Antibodies to double-stranded DNA are typically absent.There is a 5-10% risk of systemic disease (SLE)
Drug-induced LE. ANA test may become positive and typical symptoms of SLE may develop following administration of a variety of drugs ( hydrazine for hypertension) symptoms typically disappear after discontinuation of the drug. Drug-induced LE differs from SLE in that
It is not associated with antibodies to double-stranded DNAAntibodies to histones are present in 95% of affected people.Renal involvement is rare.Genetic susceptibility is indicated by a frequent association with HLA-DR4
LABORATORY DIAGNOSIS OF CONNECTIVE TISSUE DISEASES
1. Describe the four ANA patterns, including the significance of the nuclear and centromere patterns. What is the importance of DNA and SM antibodies in the diagnosis of SLE? How is serum levels of complement affected in SLE? What is the cause and
significance of low serum complement levels in SLE? What is the sensitivity of U1-RNP antibodies for mixed connective tissue disease (MCTD)?
The pattern of the ANA test can give information about the type of autoimmune disease present and the appropriate treatment program. A homogenous (diffuse) pattern appears as total nuclear fluorescence and is common in people with systemic lupus. A peripheral pattern indicates that fluorescence occurs at the edges of the nucleus in a shaggy appearance; this pattern is almost exclusive to systemic lupus. A speckled pattern is also found in lupus. Another pattern, known as a nucleolar pattern, is common in people with scleroderma.
Homogenous (diffuse)—associated with SLE, mixed connective tissue disease, and drug-
induced lupus
Speckled—associated with SLE, Sjögren syndrome, scleroderma, polymyositis, rheumatoid
arthritis, and mixed connective tissue disease
Nucleolar—associated with scleroderma and polymyositis
Centromere pattern (peripheral)—associated with scleroderma and CREST (Calcinosis,
Raynaud syndrome, Esophogeal dysmotility, Sclerodactyly, Telangiectasia)
Complement levels may be decreased due to increased consumption or, more rarely, a
hereditary deficiency. Hereditary deficiency in one of the complement proteins will usually lead
to a high frequency of recurrent microbial infections. Decreased complement levels also are
associated with an increased risk of developing an autoimmune disease. Both C3 and C4 levels
are typically depressed inSLE while C3 alone is low in septicemia and infections caused
by fungi or parasites such as malaria. If the deficiency is due to an
underlying acute or chronic condition, complement levels will usually return to normal if the
underlying condition can be resolved.
Anti-dsDNA Antibody
The anti-double-stranded DNA antibody (anti-dsDNA) is a specific type of ANA antibody found
in about 30% of people with systemic lupus. Less than 1% of healthy individuals have this
antibody, making it helpful in confirming a diagnosis of systemic lupus. [The absence of anti-
dsDNA, however, does not exclude a diagnosis of lupus.] The presence of anti-dsDNA antibodies
often suggests more serious lupus, such as lupus nephritis (kidney lupus). When the disease is
active, especially in the kidneys, high amounts of anti-DNA antibodies are usually present.
However, the anti-dsDNA test cannot be used to monitor lupus activity, because anti-dsDNA
can be present without any clinical activity. Three tests are currently used to detect anti-dsDNA
antibodies, namely enzyme-linked immunosorbent assay (ELISA), the Crithidia luciliae
immunofluorescence test, and a test called radioimmunoassay.
Anti-Smith Antibody
An antibody to Sm, a ribonucleoprotein found in the nucleus of a cell, is found almost
exclusively in people with lupus. It is present in 20% of people with the disease (although the
incidence varies among different ethnic groups), but it is rarely found in people with other
rheumatic diseases and its incidence in healthy individuals is less than 1%. Therefore, it can also
be helpful in confirming a diagnosis of systemic lupus. Unlike anti-dsDNA, anti-Sm does not
correlate with the presence of kidney lupus. Prospective studies have been performed as to
whether anti-Sm correlates with lupus flares and disease activity, although evidence seems to
suggests that it does not. The anti-Sm antibody is usually measured by one of four methods:
ELISA, counterimmunoelectrophoreses (CIE), immunodiffusion, or hemagglutination.
Anti-U1RNP Antibody
Anti-U1RNP antibodies are commonly found along with anti-Sm antibodies in people with SLE.
The incidence of anti-U1RNP antibodies in people with lupus is approximately 25%, while less
than 1% of healthy individuals possess this antibody. However, unlike anti-dsDNA and anti-Sm
antibodies, anti-U1RNP antibodies are not specific to lupus; they can be found in other
rheumatic conditions, including rheumatoid arthritis, systemic sclerosis, Sjogren’s syndrome,
and polymyositis.
Anti-U1RNP has shown to be associated with features of scleroderma, including Raynaud’s
phenomenon; it has also been linked to other conditions, such as Jaccoud’s arthropathy, a
deformity of the hand caused by arthritis. Levels of anti-U1RNP may fluctuate in individuals
over time, but this fluctuation has not proven to be a significant indicator of disease activity.
2. Select and interpret the appropriate antibody and complement test for SLE, rheumatoid arthritis, scleroderma, inflammatory myopathies, and Sjorgren’s syndrom.
3. Define rheumatoid factor (RF). What is the stimulus for RF production? How specific is this test for rheumatoid arthritis?
Rheumatoid factor (RF) is the autoantibody (antibody directed against an organism's own tissues) that was first found in rheumatoid arthritis. It is defined as an antibody against the Fc portion of IgG (an antibody against an antibody). These are produced when autoreactive B cells escape the natural tolerization process.
Autoantibodies specific for the Fc portion of IgG are known as rheumatoid factors (RFs)3 because of their common occurrence in patients with rheumatoid arthritis (RA). RFs also can be detected in up to 30% of normal individuals, but these RFs are of low affinity and low titer and do not have any pathological significance. In contrast, high-affinity RFs found in RA patients can form immune complexes, activate complement, and augment local inflammatory reactions
4. List the diseases associated with the depression of complement (c3, c4, or both) and indicate the changes in c4 and c3 associated with each of these diseases.
Decreased complement activity may be seen with:
Recurrent microbial infections (usually bacterial) – c3 alone is decreased
Autoimmune diseases, including SLE and rheumatoid arthritis –both c3 and c4
Hereditary angioedema – low cerum level of c4
Cirrhosis - c4 concentration reduced
Hepatitis – decreased specific c4 activity without c3 inclusion
INFLAMMATROY MYOPATHIES
List the most common organs affected, the pathologic findings in affected tissues, and the clinical manifestations of the three subsets of inflammatory myopathies.
Inflammatory myopathies comprise an uncommon, heterogeneous group of disorders characterized by injury and inflammation of mainly the skeletal muscles, which are probably immunologically mediated. Three distinct disorders, dermatomyositis, polymyositis, and inclusion-bodymyositis, are included in this category. These may occur alone or with other immune-mediated diseases, particularly systemic sclerosis.
A. DermatomyositisIt is a systemic autoimmune disease that typically presents with proximal muscle weakness and skin changes.Pathogenesis: It is an immunologic disease in which damage to small blood vessels contributes to muscle injury. The vasculopathic changes can beseen as telangiectasias(dilated capillary loops) in the nailfolds, eyelids, and gums, and as dropout of capillaryvessels in skeletal
muscle. Biopsies of muscle and skin mayshow deposition of the complement membrane attackcomplex (C5b-9) within capillary beds in both tissues. Aninflammatory signature enriched for genes that are upregulatedby type I interferons is seen in muscle and in leukocytes.The prominence of this signature appears to correlatewith disease activity. Various autoantibodies are often detected by serologic studies, and B lymphocytes as wellas plasma cells are part of the inflammatory infiltrate thatis seen in muscles. Certain autoantibodies tend to be associatedwith specific clinical features:• Anti-Mi2 antibodies ,Anti-Jo1 , Anti-P155/P140 antibodies
Morphology:Muscle biopsies of affected patients show infiltrates of mononuclear inflammatory cells that tend to be most pronounced in the perimysial connective tissue and around blood vessels. Sometimes there is a distinctive pattern in which myofiber atrophy is accentuated at the edges of the fascicles— perifascicular atrophy (See picture: Dermatomyositis below). Segmental fiber necrosis and regeneration may also be seen. Immunohistochemicalstudies may identify an infiltrate rich in CD4+ T-helper cells and the deposition of C5b-9 in capillary vessels. Electron microscopic studies may show tubuloreticular endothelial cell inclusions, a feature of a number of inflammatory disorders that are linked to a type I interferon response.
Clinical Features:Muscle weakness is slow in onset, symmetric, and often accompanied by myalgias. It typically affects the proximal muscles first. As a result, tasks such as getting up from a chair and climbing steps become increasingly difficult. Fine movements controlled by distal muscles are affected only late in the disease. Associated myopathic changes on electrophysiologic studies and elevation in serum creatinekinase levels are reflective of muscle damage. Various rashes are described in dermatomyositis, but the most characteristic ones are a lilac colored discoloration of the upper eyelids (heliotrope rash) associated with periorbitaledema (See picture: Dermatomyositis) and a scaling erythematous eruption or dusky red patches over the knuckles, elbows, and knees (Gottron papules). Dysphagia resulting from involvement of oropharyngeal and esophageal muscles occurs in one third of the affected individuals, and another 10% of patients have interstitial lung disease, which can sometimes be rapidly progressive and lead to death. Cardiac involvement is common, but rarely leads to cardiac failure.
B. Polymyositis
It is an adult-onset inflammatory myopathy that shares myalgia and weakness with dermatomyositisbut lacks its distinctive cutaneous features and is thereforeto some degree a diagnosis of exclusion. As in dermatomyositis,patients typically develop symmetric proximalmuscle involvement, and there may be inflammatoryinvolvement of the heart and the lungs, as well as similarautoantibodies.
Pathogenesis:The pathogenesis of polymyositis is uncertain, but it is believed to have an immunologic basis. CD8- positive cytotoxic T cells are a prominent part of the inflammatory infiltrate in affected muscle, and it is hypothesized that these cells are the mediators of tissue damage. Unlike dermatomyositis, vascular injury is not believed tohave a major role in polymyositis.
Morphology: Mononuclear inflammatory cell infiltrates are present, but in contrast to dermatomyositis, these are usually endomysial in location. Sometimes myofibers with otherwise normal morphology appear to be invaded by mononuclear inflammatory cells. Degenerating necrotic, regenerating, and atrophic myofibersare typically found in a random or patchy distribution. The perifascicularpattern of atrophy that is characteristic of dermatomyositisis absent.
C. Inclusion body myositisIs a disease of late adulthood that typically affects patients older than 50 years and is the most common inflammatory myopathy in patients older than age 65 years.Most affected individuals presentwith slowly progressive muscle weakness that tends tobe most severe in the quadriceps and the distal upperextremity muscles. Dysphagia from esophageal and pharyngealmuscle involvement is not uncommon. Laboratorystudies usually show modestly elevated creatine kinaselevels; most myositis-associated autoantibodies are absent,although an antibody to cN1A has recently been described.
Morphology: Inclusion body myositis has a number of features that are similar to those found in polymyositis, including:
• Patchy often endomysial mononuclear inflammatory cell infiltrates rich in CD8+ T-cells• Increased sarcolemmal expression of MHC class I antigens• Focal invasion of normal appearing myofibers by inflammatory cells• Admixed degenerating and regenerating myofibers
Other associated changes, however, are more typical or even specific for inclusion body myositis, as follows:• Abnormal cytoplasmic inclusions described as “rimmed vacuoles”• Tubolofilamentous inclusions in myofibers, seen by electronmicroscopiy• Cytoplasmic inclusions containing proteins typically associated with neurodegenerative diseases, like beta-amyloid, TDP-43, and ubiquitin• Endomysial fibrosis and fatty replacement, reflective of a chronic disease course
It has certain features in common with polymyositis, as discussed earlier. On the other hand, it shares some features with neurodegenerative diseases, such as the presence of abnormal protein aggregates. Furthermore, there are several familial inclusion body myopathies that are also associated with chronic myopathic changes and rimmed vacuoles. These typically lack any associated inflammation— hence the designation inclusion body “myopathy” rather than “myositis.”