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 bodys 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 bodys 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 antidouble 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 selfreactive 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 antiphospholipid 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( LibmanSacks) 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 DNA
Antibodies 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

Speckledassociated
with
SLE, Sjgren

polymyositis, rheumatoid arthritis, and mixed connective tissue disease

Nucleolarassociated with scleroderma and polymyositis

syndrome, scleroderma,

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 antiDNA 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,
Crithidia

namely
luciliae

enzyme-linked

immunosorbent

immunofluorescence

test,

assay

and

(ELISA),
test

the

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, antiSm 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, Sjogrens
syndrome, and polymyositis.
Anti-U1RNP has shown to be associated with features of scleroderma,
including Raynauds phenomenon; it has also been linked to other conditions,
such as Jaccouds 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

Sjorgrens 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
inclusionbodymyositis, are included in this category. These may occur alone or with
other immune-mediated diseases, particularly systemic sclerosis.
A. Dermatomyositis
It 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 myositis

Is 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.