Page 792 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHaPtEr 56 Inflammatory Muscle Diseases 763

mice demonstrated that abnormal accumulation of MHC class GENETICS
I molecules in the endoplasmic reticulum (ER) of muscle may
initiate the ER stress response. 20 The IIMs do not exhibit a simple mode of inheritance, and the
rare familial cases mostly reflect IBM of early onset. As noted
KEY CONCEPtS above, there are HLA associations for particular MSAs. Specifically,
Differential Histological Features of Myositis HLA-DR52 has a strong association (90%) with antisynthetase-
positive myositis in people of both European and African
22
• In dermatomyositis the earliest changes involve vessel walls, and B descent. HLA DRB1*11:01 was recently shown to be associated
cells and CD4 T cells predominate in the muscle biopsy. with an increased risk of anti-HMGCR myopathy. 23
• In polymyositis and inclusion body myositis, the dominant pathological
feature is targeting and invasion of muscle cells by CD8 cytotoxic T
cells. NATURAL HISTORY
The prognosis for patients with IIM varies greatly with clinical
Proposed pathogenic mechanisms for the development of type, autoantibodies, extraskeletal muscle involvement, and the
the sporadic forms of IBM are complex and include both autoim- interval between diagnosis and the start of treatment.
munity and degeneration. Many proteins also found in other Patients with DM or myositis accompanying another con-
neurodegenerative diseases have been shown to accumulate in nective tissue disease are likely to recover most of their strength
IBM muscle. In addition, IBM patients typically do not respond with prompt and adequate therapy. Although recurrences
to immunosuppressive medications. These findings likely suggest are common, persistent profound weakness does not usually
that IBM is a degenerative disease. However, IBM is sometimes occur. Most patients with anti-Mi-2 autoantibodies also usually
associated with other autoimmune diseases. In IBM biopsy respond well to therapy. Strength usually recovers well in patients
specimens, inflammatory cells are predominantly composed of whose myositis is cancer related, but overall mortality due to
CD8 T cells, and a majority of patients express a circulating the tumor is high. Indeed, an accompanying tumor remains
antibody to cytosolic 5′-nucleotidase 1A, supporting the role of one of the most frequent causes of death in patients with an
autoimmunity in the pathogenesis of IBM. IIM. Among the MSAs, anti-TIF-1γ and anti–NXP-2 antibodies
In necrotizing autoimmune myositis (also known as IMNM), are found with increased frequency in patients with cancer-
there is necrosis of muscle fibers with myophagocytosis and associated DM. 24
regeneration and paucity of T-cell infiltration. Complement Patients with PM fare less well, even when those with IBM are
deposition on blood vessels has been reported. In muscle biopsies rigorously excluded. A return to normal strength is very unusual,
from patients with statin-associated necrotizing autoimmune and each recurrence is likely to be followed by greater residual
myositis, MHC class-I upregulation is frequently seen. 13 weakness, even if inflammation is fully controlled. IBM has a
The pathogenic role of autoantibodies found in IIM patients poorer prognosis, but it is possible that the gradual decline in
remains uncertain. MSAs are found in 60–80% of patients and strength can be halted for long periods by corticosteroid and/
appear to delineate specific clinical entities; each group has a or cytotoxic therapy if continuing inflammation is present.
strong but not absolute human leukocyte antigen (HLA) associa- Severe muscle weakness and atrophy and very high CK levels
tion. In a patient with myositis and antihistidyl-tRNA synthetase are prominent features in patients with anti-SRP autoantibod-
(Jo-1) autoantibodies, sera available from long before the onset ies. Patients with anti-MDA5 antibodies are at increased risk
of symptoms or biochemical damage to muscle tissue contained for developing progressive interstitial lung disease. Those with
the autoantibodies, suggesting that the autoantibodies were not anti-Jo-1 autoantibodies or antibodies to another synthetase are
merely a response to release of tissue antigens. The extraordinary likely to respond to therapy initially, but they typically require
specificity of MSAs for IIM and the lack of evidence for strong continuing immunosuppression to treat frequent recurrences.
polyclonal stimulation in these diseases suggest that MSAs are In this group morbidity and mortality are heavily influenced
related to the fundamental causative process in IIM. by the progression of lung involvement. Longitudinal outcome
The structures bound by MSAs are mostly intracellular studies in DM and PM are few. Cardiac involvement, respira-
ribonucleoproteins involved in protein synthesis, such as the tory involvement, and cancer were the main causes of death
aminoacyl-tRNA synthetases and the SRP. These autoantigens in several cohort analyses. Disease course is monocyclic in
are found in every nucleated cell. In general, the antibodies bind approximately 20% of patients, polycyclic in 20%, and chronic
to conformational epitopes and, at least in the case of the in the remainder. Relapses have been noted in the initial years
antisynthetases, block enzymatic activity. It is possible that a of therapy and after prolonged disease-free intervals; therefore
structural property of muscle allows these particular proteins periodic surveillance is warranted for at least 2 years after
to be presented to the immune system when the cells are damaged; remission.
alternatively, the capacity of muscle fibers to degenerate alongside
intense regeneration within the same fiber may allow these PATIENT MANAGEMENT
21
proteins to be efficiently displayed. Experiments have suggested
that some aminoacyl-tRNA synthetases have a direct proinflam- The treatment of myositis is based on controlling skeletal muscle
matory role through a subsidiary chemokine-like action. inflammation and damage. Immunosuppressive therapy is used
A landmark study determined that cultured myoblasts express in the initial stages of the disease to reduce inflammation and
high levels of autoantigens, which are strikingly downregulated muscle damage. There are very few randomized controlled trials
as cells differentiate into myotubes in vitro. These data strongly of any of the immunosuppressive agents used; thus therapeutic
associate regenerating rather than mature muscle cells as the regimens and responses have remained largely anecdotal. After
source of continuous autoantigen supply in autoimmune the initial inflammation is controlled, strengthening exercises
myositis. 21 are useful in improving functional capabilities.