Subsequently, a biopsy was performed on an abdominal lymph node specimen. The results showed a poorly differentiated malignant neoplasm consistent with small cell carcinoma not of pulmonary origin. Immunohistochemical staining results were positive for cytokeratin AE1/AE3, synaptophysin, neuron-specific enolase, CD117, CD56, CD99, and bcl-2 antibodies. The primary site of involvement could not be identified. Two months after the diagnosis of clinically amyopathic DM (CADM), the patient died of cancer complications.
Comment
Inflammatory myopathies, including DM, are rare disorders, with an estimated prevalence rate of approximately 5.5 per million individuals worldwide.1 There are several variants of the disease, with different physical examinations and laboratory findings. Classic DM most commonly presents with proximal muscle weakness and an edematous violaceous discoloration (heliotrope rash) around the eyes. Gottron papules (violaceous papules on the metacarpophalangeal, proximal interphalangeal, and distal interphalangeal joints) also may be present in contrast to the lesions of systemic lupus erythematosus, which tend to affect the interphalangeal joints. Diagnostic criteria for classic DM were proposed by Bohan and Peter5,6 in 1975 (Table).
Patients who present with minimal or no muscle involvement are considered to have hypomyopathic or amyopathic DM. In hypomyopathic DM, the patient does not experience muscle symptoms but has elevated levels of muscle-associated enzymes, such as creatine kinase, aldolase, lactate dehydrogenase, or myoglobin, or an increased urinary creatine to creatinine ratio. As first described by Euwer and Sontheimer,7 patients with CADM will present with cutaneous manifestations but will not have signs or symptoms of muscle inflammation. Of all patients with DM, CADM represents only 5% to 11% of cases.7,8
The underlying pathogenesis of DM is a vasculopathic process,9 with deposition of the membrane attack complex (MAC) on the endothelium of capillaries in the skin as well as the muscle.10-12 This process appears to be of an autoimmune nature and involves numerous antibodies directed toward various autoantigens.
Autoantigens and DM—Antinuclear antibody screening commonly is used to detect autoimmune diseases such as DM. Although this test may yield a positive result, typically in a speckled pattern, one-third to one-half of patients with DM will have a negative antinuclear antibody test result.1,13 Myositis-specific antibodies (MSAs) may assist in the diagnosis of DM and also can help in prognostic and treatment decisions. Antisynthetases, a subset of MSAs, have targets in the cytoplasm of cells. One target is an antibody to Jo-1, also known as histidyl–transfer RNA synthetase, which is present in 80% of patients with DM with an antisynthetase antibody.14 The significance of this antibody is yet to be fully elucidated, but its presence appears to correlate with muscle weakness, Raynaud phenomenon, and nonerosive arthritis. Interestingly, the Jo-1 autoantigen shares structural homology with the picornavirus, which is known to cause myositis.15 Furthermore, increased concentrations of native Jo-1 in the body will not induce an immune response, but recombinant Jo-1 from patients with DM will induce the proliferation of HLA class II antigen–restricted peripheral T cells, meaning that Jo-1 must somehow be modified before becoming an autoantigen.16,17
The presence of any of the antisynthetase antibodies (Jo-1, PL-7, PL-12, OJ, EJ) can lead to the antisynthetase syndrome. Anti–Jo-1 is the most common and is associated with 60% to 80% of all cases of the antisynthetase syndrome.15 Patients with this syndrome have a poor prognosis compared with other patients with DM because they are more susceptible to interstitial lung disease and tend to respond poorly to therapy.1 Overall, the mortality rate of these patients is 3 times that of other patients with DM. However, the malignancy rate in these patients tends to mirror the general population rate,15 which is unusual considering that the estimated rate of malignancy in patients with DM is 50%.18 In other words, antisynthetase syndrome appears to lack an association with malignancy. Patients with antisynthetase syndrome tend to have only one specific MSA, but they may have other antibodies known as myositis-associated antibodies.15
Besides antisynthetases, there are other important MSAs that can influence prognosis and treatment response and may indicate the presence of an associated malignancy. The most specific MSA for DM is anti–Mi-2 whose target is a nuclear helicase. Ninety-seven percent of patients who test positive for the Mi-2 antibody have DM.15 In general, these patients have a better prognosis than patients with antisynthetase syndrome because interstitial lung disease and coexisting neoplasms are less common compared with all patients with DM.15 However, cutaneous findings are more common.19
A study from Japan found an antibody that reacted against a 140 kDa peptide (anti–CADM-140) that was present in 8 of 15 individuals with CADM. Although there was lesser severity of muscle involvement in this subset of patients, it appears that the anti–CADM-140 MSA is a marker for more aggressive interstitial lung disease.20 Kaji et al19 described another autoantibody that reacted against both a 155 kDa and a 140 kDa peptide (anti-155/140 antibody). Among 52 patients with DM, 7 (13%) patients had this antibody. The anti-155/140 antibody compared with DM controls without this autoantibody (n=45) correlated well with the presence of Gottron papules (100% [7/7] vs 58% [26/45], respectively; P<.05), a heliotrope rash (86% [6/7] vs 38% [17/45], respectively; P<.05), and most significantly flagellate erythema (86% [6/7] vs 20% [9/45], respectively; P<.05). Unlike anti–CADM-140, this autoantibody lacks the association with aggressive interstitial lung disease. However, the anti-155/140 antibody seemed to indicate the presence of an underlying malignancy (71% [5/7] of patients with anti-155/140 antibody vs 11% [5/45] without the antibody).19