Diagnosis: Dermatomyositis (DM) with neoplasia. Adenocarcinoma of lung. Interstitial lung disease--organizing diffuse alveolar damage.

Comment: This previously healthy woman had a 5-week course of a disease that most closely resembled dermatomyositis. A heliotrope rash on the eyelids, which responded to steroids, mechanic's hands, a skin biopsy consistent with a collagen vascular disease, a positive ANA, slight elevations of muscle enzymes aldolase and transaminases, a rapidly progressive organizing alveolar damage, and an occult lung cancer support the diagnosis. In a patient who lacks clinical evidence (no biopsy performed) of muscle disease, the diagnosis fits into the category of DM sine myositis, although muscle weakness may have occurred if she had lived longer. The lack of an anti-Jo-1 antibody in this patient with lung disease is not surprising as anti-Jo-1 antibody is only one of several anti-synthetase antibodies that occur in patients with DM or polymyositis (PM) and lung disease, and other types are more common in patients with DM compared to patients with PM. The combination of interstitial lung disease and malignancy in this case is very rare.

The diagnosis of the lung biopsy was misleading. In dermatomyositis, a diagnosis of organizing pneumonia (bronchiolitis obliterans organizing pneumonia) has a better prognosis than that of diffuse alveolar damage (DAD), which she had.

Note: Photographs of patients with heliotrope rash and other cutaneous findings may be found by clicking here: Use the "back" button to return to this page.


Adult Dermatomyositis

Clinical features: Dermatomyositis is an idiopathic inflammatory disease of muscle that also affects skin and may affect other organs including the lungs, gastrointestinal tract, and heart. DM represents between 15 and 34% of the idiopathic inflammatory myopathies, which also include polymyositis (PM) and inclusion body myositis. Typically, proximal limb girdle muscles become weak and distal strength is maintained: asymmetric muscle involvement is rare. Facial muscles are not involved. Deep tendon reflexes are intact. Arthralgia and arthritis may occur. In the past, DM and PM were lumped together in descriptions of behavior, but pathogenetic mechanisms of the muscle disease have been shown to differ (see below), indicating that the two diseases should be evaluated separately. On the other hand, results of serologic tests show similarities (see below). The natural history of the disease is not known, and there have been no controlled studies of the results of treatment with any agent except intravenous immunoglobulin, not a first line drug [1]. Other muscle disorders in the differential diagnosis of DM include myasthenia gravis, neurologic diseases, muscular dystrophy, sarcoidosis, endocrinopathies, and rhabdomyolysis [2]. Classification criteria for dermatomyositis are listed below (table 1). It should be noted that these criteria are guidelines for including patients in clinical series and are not to be used as criteria for diagnosing individual patients [3].

Table 1. Classification Criteria for DM [2]

1. Symmetrical weakness of limb-girdle muscles, neck flexors over weeks to months ± dysphagia, respiratory muscle weakness

2. Muscle biopsies consistent with the disease: necrosis, phagocytosis, regeneration, atrophy, inflammation

3. Elevation of skeletal-muscle enzymes (creatine kinase, aldolase, alanine and aspartate aminotransaminases, lactic dehydrogenase)

4. Electromyographic triad, which indicates the muscle to biopsy:

5. Dermatologic changes: Lilac color of eyelids and periorbital edema (heliotrope (like that from the sun) rash); red, macular rash on face and upper torso; scaly, red dermatitis over dorsum of metacarpophalangeal and proximal interphalangeal joints (Gottron's sign) and similar involvement of knees, elbows, medial malleoli. Dilated capillaries at base of finger nails.

Likelihood of diagnosis [2]

Definite DM

3 or 4 criteria + rash

Probable DM

2 criteria + rash

Possible DM

1 criterion + rash

Once DM has been diagnosed, it may be further classified as primary idiopathic DM, DM with neoplasia, childhood DM, DM with another collagen vascular disease (overlap syndrome) with independent criteria for 2 separate entities. The groups can then be modified by the terms definite/probable/possible [2].

Pulmonary disease in DM: Lung disease in DM may be of several types: aspiration pneumonia, ventilatory insufficiency from muscle weakness, drug-induced disease, opportunistic infection, vasculitis and pulmonary hemorrhage, malignancy, pulmonary hypertension, and interstitial lung disease, all of which must be considered in these patients. Only reports concerning interstitial lung disease (ILD) will be discussed here.

Asura, et al. reviewed 67 reported cases of PM/DM with pulmonary fibrosis from 1956 to 1980. Twenty-seven had DM. There was a 21% mortality in the entire group from progressive pulmonary disease, and persistent respiratory morbidity developed in 27% of the others. However, when analysis was confined to the 15 patients with DM and biopsy-proved ILD, 10 (67%) died by 18 mo after diagnosis of lung disease [4].

In a group of 637 patients with dermatomyositis culled from hospitals in Japan from 1973 to 1983, 85 (13%) developed pulmonary fibrosis. Of these 45 (53%) died, 24 with fulminant respiratory failure, within 2 months of onset of lung disease. In most of these, the onset of lung disease and DM occurred simultaneously [5].

This low incidence rate of pulmonary fibrosis contrasts with that reported by Takizawa, who found that 9 of 13 (69%) patients with DM seen over a period from 1972 to 1985 had ILD. Only 4 improved with therapy, and 6 of the 9 (67%) died of respiratory failure in 4 to 26 mo [6].

Hochberg, et al. found that 5 of 21 (24%) patients with DM had radiographic pulmonary fibrosis, but that 10 of 15 had decreased FVC or DLCO, suggesting that a greater percentage had some lung disease. Results of biopsies were not reported [7].

Marie, et al. found interstitial lung disease in 3 of 30 (10%) patients with DM between 1983 and 1996 [8].

Grau, et al. found interstitial lung disease in 8 of 63 (13%) patients with DM, 6 of whom had anti Jo-1 antibodies [9]. Only 3 of the 8 patients had biopsies. Although complete remission of muscular involvement occurred with treatment, lung disease improved completely in only 4 and partially in 4 [9].

In summary, in most studies the frequency of ILD in DM was around 10-15%, although subclinical forms may be more frequent. The prognosis for severe disease is poor.

Prediction of response of lung disease to therapy: In a study of response to therapy in 25 patients with DM/PM and ILD, it was found that DM patients predominated in the non-responder group (11/12), whereas only 5 of 13 in the responder group had DM. The only predictor of a response was a high ratio of CK/AST (>5:1) [10]. In our case the ratio was 22/94 (1:4.3).

Cancer and DM: It is generally believed that there is an increased frequency of cancer in patients with DM, but its magnitude, time span, and mechanism are still controversial. Confounding features are preferential reporting of such cases, misdiagnosis of DM in cases of tumor, or the biased search for tumor in DM patients [2,11]. A recent review of published studies concluded that the incidence of malignancy appears to be increased in patients with DM compared to PM (6 to 60% for DM vs 0 to 28% for PM), and that tumor types paralleled those in the general population, carcinoma of the breast and lung being the most frequent [11].

In a large series from Japan, 171 of 569 (30%) of adults with DM had a malignancy, but the authors caution that this rate is high because those without malignancy were not always followed or were excluded if the follow-up period was short. Again, the types of malignancy were similar to those in the general population [5].

A report from Israel found that cancers occurred in 45% (9/20) patients with DM, compared with 4/15 (27%) of those with PM. The risk of developing cancer before, concurrent with, or after DM/PM was 12.6 times that in the general population [12]. Hypotheses for the association include a paraneoplastic syndrome or an environmental or immune factor that triggers both [12].

Although tumors are usually advanced by the time of diagnosis, and death is caused by tumor [11], there are some reports that symptoms of DM improve after surgical excision of the tumor either with or without continued steroid therapy, but details are lacking [5].

Diagnosis of malignancy in patients with dermatomyositis can usually be made on the basis of symptoms and yearly complete physical examinations with routine laboratory tests as indicated by the age of the patient, rather than by a random search [13].

Concurrence of malignancy and lung disease: In the Japanese series mentioned above, only 8 of 569 (1.4%) patients had both malignancy and ILD, and 5 died, 2 mo to 6 yr after diagnosis of DM or cancer. Lung cancer occurred in 3 of the 8 [5].

Histologic changes: Interstitial lung disease in DM may be divided into 3 histologic types, each with a different prognosis. These types were described in a series of 10 patients with DM and interstitial lung disease. Three patients had bronchiolitis obliterans organizing pneumonia (BOOP) (2 died at less than one mo and 1 was alive at 14 mo with dyspnea), four had usual interstitial pneumonia (2 died at less than 1 mo, and 2 were alive on oxygen or with disability at 5-6 y), three had diffuse alveolar damage (DAD) (all died at 1-4 weeks). Like our patient, one of theirs had a BOOP pattern on biopsy but had a pattern of DAD at autopsy 8 days later [14]. A literature review of 27 other patients with DM/PM indicated that a BOOP or cellular interstitial pneumonia pattern had a more favorable prognosis than a UIP or DAD pattern. Diagnosis of a specific pattern of interstitial lung disease is not required, as treatment is the same for all types. For other types of lung disease that occur in these patients (see above), BAL, transbronchial biopsy, or other studies may be necessary for diagnosis [14].

Histologic changes in muscle

Serologic studies in DM: A number of autoantibodies have been found in patients with DM. In one study, non-myositis autoantibodies (ANA, La/SS-B, Ro/SS-A, Sm, U1nRNP, & others) were found in 77% of patients with DM (n=79) [15]. Myositis-specific autoantibodies were present in patients with both DM (46% of 79 patients) and PM (51% of 58 patients). The most frequent of these is the anti-synthetase antibody, anti-Jo-1 (histidyl-tRNA synthetase) (see figure). Antibodies to 4 other members of the synthetase family of enzymes have also been described in patients with DM/PM, thereby linking the two diseases. Nevertheless, the relationship between these antibodies, which are present in only one half of cases and the etiology or pathogenesis of the diseases, is not known [16]. In contrast, two other autoantibodies found in patients with myositis are more restricted. Anti-Mi2 (against a 220 kDa nuclear protein of unknown function) is found almost exclusively in patients with DM, whereas anti-SRP (against a signal recognition particle) occurs mostly in patients with PM [15].

Figure

Anti-synthetase syndrome: Love, et al. categorized a large number of myositis patients by the type of myositis-specific antibody present. Our patient may fall into the category of anti-synthetase syndrome, in which females predominated 2.7:1. Age at onset averaged 41.3 y, and the onset was acute. Interstitial lung disease was present with fevers, arthritis, and mechanic's hands. HLAs DR3 and DRw52 predominated in these patients. Whereas anti-Jo-1 antibodies were more frequent in such patients with PM than DM, other anti-synthetases, not measured in our patient, were found much more frequently in DM than PM. The response to steroids was moderate and mortality was 21% [15]. Although most patients with the anti-synthetase syndrome had myositis, it could be mild or absent, and symptoms of ILD could predominate at times during the course [16,17]. Other than the important predictive feature of the anti-synthetase antibodies for lung disease, the significance of these antibodies in the pathogenesis of disease is unknown [18].

Pathogenesis: There is little support for an infectious agent as the initiator of the disease, but there is support for a genetic susceptibility in persons with HLA DR3 and DRw52 (see above) [13]. Whatever the initiating event, a humoral response has been identified. Antibodies against endothelial cells, identified in 8 of 18 (44%) patients in one study, may play a role [19]. Activation of complement and formation and deposition of the complement membrane attack complex (C5b-9) on endomysial capillaries have been described (negative controls included biopsies of patients with polymyositis, muscular dystrophy, denervation atrophy, and normal muscle) [20,21]. This deposition causes capillary destruction, muscle ischemia, perifascicular atrophy, inflammation, and endomysial fibrosis [20,22]. Cytokines and adhesion molecules (VCAM and ICAM) direct lymphocytes and macrophages from the blood vessels to the muscle and upregulate MHC-I antigen on the perifascicular muscle fibers [1]. Evidence for a cell-mediated response is based on the presence of CD8+ T cells and macrophages in the perifascicular connective tissue and upregulation of MHC class I antigen on muscle fibers, suggesting a T cell-mediated/MHC class I-restricted cytotoxic mechanism [18].

The course of events just described for DM is based on observation of biopsies taken in early and advanced stages of the disease [21,22]. Confirmation of these findings and additional observations have been made on biopsies taken before and after therapy with intravenous immunoglobulin (IVIg) [1]. Biopsies were taken from 5 patients refractory to immunosuppressive therapy alone, who showed major improvement after treatment with three monthly injections of IVIg, in addition to prednisone. Post-treatment biopsies showed increases in muscle fiber diameter, an increase in number of capillaries, and a reduction of inflammation and connective tissue. IVIg decreased the deposition of membrane attack complex on the capillaries (by inhibiting the incorporation of C3 into the complex). It down-regulated ICAM-1 on capillaries and MHC-I on muscle fibers. It also reduced the expression of TGF-beta protein and its mRNA in the connective tissue, suggesting that inhibitors of TGF-beta might be useful as therapy [23,24]. Muscle from 5 control patients with inclusion body myositis, who were also treated with IVIg but had no response, showed no changes in TGF-beta or its mRNA after therapy [24].

Summary of Possible Pathogenetic Events in DM [18]

Summary of Possible Effects of IVIg in Inflammatory Myopathies [23]

Treatment: Corticosteroids in combination, when necessary, with azathioprine, methotrexate, cyclosporine, or cyclophosphamide are the main drugs used to treat the disease. For those patients who are resistant to these drugs, intravenous immunoglobulin (IVIg) (an expensive drug) was shown to be useful in a small, double-blind, crossover study in 9 of 12 patients [1]. It is recommended as a steroid-sparing drug, although resistance may occur with time. IVIg can also be used in patients who are immunodeficient or cannot take the other drugs [24]. Myositis and cutaneous rashes improved with IVIg, but there are no reports of its efficacy for ILD.

Prognosis: Overall mortality rates for DM separate from PM are not available, but a survey of the literature described unfavorable prognostic signs, which include older age, malignancy, and lung disease, all of which were present in our patient [26].

References

1. Dalakas M, Illa I, Dambrosia J, Soueidan S, Stein D, Otero C, Dinsmore S, et al. A controlled trial of high-dose intravenous immune globulin infusions as treatment for dermatomyositis. N Engl J Med 1993; 329:1993-2000.

2. Bohan A, Peter J. Polymyositis and dermatomyositis. N Engl J Med 1975; 292:344-347, 403-407.

3. Piette J-C, Fieschi C, Amoura Z. Classification of vasculitis. N Engl J Med 1999; 341:1774-1775.

4. Arsura E, Greenberg A. Adverse impact of interstitial pulmonary fibrosis on prognosis in polymyositis and dermatomyositis. Sem Arthritis Rheum 1988; 18:29-37.

5. Hidano A, Kaneko K, Arai Y, Kikuchi R. Survey of the prognosis for dermatomyositis, with special reference to its association with malignancy and pulmonary fibrosis. J Dermatol 1986; 13:233-241.

6. Takizawa H, Shiga J, Moroi Y, Miyachi S, Nishiwaki M, Miyamoto T. Interstitial lung disease in dermatomyositis: clinicopathological study. J Rheumatol 1987; 14:102-107.

7. Hochberg M, Feldman D, Stevens M. Adult onset polymyositis/dermatomyositis: an analysis of clinical and laboratory features and survival in 76 patients with a review of the literature. Sem Arthritis Rheum 1986; 15:168-178.

8. Marie I, Hatron P-Y, Hachulla E, Wallaert B, Michon-Pasturel U, Devulder B. Pulmonary involvement in polymyositis and in dermatomyositis. J Rheumatol 1998; 25:1336-1343.

9. Grau J, Miró O, Pedrol E, Casademont J, Masanés F, Herrero C, Haussman G, et al. Interstitial lung disease related to dermatomyositis. Comparative study with patients without lung involvement. J Rheumatol 1996; 23:1921-1926.

10. Takada T, Suzuki E, Nakano M, Kagamu H, Tsukada H, Hasegawa T, Satoh M, et al. Clinical features of polymyositis/dermatomyositis with steroid-resistant interstitial lung disease. Intern Med 1998; 37:669-673.

11. Richardson J, Callen J. Dermatomyositis and malignancy. Med Clin N Am 1989; 73:1211-1220.

12. Maoz C, Langevitz P, Livneh A, Blumstein Z, Sadeh M, Bank I, Gur H, et al. High incidence of malignancies in patients with dermatomyositis and polymyositis: an 11-year analysis. Sem Arthritis Rheum 1998; 27:319-324.

13. Dalakas M. Polymyositis, dermatomyositis, and inclusion-body myositis. N Engl J Med 1991; 325:1487-1498.

14. Tazelaar H, Viggiano R, Pickersgill J, Colby T. Interstitial lung disease in polymyositis and dermatomyositis. Clinical features and prognosis as correlated with histologic findings. Am Rev Respir Dis 1990; 141:727-733.

15. Love L, Leff R, Fraser D, Targoff I, Dalakas M, Plotz P, Miller F. A new approach to the classification of idiopathic inflammatory myopathy: myositis-specific autoantibodies define useful homogeneous patient groups. Medicine 1991; 70:360-374.

16. Targoff I, Arnett F. Clinical manifestations in patients with antibody to PL-12 antigen (alanyl-tRNA synthetase). Am J Med 1990; 88:241-251.

17. Targoff I, Trieu E, Plotz P, Miller F. Antibodies to glycyl-transfer RNA synthetase in patients with myositis and interstitial lung disease. Arthritis Rheum 1992; 35:821-830.

18. Dalakas M. Immunopathogenesis of inflammatory myopathies. Ann Neurol 1995; 37:S74-S86.

19. Cervera R, Ramírez G, Fernández-Solà J, D'Cruz D, Casademont J, Grau J, Asherson R, et al. Antibodies to endothelial cells in dermatomyositis: association with interstitial lung disease. BMJ 1991; 302:880-881.

20. Kissel J, Mendell J, Rammohan K. Microvascular deposition of complement membrane attack complex in dermatomyositis. N Engl J Med 1986; 314:329-334.

21. Kissel J, Halterman R, Rammohan K, Mendell J. The relationship of complement-mediated microvasculopathy to the histologic features and clinical duration of disease in dermatomyositis. Arch Neurol 1991; 48:26-30.

22. Emslie-Smith A, Engel A. Microvascular changes in early and advanced dermatomyositis: a quantitative study. Ann Neurol 1990; 27:343-356.

23. Dalakas M. Intravenous immunoglobulin in the treatment of autoimmune neuromuscular diseases: present status and practical therapeutic guidelines. Muscle Nerve 1999; 22:1479-1497.

24. Amemiya K, Semino-Mora C, Granger R, Dalakas M. Downregulation of TGF-beta1 mRNA and protein in the muscles of patients with inflammatory myopathies after treatment with high-dose intravenous immunoglobulin. Clin Immunol 2000; 94:99-104.

25. Yu Z, Lennon V. Mechanism of intravenous immune globulin therapy in antibody-mediated autoimmune diseases. N Engl J Med 1999; 340:227-228.

26. Benbassat J, Gefel D, Larholt K, Sukenik S, Morgenstern V, Zlotnick A. Prognostic factors in polymyositis/dermatomyositis. A computer-assisted analysis of ninety-two cases. Arthritis Rheum 1985; 28:249-255.

Clinical summary

Comments: mw6825@itsa.ucsf.edu

Last revised 8/13/00

Copyright 2000 by Martha L. Warnock. All rights reserved.

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