Most Patients With Cancer-Associated Dermatomyositis Have Antibodies to Nuclear Matrix Protein NXP-2 or Transcription Intermediary Factor 1γ

Dermatomyositis (DM) is a systemic disease characterized by chronic inflammation in the skin and muscle. There is significant clinical heterogeneity with respect to lung or muscle inflammation, patterns of cutaneous inflammation, association with internal malignancy, and response to therapy. Many patients with DM have circulating autoantibodies, which are often associated with distinct clinical phenotypes (1,2). Interestingly, autoantibodies in DM tend to be mutually exclusive, suggesting that specific immune responses might play a role in shaping different phenotypes. It is well established that a subset of DM patients (10–20%) is at increased risk of internal malignancy around the time of DM diagnosis (3). Identification of patients at high risk of cancer remains a high priority for physicians treating these patients. Recent studies have identified 3 new autoantibody specificities in DM: melanoma differentiation–associated protein 5 (MDA-5), transcription intermediary factor 1γ (TIF-1γ), and nuclear matrix protein NXP-2 (also known as MORC3) (4–9). These antigens all migrate similarly on sodium dodecyl sulfate–polyacrylamide gel electrophoresis (SDS-PAGE) gels (145–155 kd). Anti–MDA-5 antibodies are found in ~10–20% of DM patients (7,10–12) (and in up to 65% of patients with clinically amyopathic disease [6,10,13,14]) and are associated with interstitial lung disease (often rapidly progressive, especially in Asians), mild or absent muscle disease, cutaneous ulceration, palmar papules, arthritis/arthralgia, and alopecia (6,11,15). Anti–TIF-1γ antibodies are frequently found in cancer-associated DM (4,13,16–18), including in 2 studies with largely Caucasians (19,20). For adult DM patients with antibodies to TIF-1γ, the percentage of patients harboring a malignancy ranges from 42% to 100%, depending on the study (4,13,16–18). In juvenile DM patients, antibodies to TIF-1γ are not associated with malignancy, but rather, with skin ulceration and more extensive cutaneous disease (21). NXP-2 has also been identified as an autoantibody target in a subset (1.6–30%) of adult DM patients (22–25). Originally identified as MJ in the juvenile DM population, this antigen appeared to be targeted by antibodies in patients with a higher risk of cutaneous calcinosis cutis (5,26). In adult DM patients, antibodies to NXP-2 are not associated with any obvious phenotype other than a trend toward increased risk of calcinosis cutis in 1 study (23). One study of adult Japanese DM patients suggested an association with malignancy (3 of 7 anti–NXP-2–positive patients had a primary malignancy); however, this association was difficult to verify given the small numbers of anti–NXP-2–positive patients (24). There are several major drawbacks of previous studies looking at antibody associations with cancer in DM. The assays used to detect these antibodies lack sensitivity and specificity, given that NXP-2, TIF-1γ proteins, and MDA-5 migrate similarly on gel electrophoresis and may not be optimally expressed using standard cell lines and culture conditions. Additionally, many of the cohorts or antibody-positive patients have been relatively small in number. In this study, we provide definitive evidence that antibodies to NXP-2 and TIF-1γ identify the vast majority of the patients with cancer-associated DM in 2 separate, well-defined DM cohorts.