Autoantibodies Signal Reduced Cancer Risk in Dermatomyositis

Neil Osterweil

February 17, 2023

Adults with the inflammatory autoimmune myopathy dermatomyositis are at increased for concurrent cancers, but new research suggests that certain autoantibodies in patients with a specific dermatomyositis subtype may actually protect against cancer.

A study of cohorts of patients with dermatomyositis, other rheumatic diseases, and those without disease showed that among patients with dermatomyositis positive for anti-transcriptional intermediary factor 1 (anti-TIF1-γ) autoantibodies — a disease subtype associated with increased cancer risk — the presence of autoantibodies directed against cell division cycle and apoptosis regulator 1 (CCAR1) was associated with reduced cancer risk "to a level comparable to that seen in the general population," reported David Fiorentino, MD, PhD, of Stanford University in Redwood City, California, Christopher A. Mecoli, MD, MHS, of Johns Hopkins University in Baltimore, Maryland, and colleagues.

"Our prior data suggest that there are autoantigens that, when targeted simultaneously with CCAR1, provide additional cancer protection. Although these autoantigens are less frequently targeted, it is likely that additional, more prevalent 'autoantigen hubs' remain undiscovered," they wrote in Arthritis & Rheumatology.

Identification of other autoantibodies both in the anti-TIF1-γ–positive and other dermatomyositis subgroups may help with cancer risk stratification in patients with the disease and may ultimately improve cancer screening for adults with dermatomyositis, the investigators said.

Toward Precision Medicine

"I think this is a step towards precision medicine in patients with rheumatic disease, specifically myositis," Mecoli said in an interview with Medscape Medical News.

The study supports earlier work showing that dermatomyositis and related myopathies are heterogeneous, he said, noting that "if you put 10 myositis patients in the same room, you wouldn't get that they all have the same disease because they can look so different from one another," he said.

The association of dermatomyositis with concurrent cancers has been known for decades, but in recent years his team and other investigators have noted that the association holds true for only some patients with dermatomyositis, most notably those patients positive for anti-TIF1-γ autoantibodies.

"And then, of course, once you really start studying just one gamma-positive dermatomyositis patient, you realize that even among that group it is heterogeneous in terms of their cancer risk, and that was the main focus of this study: to reconcile this clinical observation that I had a lot of patients with TIF1-γ dermatomyositis who never get diagnosed with cancer," Mecoli said.

Study Details

Fiorentino, Mecoli, and colleagues had previously reported that immune responses to CCAR1 and other autoantigens seen in patients with dermatomyositis were associated with lower probability of cancer occurrence.

In the current study, they focused on the disease specificity, clinical phenotype, and cancer risk for patients with dermatomyositis and anti-CCAR1 autoantibodies.

They looked at all patients aged 18 or older with a probable or definite finding of dermatomyositis, according to 2017 American College of Rheumatology (ACR)/European Alliance of Associations for Rheumatology (EULAR) Idiopathic Inflammatory Myopathy criteria, who were seen at Stanford University Medical Center from August 2004 through April 2020 (101 patients), or the Johns Hopkins Myositis Center (141 patients) from January 2007 through December 2020.

Controls included 44 patients evaluated at the Johns Hopkins Myositis Center with immune-mediated necrotizing myopathy, 186 patients with anti-TIF1-γ–negative dermatomyositis (defined as an ELISA readout of less than seven units) evaluated at either Stanford or Johns Hopkins, 44 patients with inclusion body myositis evaluated at Johns Hopkins, and 46 patients with systemic lupus erythematosus from the Hopkins Lupus Cohort. The investigators also assayed serum from 32 healthy individuals.

They found that patients with anti-TIF1-γ–positive dermatomyositis were significantly more likely than those with anti-TIF1-γ–negative dermatomyositis to have anti-CCAR1 autoantibodies (32% vs 8%; P < .001). Additionally, they noted that the anti-CCAR1 autoantibodies were not seen in serum from healthy controls and were found at only very low frequencies among patients with other rheumatic diseases.

When they looked at the incidence of cancer from the time of dermatomyositis onset (defined as the first patient-reported symptoms of rash, weakness, myalgia, or dyspnea) they found that the standardized incidence ratio (SIR) in anti-TIF1-γ–positive patients in both the Stanford and Hopkins cohorts was higher than expected, with SIRs of 3.49 and 4.54, respectively (P < .001 for each comparison).

However, among those patients who were both anti-TIF1-γ–positive and anti-CCAR1-positive, the SIRs were 1.78 in the Stanford cohort and 1.61 in the Hopkins cohort, and neither SIR was significantly higher than that of the general population.

Risk Prediction

Their findings suggest that autoantibody profiles might be used for cancer risk stratification in patients with anti-TIF1-γ–positive dermatomyositis, Mecoli told Medscape.

"Are we over-screening? What is the cost in terms of patient anxiety, in terms of radiation, and in terms of false positive results?" he said. "If I had a patient in front of me with anti-TIF1-γ dermatomyositis, I would probably manage them differently if I knew that they were CCAR-1 positive, because the presence of that additional autoantibody attenuates their cancer risk relative to the general population."

In an editorial accompanying the study, Manabu Fujimoto, MD, of the Department of Dermatology at Osaka University Graduate School of Medicine in Osaka, Japan, commented that it "is of clinical importance in that combination of autoantibodies can predict cancer risk with more accuracy. At the same time, this study will give an insight into the pathomechanisms of how anti-tumor activity may shape autoimmunity in dermatomyositis."

It will be "intriguing" to discover whether anti-CCAR1 autoantibodies act only against tumors or might also have an impact on dermatomyositis itself, Fujimoto said.

The research was supported by grants from the National Institutes of Health, Huayi and Siuling Zhang Discovery Fund, Peter Buck, MD, and the Donald B. and Dorothy L. Stabler Foundation. The authors and Fujimoto report no relevant financial relationships.

Arthritis Rheumatol. Published online February 10, 2023. Full text.

Neil Osterweil, an award-winning medical journalist, is a long-standing and frequent contributor to Medscape.

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