The temporal relationship between cancer and adult onset anti-transcriptional intermediary factor 1 antibody–positive dermatomyositis

Abstract

Objectives To characterize the 10 year relationship between anti-transcriptional intermediary factor 1 antibody (anti-TIF1-Ab) positivity and cancer onset in a large UK-based adult DM cohort. Methods Data from anti-TIF1-Ab-positive/-negative adults with verified diagnoses of DM from the UK Myositis Network register were analysed. Each patient was followed up until they developed cancer. Kaplan–Meier methods and Cox proportional hazard modelling were employed to estimate the cumulative cancer incidence. Results Data from 263 DM cases were analysed, with a total of 3252 person-years and a median 11 years of follow-up; 55 (21%) DM cases were anti-TIF1-Ab positive. After 10 years of follow-up, a higher proportion of anti-TIF1-Ab-positive cases developed cancer compared with anti-TIF1-Ab-negative cases: 38% vs 15% [hazard ratio 3.4 (95% CI 2.2, 5.4)]. All the detected malignancy cases in the anti-TIF1-Ab-positive cohort occurred between 3 years prior to and 2.5 years after DM onset. No cancer cases were detected within the following 7.5 years in this group, whereas cancers were detected during this period in the anti-TIF1-Ab-negative cases. Ovarian cancer was more common in the anti-TIF1-Ab-positive vs -negative cohort: 19% vs 2%, respectively (P < 0.05). No anti-TIF1-Ab-positive case <39 years of age developed cancer, compared with 21 (53%) of those ≥39 years of age. Conclusion Anti-TIF1-Ab-positive-associated malignancy occurs exclusively within the 3 year period on either side of DM onset, the risk being highest in those ≥39 years of age. Cancer types differ according to anti-TIF1-Ab status, and this may warrant specific cancer screening approaches.

Microbial and autoantibody immunogenic repertoires in TIF1γ autoantibody positive dermatomyositis

“…Conversely TRIM3 has tumour suppressor activity, inhibiting the growth of liver, colorectal and gastric cancer (Boulay et al, 2009). The presence of autoantibodies against cancerassociated TRIMs accords with the strong temporal association between myositis and the development of malignancies in adult-onset anti-TIF1γ positive DM (Oldroyd et al, 2019), consistent with the high proportion of cancer-associated myositis cases in the current study (45%). Overall, the expanded targeting of TRIM proteins we observed in DM plasma supports the role of the TRIM RING-type E3 ubiquitin ligase subfamily as powerful regulators of the immune system through post-translational modification (Hage and Rajsbaum, 2019;van Tol et al, 2017).…”

“…Individuals with autoantibodies targeting the cytoplasmic nucleic acid sensor MDA5 (also called interferon induced with helicase C domain 1, IFIH1) can present with rapidly progressive interstitial lung disease which is associated with high mortality (Abe et al, 2017;Betteridge et al, 2019). Several members of the tripartite motif (TRIM) protein family are known autoantibody targets in IIM, and there is a strong temporal association between adult-onset dermatomyositis and malignancy onset in individuals with antibodies to transcription intermediary factor 1γ (TIF1γ, TRIM33) (Oldroyd et al, 2019). Many TRIM proteins are important immune regulators (van Tol et al, 2017;Versteeg et al, 2014), and dysregulation of TRIM proteins leading to reduced ability to restrict viral infection has been reported in several autoimmune diseases, including systemic lupus erythematosus and inflammatory bowel disease (Oke et al, 2009;Zhou et al, 2018).…”

Clinical significance of serum levels of anti‐transcriptional intermediary factor 1‐γ antibody in patients with dermatomyositis

“…There is a case report on ovarian cancer complicating DM in a patient with a breast cancer susceptibility gene (BRCA) mutation. 18 Although few studies have reported on the sites of malignancy in anti-TIF1-c Ab-positive DM patients, 19 our study observed a high frequency of ovarian and breast cancer in patients with Anti-TIF1-c Ab, anti-transcriptional intermediary factor 1-c antibody; CADM, clinically amyopathic dermatomyositis; CAM, cancer-associated myositis; CI, confidence interval; CK, creatine phosphokinase; ILD, interstitial lung disease.…”

“…In all patients, the Ab titer decreased by 50% or more; in addition, three of four patients demonstrated a negative final Ab test. In contrast, eight patients had advanced stages of malignancy (patients [16][17][18][19][20][21][22][23]. Three patients (patients 16, 22 and 23) were treated for DM and not for malignancy.…”

A novel autoantibody targeting calreticulin is associated with cancer in patients with idiopathic inflammatory myopathies

“…The strong association and close temporal relationship between anti-TIF-1c Ab and the onset of cancer in adult DM patients have been wellestablished. 25,26 A recent systematic review and meta-analysis confirmed that anti-TIF-1c Ab could be a valuable tool for diagnosing cancerassociated DM, with a pooled sensitivity of 52%. 27 In our study, the association between anti-CRT Ab positivity and cancer occurrence was not as strong as that of anti-TIF-1c Ab.…”