CME Author: Zeena Nackerdien
Study Authors: Alexander Oldroyd, Jamie C. Sergeant, et al.
Target Audience and Goal Statement: Rheumatologists, neurologists, dermatologists, pulmonologists, cardiologists, physiotherapists, and oncologists
The goal is to comprehend the 10-year temporal relationships between anti-transcriptional intermediary factor 1 antibody (anti-TIF1-Ab) positivity and the onset of neoplasms in a large U.K.-based adult dermatomyositis (DM) cohort.
Since the long-term risk of cancer associated with anti-TIF1-Ab positivity in patients with DM is unclear, the current study aimed to compare the 10 year cancer risk of anti-TIF1-Ab-positive vs -negative DM cases.
Idiopathic inflammatory myopathies (IIMs) can affect multiple organs apart from muscle and often lead to a severe impairment of the quality of life, as well as the necessity of involving numerous specialists to treat every condition. Two of the IIMs sharing features of proximal skeletal muscle weakness and evidence of muscle inflammation are dermatomyositis (DM) and polymyositis (PM). According to an article by Italian researchers, “DM is a humorally mediated microangiopathy, while PM is a T-cell mediated disorder in which a cytotoxic attack against single non-necrotic muscle fibers occurs.” The onset of PM is difficult to ascertain, and the clinical course is subacute. Adult-onset DM, on the other hand, is known to occur more in women than men (2:1 respectively), usually between the ages of 40 and 60, and is seen most often in the fifth decade of life. The female to male ratio increases to 10:1 for DM coexisting with other connective tissue conditions.
Several epidemiological studies have reported that a diagnosis of DM or PM may be associated with increased cancer risk. The association appears stronger for DM than PM. Based on a meta-analysis, DM cancer risk is five times higher than in the general population and twice that compared with PM cancer risk.
The diagnosis for DM is challenging and is usually made on the basis of laboratory studies (e.g., aldolase and creatinine kinase) and histopathology from a muscle and/or skin biopsy, especially within the first 5 years after symptom onset. Thereafter, patients have to be closely monitored for the possible development of cancer. Patients with IIMs, especially adults with DM who do not have anti-synthetase antibodies (antisynthetase syndrome, present in about 20% of patients with DM, is characterized by the presence of serum autoantibodies directed against aminoacyl-tRNA synthetases) have an elevated risk of cancer. Diagnosed cancers resemble those seen in the general population, and include malignancies of the lung, breast, prostate, and ovaries.
About 40% of patients with myositis have myositis-specific or myositis-associated autoantibodies (MSAs/MAAs). As in the case of other autoimmune rheumatic diseases, phenotype-specific autoantibodies may be important clinical tools for DM. For instance, autoantibodies against a protein doublet (p155/140, where the numbers refer to the molecular weights) define another distinct group of DM patients – those with an increased incidence of cancer compared with DM patients without malignancies. The anti-TIF1-Ab is one of the most common antibodies in juvenile DM (where it is not associated with cancer); however the long-term risk of cancer associated with anti-TIF1-Ab positivity in adults is unclear.
Findings from a 2007 analysis of the prevalence of anti-IF1-Ab in IIM cases showed that 50% of anti-TNF1-Ab-positive cases also had cancer-associated myositis (CAM). Additional anti-TIF1-Ab-positive/-negative patients were recruited in this follow-up study of the same cohort up to 10 years. The overall goal was to compare the 10-year cancer risk in anti-TIF-Ab-positive vs –negative DM cases using UKMyoNet data.
“Further knowledge of the longer-term risk of cancer, common sites of malignancy, and age association would usefully inform cancer screening strategies and optimize patient management,” Oldroyd and colleagues wrote about the current study.
Study Synopsis and Perspective
Patients were recruited from 74 centers throughout the U.K. Data about demographics and clinical patterns were collected, and all participants had blood samples taken to detect autoantibodies to determine the presence of MSA anti-synthetases (anti-Jo-1, -PL7, -PL12, -EJ, -OJ, -KS, -Zo), other MSAs (anti-TIF1, -Mi-2, -SAE, -SRP, -MDA5, -NXP2, -HMGCR), and MAA (anti-PM-Sci, -Ku, -U1-RNP, -U3-RNP). A total of 55 out of 263 DM cases (21%) were anti-TIF1-Ab positive. The majority were women, and median age at DM diagnosis was 47.
An increased proportion of anti-TIF1-Ab-positive cases developed cancer throughout the study period compared with anti-TIF1-Ab-negative cases (38%) vs (15%). Cancer development in the anti-TIF1-Ab-positive cohort occurred between 3.5 years prior to and 2.5 years after DM onset. While 21 of the anti-TIF1-Ab-positive cases (53%) who were at least 39 years old developed cancer, those matched patients younger than age 39 did not develop cancer over the study period.
In the anti-TIF1 positive group, the most common types of malignancy were breast cancer (33%), ovarian cancer (19%), and lymphoma (14%). In the anti-TIF1 negative group, the most common tumors were breast cancer (25%), lymphoma (13%), and bowel cancer (13%). Ovarian cancer was markedly higher in the anti-TIF1 positive group (19% vs 2%, P<0.05).
Strengths of this study include the large datasets used and long-term detection; however, by definition patients would have had to survive long enough to be recruited into the UKMyoNet. According to the National Institutes of Health, the 2017 European League Against Rheumatism (EULAR) /American College of Rheumatology (ACR) EULAR/ACR classification criteria for adult and juvenile IIM are based on a probability score in which 16 clinical and laboratory features are summed to develop a probability of having an IIM; further sub-classification is needed to identify DM. Since this consensus was only developed recently, there may be inaccuracy in the diagnosis of symptom onset; however, the investigators deemed this to be unlikely, as there was a substantial difference in cancer incidence between the anti-TIF1-Ab-positive and –negative cohorts.
Source Reference: Rheumatology, Dec. 7, 2018; DOI:10.1093/rheumatology/key357
Study Highlights: Explanation of Findings
The long-term relationship between anti-TIF1-positive-Ab status and cancer onset was analyzed in this retrospective U.K. study. Patients with DM who were also positive for the anti-TIF1-Ab were at more than threefold increased risk for cancer, the investigators found. In keeping with separate findings, this study identified that the significant association between anti-TIF1-Ab positivity and early cancer diagnosis exists only for those >39 years of age. Anti-TIF1 positive cancer occurred within 3 years either side of the DM onset, and no incident malignancies were detected in this group within the next 7.5 years, whereas cancers were detected during this later period in the anti-TIF1-Ab-negative cases.
Looking for anti-TIF1-Ab in newly diagnosed DM cases could help with the development of a cancer screening plan of action. Previous studies have noted the increased risk for ovarian cancer among women with DM, but this is also the first study to determine that the risk was primarily among the anti-TIF1 positive group, “suggesting that the true association between DM and ovarian cancer may be through possession of anti-TIF1 antibodies. Clinicians should therefore apply increased vigilance for potential ovarian pathology in anti-TIF1 antibody positive cases,” the researchers wrote.
“Our findings also strengthen the hypothesis that inflammatory myopathies represent a paraneoplastic reaction initiated by attempted immune-mediated clearance of a cancer,” the team concluded.
Nancy Walsh wrote the original story for MedPage Today