Precision medicine in rheumatoid arthritis: Hype or hope?
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I heard my first lecture about personalized or precision medicine in the early 1980s.
Precision medicine in rheumatoid arthritis involves personalized approaches to diagnosis, treatment and management of the disease, using analyses of genetic, molecular and environmental factors to tailor strategies that are specific to each patient. Tremendous advances in oncology, using molecular biology, have identified various protein kinases and growth factors for tumors that could be targeted with therapies such as trastuzumab (Herceptin, Genentech) and EGFR inhibitors, which have dramatically improved survival in multiple types of cancer, including breast and lung cancer.
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Progress in rheumatology, primarily focusing on RA, has yet to yield treatment biomarkers that enhance disease management. Clinical response to our targeted therapies has improved dramatically over the last 25 years with biologics and targeted synthetic disease-modifying antirheumatic drugs (DMARDs), but in clinical trials all these therapies rarely demonstrate efficacy greater than the classical 60/40/20 ACR response. Prior to the use of genomics/transcriptomics, and now machine learning, treatment decisions after conventional synthetic DMARD failures have remained empirical. Limited data sets suggested that patients seropositive for rheumatoid factor (RF)/ cyclic citrullinated peptide (CCP) were more likely to respond to the B-cell depleter rituximab (Rituxan, Genentech) and more recent data has suggested an enhanced response to abatacept (Orencia, Bristol Myers Squibb) in high-titer CCP-positive patients.
There is, however, hope that in using modern molecular biology techniques we are on the cusp of actually developing biomarkers that may direct appropriate treatment. Work from our European colleagues and the NIH Accelerating Medicines Partnership program have identified different patterns of synovial disease pathotypes — lympho-myeloid, diffuse myeloid and pauci-immune. Early clinical trials have demonstrated differential response to rituximab and tocilizumab (Actemra, Genentech) based on synovial pathotype, and in the pauci-immune pathotype enrichment of fibroblast genes has been recognized, suggesting therapies targeting synovial fibroblasts may be effective in these refractory patients.
In addition to synovial biopsy data, the development of “liquid biopsies” is being pursued. PrismRA (Scipher Medicine) is a molecular response classifier developed with genomics/transcriptomics and machine learning, using differential gene expression in patients who were responders or non-responders to TNF inhibitors, along with clinical features including CCP positivity, sex, BMI and patient global assessment. Genes identified were common and involved in the pathogenesis of RA.
The assay, requiring a simple blood test, has been demonstrated to predict non-response to TNF inhibitors, with an OR for non-response of 3.4 to 8.8 in biologic naïve patients, and 3.3 to 26.6 in biologic-experienced patients, in small cohorts of several hundred participants. If confirmed in larger patient populations, this test may result in directing patients away from less effective therapies and toward better treatment response.
PrismRA recently received coverage by CMS, which should allow for a greater number of patients to be evaluated and confirm the clinical trial observations. It is my understanding that the sponsor is working on other biomarkers to predict response to other biologics and targeted synthetic DMARDs. Additionally, others are looking at circulating cell-free DNA, similar to what is being done in oncology evaluating epigenomics, in RA, which may provide information on treatment selection and treatment response.
Precision medicine has been a challenge in RA, as it is a complex polygenic disease that is influenced by environmental features, such as smoking, and epigenetic modifications. However, with the advent of the “omic” era, there is renewed hope that the development of treatment biomarkers may be achievable.
- References:
- Lin CMA, et al. Nat Rev Rheumatol. 2022;doi:10.1038/s41584-022-00845-w.
- Rivellese F, et al. Nat Med. 2022; doi:10.1038/s41591-022-01789-0.
- Cohen S, et al. Rheumatol Ther. 2021;doi:10.1007/s40744-021-00330-y.
- For more information:
- Stanley Cohen, MD, is a member of the Healio Rheumatology Peer Perspective Board, clinical professor in the department of internal medicine at the University of Texas Southwestern Medical Center, co-director of the division of rheumatology at Presbyterian Hospital, in Dallas, co-medical director of the Metroplex Clinical Research Center, and a physician with Rheumatology Associates.
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