Precision medicine already exists in rheumatology. Current strategies include treat-to-target therapies in rheumatoid arthritis (RA), autoantibody testing for patient stratification in rheumatic diseases, and individual dose escalation of uric acid in patients with gout. However, further developments are needed to ensure optimized outcomes across all rheumatic diseases.
Judith A. James, MD, PhD, professor of medicine and associate vice provost of clinical and translational science at University of Oklahoma Health and Sciences Center spoke about developments of precision medicine in rheumatology at the 2018 State-of-the-Art Clinical Symposium in Chicago, Illinois.
Rheumatologists have become increasingly interested in precision medicine because of its personalized approach toward treatment of rheumatic conditions such as RA and systemic lupus erythematosus (SLE). Precision medicine incorporates individual factors that contribute to immune responses, including a patient’s phenotype, genetics, biomarkers, environment, and lifestyle. Benefits of precision medicine include earlier diagnosis of rheumatic conditions and the ability to design customized treatment plans.
Patient populations are significantly heterogeneous; many patients have the same disease with different presentations. The hope of precision medicine, according to Dr James, is to be able to use molecular information to take patients and divide them into more homogenous subsets, which may help researchers identify effective treatment options for individual patients.
There is extensive immunophenotyping being performed in SLE, according to Dr James. Immunophenotyping encompasses high-content flow cytometry, mass cytometry time of flight, single cell gene expression profiling, and tissue-based evaluations.
“A big challenge with lupus is that we have a lot of heterogeneity,” Dr James stated. “We know that if we could find different ways to subset patients, perhaps by molecular information, that will help us stratify organ involvement, demographics, biomarkers, and other clinical pathways that are involved.” This stratification could help clinicians personalize treatment selection, dose, route, and affect disease activity monitoring.
Dr James also noted that precision medicine can be useful for clinicians who treat patients with RA. There are disease-modifying antirheumatic drug (DMARD) efficacy predictors that have been identified in RA, including that men respond better to methotrexate than women and that active smokers show a poorer response. Patients with earlier disease also generally respond better to DMARDs, and DMARD response may also be worse with higher baseline disease activity or in patients with prior DMARD use. Concomitant corticosteroids have also been associated with better response, and radiographic scores have no effect on response.
Dr James added that increased body mass index (BMI) is associated with worse outcomes in RA and with poorer tumor necrosis factor inhibitor (TNFi). Smoking also adversely affects TNFi outcomes and is linked to worse outcomes with increased extra-articular manifestations, radiographic progression, and impaired response to DMARDs and nonsteroidal anti-inflammatory drugs.
All biologics perform better when combined with methotrexate. If patients are intolerant to methotrexate, then tocilizumab may yield better results compared with TNFi. High BMI is a strong predictor of low drug levels in patients with RA treated with etanercept or adalimumab.
Dr James also stated that TNFi trough levels can be an effective indicator of biologic efficacy in RA. The strongest predictor of low drug levels is high BMI, and they are also heavily influenced by anti-drug antibodies, which are less common with concurrent methotrexate. The maximum clinical benefit is in the range of 5 to 8 mg/L, but if the levels are low, it may be beneficial to consider switching to another TNFi. If levels are >5 mg/L and the patient is nonresponsive, then it may be beneficial to switch to a different mechanism of action.
Dr James concluded that precision medicine is an evolving area with future potential in rheumatology. However, more insight is needed from rheumatologists to support precision medicine initiatives such as All of Us and the Precision Medicine Initiative to improve research efforts and enhance personalization of treatment.
“We need more systems biology approaches to take all of this collective information and distill it down into something we can use practically in the clinic for an individual patient on a given day,” Dr James concluded. “And we’re going to need different types of interactions with different kinds of health professionals that we haven’t historically used in rheumatology, like molecular pathologists who are really focused on the genetic information, genetic counselors, and health coaches.”
James J. Precision medicine: dawn of a new era. Presented at: 2018 State-of-the-Art Clinical Symposium; Chicago, Illinois; April 13-15, 2018.