Molecular stratification and precision medicine approaches are challenging in rheumatology due to the polygenic nature of this disease type, in addition to the complex interactions between genetics and environmental factors.
DMARDs are effective targeted treatments in systemic autoimmune rheumatic diseases, but there are no biomarkers to predict their efficacy.
The recognition of molecular subtypes and the molecular stratification of subgroups in clinical trials could advance precision medicine efforts in rheumatology.
Unlike traditional care, precision medicine employs targeted approaches that reflect a patient’s molecular characteristics—a practice already established in areas like cancer treatment. However, this approach is challenging in rheumatology, due to the polygenic nature of this disease type and other factors.
Precision medicine could help determine crucial differences in treatment response—ie, the ability to detect treatment response at treatment initiation or shortly thereafter could mean either improved remission rates, improved drug survival, or both.
As such, a long-term goal of rheumatology is to bring precision medicine approaches to the forefront.
Precision medicine as a treatment avenue
In oncology, precision-based medicine has made significant strides. Molecularly based treatments are determined using tumor-specific genomic markers. For instance, any solid tumor with neurotrophic tyrosine receptor kinase gene fusions is treated with a tropomyosin receptor kinase inhibitor, such as entrectinib or larotrectinib, regardless of tumor type. In other words, this therapy is tumor-agnostic and only takes aim at molecular and genetic features.
In rheumatology, however, impediments deter a precision medicine approach. Systemic autoimmune rheumatic diseases are polygenic and reflect a complicated interaction of genetic and environmental factors. Moreover, it remains to be seen whether precision medicine strategies in rheumatology are cost-effective.
Although disease-modifying antirheumatic drugs (DMARDs) have transformed the treatment of rheumatoid arthritis (RA), authors publishing in Nature Reviews Rheumatology report that many randomized controlled trials have demonstrated that about 40% of patients are unresponsive to this type of therapy.e demonstrated that about 40% of patients are unresponsive to this type of therapy.
A critical unmet need in RA is the identification of predictive biomarkers that signify which of the available medications will be most effective for a particular patient, while allowing this determination to be made more quickly relative to the current treat-to-target approach.
This is where personalized treatment could play a pivotal role in helping determine crucial differences in treatment response. The prediction of treatment response is best done before treatment initiation or shortly thereafter, given the time span for the optimal effect of DMARDs is at least 6 to 12 weeks, according to an article published in RMD Open.
The Nature Reviews Rheumatology authors summarized the limitations of DMARDs: “In RA, the use of DMARDs follows an algorithm based mainly on clinical features, historical licensing and health economics rather than a rational, target pathway-driven approach,” they wrote. “In addition, the lack of biomarkers to predict response to individual drugs for RA maintains the current trial and error practice whereby patients are cycled from one DMARD to the next."
"[This] leads to unnecessary exposure to potentially toxic drugs that have a low probability of success, delays disease control and allows progression of structural joint damage."
— Authors, Nature Reviews Rheumatology
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Early inroads in precision medicine
Researchers writing in Nature Medicine describe several advances in molecularly based precision medicine treatment strategies for rheumatology patients, despite the field still being in its inception.
For instance, in an emerging example of molecular stratification used in rheumatology clinical trials, the results of a phase II trial of iberdomide (which targets the transcription factor Aiolos, among others) demonstrated that higher levels of Aiolos or type I IFN signatures at baseline predicted better treatment responses in patients with moderate to severe systemic lupus erythematosus.
Another area of advancement is the molecular characterization of systemic autoimmune rheumatic disease (SARD) subgroups. “Recently, technological advances in molecular characterization and computational biology approaches have allowed for the identification of patient subgroups within each SARD, suggesting that diverse molecular pathways contribute to disease pathogenesis,” the Nature Medicine authors wrote.Related: Ankylosing spondylitis and RA: Possible comorbidities?
"Therefore, as in cancer and autoinflammatory diseases, tailoring treatments to the underlying molecular pathways of each disease using precision medicine is a promising approach to treating SARDs."
— Authors, Nature Medicine
For instance, early RA can be subdivided into clinical phenotypes due to distinct pathophysiology and different diagnosis, explain the authors writing in RMD Open. These three phenotypes are undifferentiated arthritis (UA), autoantibody (anti-citrullinated peptide antibodies [ACPA] and rheumatoid factor [RF]) negative RA (RA−), and autoantibody positive RA (RA+).
“These features are prerequisites for personalised treatment, but more importantly growing evidence is showing that UA and RA− can be treated with less intensive treatment compared with RA+,” the RMD Open authors wrote.
Advances in the field of rheumatology have also elucidated the mechanisms of monogenic autoinflammatory diseases, which are marked by dysregulated innate immunity.
Consequently, as noted in Nature Medicine, IL-1 receptor antagonists are now a precision treatment for inflammasome-mediated autoinflammatory diseases.
Focus on synovium
By and large, the search for peripheral blood biomarkers in RA has been disappointing, as the predictive value of biomarkers has been low. One notable exception, according to the authors in Nature Reviews Rheumatology, is seropositive vs seronegative RA. Seropositive patients harboring ACPA or RF, for instance, have responded better to rituximab in clinical trials, although the differences were modest.
A new area of interest is the synovium. Results from various biopsy-driven observational studies that assessed synovial signatures in patients before the initiation of biologic DMARD treatment found that some signatures were related to treatment response to anti-TNF, anti-IL-6 receptor, or B-cell depletion therapy. These observational results, however, have yet to be confirmed in independent controlled studies.
Another major issue with the uptake of precision medicine in rheumatology will be the high cost. Although studies support that precision medicine is cost-effective compared with standard of care in general, various factors are at play, including the prevalence of the genetic condition and costs of genetic testing. There is also the "willingness-to-pay" threshold to contend with.
What this means for you
The complex polygenic nature of SARDs makes it difficult to treat this disease via molecularly targeted therapies. However, experts find molecular stratification strategies promising in the pursuit of drug discovery and enhanced treatment effectiveness.
Looking forward, the use of molecularly identified subgroups in clinical trials may help determine stratification algorithms. It could also be helpful to run deep molecular profiling on multiple SARDs to assess signature stability, disease overlap, and precise patient stratifications for translation to patient care. Finally, the cost of precision medicine in rheumatology must be considered as a potential roadblock.