Precision Therapy for Rheumatoid Arthritis Using Biologic DMARDs

The advent of disease-modifying antirheumatic drugs (DMARDs) provided the opportunity to not only relieve clinical symptoms of rheumatoid arthritis (RA) but also to slow disease progression. These include the conventional synthetic DMARDS (csDMARDs) leflunomide and sulfasalazine, and most prominently methotrexate, which is still a first-line therapy. Unfortunately, while therapy worked for many patients, others still had little or no clinical response to csDMARDS and continued to experience RA symptoms and disease progression.¹

In the last decade, a newer class of biologic DMARDs (bDMARDs) including anakinra, infliximab, etanercept, adalimumab, rituximab, abatacept, tocilizumab, golimumab, and certolizumab pegol offered relief from pain and inflammation significant enough to achieve clinical remission, while also inhibiting joint destruction to halt disease progression.² These agents have brought the ultimate goal of a complete cure within sight, especially when RA is diagnosed promptly and early treatment is initiated.^3,4

While bDMARDs and methotrexate have become the mainstays of RA therapy, many patients fail to achieve optimal success with these agents due to extensive variation in individual patient response to therapies.^4,5 In fact, as many as 40% never achieve the minimally acceptable response to biologic agents.³ This, together with the fact that bDMARDs are associated with toxicity, means that their use has to be carefully weighed in each patient.

Safety

Risk of infection is increased with the use of bDMARDs compared with conventional DMARDs, as is risk for infusion and injection site reactions.^2,6 Annual screening for tuberculosis and vaccination against pneumococcal disease, influenza, and hepatitis B virus are critical to preventing complications with biologic therapies.²

Risks of serious infections, tuberculosis, and herpes zoster with tumor necrosis factor (TNF) inhibitors are particularly high compared with csDMARDs, and the risk for melanoma (but not other malignancies) may be slightly increased.^2,6 The risk for malignancy other than hematologic malignancies is also increased with bDMARDs.⁶

Multiple Mechanisms

The bDMARDs encompass a broad range of agents that work via many different mechanisms, including interactions with antigen-presenting cells that interact with the adaptive immune system (CD4+ T cells and B cells). They can also affect various mediators of joint inflammation and destruction in RA, including TNF-alpha, interleukin-1 (IL-1), IL-6, chemokines, and proteases, each of which plays a different role in autoimmunity.⁷ Biologic agents alpha infliximab, etanercept, adalimumab, golimumab, and certolizumab pegol inhibit TNF; tocilizumab and anakinra are interleukin-1 (IL-1) and IL-6 antagonists; rituximab is a B-cell-depleting agent; and abatacept is a T-cell co-stimulation inhibitor.

Choosing the wrong agent with the wrong mechanism is the main cause of bDMARD failure in RA. One of the keys to the effective use of these powerful new therapies is to better identify patients who will benefit from therapy with each individual agent.

Predicting Response to Therapy

One of the most significant predictors of response to bDMARD therapy is the patient’s response to methotrexate; therefore, it has been recommended that all bDMARDs be given in combination with methotrexate to help modulate the immunogenicity of the therapy.³ Current smoking is associated with a significantly poorer response to TNF inhibitors and is the most modifiable predictive factor.³ Being male, younger, having early disease status, and having received fewer DMARD therapies are all predictive of a better response to bDMARDs.

A number of biologic predictors have also been identified for specific agents. The presence of rheumatoid factor along with anticitrullinated protein antibodies is used to stratify patients across multiple agents: seropositivity to rheumatoid factor and/or anticitrullinated protein antibodies strongly supports the use of rituximab and the use of TNF inhibitors in seronegative patients. Various types of cellular and molecular markers that characterize changes in synovial tissue and blood are under investigation, although clear patterns have not yet emerged consistently across studies.³

Targeting Therapy

Personalized medicine is designed to individualize therapy so that the right person gets the right drug for the right amount of time to achieve remission in RA. Genomic research over recent years has helped identify specific molecular and cellular targets for bDMARD therapy along with milestones to guide treatment decisions.

Many variations of therapy are now possible, and determining the optimal strategy for each patient is crucial to the success of treatment. A 2017 update of EULAR recommendations for RA reported that treatment with a bDMARD plus a csDMARD achieved better efficacy than  treatment with a csDMARD alone.¹ Starting csDMARD therapy, escalating the dose, and adding a bDMARD in cases of nonresponse to the therapy was considered an effective treat-to-target strategy.¹ When a bDMARD fails, the European League Against Rheumatism (EULAR) guidelines suggested that switching to another bDMARD could produce a better response, although choosing an agent with a different mechanism of action showed no greater benefit with a similar agent.¹ They further recommended continuation of therapy to maintain low disease activity, although bDMARD dose reduction, or extending the spacing of doses, did not appear to alter remission status.¹

These recommendations are still based on early research and are designed to provide a basis for rational decision-making in RA therapy, with room for updates as new evidence emerges. In the near future, researchers hope to identify novel biomarkers that can lead clinicians to the optimal agents for all patients and drive RA treatment toward a cure. That goal seems attainable, but much evidence still needs to be gathered to put together a complete algorithm in the treatment of RA.

References

1. Nam JL, Takase-Minegishi K, Ramiro S, et al. Efficacy of biological disease-modifying antirheumatic drugs: a systematic literature review informing the 2016 update of the EULAR recommendations for the management of rheumatoid arthritis. Ann Rheum Dis. 2017;76:1113-1136.
2. Agarwal SK. Biologic agents in rheumatoid arthritis: an update for managed care professionals. J Manag Care Pharm. 2011;17:S14-S18.
3. Romão VC, Vital EM, Fonseca JE, Buch MH. Right drug, right patient, right time: aspiration or future promise for biologics in rheumatoid arthritis? Arthritis Res Ther. 2017;19:239.
4. Sen D, Paul JR, Ranganathan P. Pharmacogenetics in rheumatoid arthritis. Methods Mol Biol 2014;1175:625-660.
5. Bluett J, Barton A. Precision medicine in rheumatoid arthritis. Rheum Dis Clin North Am. 2017;43(3):377-387.
6. Cho S-K, Lee J, Han M, Bae S-C, Sung Y-K. The risk of malignancy and its incidence in early rheumatoid arthritis patients treated with biologic DMARDs. Arthritis Res Ther. 2017;19:277.
7. Wang D, Li Y, Liu Y, Shi G. The use of biologic therapies in the treatment of rheumatoid arthritis. Curr Pharm Biotechnol. 2014;15(6):542-548.