Adapting to a Changing Landscape of Rheumatoid Arthritis Therapies

Rheumatoid arthritis (RA) continues to affect as many as 1.5 million adults in the United States.¹ Women are 2 to 3 times as likely to be affected as men.²

The burden of this disease is high; patients with RA have a 60%-70% higher mortality risk compared with those in the general population, and the survival gap appears to be widening.³ A 2007 study found increased mortality from cardiovascular disease (31%), pulmonary fibrosis (4%), and lymphoma (2.3%) in patients with RA.⁴ Psychiatric disorders, particularly depression, are also common in these patients, with approximately 16.8% of RA patients suffer from depression—a significantly higher rate than in the general population.⁵ Additionally, a study reported that patients with RA were hospitalized at a greater rate for diabetes mellitus than were people without RA.⁶

At the same time, global mortality rates attributable to RA have declined globally. As the population ages and patients with this disease live longer, the economic burden of RA is expected to increase.⁷

A major source of health care utilization and costs associated with RA is hospitalization,⁶ though the annual hospitalization rate for patients with RA is in decline.⁸ The lost productivity associated with RA is substantial. Approximately 20% to 70% of individuals who were working at the inception of their RA were disabled after 7 to 10 years. Because of its progressive nature, many individuals report missing work or choose not to work because of disease-related disabilities.⁹ The indirect cost of RA due to lost productivity has been estimated to be nearly three times greater than the costs associated with treating the disease.¹⁰ In 2015, estimated national indirect costs of RA-related absenteeism from work were $252 million annually.¹¹

Approved Treatments for RA

High quality evidence suggests that methotrexate and other conventional nonbiologic disease-modifying antirheumatic drugs (DMARD) are effective in many patients with RA. Initial therapy for RA should be a conventional nonbiologic DMARDs unless these are contraindicated.¹²

If a patient has had an inadequate response to methotrexate with or without other nonbiologic DMARD during an initial 3-month trial, then biologic therapy can be considered. Exceptions include patients with high disease activity and poor prognostic features (functional limitations, disease outside the joints, seropositivity or bony damage), where biologic therapy may be appropriate first-line treatment.¹²

Several biologic DMARDS approved for RA interfere with cytokine function (inhibit or block tumor necrosis factor [TNF] and several of the interleukins (IL-1, IL-6, IL-17, IL-12/23), to inhibit the second signal needed for T-cell activation, and to deplete B cells. TNF-blocking therapies include Humira (adalimumab) and its biosimilar Amjevita (adalimumab-atto); Cimzia (certolizumab); Remicade (infliximab); Simponi Aria (golimumab); and Enbrel (etanercept). These drugs can be used alone or in combination with methotrexate.

Orencia (abatacept) is a biologic response modifier that binds to CD80 and CD86 receptors on the antigen-presenting cell and prevents these receptors from binding to CD28 receptors on T cells, which decrease inflammation by downregulating T-cell activation. Activated T lymphocytes are implicated in the pathogenesis of RA and are found in the synovium of patients with RA. Other biologics include Rituzam (rituximab), a genetically engineered chimeric murine/human monoclonal IgG, κ antibody directed against the CD20 antigen; Actemra (tocilizumab), a recombinant humanized anti-human IL-6 receptor monoclonal antibody of the immunoglobulin IgG1κ subclass; and Kineret (anakinra), a recombinant, nonglycosylated form of the human interleukin-1 receptor antagonist (IL-1Ra). These may be used as monotherapy or concomitantly with DMARDs other than TNF antagonists.

A Janus kinase (JAK) inhibitor is not classified as a biologic drug. Instead, it is classified as a small molecule DMARD. The target of a JAK inhibitor is the JAK pathway, which has a prominent role in the inflammatory process associated with RA.

The first JAK inhibitor, Xeljanz (tofacitinib citrate), was approved by the FDA on November 6, 2012. Olumiant (baricitinib) is a another JAK inhibitor indicated for the treatment of adult patients with moderately to severely active RA who have had an inadequate response to one or more TNF antagonist therapies. These drugs may be used as monotherapy or in combination with methotrexate or other nonbiologic DMARDs, but it should not be used with biologic drugs.

Awaiting New Clinical Guidelines

Given the array of treatments that are now available for patients with RA, practitioners are anxiously awaiting updated clinical practice guidelines from the American College of Rheumatology (ACR). The most recent Guideline for the Treatment of Rheumatoid Arthritis was published in 2015, before many of the above treatments were approved. The guideline development committee has stated that goals of the update include¹³:

• Develop recommendations for the use of DMARDs (including conventional synthetic DMARDs, targeted biologic DMARDs and targeted synthetic DMARDs), as well as glucocorticoids.
• Clarify differences in treatment recommendations for patients who are DMARD-naïve vs those who have already been treated with one or more DMARDs.
• Clarify differences in treatment recommendations for patients with low vs moderate to high disease activity.
• Develop recommendations for tapering DMARDs.
• Include recommendations for nonpharmacologic therapies in the management of RA.
• Include recommendations related to co-morbid conditions (eg, congestive heart failure, hepatitis B or C, cancer, history of serious infections).
• Include recommendations for vaccine administration.

As some of the newer biologics and JAK inhibitors become incorporated into clinical practice, there will also be a need for updated cost-effectiveness analyses for these treatments to guide payers in their coverage decisions.

References 

1. Myasoedova E, Croson CS, Kremers HM, et al. Is the incidence of rheumatoid arthritis rising? Results from Olmsted County, Minnesota, 1955-2007. Arthritis Rheum. 2010;62(6):1576-1582. 
2. Vollenhoven RFV. Sex differences in rheumatoid arthritis: more than meets the eye. BMC Med. 2009;7:12.
3. Mikuls TR. Rheumatoid arthritis incidence: what goes down must go up? Arthritis Rheum. 2010;62(6):1565-1567. 
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6. arthritis: a systematic review and meta-analysis. Rheumatology (Oxford). 2013;52:2136-2148.
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8. Kiadaliri AA, Felson DT, Neogi T, Englund M. Brief report: Rheumatoid arthritis as the underlying cause of death in thirty-one countries, 1987-2011: trend analysis of World Health Organization Mortality Database. Arthritis Rheumatol. 2017;69(8):1560-1565.
9. Lim SY, Lu N, Oza A, et al. Trends in gout and rheumatoid arthritis hospitalizations in the United States, 1993-2011. JAMA. 2016;315(21):2345-2347.
10. Burton W, Morrison A, Maclean R, Ruderman E. Systematic review of studies of productivity loss due to rheumatoid arthritis. Occup Med (Lond). 2006;56:18-27.
11. Agarwal SK. Core management principles in rheumatoid arthritis to help guide managed care professionals. J Manag Care Pharm. 2011;17(9 suppl B):S03-S08.
12. Gunnarsson C, Chen J, Rizzo JA, et al. The employee absenteeism costs of rheumatoid arthritis: evidence from US national survey data. J Occup Environ Med. 2015;57(6):635-642.
13. Yazdany J, Schmajuk G, Robbins M, et al; The American College of Rheumatology Core
14. Membership Group. Choosing wisely: the American College of Rheumatology’s Top 5 list of things physicians and patients
15. should question. Arthritis Care Res. 2013;65(3):329-339.
16. American College Of Rheumatology. American College Of Rheumatology Updated Guideline for the Management of Rheumatoid Arthritis. Project Plan. Published October 2018. ACR website. https://www.rheumatology.org/Portals/0/Files/Rheumatoid-Arthritis-Guideline-Project-Plan.pdf. Accessed February 26, 2019