INTRODUCTION — The treatment of rheumatoid arthritis (RA) is directed at the control of synovitis, the prevention of joint injury, and, increasingly, the reduction of attendant comorbidities with the overall aim of maintaining function and quality of life. The choice of therapies depends upon several factors, including the severity of disease activity and the response of the patient to prior therapeutic interventions, as well as comorbidities, patient preferences, and regulatory and cost limitations. Advances in treatment have come both from new approaches to the use of available therapies, particularly strategic initiatives to treat early and to treat-to-target, and from the development of novel agents that more effectively and safely target key elements of the immune response and pathways involved in the disease process. Despite these advances, many patients do not respond adequately, and treatments can have adverse effects.

A cornerstone of therapy is the use of disease-modifying antirheumatic drugs (DMARDs), including conventional or traditional small-molecule drugs (eg, methotrexate [MTX], so-called conventional synthetic [cs]DMARDs); targeted biologic agents (eg, tumor necrosis factor [TNF] inhibitors, so-called biologic [b]DMARDs) and biosimilar copies of these drugs; and orally active targeted small-molecule Janus kinase (JAK) inhibitors (eg, tofacitinib, forming a new group termed targeted synthetic [ts]DMARDs). Additional therapeutic agents are directed at inflammation, such as nonsteroidal antiinflammatory drugs (NSAIDs) and glucocorticoids. The development of new DMARDs, including novel and biosimilar biologic agents and targeted orally active small molecules, is an active area of investigation. (See "Overview of biologic agents and kinase inhibitors in the rheumatic diseases".)

Novel investigational agents in advanced stages of development for RA will be reviewed here. Existing therapies for RA and the pathogenesis of the disorder are described in detail separately. (See "Nonpharmacologic therapies for patients with rheumatoid arthritis" and "Alternatives to methotrexate for the initial treatment of rheumatoid arthritis in adults" and "Initial treatment of rheumatoid arthritis in adults" and "Treatment of rheumatoid arthritis in adults resistant to initial conventional synthetic (nonbiologic) DMARD therapy" and "Treatment of rheumatoid arthritis in adults resistant to initial biologic DMARD therapy" and "Pathogenesis of rheumatoid arthritis".)

INTERLEUKIN 6 ANTAGONISTS — Several commercially available therapies for rheumatoid arthritis (RA) target the interleukin (IL) 6 pathway, including antibodies directed against the IL-6 receptor (IL-6R) such as tocilizumab and sarilumab. Another investigational antibody that showed efficacy in clinical trials was sirukumab, which targeted IL-6 directly; however, it remains to be seen if targeting IL-6 directly offers a strategic advantage over targeting of the receptor and whether this approach will exhibit sufficient safety to merit approval. Other anti-IL-6 agents are also under study. (See 'Sirukumab' below and 'Other anti-IL-6 agents' below.)

IL-6 is a proinflammatory cytokine, originally described as B cell differentiation factor, which mediates pleiotropic functions in immunologic responses during host infection, inflammatory disease, hematopoiesis, and oncogenesis. IL-6 is expressed in RA synovial tissues and is implicated in upregulation of endothelial adhesion molecule expression, in osteoclast maturation, and in bone erosion. IL-6 also mediates systemic features of disease, including fatigue, cognitive dysfunction, and metabolic shift.

IL-6 utilizes a receptor comprising two functional chains, namely IL-6R-alpha (IL-6Ra) and a 130 kD non-ligand-binding but signal-transducing chain (glycoprotein 130 [gp130]). IL-6 may bind IL-6R/gp130 complexes on target cells and may promote signals. However, expression of gp130 in the absence of IL-6Ra is widespread and confers on the expressing cell the capacity to respond to circulating IL-6/IL-6Ra complex.

Sirukumab — Sirukumab, a human anti-IL-6 monoclonal antibody, was effective in two phase 3 trials involving a total of over 2500 patients, including in patients with inadequate responses to methotrexate (MTX) and in patients resistant to tumor necrosis factor (TNF) inhibitor therapy [1,2]; however, based upon safety concerns, the US Food and Drug Administration (FDA) Arthritis Advisory Committee did not recommend drug approval, noting evidence of imbalances in death, serious adverse events, major adverse cardiovascular events, serious infection, and malignancy in the sirukumab development program, although the results were imprecise [3,4]. The FDA therefore indicated that additional clinical data were needed to further evaluate safety, and the manufacturer subsequently withdrew its application and is no longer developing this agent for the treatment of RA.

Other anti-IL-6 agents — A humanized rabbit anti-IL-6 monoclonal antibody, clazakizumab, has shown benefit in patients with RA and an inadequate response to MTX when used either alone or in combination with MTX in a phase 2 randomized dose-ranging trial [5]. Adverse effects in the trial were similar to those seen with other anti-IL-6 and anti-IL-6R agents. Further studies are ongoing with novel IL-6 inhibitor antibodies.

GM-CSF LIGAND AND RECEPTOR ALPHA CHAIN INHIBITORS — Both the granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor and GM-CSF itself have been targets of inhibitory monoclonal antibodies. Mavrilimumab, a human monoclonal antibody targeting the GM-CSF receptor-alpha, has shown benefit in randomized phase 1 and 2 trials in patients with active rheumatoid arthritis (RA) [6-9]. GM-CSF is a proinflammatory cytokine involved in pathogenesis of RA through its capacity to promote the activation, differentiation, and survival of macrophages, dendritic cells, and neutrophils. It is upregulated in synovial tissue and circulating cells from patients with RA, and there is interest in the therapeutic utility of targeting the GM-CSF receptor and other colony-stimulating factors in patients with RA.

A randomized phase 1 trial of mavrilimumab showed evidence of pharmacodynamic activity, with adequate tolerability and safety in patients on stable doses of methotrexate (MTX) to proceed with further study [6]. In phase 2 clinical trials in RA, mavrilimumab demonstrated benefits over placebo in patients with an inadequate response to conventional disease-modifying antirheumatic drugs (conventional synthetic [cs]DMARDs) and in patients with inadequate responses to tumor necrosis factor (TNF) inhibitor therapy [7-9]. Additional trials with better optimized dosing would be required to adequately compare the efficacy and safety of mavrilimumab with other biologic agents but have not been undertaken.

Other agents are under trial that are targeting the cytokine itself [10,11]. Foremost among these and following phase 2 evaluation is a phase 3 study program of otilimab. This is an anti GM-CSF monoclonal antibody, which is being evaluated for patients with moderate to severe RA who have had an inadequate response to DMARD or targeted therapies.

JANUS KINASE INHIBITORS — Several pathways that mediate receptor signal transduction have been targeted by the use of small molecules that are kinase inhibitors [12]. The Janus kinases (JAK) are cytoplasmic protein tyrosine kinases that are critical for signal transduction to the nucleus from the common gamma chain of the plasma membrane receptors for interleukin (IL) 2, IL-4, IL-7, IL-9, IL-15, and IL-21. Some of these agents have become available for clinical use in many or a few countries, including tofacitinib, baricitinib, upadacitinib, and peficitinib. (See "Treatment of rheumatoid arthritis in adults resistant to initial conventional synthetic (nonbiologic) DMARD therapy", section on 'JAK inhibitor therapy' and "Treatment of rheumatoid arthritis in adults resistant to initial biologic DMARD therapy", section on 'JAK inhibitors'.)

Other agents are also under evaluation (eg, filgotinib). (See 'Filgotinib' below.)

Filgotinib — Filgotinib is a small-molecule, orally active investigational drug that selectively inhibits JAK-1 in vitro. The efficacy and safety of filgotinib have been examined in several trials, where it has shown efficacy generally similar to the marketed JAK inhibitors, including the JAK-1 selective inhibitor, upadacitinib, and was well tolerated.

The efficacy and relative safety of filgotinib was evaluated in a randomized trial involving 449 patients with moderate to severely active RA who had an inadequate response or intolerance to prior therapy with one or more biologic disease-modifying antirheumatic drugs (bDMARDs) [13]. At week 12, patients treated with filgotinib (200 or 100 mg once daily by mouth) were more likely to achieve an American College of Rheumatology (ACR) 20 percent improvement (ACR20) response, compared with patients receiving placebo (66 and 58 versus 31 percent, respectively). ACR20 responses were also more likely among patients with prior exposure to three or more bDMARDs (70 and 59 versus 8 percent), and responses were sustained at week 24. By week 12, low disease activity (disease activity score in 28 joints using the C-reactive protein [DAS28-CRP] ≤3.2) was more common with filgotinib (41 and 37 versus 16 percent, respectively). Physical function and fatigue also improved. Serious adverse events from weeks 0 to 24 were observed in in 4, 5, and 3 percent, respectively; and drug discontinuation for treatment-related events occurred in 3, 4, and 2 percent, respectively. Most patients were receiving ongoing methotrexate (MTX) during the trial.

In phase 2 trials in patients with an inadequate response to MTX, filgotinib has shown benefit (in several doses), compared with placebo, both when combined with continued MTX therapy [14,15] and as monotherapy [16]. Patient-reported outcomes also improved with this agent [14]. An extensive phase 3 trial program is now underway in patients with RA at different stages of therapy.

Use of filgotinib was associated with improvements in hemoglobin levels. Greater experience with the JAK inhibitors is needed to determine whether differences in the in vitro selectivity of different JAK inhibitors will translate into meaningful differences in their adverse event profiles in clinical practice.

BIOSIMILARS — Biosimilars, which are a type of copy of the originally marketed versions of biologic agents (eg, of several of the tumor necrosis factor [TNF] inhibitors), are under development or have already been approved by regulatory agencies for use in the treatment of rheumatoid arthritis (RA). These agents and their general features are described separately. (See "Overview of biologic agents and kinase inhibitors in the rheumatic diseases", section on 'Biosimilars for biologic agents'.)

DIETARY THERAPIES — Many different dietary manipulations have been proposed as therapy in rheumatoid arthritis (RA), but the majority are unproven. An exception to this may be that diets rich in fish oil or a diet to which eicosapentaenoic acid or docosahexaenoic acid is added may result in decreased arachidonic acid metabolites and cytokines, with a concurrent decrease in symptoms [17-19].

In one randomized trial, involving 139 patients with recent-onset RA, the addition of high-dose fish oil (5.5 g daily) to triple therapy with traditional disease-modifying antirheumatic drugs (DMARDs) (methotrexate [MTX] plus sulfasalazine [SSZ] plus hydroxychloroquine) significantly reduced the proportion of patients failing to achieve remission or low disease activity on the initial treatment regimen, compared with the addition of low-dose fish oil (0.4 g daily) (11 versus 32 percent, hazard ratio [HR] 0.28, 95% CI 0.12-0.63) [20].

SELECTED AGENTS WITH INADEQUATE BENEFIT IN RA — Numerous compounds have been evaluated for the treatment of rheumatoid arthritis (RA) based upon their biologic features and expected potential clinical benefit, but many such agents do not reach the clinical trial stage or fail to exhibit adequate benefit relative to their adverse effects and potential risks in patients with RA, even when they show benefit in patients with other forms of inflammatory arthritis. Examples of agents that have been studied and entered clinical trials but whose further development for RA has not gone forward include:

●Anti-IL-12/-23 and anti-IL-17 – Drugs that target interleukin (IL) 12/23 (eg, ustekinumab, guselkumab) and IL-17 (eg, secukinumab), which have been effective in patients with psoriatic arthritis or spondyloarthritis, are no longer under investigation for RA, as they have not been shown to be sufficiently effective and safe in patients with RA to justify use in this disorder [21-23]. (See "Treatment of psoriatic arthritis".)

●Syk inhibition – Fostamatinib, a spleen tyrosine kinase (Syk) inhibitor that showed benefit in early trials, was also found insufficiently effective to warrant continued development [24-28].

●RANK ligand inhibition – Denosumab is a human monoclonal antibody against the ligand for the receptor activator of nuclear factor kappa B (RANK ligand or RANKL); it is available for the treatment of osteoporosis and has been studied in RA [29]. Although it decreased the development of erosions, it had no effect upon RA disease activity. As such, it should not be used for the primary purpose of treating RA. (See "Denosumab for osteoporosis".)

SUMMARY

●The development of new disease-modifying antirheumatic drugs (DMARDs), including novel and biosimilar biologic agents and targeted orally active small molecules, is an active area of investigation. Major novel biologics in development include:

•Otilimab, an inhibitory granulocyte-macrophage colony-stimulating factor (GM-CSF)-targeted monoclonal antibody, is under development. (See 'GM-CSF ligand and receptor alpha chain inhibitors' above.)

•Biosimilars, which are copies of the originally marketed versions of biologic agents, are under development or have already been approved by regulatory agencies for use in the treatment of rheumatoid arthritis (RA). These agents and their general features are described separately. (See 'Biosimilars' above and "Overview of biologic agents and kinase inhibitors in the rheumatic diseases", section on 'Biosimilars for biologic agents'.)

●Small-molecule inhibitors of receptor signal transduction in development include inhibitors of the Janus kinase (JAK) family. Filgotinib is a JAK-1 selective inhibitor currently in development. (See 'Janus kinase inhibitors' above and 'Filgotinib' above.)

●Dietary manipulations have been proposed and studied as therapy in RA. One focus of these trials has been on diets rich in fish oil or a diet to which eicosapentaenoic acid or docosahexaenoic acid is added. (See 'Dietary therapies' above.)