Comparative Efficacy (DAS28 Remission) of Targeted Immune Modulators for Rheumatoid Arthritis: A Network Meta-Analysis

This article is published with digital features, including a summary slide, to facilitate understanding of the article. To view digital features for this article go to https://​doi.​org/​10.​6084/​m9.​figshare.​14573544.

Rheumatoid arthritis (RA) is the most common chronic inflammatory arthritis in adults, affecting between 1.3 and 1.8 million people in the United States (US) alone [1‐3]. RA is a chronic, systemic, progressive, and sometimes disabling autoimmune disease that causes swelling, stiffness, and tenderness in and around the joints [4]. It is characterized by persistent symmetric polyarthritis (synovitis), which may affect any joint lined by a synovial membrane such as hands (metacarpophalangeal and proximal interphalangeal joints), wrists, and feet and may also lead to extra-articular involvement of organs such as the skin, heart, lungs, and eyes [4]. RA is considered a clinical syndrome that, if not controlled, can lead to permanent joint damage and deformity in some individuals [4].

As the guidelines from the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) state, effective treatment of RA requires an integrated approach involving patient education, diet and exercise, psychosocial support, physical and occupational therapy, pharmacotherapy, and surgery [5, 6]. Pharmacotherapies are broadly distinguished by whether they provide symptomatic relief only (such as nonsteroidal anti-inflammatory drugs [NSAIDs]) or prevent disease progression (disease-modifying antirheumatic drugs [DMARDs]) and, thus, tissue damage. Conventional synthetic DMARDs (cDMARDs) include older systemic agents such as methotrexate, hydroxychloroquine, sulfasalazine, and leflunomide that decrease inflammation and slow radiographic progression. Methotrexate is the most frequently prescribed medication as an initial treatment, but only an estimated 30% of patients demonstrate low disease activity with methotrexate monotherapy, while combinations of cDMARDs and biologics are significantly more effective than methotrexate alone in such patients [7]. Therefore, in patients who fail initial therapy with cDMARDs, treatment guidelines recommend adding targeted therapies such as interleukin (IL)-6 inhibitors, Janus kinase (JAK) inhibitors, tumor necrosis factor (TNF)-α inhibitors, T-cell inhibitors, and CD20-directed cytolytic B-cell antibodies that selectively block mechanisms involved in the inflammatory response [5, 6]. Collectively known as targeted immune modulators (TIMs), these biologic and nonbiologic therapies have been extensively used and have shown benefits in reducing or preventing joint damage as well as preserving joint integrity and function.

Treat-to-target (T2T) is a widely accepted guiding principle wherein patients are carefully managed to achieve and maintain clearly specified and sequentially measured goals that signal either remission or lowered disease activity [8]. While treatment response assessment at 24 weeks is the standard in clinical trials, assessment as early as 4–12 weeks after the start of treatment is recommended by guidelines following a T2T approach [6]. One key measure of disease activity in patients with RA is the 28-joint disease activity score (DAS28) [9]. The DAS28 combines single measures of 28 joints into an overall measure of disease that includes a composite of swelling, tenderness, blood markers of inflammation (erythrocyte sedimentation rate [ESR] and C-reactive protein [CRP]), and a global assessment of health. A DAS28 score > 5.1 implies active disease, between 2.6 and 3.2 implies low disease activity, and < 2.6 implies remission [5]. The DAS28 score allows clinicians to use multiple indices to assess an overall level of disease activity and provides a useful measure to guide disease management following a T2T approach in the clinical setting.

Two systematic literature reviews (SLRs) on RA were conducted by the Institute for Clinical and Economic Review (ICER). An evidence report was published by ICER in 2017 on the clinical and cost effectiveness of TIMs in patients with moderately to severely active RA who experienced an inadequate response to or intolerance of prior methotrexate or other cDMARDs [10]. The SLR included all TIMs available as of 2016, including baricitinib and sarilumab, which were then under Food and Drug Administration (FDA) review for the treatment of RA. The report identified DAS28-ESR as the most frequently used measure of disease activity across clinical trials, reported in about 80% of the trials that included disease activity measures, with most studies using remission rates (defined as DAS28 score < 2.6) as one of the study endpoints. However, the network meta-analysis (NMA) in the review assessed ACR20 response because it was the primary endpoint in the majority of the included randomized controlled trials (RCTs). ICER published an updated SLR and report in early 2020 focused on assessing the clinical and cost-effectiveness of JAK inhibitors (upadacitinib, tofacitinib, and baricitinib) in patients with moderately to severely active RA who experienced an inadequate response to or intolerance of prior methotrexate or other cDMARDs) [11]. Similarly, a NMA was conducted for ACR response outcomes but not for disease activity measures. In addition, no conclusions were made comparing JAK inhibitors with each other or with other TIMs.

While these two reviews provided comprehensive assessments of the RA evidence base, disease activity measures were only evaluated descriptively in both reviews, and the comparative efficacy among TIMs for achieving DAS28 remission is unclear without quantitative synthesis. In addition, while the 2020 review included upadacitinib, which was the most recently approved TIM for RA, the review was limited to JAK inhibitors only and did not involve a full analysis including all TIMs (e.g., a newer JAK inhibitor, filgotinib, was not included). Clinical evidence of filgotinib is available from two recent phase III RCTs: FINCH-1 and FINCH-2 [12, 13]. In order to inform the clinical community with comparative efficacy data for all TIMs, including filgotinib, we developed an RA evidence base by using evidence published in the two prior SLRs [10, 11], with additional clinical evidence from the FINCH-1 and FINCH-2 trials. An NMA was conducted using this evidence base in order to evaluate the comparative efficacy of achieving DAS28 remission with RA treatments in populations with moderately to severely active disease that are TIM naïve/mixed or TIM experienced.

The primary objective of this NMA was to evaluate the comparative efficacy of TIM therapies for DAS28 remission. DAS28 is scored on a continuous scale (0–10.0) based on tender and/or swollen joint counts (up to 28 each), ESR or CRP findings, and patient global visual analog scale (VAS) score. The NMA included evidence from RCTs.

The results of this NMA showed consistently more favorable response for DAS28 remission with TIM therapies, as both monotherapy and combination therapy with cDMARDs, compared with a cDMARD alone. Favorable results with TIM therapies were seen at 12 and 24 weeks, and in both TIM-naïve/mixed populations as well as TIM-experienced patients. JAK inhibitors, as a relatively new class of drugs for the treatment of moderate to severe RA, have similar efficacy to other approved TIM therapies in lowering disease activity and achieving DAS28 remission. In all of our analyses, tocilizumab had the highest probability of being ranked as the best treatment for DAS28 remission. Tocilizumab IV also had the highest odds ratio of achieving DAS28 remission among all TIMs compared with a cDMARD alone.

Our results are consistent with previous NMAs in the evaluation of other measures of treatment response (i.e., ACR). Ollendorf et al. also analyzed ACR response criteria in populations with moderate to severe RA who are TIM-naïve/mixed and TIM-experienced [10]. They reported that all TIMs produced statistically and clinically superior improvements in ACR response compared with a cDMARD alone. Their results were also consistent regardless of whether TIMs were used in combination with a cDMARD or as monotherapy. Ollendorf et al. also reported that tocilizumab IV monotherapy had the highest likelihood of achieving ACR20 or better in the TIM-naïve/mixed population. When analyzing JAK inhibitors on ACR response in the same population, Tice et al. and Pope et al. reported that proportions of patients achieving low disease activity or remission at 12 weeks and 24 weeks were substantially greater in the JAK inhibitor group, with or without combination cDMARD therapy, compared with those receiving cDMARDs alone [11, 19]. Similar to our findings, Pope et al. also quantitatively assessed DAS28 remission rates through a Bayesian NMA and reported that the JAK inhibitor + cDMARD groups had a higher odds ratio of achieving DAS28 remission compared to cDMARD alone. However, this analysis only quantitatively compared JAK inhibitors and cDMARDs, indicating that further studies comparing other treatments (i.e., biologic therapy) is necessary. Lee et al. evaluated the efficacy of biologics and tofacitinib in patients with inadequate response to TNFi and reported that tocilizumab was associated with the most favorable SUCRA for the ACR20 response rate and that the tocilizumab 8-mg group showed a significantly higher ACR20 response rate compared with abatacept and tofacitinib [20]. However, Lee et al. acknowledged that remission rates in each group were too small to allow an NMA. In the previous NMAs that included both biologics and JAK inhibitors, only ACR response was used for the quantitative synthesis, while DAS28 remission was presented as descriptive findings. Using DAS28 remission as the NMA outcome, our study provided a comprehensive comparison of all the eligible TIM therapies for their disease activity–lowering effects, which could be useful to guide disease management strategies in different populations.

This study has some limitations. First, the studies included in the analysis were based on previous reviews by Ollendorf et al., and Tice et al., therefore, it was assumed that the screening process and study selection were accurate in the previous reviews [10, 11]. We evaluated the eligibility criteria and comparability of studies before conducting the NMA to ensure potential effect modifiers were balanced across studies. After review by a clinician, we concluded studies were similar. Second, due to the limited evidence base and lack of available treatment comparisons, weaker networks were seen in the evaluation of monotherapy in the TIM-naïve/mixed population and combination therapy in the TIM-experienced population, with only one or two studies informing each comparison. Moreover, as also reported by Ollendorf et al., and Tice et al., our treatment efficacy estimates were limited to the population with moderate to severe RA [10, 11]. Therefore, the applicability of these results should be limited to that population. Lastly, the DAS28-ESR and CRP measurements have inherent drawbacks. If a patient has a high ESR blood result, or if RA is present in the feet (which are not included in the 28-joint count), the score may be misleadingly high or low. Agents inhibiting IL-6 and JAK signaling may also lead to a rapid reduction in either CRP or ESR levels while not affecting the other to a similar extent [21, 22]. As a result, using DAS28-CRP when DAS28-ESR was not available may overestimate treatment effect and remission rates. Although the effect on acute-phase reactants (ESR or CRP) by these agents might have an impact on the disease activity measure by DAS28, DAS28 remission is still considered appropriate since composite eligibility criteria involving joint counts and acute phase reactant levels were applied at trial entry, such that changes in ESR or CRP alone were not likely to drive remission at week 12 or week 24.

Our NMA presents a comprehensive and simultaneous evaluation of all FDA-approved TIM therapies and those undergoing FDA review using direct and indirect evidence. Our results suggest that TIM therapies, particularly tocilizumab IV, are effective in achieving DAS28 remission as early as 12 weeks compared with a cDMARD alone. These results have important clinical implications that coincide with the increasing use of the T2T approach for patients with RA. RA is heterogeneous in terms of clinical presentation and disease management. As guidelines recommend more frequent monitoring of disease activity to better assess the likelihood of reaching the treatment target, using the DAS28 as a measure of disease activity can guide patient treatment and optimize outcomes. The DAS28 has validated thresholds for high and low disease activity and shows a clear relationship between clinically inactive RA and remission. Thus, therapies demonstrating achievement of low disease activity or remission at early follow-up, such as 12 weeks after treatment initiation, may have a higher likelihood of achieving success and improving outcomes.