Meaningful Improvement and Worsening in Patients Who Do Not Achieve Low Disease Activity and Switch Therapy to a New Biologic or Targeted Disease-Modifying Antirheumatic Drug: Results From the CorEvitas RA Registry : JCR: Journal of Clinical Rheumatology

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Meaningful Improvement and Worsening in Patients Who Do Not Achieve Low Disease Activity and Switch Therapy to a New Biologic or Targeted Disease-Modifying Antirheumatic Drug

Results From the CorEvitas RA Registry

Curtis, Jeffrey R. MD, MS, MPH; Fiore, Stefano MD; Ford, Kerri Pharm D; Janak, Jud C. PhD§; Chang, Hong PhD§; Pappas, Dimitrios A. MD§,∥; Blachley, Taylor MS§; Emeanuru, Kelechi MPH, CPH§; Bykerk, Vivian P. MD

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JCR: Journal of Clinical Rheumatology 29(4):p e47-e51, June 2023. | DOI: 10.1097/RHU.0000000000001956


The main goal of treatment in patients with rheumatoid arthritis (RA) is clinical remission or low disease activity (LDA), which can be achieved by a “treat-to-target” approach. For this, clinical practice guidelines recommend adding a biologic/targeted synthetic (b/ts) disease-modifying antirheumatic drug (DMARD) to the first-line therapy of conventional synthetic (cs) DMARD. Further, if treatment with 1 b/tsDMARD fails, switching to another b/tsDMARD can be considered.1,2

Real-world data have shown that one-third to two-thirds of patients decline a modification of their RA treatment, despite not achieving LDA or remission.3 In a setting of a partial but incomplete response to RA treatment, patients express aversion to the new treatment and often decline to switch therapy because of the fear of potential adverse effects of new medications, worsening of RA symptoms, or loss of improvement that has been achieved, despite the potential for clinical benefit.4,5 Because of this risk-averse behavior, patients put greater weight on the certainty of their current disease control and medications than the uncertainty (of risks and benefits) associated with changing medications.5 This human tendency to give more importance to negative consequences/events than the positive ones is well explained by the prospect theory, which suggests that individuals have stronger psychological responses to the losses than the gains associated with an outcome and prefer avoiding losses over pursuing gains (loss aversion).6

There is sufficient evidence that shows that many patients benefit by switching to a drug with an alternative mechanism of action, including improvements in disease control and physical function.7 However, data addressing the likelihood of worsening after switching therapies are limited. Recently, a post hoc analysis of MONARCH, a head-to-head randomized, active comparator-controlled, double-blind trial, showed that partial responders to adalimumab (a tumor necrosis factor inhibitor) who switched to sarilumab (an interleukin-6 receptor inhibitor [IL-6Ri]) were less likely to experience meaningful worsening, with majority of patients experiencing meaningful improvement or no change in disease activity.8

The present study was conducted to assess the propensity of disease activity (ie, either worsening or improvement) after switching therapies in a real-world setting. The aim of this analysis was to describe the demographics, clinical characteristics, and change in clinical outcomes in patients with RA who switched to another b/tsDMARD after 6 to 12 months on their initial b/tsDMARD therapy because of an inadequate improvement in clinical disease activity index (CDAI; LDA not achieved).


Data Source and Patients

The CorEvitas (formerly known as Corrona) RA Registry is a longitudinal, multicenter, observational, disease-based registry launched in the United States in 2001. The present study included adult patients with RA from the registry who were inadequately responding to b/tsDMARDs. Patients were included if they started a b/tsDMARD (tumor necrosis factor inhibitor, IL-6Ri, T-cell costimulatory inhibitor, anti-CD20 antibody, or Janus kinase inhibitor) between January 2010 and November 2020 (index or prebaseline visit [VPre-BL]) with a CDAI >10, had any CDAI improvement (ie, decrease >0 unit) but were not in LDA or remission at a subsequent visit (baseline visit [VBL]) occurring 6 to 12 months (±3 months) after VPre-BL, and had a third visit (follow-up visit [VF/U]) at 6 to 12 months (±3 months) after VBL with a CDAI measure. Our analysis restricted the eligible population to those patients who switched to a new b/tsDMARD at VBL or between VBL and VF/U, with the switch occurring at least 3 months before the VF/U; the patients were allowed to switch from any class of b/tsDMARD to another b/tsDMARD.

The study was performed in accordance with the Declaration of Helsinki, and all participating investigators were required to obtain full ethics board approval for conducting research involving human subjects. Sponsor approval and continuing review of the study were obtained through a central institutional review board (IRB) (New England Independent Review Board number 120160610). For academic sites that did not receive a waiver to use the central IRB, approval was obtained from the respective governing IRBs, and documentation of approval was submitted to the Sponsor before initiating any study procedures. All registry patients were required to provide written informed consent before participation.


Demographic characteristics, including duration of RA and lifestyle parameters, were described for the switchers at VPre-BL and VBL. Disease activity measures including CDAI and components of CDAI, patient-reported outcomes (including Health Assessment Questionnaire, pain visual analog scale [VAS; 0–100], patient global assessment VAS [0–100], fatigue VAS [0–100], and morning stiffness), and treatment modifications were evaluated at each visit.

Meaningful change in CDAI was assessed at VBL and VF/U. Two thresholds of meaningful change were used for all switchers (regardless of their preswitch CDAI value): a lower (more sensitive; ≥6 units) threshold and a higher (more specific; ≥12 units) threshold. Meaningful worsening was defined as an increase of ≥6 or ≥12 units and meaningful improvement as a decrease of ≥6 or ≥12 units; no meaningful change was defined as a change between −6 to +6 units and −12 to +12 units, using the respective thresholds.9

Statistical Analyses

Descriptive statistics were reported for demographics and clinical characteristics. All outcomes and time-variant clinical characteristics were evaluated at VPre-BL, VBL, and VF/U. Mean ± SD values were reported for continuous measures, and total counts and percentages were reported for categorical measures.


Patient Disposition and Demographic Characteristics

In total, 9555 b/tsDMARD initiations were initially considered for this analysis at VPre-BL, of which 8329 initiators were excluded due to various reasons: no qualifying VBL (n = 3309), discontinuation of index therapy before VBL (n = 1736), achievement of CDAI LDA at VBL (n = 1834), worsening of CDAI at VBL (n = 815), no qualifying VF/U (n = 630), and switch of therapy within 3 months before VF/U (n = 5) (Fig. 1).

Patient disposition. aA total of 7566 patients accounted for 9555 initiations. bA total of 87 patients contributed 1 initiation and 3 patients contributed 2 initiations each to the cohort; around half of the patients were on methotrexate at VBL.

Of the remaining 1226 initiators fulfilling the inclusion criteria, only 93 (7.6%) switched therapy after not achieving an adequate response on the initial b/tsDMARD. Of these 93 switchers, 28 discontinued the new therapy at or before VF/U. The average time from VPre-BL to VBL was 6.3 ± 2.5 months, and from VBL to VF/U was 7.4 ± 2.7 months.

Among 93 switchers, the majority were female patients (82%) and White (89%), with a mean age of 53 years and RA duration of 10 years. Approximately 53% of the switchers were initiated on their first b/tsDMARDs at the index visit (ie, VPre-BL) (Table 1).

TABLE 1 - Demographic and Clinical Characteristics for Switchers at Index and Baseline Visits
Characteristic VPre-BL (Na = 93) VBL (Na = 93)
Age, mean (SD), y 52.6 (14.0) 53.1 (14.0)
Female sex, n (%) 76 (81.7) 76 (81.7)
RA duration, mean (SD), y 10.3 (10.3) 10.7 (10.4)
White race, n (%) 83 (89.2) 83 (89.2)
Insurance,b n (%)
 Medicaid 9 (9.7) 7 (7.5)
 Medicare 24 (25.8) 24 (25.8)
 Private insurance 75 (80.6) 69 (74.2)
 No insurance ≥5 <5
Work status, n (%)
 Full time 39 (41.9) 38 (40.9)
 Part time 7 (7.5) 6 (6.5)
 Not working/not disabled 26 (28.0) 30 (32.3)
 Disabled 20 (21.5) 17 (18.3)
Smoking status, n (%)
 Never 42 (45.2) 42 (45.2)
 Previous 28 (30.1) 28 (30.1)
 Current 23 (24.7) 23 (24.7)
BMI, mean (SD), kg/m2 31.0 (8.5) 31.2 (8.6)
BMI category, n (%)
 Normal weight (20 ≤ BMI < 25) 23 (24.7) 24 (25.8)
 Overweight (25 ≤ BMI < 30) 22 (23.7) 21 (22.6)
 Obese (30 ≤ BMI) 46 (49.5) 46 (49.5)
Prior use of csDMARDs, n (%)
 0 30 (32.3) 22 (23.7)
 1 26 (28.0) 34 (36.6)
 2+ 37 (39.8) 37 (39.8)
b/tsDMARD line of therapy at initiation, n (%)
 First 49 (52.7) 0 (0)
 Second 19 (20.4) 49 (52.7)
 Third 16 (17.2) 19 (20.4)
 Fourth+ 9 (9.7) 25 (26.9)
aN refers to initiation episodes; a total of 87 patients contributed 1 initiation and 3 patients contributed 2 initiations each to the cohort.
bThe total may add up to more than 100% since patients may have more than 1 type of insurance.
BMI, body mass index.

Meaningful Improvement and Worsening in CDAI

At VBL, 64.5% and 35.5% of switchers had moderate and high disease activity, respectively. From VBL to VF/U, using a CDAI threshold of ≥6 and ≥12 units, 30.1% and 12.9% of switchers experienced meaningful worsening, whereas 34.4% and 20.4% of switchers experienced meaningful improvement, respectively; the remaining switchers showed no meaningful change in disease activity (Fig. 2). For other outcomes and time-variant clinical characteristics at each visit for switchers, see Table, Supplemental Digital Content 1,

Change in CDAI for switchers. aA total of 87 patients contributed 1 initiation and 3 patients contributed 2 initiations each to the cohort. bNo meaningful worsening was noted from VPre-BL to VBL as those patients were excluded from the study.


This study evaluated meaningful worsening (increase) or improvement (decrease) in CDAI associated with switching of b/tsDMARDs in patients with RA who started with moderate-to-high disease activity and who had a partial but inadequate response to their new RA therapy. Only a minority (<10%) of the patients who did not achieve the target of LDA or remission switched within the eligible period of the study. Of these switchers, the majority had either meaningful improvement or no meaningful change in disease activity after the switch. Recognizing that patients had no requirement to stay on therapy, only 30% and 13% of the switchers experienced meaningful worsening using the CDAI thresholds of ≥6 (lower, more sensitive) and ≥12 (higher, more specific), respectively. Regardless of these thresholds, the likelihood of meaningful improvement was numerically greater than the likelihood of meaningful worsening. These findings may help overcome the hesitancy that patients and physicians may have when considering switching therapies for those patients who have experienced some response, yet do not reach at least LDA.

A recent post hoc analysis (using data from the open-label extension of the MONARCH trial) evaluated the effect of switching in a subset of RA patients who were partial responders to adalimumab during the double-blind phase and switched to sarilumab upon entry in the open-label extension (per-protocol); these patients were less likely to experience meaningful worsening (6% using CDAI threshold ≥6; 2% using CDAI threshold ≥12), with most patients experiencing meaningful improvement or no change (57% and 37% using CDAI threshold ≥6; 27% and 71% using CDAI threshold ≥12, respectively).8 Similarly, in the observational analysis of the SELECT-COMPARE trial, 20% and 7% of RA patients who switched (after an inadequate response) from upadacitinib to adalimumab, and 4% and 1% of patients who switched from adalimumab to upadacitinib experienced a clinically meaningful worsening based on the thresholds of 0.6 and 1.2, respectively, using Disease Activity Score-28 for RA with C-reactive protein.7 Although our findings are in line with those from the MONARCH and SELECT-COMPARE trials,7,8 the proportion of patients with meaningful worsening was higher in the present analysis. This difference could be due to the factors relevant to the real-world clinical practices that are not present in predefined treatment protocols in the clinical trials, or the phenotype and disease characteristics (including prevalence of multimorbidity) of the patients in this registry compared with a more selected clinical trial population.10 Specifically, patients in our study had received multiple prior biologics (with lower use of methotrexate), and a larger proportion of patients had poor prognostic factors (including obesity, smoking, and disability), which are known as predictors of poor treatment outcomes in RA.10–12 In addition, a substantial number of people in our study did not have meaningful improvement before switch (at VBL; 35.5% and 65.6% patients based on CDAI thresholds of ≥6 and ≥12, respectively); the poor magnitude of prior response could be another reason for poorer treatment outcomes.13 The fact that the MONARCH results are similar to the findings noted for the patients switching from adalimumab to upadacitinib in the SELECT-COMPARE trial (both of which had similar patient populations) supports the hypothesis that differences in the patient characteristics could have affected the study results.7,8 Interestingly, our findings were consistent with those reported for the patients switching from upadacitinib to adalimumab, while higher than those switching from adalimumab to upadacitinib in the SELECT-COMPARE trial,7 suggesting that the specific drug to which the patients are switched from and to may affect overall outcomes. Because the present analysis allowed for any class of switch, this may have affected the magnitude of our study results. Our findings can nevertheless be informative, when considering the range of possible treatment switches in the clinical scenario that we examined.

The low switch rate in our findings is likely a reflection of the inclusion criteria of the study, which resulted in the exclusion of a large number of patients. For example, among initiators who were excluded because they did not have an eligible VBL but were not lost to follow-up, 52.5% discontinued therapy within 12 months (data not shown). Furthermore, among initiators who were excluded because of worsening CDAI but were not lost to follow-up, 59.2% discontinued therapy within 1 year (data not shown). Overall, these findings are consistent with those reported in the previous retrospective analyses, where 53% of patients on their first biologic and 47% to 55% of patients on their 2+ biologics discontinued or switched to a different biologic within 1 year.14,15

The main strength of this study was evaluating outcomes based on the real-world clinical practices in a selected patient population from a large data set of the US registry, and despite the strict inclusion criteria, the study ended up with an analyzable population. Although the overall percentage of the switchers was small, these findings were as reported in the registry, as physicians in the clinical practice may allow longer time for b/tsDMARDs effect or consider changing the other ongoing therapies (such as addition of steroids or change of concurrent csDMARDs). Further, many patients could have already failed biologics and may have had limited opportunity to switch to yet another therapy. Payors may also have specific criteria for switching therapies, such as duration of a particular treatment or specific levels of disease activity. Overall, patient characteristics in this study were similar to that observed in the larger population of b/tsDMARD initiators in the registry (data not shown). However, there were few limitations. Because only 93 patients met the inclusion criteria, the findings may not be generalizable to the whole population. Further, not all switchers stayed on the treatment until follow-up, and there could be missing data, which might have impacted the study findings. There could also be differences in the characteristics of switchers and nonswitchers that may not be fully captured by the CDAI, which might have contributed to the low switch rate; for example, some patients might have observed a meaningful reduction in pain (including nonarticular pain) without a corresponding improvement in CDAI, resulting in unwillingness to switch therapies. However, only CDAI was selected for disease activity measurement in this study, considering it is one of the frequently available parameters in the registry and does not require measurement of any laboratory parameters such as C-reactive protein or erythrocyte sedimentation rate for calculation; reporting of other laboratory values was not mandatory in this registry. Notably, CDAI is the most commonly measured RA disease activity metric that incorporates physician-derived measurements used by providers in the United States.3 The comparison of switchers with nonswitchers and analysis of factors that may predict the switch were outside the scope of this analysis. Because of the small sample size, statistical comparison (including multivariate analysis) for the switchers attaining meaningful improvement versus those with meaningful worsening and no improvement was not possible, which could have strengthened the study findings. The thresholds used for defining meaningful worsening in RA are also not well-established compared with the thresholds for defining improvement and are challenging to define for patients who do not start in LDA or remission.9 Lastly, our study did not evaluate meaningful change based on patient-reported outcomes and associated adverse effects, which could be important from the patient perspective and need further studies.


This observational study suggests that patients with difficult-to-treat RA, who had some improvement but did not achieve LDA, are more likely to experience meaningful improvement or maintain the existing improvement, rather than meaningful worsening on switching to a new b/tsDMARD. This observation may allow more informed decisions and could help some patients overcome their fear of worsening with switching, potentially improving outcomes. Additional research is warranted to better understand the dynamics around switching treatment in inadequately responding RA patients, in order to reduce the barriers to switching therapies and to improve clinical outcomes.


Medical writing support for this manuscript was provided by Vasudha Chachra (Sanofi) and Nupur Chaubey (former employee of Sanofi).


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CDAI; disease activity; DMARDs; registry; rheumatoid arthritis

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