Development of an Interactive Tool to Support Shared Decision-Making in Rheumatoid Arthritis: Treatment Attribute Preference.

OBJECTIVE: An interactive tool identifying treatment attributes important to patients can enhance shared decision-making (SDM) in rheumatoid arthritis (RA). A formative survey was conducted to identify the most important treatment attributes from patients' perspective, which can be used to develop an interactive SDM tool. METHODS: The survey was performed in two phases: qualitative interviews and quantitative surveys. The qualitative interviews were conducted to inform the design of the quantitative survey. In qualitative interviews, patients with RA (n = 10) and rheumatologists (n = 10) were introduced to the SDM tool concept. Feedback on the design and scope of the SDM tool was used to develop a quantitative survey, conducted in a large sample size of patients. Patient preferences for treatment attributes (route of administration and dosing frequency, serious side effects, out-of-pocket costs, efficacy, and monitoring requirement) were assessed via adaptive conjoint exercise involving ranking of hypothetical RA treatment configurations. RESULTS: A total of 944 patients (males: 43%, females: 57%) with RA participated in the quantitative survey. Route of administration and dosing frequency (38%) followed by serious side effects (33%) were the two most important treatment attributes for individual patients. The recontact survey (n = 172/944) estimated tool stability of 72% (n = 124/172) in terms of the relative importance of treatment attributes. CONCLUSION: The findings of this survey could be used in the development of an SDM tool that can potentially provide insights into patient preferences and is generally well received by patients and rheumatologists with good agreement and reliability.

Clinical Outcomes in Patients with Rheumatoid Arthritis After Switching Between Interleukin-6-Receptor Inhibitors and Janus Kinase Inhibitors: Findings from an Observational Study.

INTRODUCTION: This observational study evaluated response in patients with rheumatoid arthritis (RA) who switched from an interleukin-6 receptor inhibitor (IL-6Ri) to a Janus kinase inhibitor (JAKi) and vice versa. METHODS: Adult patients with RA, who initiated IL-6Ri or JAKi (following discontinuation of JAKi or IL-6Ri, respectively) during/after December 2012 and had a 6-month follow-up visit were enrolled. Clinical outcomes were evaluated at baseline and the follow-up visit. Continuous outcomes included Clinical Disease Activity Index (CDAI), Health Assessment Questionnaire (HAQ), pain, fatigue, tender joint count, swollen joint count, Physician Global Assessment (MDGA), Patient Global Assessment (PtGA), and morning stiffness duration. Categorical outcomes included the proportion of patients achieving CDAI low disease activity (LDA), remission, and minimal clinically important differences (MCIDs) for HAQ, pain, fatigue, MDGA, and PtGA. Continuous outcomes were summarized as mean changes from baseline, and categorical outcomes as response rates. Differences in the outcome measures between groups were evaluated using linear and logistic regression models. RESULTS: Between IL-6Ri (n = 100) and JAKi initiators (n = 129), no significant differences were noted for continuous outcomes. Within both groups, a significant proportion of patients achieved LDA, remission, and MCIDs for other measures, although the odds of achieving LDA were higher among IL-6Ri (vs. JAKi) initiators with moderate-to-severe disease (adjusted odds ratio: 3.30 [1.01, 10.78]). CONCLUSIONS: Patients with RA can achieve improvement in response when switching between IL-6Ri and JAKi. Although both therapies affect the IL-6 pathway, there are distinct mechanisms of action, which likely contribute to their clinical improvement, when reciprocally switched as follow-on treatments.

Real-World Sarilumab Use and Rule Testing to Predict Treatment Response in Patients with Rheumatoid Arthritis: Findings from the RISE Registry.

INTRODUCTION: Clinical trial findings may not be generalizable to routine practice. This study evaluated sarilumab effectiveness in patients with rheumatoid arthritis (RA) and tested the real-world applicability of a response prediction rule, derived from trial data using machine learning (based on C-reactive protein [CRP] > 12.3 mg/l and seropositivity [anticyclic citrullinated peptide antibodies, ACPA +]). METHODS: Sarilumab initiators from the ACR-RISE Registry, with ≥ 1 prescription on/after its FDA approval (2017-2020), were divided into three cohorts based on progressively restrictive criteria: Cohort A (had active disease), Cohort B (met eligibility criteria of a phase 3 trial in RA patients with inadequate response/intolerance to tumor necrosis factor inhibitors [TNFi]), and Cohort C (characteristics matched to the phase 3 trial baseline). Mean changes in Clinical Disease Activity Index (CDAI) and Routine Assessment of Patient Index Data 3 (RAPID3) were evaluated at 6 and 12 months. In a separate cohort, predictive rule was tested based on CRP levels and seropositive status (ACPA and/or rheumatoid factor); patients were categorized into rule-positive (seropositive with CRP > 12.3 mg/l) and rule-negative groups to compare the odds of achieving CDAI low disease activity (LDA)/remission and minimal clinically important difference (MCID) over 24 weeks. RESULTS: Among sarilumab initiators (N = 2949), treatment effectiveness was noted across cohorts, with greater improvement noted for Cohort C at 6 and 12 months. Among the predictive rule cohort (N = 205), rule-positive (vs. rule-negative) patients were more likely to reach LDA (odds ratio: 1.5 [0.7, 3.2]) and MCID (1.1 [0.5, 2.4]). Sensitivity analyses (CRP > 5 mg/l) showed better response to sarilumab in rule-positive patients. CONCLUSIONS: In real-world setting, sarilumab demonstrated treatment effectiveness, with greater improvements in the most selective population, mirroring phase 3 TNFi-refractory and rule-positive RA patients. Seropositivity appeared a stronger driver for treatment response than CRP, although optimization of the rule in routine practice requires further data.

Rheumatoid arthritis (RA) is a condition that may cause joint damage, if untreated. Sarilumab is an advanced medication, approved for treating moderate-to-severe RA in patients not responding to initial standard medicines. Clinical trials have shown that sarilumab improves RA symptoms; however, some people do not respond. This is a common problem in RA treatment. Physicians measure proteins in people's blood (called biomarkers; e.g., anticyclic citrullinated peptide antibodies [ACPA], C-reactive protein [CRP], and rheumatoid factor [RF]) to predict a medicine's response. A previous study showed that people with positive blood tests for ACPA and CRP (> 12.3 mg/l) responded well to sarilumab; this study was based on machine learning (a branch of science using computers) and identified factors that could be linked to treatment benefits. The present study analyzed routine data of 2949 people from the ACR-RISE Registry and showed an improvement in RA symptoms after 6 and 12 months of sarilumab, with a greater improvement noted in patients previously treated with other medicines. Biomarkers were tested in 205 people to check whether they could predict treatment response in day-to-day life. People were called rule-positive if they tested positive for RF and/or ACPA with CRP > 12.3 mg/l, and otherwise rule-negative. After 24 weeks of treatment, rule-positive people had a greater chance of disease improvement than rule-negative people. These results showed the benefits of sarilumab in RA in routine care and suggested the usefulness of machine learning in identifying biomarkers that physicians can use to make treatment decisions.

Comparative effectiveness of TNF inhibitor vs IL-6 receptor inhibitor as monotherapy or combination therapy with methotrexate in biologic-experienced patients with rheumatoid arthritis: An analysis from the CorEvitas RA Registry.

OBJECTIVE: Randomized controlled trials (RCTs) in biologic-naïve rheumatoid arthritis (RA) patients with high disease activity and inadequate response/intolerance to methotrexate have shown interleukin-6 (IL-6) receptor inhibitors (IL-6Ri) to be superior to tumor necrosis factor inhibitors (TNFi) as monotherapy. This observational study aimed to compare the effectiveness of TNFi vs IL-6Ri as mono- or combination therapy in biologic/targeted synthetic (b/ts) -experienced RA patients with moderate/high disease activity. METHODS: Eligible b/ts-experienced patients from the CorEvitas RA registry were categorized as TNFi and IL-6Ri initiators, with subgroups initiating as mono- or combination therapy. Mixed-effects regression models evaluated the impact of treatment on Clinical Disease Activity Index (CDAI), patient-reported outcomes, and disproportionate pain (DP). Unadjusted and covariate-adjusted effects were reported. RESULTS: Patients initiating IL-6Ri (n = 286) vs TNFi monotherapy (n = 737) were older, had a longer RA history and higher baseline CDAI, and were more likely to initiate as third-line therapy; IL-6Ri (n = 401) vs TNFi (n = 1315) combination therapy initiators had higher baseline CDAI and were more likely to initiate as third-line therapy. No significant differences were noted in the outcomes between TNFi and IL-6Ri initiators (as mono- or combination therapy). CONCLUSION: This observational study showed no significant differences in outcomes among b/ts-experienced TNFi vs IL-6Ri initiators, as either mono- or combination therapy. These findings were in contrast with the previous RCTs in biologic-naïve patients and could be explained by the differences in the patient characteristics included in this study. Further studies are needed to help understand the reasons for this discrepancy in the real-world b/ts-experienced population.

Improvement or Worsening of Disease Activity After Switch to Sarilumab in Patients With Rheumatoid Arthritis With a Partial Response to Adalimumab.

OBJECTIVE: The aim of this study was to assess the effect of switching from adalimumab to sarilumab monotherapy in partial responders with rheumatoid arthritis from the MONARCH randomized trial and its open-label extension (OLE). METHODS: Partial response was defined as improvement in Clinical Disease Activity Index (CDAI) of 12 or 6 units (baseline score: >22 or >10 and ≤22, respectively). Proportions of adalimumab partial responders with meaningful worsening or improvement at OLE weeks 12 and 24 were evaluated using 2 CDAI thresholds (≥6 and ≥12 points), 28-joint Disease Activity Score using erythrocyte sedimentation rate (≥0.6 and ≥1.2 points), Health Assessment Questionnaire Disability Index (≥0.22 and ≥0.30 points), Simple Disease Activity Index (≥7 and ≥13 points), physician and patient global assessments (≥10 and ≥20), and 28-joint swollen and tender joint counts (≥1 and ≥2 joints). Outcomes were analyzed using mixed-effect models with repeated measures for observed cases. The p values were produced using Wilcoxon tests. RESULTS: Of 369 enrolled patients, 320 (87%) entered the OLE and 155 switched from adalimumab to sarilumab; 59% (91/155) were partial responders. At week 24, 4%-17% and 2%-12% of partial responders experienced a worsening using the lower and higher thresholds, respectively, whereas 47%-78% and 27%-66% experienced improvement. CONCLUSIONS: Partial responders to adalimumab who switched to sarilumab had a low likelihood of experiencing meaningful worsening, with most patients showing meaningful improvement or no change in disease activity. This may help alleviate patients' fears of worsening when considering switching to a treatment with a different mechanism of action.

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.

OBJECTIVE: The aim of this study was to assess the change in disease activity associated with switching from 1 biologic/targeted synthetic disease-modifying antirheumatic drug (b/tsDMARD) to another in patients with rheumatoid arthritis who did not achieve low disease activity (LDA) after 6 to 12 months of their initial treatment. METHODS: This observational study included patients from the CorEvitas Rheumatoid Arthritis Registry, who initiated a b/tsDMARD at the index visit (prebaseline), had any clinical disease activity index (CDAI) improvement but did not achieve LDA/remission at the subsequent visit (baseline), and switched therapy at baseline or between baseline and follow-up visits. Regardless of the preswitch CDAI value, 2 thresholds of CDAI change were used to define meaningful improvement and worsening for all patients: ≥6 units and ≥12 units; no meaningful change was defined as any change between -6 to +6 units and -12 to +12 units, based on respective thresholds. RESULTS: Of 1226 patients fulfilling the inclusion criteria, 93 (7.6%) switched therapy at baseline or between baseline and follow-up, after an inadequate response at the baseline visit. At follow-up, meaningful worsening occurred in 30.1% and 12.9% of switchers, whereas the remaining switchers achieved meaningful improvement (34.4% and 20.4%) or had no meaningful change (35.5% and 66.7%), based on the thresholds of ≥6 and ≥12 units, respectively. CONCLUSIONS: Rheumatoid arthritis patients, who had not achieved LDA and switched b/tsDMARD, were more likely to have meaningful improvement or no change, rather than meaningful worsening. These data may help some patients overcome their hesitancy to switch therapy, potentially improving clinical outcomes.

Disproportionate articular pain is a frequent phenomenon in rheumatoid arthritis and responds to treatment with sarilumab.

OBJECTIVES: In some patients with RA, joint pain is more severe than expected based on the amount of joint swelling [referred to as disproportionate articular pain (DP)]. We assessed DP prevalence and the effects of sarilumab, an IL-6 inhibitor, on DP. METHODS: Data from RA patients treated with placebo or 200 mg sarilumab in the phase 3 randomized controlled trials (RCTs) MOBILITY and TARGET, adalimumab 40 mg or sarilumab 200 mg in the phase 3 RCT MONARCH and sarilumab 200 mg in open-label extensions (OLEs) were used. DP was defined as an excess tender 28-joint count (TJC28) over swollen 28-joint count (SJC28) of ≥7 (TJC28 - SJC28 ≥ 7). Treatment response and disease activity were determined for patients with and without DP. RESULTS: Of 1531 sarilumab 200 mg patients from RCTs, 353 (23%) had baseline DP. On average, patients with DP had higher 28-joint DAS using CRP (DAS28-CRP) and pain scores than patients without DP, whereas CRP levels were similar. After 12 and 24 weeks, patients with baseline DP treated with sarilumab were more likely to be DP-free than those treated with placebo or adalimumab. In RCTs, more sarilumab-treated patients achieved low disease activity vs comparators, regardless of baseline DP status. In OLEs, patients were more likely to lose rather than gain DP status. CONCLUSION: About one-quarter of patients with RA experienced DP, which responded well to sarilumab. These data support the concept that other mechanisms (potentially mediated via IL-6) in addition to inflammation may contribute to DP in RA. TRIAL REGISTRATIONS: NCT01061736, NCT02332590, NCT01709578, NCT01146652.

The effect of targeted rheumatoid arthritis therapeutics on systemic inflammation and anemia: analysis of data from the CorEvitas RA registry.

BACKGROUND: To evaluate the effects of tumor necrosis factor inhibitors (TNFi), interleukin-6 receptor inhibitors (IL-6Ri), and Janus kinase inhibitors (JAKi) on hemoglobin (Hb) and C-reactive protein (CRP) levels in adults enrolled in CorEvitas (formerly Corrona), a large US rheumatoid arthritis (RA) registry. METHODS: Patients who initiated TNFi, IL-6Ri, or JAKi treatment during or after January 2010, had Hb and CRP measurements at baseline and 6-month follow-up (± 3 months) and had continued therapy at least until that follow-up, through March 2020, were included in the analysis. Changes in Hb and CRP were assessed at month 6. Abnormal Hb was defined as < 12 g/dL (women) or < 13 g/dL (men); abnormal CRP was ≥ 0.8 mg/dL. Differences in Hb and CRP levels were evaluated using multivariable regression. RESULTS: Of 2772 patients (TNFi, 65%; IL-6Ri, 17%; JAKi, 17%) evaluated, 1044 (38%) had abnormal Hb or CRP at initiation; an additional 252 (9%) had both abnormal Hb and CRP. At month 6, the IL-6Ri group had a greater Hb increase than the TNFi (mean difference in effect on Hb: 0.28 g/dL; 95% CI 0.19-0.38) and JAKi (mean difference in effect on Hb: 0.47 g/dL; 95% CI 0.35-0.58) groups, regardless of baseline Hb status (both p < 0.001). The CRP decrease at month 6 was greater with IL-6Ri compared with TNFi and JAKi, regardless of baseline CRP status (both p < 0.05). CONCLUSION: These real-world results align with the mechanism of IL-6R inhibition and may inform treatment decisions for patients with RA.

Outcomes and costs of incorporating a multibiomarker disease activity test in the management of patients with rheumatoid arthritis.

OBJECTIVE: The multibiomarker disease activity (MBDA) blood test has been clinically validated as a measure of disease activity in patients with RA. We aimed to estimate the effect of the MBDA test on physical function for patients with RA (based on HAQ), quality-adjusted life years and costs over 10 years. METHODS: A decision analysis was conducted to quantify the effect of using the MBDA test on RA-related outcomes and costs to private payers and employers. Results of a clinical management study reporting changes to anti-rheumatic drug recommendations after use of the MBDA test informed clinical utility. The effect of treatment changes on HAQ was derived from 5 tight-control and 13 treatment-switch trials. Baseline HAQ scores and the HAQ score relationship with medical costs and quality of life were derived from published National Data Bank for Rheumatic Diseases data. RESULTS: Use of the MBDA test is projected to improve HAQ scores by 0.09 units in year 1, declining to 0.02 units after 10 years. Over the 10 year time horizon, quality-adjusted life years increased by 0.08 years and costs decreased by US$457 (cost savings in disability-related medical costs, US$659; in productivity costs, US$2137). The most influential variable in the analysis was the effect of the MBDA test on clinician treatment recommendations and subsequent HAQ changes. CONCLUSION: The MBDA test aids in the assessment of disease activity in patients with RA by changing treatment decisions, improving the functional status of patients and cost savings. Further validation is ongoing and future longitudinal studies are warranted.

Impact of a multi-biomarker disease activity test on rheumatoid arthritis treatment decisions and therapy use.

OBJECTIVE: To assess how use of a multi-biomarker disease activity (MBDA) blood test for rheumatoid arthritis (RA) affects treatment decisions made by health care providers (HCPs) in clinical practice. RESEARCH DESIGN AND METHODS: At routine office visits, 101 patients with RA were assessed by their HCPs (N = 6), and they provided blood samples for MBDA testing. HCPs completed surveys before and after viewing the MBDA test result, recording dosage and frequency for all planned RA medications and physician global assessment of disease activity. Frequency and types of change in treatment plan that resulted from viewing the MBDA test result were determined. MAIN OUTCOME MEASURE: Percentage of cases in which the HCP changed the planned treatment after viewing the MBDA test result. RESULTS: Prior to HCP review of the MBDA test, disease modifying anti-rheumatic drug (DMARD) use by the 101 patients included methotrexate in 62% of patients; hydroxychloroquine 29%; TNF inhibitor 42%; non-TNF inhibitor biologic agent 19%; and other drugs at lower frequencies. Review of MBDA test results changed HCP treatment decisions in 38 cases (38%), of which 18 involved starting, discontinuing or switching a biologic or non-biologic DMARD. Other changes involved drug dosage, frequency or route of administration. The total frequency of use of the major classes of drug therapy changed by <5%. Treatment plans changed 63% of the time when the MBDA test result was perceived as being not consistent or somewhat consistent with the HCP assessment of disease activity. STUDY LIMITATIONS: Limited sample size; lack of control group; no longitudinal follow-up. CONCLUSIONS: The addition of the MBDA test to clinical assessment led to meaningful changes in the treatment plans of 38% of RA patients being cared for by HCPs in office practice. Even though treatment was potentially improved, the overall quantity of drug use was minimally affected.

Validation of a novel multibiomarker test to assess rheumatoid arthritis disease activity.

OBJECTIVE: Quantitative assessment of disease activity in rheumatoid arthritis (RA) is important for patient management, and additional objective information may aid rheumatologists in clinical decision making. We validated a recently developed multibiomarker disease activity (MBDA) test relative to clinical disease activity in diverse RA cohorts. METHODS: Serum samples were obtained from the Index for Rheumatoid Arthritis Measurement, Brigham and Women's Hospital Rheumatoid Arthritis Sequential Study, and Leiden Early Arthritis Clinic cohorts. Levels of 12 biomarkers were measured and combined according to a prespecified algorithm to generate the composite MBDA score. The relationship of the MBDA score to clinical disease activity was characterized separately in seropositive and seronegative patients using Pearson's correlations and the area under the receiver operating characteristic curve (AUROC) to discriminate between patients with low and moderate/high disease activity. Associations between changes in MBDA score and clinical responses 6-12 weeks after initiation of anti-tumor necrosis factor or methotrexate treatment were evaluated by the AUROC. RESULTS: The MBDA score was significantly associated with the Disease Activity Score in 28 joints using the C-reactive protein level (DAS28-CRP) in both seropositive (AUROC 0.77, P < 0.001) and seronegative (AUROC 0.70, P < 0.001) patients. In subgroups based on age, sex, body mass index, and treatment, the MBDA score was associated with the DAS28-CRP (P < 0.05) in all seropositive and most seronegative subgroups. Changes in the MBDA score at 6-12 weeks could discriminate both American College of Rheumatology criteria for 50% improvement responses (P = 0.03) and DAS28-CRP improvement (P = 0.002). Changes in the MBDA score at 2 weeks were also associated with subsequent DAS28-CRP response (P = 0.02). CONCLUSION: Our findings establish the criterion and discriminant validity of a novel multibiomarker test as an objective measure of RA disease activity to aid in the management of RA in patients with this condition.