A window of opportunity for abatacept in RA: is disease duration an independent predictor of low disease activity/remission in clinical practice?

The Corrona registry collects and analyses treatment and outcomes data for patients with chronic rheumatologic and dermatologic diseases. The Corrona RA registry is an independent, prospective, national, observational cohort study. Patients are recruited from 168 private and academic practice sites across 40 states in the USA, with 654 participating rheumatologists. As of 31 March 2016, the Corrona database included information on approximately 42,621 patients with RA. Data on 321,001 patient visits and approximately 141,984 patient-years of follow-up observation time have been collected. This study was carried out in accordance with the Declaration of Helsinki. All participating investigators were required to obtain full board approval for conducting non-interventional research involving human subjects with a limited dataset. Sponsor approval and continuing review was obtained through a central Institutional Review Board (IRB; New England Independent Review Board, NEIRB No. 120160610). For academic investigative sites that did not receive a waiver to use the central IRB, full board approval was obtained from the respective governing IRBs and documentation of approval was submitted to Corrona, LLC prior to initiating any study procedures. All registry patients were required to provide written informed consent and authorization prior to participating.

This analysis included patients with RA >18 years of age who were biologic naïve and who had started treatment with abatacept during follow-up in the Corrona RA registry between February 2006 and January 2015. Eligible patients had to have a follow-up visit at 12 months (±3 months) after the initiation of treatment (using the visit closest to 12 months if there was >1 visit) and Clinical Disease Activity Index (CDAI) measured at or prior to the initiation of treatment. If the physician reported a treatment start date, CDAI score was measured within 4 months prior to initiation. If the physician did not report a start date for treatment, disease activity from the prior visit was used if this visit was within 6 months of the date of initiation. Other inclusion criteria were measurement of CDAI score at 12 months (±3 months) or at the time of switch if this occurred prior to the 12-month visit and no prior bDMARD use.

Patient demographics, baseline characteristics and clinical outcomes were assessed across four disease duration groups (0–2, 3–5, 6–10, >10 years). Disease duration was collected from the rheumatologist based on the year of RA onset and the visit of initiation. Data were collected from patients and their treating rheumatologists using standard clinical research forms at the time of the clinical encounter. These forms gather information on disease severity and activity (including components of ACR response criteria), medical comorbidities, use of medications including conventional (c)DMARDs and adverse events. Data elements collected in the registry that were relevant to this study included components of CDAI (swollen joint count, 28 tender joint count, physician global assessment and patient global assessment), patient assessment of pain, DAS28 (erythrocyte sedimentation rate; ESR) and the modified (m)HAQ assessing physical function [9]. Data on demographics, insurance status, comorbid conditions, RA disease characteristics and RA medications were available for >98% of patients. The scope of the data collected and comparison with other registries have been previously described [10].

The primary outcome was mean change in CDAI (ΔCDAI) at 12 months (CDAI score at 12 months minus CDAI score at initiation). The secondary outcomes were achievement of LDA (CDAI score ≤10) among patients who initiated abatacept with moderate or high disease activity and achievement of remission (CDAI score ≤2.8) in those who initiated abatacept with low, moderate or high disease activity. Discontinuations and switching status were also examined. Patients were categorized into one of three mutually exclusive groups: those who switched from abatacept to a new biologic, those who discontinued abatacept without initiating a new biologic before their 12-month visit and those who remained on abatacept until their 12-month visit.

Baseline characteristics of patients in the different disease duration groups were compared using descriptive statistics. A two-sided 5% significance level was used to assess statistical differences. For patients who switched agents before 12 months, the last observation before the switch was used to calculate mean ΔCDAI. Switchers were imputed as non-responders for calculation of LDA and remission. For patients who discontinued an agent and did not start another before 12 months and those who continued on their original agent through their 12-month visit, measurement at the 12-month visit was used to calculate outcomes. Mean ΔCDAI from baseline was calculated by disease duration group. The rates of LDA/remission and remission at 12 months by disease duration group were estimated (unadjusted). p values were based on omnibus tests of any differences in the duration groups. Fisher’s exact test was used when there were small counts, as for switching status. Multivariable linear regression models were fit to assess the association of ΔCDAI from baseline by disease duration group. Multivariable logistic regression models were conducted to assess the association of disease duration and LDA/remission and remission at 12 months. Baseline characteristics that were indicative of a difference (p < 0.1) across the disease duration groups, as well as characteristics that were chosen a priori by investigators (age, sex, baseline CDAI score and number of prior cDMARDs), were used as covariates in the models. Of note, MTX use did not meet criteria for inclusion in the adjusted models. However, as MTX use may influence results, we re-ran the above-mentioned adjusted models with the addition of MTX. The results were unchanged (data not shown) from the original models and thus are not included in this manuscript.

There were a total of 281 abatacept initiators who were biologic naïve and met the inclusion criteria (disease duration 0–2 years, 107 [38.1%]; 3–5 years, 45 [16.0%]; 6–10 years, 50 [17.8%]; >10 years, 79 [28.1%]). In general, baseline characteristics were similar across the four disease duration groups (Table 1), with a similar percentage of female patients (76–89%) and similar distributions for level of education, comorbid conditions, smoking status and morning stiffness. The average weight, body mass index, blood pressure and most of the disease activity measures including CDAI, DAS28 (ESR), patient pain, mHAQ and patient-reported fatigue were also similar across the disease duration groups. Patients with disease duration >10 years were older (median [IQR] 67 [16] years), were on average younger at onset of RA (mean [SD] 46.5 [13.2] years) and had higher prior cDMARD use (median [IQR] of 2 [2]) versus patients in other disease duration groups.

The results for the primary and secondary efficacy outcomes are presented in Table 2. In the unadjusted analysis, the greatest ΔCDAI from baseline occurred in the group of patients with the shortest disease duration (0–2 years: mean ΔCDAI [SE]: −10.22 [1.19]) and the smallest change occurred in the group with the longest disease duration (>10 years; −4.63 [1.38]; overall p = 0.017). Response rates for the binary outcomes of LDA and remission did not differ significantly according to disease duration group (p = 0.21 and 0.23, respectively; Table 2).

After adjustment for age, sex, baseline CDAI score and prior number of cDMARDs used, the significant difference between the disease duration groups in ΔCDAI from baseline remained (0–2 years, mean ΔCDAI [SE], −9.65 [1.02]); >10 years, −4.58 [1.19]; overall p = 0.015). In addition, there was a significant difference in achievement of LDA across the four groups, with the group of patients with disease duration of 0–2 years being nearly three times as likely to reach LDA at 12 months following abatacept initiation as the group with >10 years of disease duration (odds ratio [95% confidence interval] 2.76 [1.28, 5.97]; p = 0.048). Similarly, those with 0–2 years of disease duration were three times more likely to achieve remission at 12 months than those with >10 years of disease duration (odds ratio [95% confidence interval] 3.12 [1.30, 7.46]; p = 0.055). Of note, the proportion of patients who remained on abatacept at 12 months was similar across the disease duration groups, ranging from 67 to 74% (p = 0.60; Table 3).