Faculty Bibliography

OBJECTIVE:Tocilizumab (TCZ) had similar efficacy when used as monotherapy or in combination with other treatments for rheumatoid arthritis (RA) in randomized controlled trials (RCT). We derived a remission prediction score for TCZ monotherapy (TCZm) using RCT data and now performed an external validation of the prediction score using "real world data" (RWD). METHODS:We identified patients in Corrona-RA who used TCZm (n=453), matching the design and patients from four RCTs used in previous work (n=853). Patients were followed to determine remission status at 24 weeks. We compared the performance of remission prediction models in RWD, first based on variables determined in our prior work in RCTs, and then using an extended variable set, comparing logistic regression and random forest models. We included patients on other biologic DMARD monotherapies (bDMARDm) to improve prediction. RESULTS:The fraction of patients observed reaching remission on TCZm by their follow-up visit was 12% (n=53) in RWD vs 15% (n=127) in RCTs. Discrimination was good in RWD for the risk score developed in RCTS with AUROC of 0.69 (95% CI 0.62, 0.75). Fitting the same logistic regression model to all bDMARDm patients in the RWD improved the AUROC on held-out TCZm patients to 0.72 (95% CI 0.63, 0.81). Extending the variable set and adding regularization further increased it to 0.76 (95% CI 0.67, 0.84). CONCLUSION/CONCLUSIONS:The remission prediction scores, derived in RCTs, discriminated patients in RWD about as well as in RCTs. Discrimination was further improved by retraining models on RWD.

OBJECTIVE:Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). We compared 5-year adverse event (AE) incidence rates (IRs) between patients initiating tofacitinib and those initiating new biological disease-modifying antirheumatic drugs (bDMARDs) within the United States (US) Corrona RA registry. METHODS:IRs (number of first events/100 patient-years) of major adverse cardiovascular events (MACE), serious infection events (SIEs), herpes zoster (HZ), malignancies, and death were estimated among tofacitinib and bDMARD initiators, regardless of dose/schedule, between November 6, 2012 (US Food and Drug Administration tofacitinib approval), and July 31, 2018 (follow-up through January 31, 2019). Propensity score (PS) methods were used to control for nonrandom prescribing practices. Hazard ratios (HRs) were calculated to compare rates using multivariable-adjusted Cox regression. Different risk windows were used for acute (MACE, SIEs, HZ, and venous thromboembolic events [VTEs]) and long-term (malignancy and death) events. VTEs were assessed descriptively. RESULTS:For MACE, SIEs, and HZ, 1999 (3152.1 patient-years) and 8358 (12 869.4 years) tofacitinib and bDMARD initiators were included, respectively; for malignancy/death, 1999 (4505.6 patient-years) and 6354 (16 670.8 patient-years) initiators were included, respectively. AE rates were similar across cohorts, except for HZ, which was significantly higher with tofacitinib versus bDMARDs (PS-trimmed adjusted HR 2.32; 95% confidence interval [CI] 1.43-3.75). There were 45 (zero serious) and 88 (five serious) HZ events with tofacitinib and bDMARDs, respectively. Sensitivity analyses demonstrated similar results. VTE IRs (95% CI) were 0.29 (0.13-0.54) and 0.33 (0.24-0.45) for tofacitinib and bDMARDs, respectively. CONCLUSION/CONCLUSIONS:In this registry analysis, both cohorts had similar MACE, SIE, malignancy, death, and VTE rates; HZ rates were higher for tofacitinib initaitors than for bDMARD initiators.

OBJECTIVES/OBJECTIVE:Tofacitinib is a Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA), psoriatic arthritis (PsA) and ulcerative colitis, and has been investigated in psoriasis (PsO). Routine pharmacovigilance of an ongoing, open-label, blinded-endpoint, tofacitinib RA trial (Study A3921133; NCT02092467) in patients aged ≥50 years and with ≥1 cardiovascular risk factor identified a higher frequency of pulmonary embolism (PE) and all-cause mortality for patients receiving tofacitinib 10 mg twice daily versus those receiving tumour necrosis factor inhibitors and resulted in identification of a safety signal for tofacitinib. Here, we report the incidence of deep vein thrombosis (DVT), PE, venous thromboembolism (VTE; DVT or PE) and arterial thromboembolism (ATE) from the tofacitinib RA (excluding Study A3921133), PsA and PsO development programmes and observational studies. Data from an ad hoc safety analysis of Study A3921133 are reported separately within. METHODS:This post-hoc analysis used data from separate tofacitinib RA, PsO and PsA programmes. Incidence rates (IRs; patients with events per 100 patient-years' exposure) were calculated for DVT, PE, VTE and ATE, including for populations stratified by defined baseline cardiovascular or VTE risk factors. Observational data from the US Corrona registries (including cardiovascular risk factor stratification), IBM MarketScan research database and the US FDA Adverse Event Reporting System (FAERS) database were analysed. RESULTS:average tofacitinib 5 mg and 10 mg twice daily treated patients for RA, respectively, were: DVT (0.17 (0.09-0.27) and 0.15 (0.09-0.22)); PE (0.12 (0.06-0.22) and 0.13 (0.08-0.21)); ATE (0.32 (0.22-0.46) and 0.38 (0.28-0.49)). Among PsO patients, IRs were: DVT (0.06 (0.00-0.36) and 0.06 (0.02-0.15)); PE (0.13 (0.02-0.47) and 0.09 (0.04-0.19)); ATE (0.52 (0.22-1.02) and 0.22 (0.13-0.35)). Among PsA patients, IRs were: DVT (0.00 (0.00-0.28) and 0.13 (0.00-0.70)); PE (0.08 (0.00-0.43) and 0.00 (0.00-0.46)); ATE (0.31 (0.08-0.79) and 0.38 (0.08-1.11)). IRs were similar between tofacitinib doses and generally higher in patients with baseline cardiovascular or VTE risk factors. IRs from the overall Corrona populations and in Corrona RA patients (including tofacitinib-naïve/biologic disease-modifying antirheumatic drug-treated and tofacitinib-treated) with baseline cardiovascular risk factors were similar to IRs observed among the corresponding patients in the tofacitinib development programme. No signals of disproportionate reporting of DVT, PE or ATE with tofacitinib were identified in the FAERS database. CONCLUSIONS:DVT, PE and ATE IRs in the tofacitinib RA, PsO and PsA programmes were similar across tofacitinib doses, and generally consistent with observational data and published IRs of other treatments. As expected, IRs of thromboembolic events were elevated in patients with versus without baseline cardiovascular or VTE risk factors, and were broadly consistent with those observed in the Study A3921133 ad hoc safety analysis data, although the IR (95% CI) for PE was greater in patients treated with tofacitinib 10 mg twice daily in Study A3921133 (0.54 (0.32-0.87)), versus patients with baseline cardiovascular risk factors treated with tofacitinib 10 mg twice daily in the RA programme (0.24 (0.13-0.41)).

OBJECTIVES/OBJECTIVE:To determine the effect of hydroxychloroquine on the incidence of new respiratory infections in a large registry of rheumatoid arthritis (RA) patients compared with a matched cohort receiving other conventional disease-modifying antirheumatic drugs (csDMARDs). METHODS:We reviewed physician-reported infections including upper respiratory infections (URI), bronchitis and pneumonia in the Corrona RA registry from June 2008 to February 2020 with the goal of comparing infections in biologic/targeted synthetic (b/ts) DMARDs naive HCQ starts compared with starts of other csDMARDs and no HCQ. Patients on different interventions were compared using time-varying adjusted Cox models adjusting for age, sex, duration of RA, BMI, disease activity, smoking status, concurrent medications, season of the year, year of onset and history of serious infections, diabetes or cardiovascular disease (CVD). A secondary analysis in a set of propensity-matched starts were also compared adjusting for time-varying covariates. The analysis was repeated including URI and bronchitis only and also for serious respiratory infections only. RESULTS:No evidence of differences was found in the incidence of any respiratory infection (URI, bronchitis, pneumonia) in patients receiving HCQ compared with other csDMARDs: HR=0.87 (0.70 to1.07) in adjusted analyses and HR=0.90 (0.70 to 1.17) in adjusted matched analysis. Similar results were found in the analysis of URI and bronchitis only and for serious respiratory infections only. CONCLUSIONS:In patients with RA, the risk for respiratory infections was similar among patients using HCQ as compared to other non-biologic DMARDs.

Background/Purpose: Some rheumatoid arthritis (RA) patients rate their disease activity worse than their physician does, but recent prevalence and factors associated with such discordance have not been reviewed in a large real-world database. This study describes discordance at biological initiation (index visit) and over time. We hypothesized that higher levels of pain, morning stiffness, fatigue, Health Assessment Questionnaire (HAQ) score, Clinical Disease Activity Index (CDAI), and depression are associated with discordance at the index visit.
Method(s): We included patients enrolled in the Corrona RA Registry who initiated their first biological or Janus kinase inhibitor on or after 2/1/2015 with both 6- and 12-month (+/- 3 mo) follow-up visits. Patient global assessment (PtGA) - physician's global assessment (PhGA) (disease severity) >= 30 points on a 0-100 VAS scale was defined as positive discordance; > -30 to < 30 as concordance; and <= -30 as negative discordance. Patients with negative discordance were excluded based on prior studies. Positive discordance at all three (index, 6-, 12-mo) visits was classified as persistent discordance. Differences between discordant and concordant patients at index visit were quantified using effect sizes (standardized differences) based on Cohen's descriptions for continuous variables (
d
): ~0.2 small effect size, ~0.5 medium, ~0.8 large; for categorical variables (w): ~0.1 small, ~0.3 medium, ~0.5 large. Mixed-effects logistic regression was used to test our a priori hypothesis.
Result(s): Among 54,307 patients in the registry, 758 patients met the inclusion criteria for analysis at the index visit, and of these, 752 were included in the analysis of persistent discordance. A total of 80 patients with negative discordance at any visit were excluded. Discordance prevalence was similar at the index (27%), 6- (30%), and 12-mo (30%) visits; 10% (n=65) had persistent discordance. At the index visit (Table 1), large differences for discordant vs concordant patients included RAPID3 score (mean 16 vs 7.3,
d
= 1.5), pain (mean 63 vs 32,
d
= 1.2), fatigue (mean 61 vs 35,
d
= 0.9), morning stiffness severity (61 vs 40, w = 0.9), and HAQ (0.7 vs 0.3, w = 0.9), and a medium effect size for DAS28-ESR (mean 4.3 vs 3.6,
d
= 0.5). Results were similar for patients with persistent discordance (Table 2). In a logistic regression model regressed on age, CDAI, opioid (including tramadol) use, pain, morning stiffness, fatigue, HAQ, depression, academic site; discordance (vs concordance) was positively associated with pain (OR=1.04, p=0.001) and HAQ (OR=1.72, p=0.053), and inversely associated with CDAI (OR=0.94, p=0.001). Morning stiffness, fatigue, and depression were not associated with discordance (Table 3).
Conclusion(s): About 30% of RA patients who initiated DMARDs had patient-physician discordance at any visit, and one-third of these (10% total) persisted at all three visits. Greater patient-reported pain and functional impairment were associated with discordance in adjusted models. Understanding factors associated with patient-physician discordance will help clinicians foster a more patient-centric discussion in treatment decisions

Background/Purpose: There is limited information on the real-world safety of disease-modifying anti-rheumatic drugs (DMARDs) approved for treating rheumatoid arthritis (RA) in Japan. Using a Japanese RA registry, rates of serious adverse events among initiators of methotrexate (MTX), TNFi, nonTNFi, and tofacitinib were calculated.
Method(s): We identified RA patients (pts) in the Corrona RA Japan Registry who initiated a DMARD between 03/01/2016 to 12/31/2019 and had at least one follow-up (FU) visit or had an adverse event before the first FU visit. If pts switched to another drug in the same drug class, they remained in the original drug group. Each initiation was considered so pts could be in >= 1 drug group. Adverse events of interest were cardiovascular disease (CVD), serious infections, Herpes Zoster [(HZ) serious and non-serious], and malignancy, excluding non-melanoma skin cancer (NMSC). The incidence of adverse events was calculated. For all events except malignancy, person-time at risk was estimated from time of drug initiation until the occurrence of the first event or 90 days after discontinuation. For risk of malignancies, the risk window for any therapy included all person-time in the designated period (time since starting therapy) and extended until the end of data collection. Incidence rates (IR), expressed as number of first events per 100 person-years (PY), were calculated with 95% confidence intervals (CI) assuming a Poisson distribution.
Result(s): There were 1,546 pts with first-time use of MTX, TNFi, nonTNFi, or tofacitinib who had at least one FU visit or had an adverse event before the first FU visit. Drug groups included 296 MTX, 491 TNFi, 560 nonTNFi, and 199 tofacitinib initiators. History of prior CVD, serious infection, HZ, and malignancy ranged from 8-14%, 9-15%, 10-14%, and 6-16%, respectively (Table 1). The average PY of FU time was 2.0, 1.6, 1.5, and 1.4 PY for MTX, TNFi, nonTNFi, and tofacitinib initiators, respectively (Table 2). The IR for serious infections was (IR=6.47, 95% CI, 4.70-8.68) for nonTNFi, (3.86, 1.77-7.33) for tofacitinib, (3.46, 2.17-5.24) for TNFi, and (2.16, 1.04-3.97) for the MTX groups. The tofacitinib group had the highest IR for HZ (9.31, 5.76-14.23) and nonTNFi (2.02, 1.11-3.40), TNFi (0.93, 0.34-2.03), and the MTX (0.86, 0.23-2.20) groups were lower. All the HZ events were non-serious (e.g., did not require hospitalization or intravenous antivirals). Total CVD was (0.43, 0.05-1.54), (0.77, 0.25-1.80), (1.57, 0.79-2.82), and (1.27, 0.26-3.72 in the MTX, TNFi, nonTNFi, and the tofacitinib groups, respectively. For malignancy excluding NMSC, the IRs were (1.65, 0.88-2.82) in TNFi, (1.52,0.70-2.89) in MTX, (1.20, 0.58-2.21) in nonTNFi, and (0.35, 0.01-1.96) in the tofacitinib groups (Table 3).
Conclusion(s): There were similar rates of serious infection, CVD, and malignancy adverse events among pts initiating MTX, TNFi, nonTNFi, and tofacitinib. Yet, the rate of HZ, due to non-serious events, was greater in those initiating tofacitinib, which is consistent with what is known from Japanese tofacitinib clinical trial data

Background/Purpose: There are several conventional synthetic, targeted synthetic and biological disease-modifying anti-rheumatic medications (DMARDs) approved for the treatment of rheumatoid arthritis (RA) in Japan. Little is known regarding the characteristics of patients treated by these DMARD classes and their respective effectiveness in a real-world cohort of patients in Japan.
Method(s): We identified RA patients in the Corrona RA Japan Registry who initiated a DMARD (methotrexate [MTX], TNFi, nonTNFi, tofacitinib) between March 1, 2016 to December 31, 2019 with enrollment capping for some drug classes. We characterized the four drug groups in terms of sociodemographics, comorbidities, disease characteristics, medications (current and prior), disease activity, and patient-reported outcomes (PROs). Drug effectiveness in each of the drug groups was assessed for all initiators with baseline and 6-month follow-up (FU) visits available by change in Clinical Disease Activity Index (CDAI) and PROs (pain, fatigue, patient global assessment, and J-HAQ), as well as the achievement of minimal clinically important difference (MCID) in CDAI and modified ACR20/50/70s in the six months following medication initiation.
Result(s): There were 1293 patients in the registry with 275 MTX, 331 TNFi, 525 nonTNFi, and 162 tofacitinib initiators that had both baseline and 6-month FU visits available. Mean disease duration was 2.4, 7.2, 9.8, and 11.8 years, respectively, in the MTX, TNFi, nonTNFi, and tofacitinib groups. Almost all MTX initiators (99.3%) were biological naive. Among TNFi initiators, 76.7%, 16.9%, 3.6%, and 2.7% received their drug as their 1st, 2nd, 3rd, and 4th biological/Janus Kinase inhibitor (JAKi), respectively. For patients in the nonTNFi group, it was 62.7% 21.3%, 9.3%, and 6.7%, respectively. Among tofacitinib initiators, 26.5% of patients received the drug as their 1st, 35.2% as their 2nd, 21.0% as their 3rd, and 17.3% as their 4th biological/JAKi. At initiation, mean disease activity, as measured by CDAI, was 19.0, 22.6, 21.9, and 23.1 for the MTX, TNFi, nonTNFi, and tofacitinib patients, respectively (Table 1). At the 6-month FU visit following initiation, mean change in CDAI was -9.9, -11.6, -11.8 and -12.4 in the MTX, TNFi, nonTNFi, and tofacitinib initiators, respectively. Additionally, the majority of the patients (61.0%, 62.6%, 67.1%, and 66.7% for the MTX, TNFi, nonTNFi, and tofacitinib initiators, respectively) reached MCID in CDAI. Almost half of all initiators achieved ACR20 responses (46.9%, 42.6%, 48.2%, and 45.1% of the MTX, TNFi, nonTNFi, and tofacitinib initiators, respectively). Approximately 80% or more initiators remained on the drug until their 6-month FU visit (79.6%, 82.8%, 85.1%, and 85.2% for MTX, TNFi, nonTNFi, and tofacitinib, respectively) (Table 2).
Conclusion(s): There were distinct patient profiles for those initiating each of the four drug classes in Japan. Overall, the majority of patients receiving MTX, TNFi, nonTNFi, and tofacitinib all had good responses. This positive patient response to DMARDS in a Japanese population adds to the growing scientific literature for those seeking to understand real-world outcomes

Background/Purpose: Little is known regarding differences in DMARD utilization across countries. A better understanding is needed to contextualize findings from different countries.1 Using the same type of registry and design approach, our study describes baseline characteristics and clinical measures among rheumatoid arthritis (RA) patients who initiated a disease-modifying anti-rheumatic drug (DMARD) in Japan and the US.
Method(s): We identified RA patients in the Corrona RA Japan (RA-J) and Corrona RA US (RA-US) Registries who initiated a DMARD (methotrexate, TNF, nonTNF, Janus kinase inhibitor (JAKi)) between 01/March/2016 to 31/January/2020. We compared cohorts overall and by drug group for sociodemographics, disease characteristics, comorbidities, patient-reported outcome measures (PROMs), and medications (current and prior). Of note, 2nd, 3rd, and 4th DMARDs were initiated later in RA-J in terms of disease duration. Descriptive statistics were provided; t-tests were used for continuous variables, chi-squared tests for categorical or dichotomous variables, and Fisher's exact tests for categorical/dichotomous variables with a category size smaller than five.
Result(s): Baseline data were available for 1996 RA-J and 6846 RA-US drug initiators. Overall, the two cohorts differed in most of the variables except that both groups were 79% female. At baseline, RA-J vs RA-US had a shorter mean duration of RA disease (8.1 yrs vs 10.4 yrs), higher percentage of history of serious infections (12% vs 9%), higher level of disease activity (CDAI: 22.5 vs 18.8), swollen joint count (6.2 vs 4.6), and physician global assessment (45.5 vs 31.7), but a lower percentage of history of cardiovascular disease (11% vs 14%) (Table 1). When RA-J vs RA-US were stratified by drug class, the pattern of the differences between the two cohorts was mostly consistent with the overall analysis, except that the RA-J MTX initiators had a lower level of CDAI (19.1 vs 21.2) and prednisone use (17% vs 37%) than RA-US MTX initiators, while among the other groups (TNFi, nonTNFi, and JAKi) the pattern was reverse for CDAI or not present for prednisone use (Table 2). Disease activity, PROMs, and current medication use was different between the two cohorts by line of therapy. Among RA-J vs RA-US, mean pain scores were higher (52.9 vs 45.9) in the 3rd line of therapy, and mean CDAI scores were higher [(21.8 vs 17.7), (22.3 vs 16.1), (25.1 vs 19.8)] and more prednisone use occurred [(30% vs 26%), (33% vs 26%), (37% vs 33%)] in the 2nd, 3rd, and 4th lines of therapy, respectively. A greater percentage of RA-J vs RA-US used nonTNFi in the 1st (12% vs 3%), 2nd (41% vs 10%), and 3rd line (40% vs 22%) of therapy. By contrast in RA-J vs RA-US, TNFi use was lower in the 1st (4% vs 8%), 2nd (40% vs. 63%), 3rd (32% vs 60%) and 4th line (23% vs 36%) of therapy.
Conclusion(s): Patients in RA Japan and RA US Registries differed in many aspects of demographics, comorbidity histories, clinical measures, and the utilization of DMARDs. Understanding cross-cultural differences in RA management is essential when interpreting results of studies from different countries. Verstappen SM, et al. Arthritis Care Res (Hoboken). 2015 Dec;67(12):1637-45

INTRODUCTION/BACKGROUND:The National Psoriasis Foundation (NPF) published treat-to-target guidelines for psoriasis, yet their applicability in clinical practice remains unknown. OBJECTIVES/OBJECTIVE:To estimate the proportion of psoriasis patients meeting the NPF's body surface area (BSA) 'target' (≤1%) and 'acceptable' (≤3%) response criteria and the cross-sectional associations of these criteria with patient-reported outcomes (PROs) in the Corrona Psoriasis Registry. METHODS:Separately for three independent cross-sectional cohorts of patients at the 1) enrollment, 2) 6-month and 3) 12-months visits, we calculated the proportion of patients with BSA≤1% and ≤3%. Furthermore, we calculated odds ratios estimating the risk of PROs associated with not meeting criteria in the 6-month cohort. RESULTS:The enrollment, 6- and 12-month cohorts included 2,794, 1,310 and 629 patients, respectively. At enrollment, 24% of patients had a BSA≤1% and 41% a BSA≤3%. In the 6-month cohort, 43%/64% had BSA≤1%/BSA≤3%. In the 12-month cohort 46%/69% of patients BSA≤1%/BSA≤3%. Patients not at target/acceptable criteria had higher odds for worse quality of life compared to those who were. CONCLUSION/CONCLUSIONS:While most patients at 6 and 12-month visits were at the 'acceptable' response, less than half were at the 'target' response despite systemic therapy. There remain unmet needs to optimize psoriasis therapy and further validate current treat-to-target guidelines.