Tofacitinib Efficacy in Patients with Rheumatoid Arthritis and Probable Depression/Anxiety: Post Hoc Analysis of Phase 3 and 3b/4 Randomized Controlled Trials.

INTRODUCTION: The aim of our work is to assess the prevalence of probable major depressive disorder and/or probable generalized anxiety disorder (pMDD/pGAD) in patients with moderate to severe rheumatoid arthritis (RA), and to evaluate the efficacy of tofacitinib on RA symptoms stratified by baseline pMDD/pGAD status. METHODS: Data were pooled from five phase 3 randomized controlled trials (RCTs) and one phase 3b/4 RCT, assessing tofacitinib 5 or 10 mg twice daily (BID), adalimumab (two RCTs), or placebo. pMDD/pGAD was defined as Short Form-36 Health Survey (SF-36) Mental Component Summary (MCS) score ≤ 38. Efficacy outcomes over 12 months included least squares mean change from baseline in SF-36 MCS score and Health Assessment Questionnaire-Disability Index, proportions of patients with pMDD/pGAD in those with baseline pMDD/pGAD, and American College of Rheumatology 20/50/70 response, and Disease Activity Score in 28 joints, erythrocyte sedimentation rate remission (< 2.6) rates. RESULTS: A total of 4404 patients with non-missing baseline values were included. Baseline pMDD/pGAD was reported by 44.5%, 39.8%, 45.4%, and 39.1% of patients receiving tofacitinib 5 mg BID, tofacitinib 10 mg BID, adalimumab, and placebo, respectively. SF-36 MCS improvements were greater for tofacitinib versus adalimumab/placebo through month 6, with numerical improvements for tofacitinib versus adalimumab sustained through month 12, when the proportions of patients with baseline pMDD/pGAD who continued to have pMDD/pGAD were reduced. RA efficacy outcomes were generally similar in patients with/without baseline pMDD/pGAD. CONCLUSIONS: The percentage of patients with pMDD/pGAD reduced from baseline over 1 year of treatment with tofacitinib or adalimumab. Effective treatment of underlying RA may lead to improvements in depression and anxiety, based on the SF-36 MCS. Specially designed studies using gold-standard diagnostic tools would be warranted to investigate this further. Video Abstract available for this article. TRIAL REGISTRATION: NCT00960440, NCT00847613, NCT00814307, NCT00856544, NCT00853385, NCT02187055. Video Abstract (MP4 204475 KB).

Tofacitinib is a medicine used to treat rheumatoid arthritis (swollen and painful joints). A total of 4400 patients with moderate or severe rheumatoid arthritis who were taking part in tofacitinib clinical trials completed a survey about their general health and well-being at that time. We used their answers to determine whether they were likely to have depression or anxiety. We then looked at how common depression or anxiety was in patients with rheumatoid arthritis, and whether having depression or anxiety affected how patients responded to tofacitinib treatment. It is important to note that tofacitinib is not approved for the treatment of depression or anxiety, and these clinical trials were not designed to assess whether tofacitinib improved depression or anxiety symptoms. About 40% of patients likely had depression or anxiety when they started a clinical trial. This percentage decreased among patients who received tofacitinib treatment over a year. Patients treated with tofacitinib showed more improvement in their depression or anxiety than those treated with placebo. Over a year of treatment, tofacitinib improved signs and symptoms of rheumatoid arthritis, for example, the number of swollen or painful joints and fatigue. Having depression or anxiety did not change the way that patients responded to tofacitinib. This research shows how treating rheumatoid arthritis symptoms may also improve depression and anxiety symptoms. However, specially designed studies are needed to confirm this.

Impact of access to treatment on patient-reported outcomes among rheumatoid arthritis patients with tDMARDs and bDMARDS in two Latin-American countries: A prospective observational study.

Background and Aims: A noninterventional prospective study was performed in Colombia and Peru. The aim was to describe the impact of access to treatment on Patient-reported outcomes (PRO) in patients with Rheumatoid arthritis (RA) after failure to conventional disease-modifying antirheumatic drugs (DMARDs) in real-life conditions. Methods: The impact of access to treatment was measured by access barriers, time to supply (TtS) and interruption evaluating their effect in changes of PROs between baseline and 6-month follow-up between February 2017 and November 2019. The association of access to care with disease activity, functional status, health-related quality of life was assessed using bivariate and multivariable analysis. Results are expressed in least mean difference; TtS in mean number of days for delivery of treatment at baseline. Variability measures were standard deviation and standard error. Results: One hundred seventy patients were recruited, 70 treated with tofacitinib and 100 with biological DMARDs. Thirty-nine patients reported access barriers. The mean of TtS was 23 ± 38.83 days. The difference from baseline to 6-month visit in PROs were affected by access barriers and interruptions. There was not statistically significant difference in the of PRO's score among visits in patients that reported delay of supply of more than 23 days compared to patients with less days of delay. Conclusion: This study suggested the access to treatment can affect the response to the treatment at 6 months of follow-up. There seems to be no effect in the PROs for delay of TtS during the studied period.

Association of C-reactive Protein and Partial Mayo Score With Response to Tofacitinib Induction Therapy: Results From the Ulcerative Colitis Clinical Program.

BACKGROUND: Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of ulcerative colitis (UC). These post hoc analyses assessed associations between C-reactive protein (CRP), partial Mayo score (PMS), and efficacy outcomes during tofacitinib induction in UC. METHODS: Patients received tofacitinib 10 mg twice daily (BID) in an 8-week, phase 2 induction study and 2 identical, 8-week, phase 3 induction studies (OCTAVE Induction 1&2); induction nonresponders (IndNR) received an additional 8 weeks of tofacitinib 10 mg BID in an open-label, long-term extension study. Associations between CRP and PMS, and efficacy outcomes (clinical response, clinical remission, endoscopic improvement, and endoscopic remission) were analyzed using univariate and multivariable logistic regression and receiver operating characteristic curves. RESULTS: Changes from baseline in the logarithm of CRP ([log]CRP) and PMS at week 4 were associated with clinical response at week 8 (univariate: per unit, odds ratio [OR], 0.55 [95% confidence interval (CI), 0.48-0.62]; and 0.42 [0.37-0.47], respectively). Among IndNR, change from baseline in PMS at week 8 was associated with clinical response at week 16 (univariate: per unit, OR, 0.59; 95% CI, 0.46-0.75). C-reactive protein at week 4 (area under the curve [AUC] > 0.6) and PMS at weeks 2 and 4 (AUC, > 0.7) generally exhibited predictive value for week 8 efficacy outcomes. CONCLUSIONS: Patients who achieved clinical response at week 8 had larger decreases in CRP and PMS at week 4 than patients who did not. IndNR who achieved clinical response at week 16 with extended tofacitinib induction had a larger decrease in PMS at week 8 vs those who did not. ClinicalTrials.gov:NCT00787202;NCT01465763;NCT01458951;NCT01470612.

Early decreases in partial Mayo score and C-reactive protein were found to be associated with achieving efficacy outcomes following tofacitinib 10 mg twice daily induction therapy in the ulcerative colitis clinical program.

Treatment patterns and sequencing in patients with rheumatic diseases: a retrospective claims data analysis.

OBJECTIVES: Long-term real-world management of inflammatory rheumatic diseases remains unclear, especially with the advent of new treatment options. This study characterizes the number of advanced treatments used by patients with selected rheumatic diseases (rheumatoid arthritis [RA], psoriatic arthritis [PsA], ankylosing spondylitis, juvenile idiopathic arthritis) and provides a contemporary portrait of treatment patterns and therapeutic sequencing among patients with RA and PsA. METHOD: Patients were selected from a large US claims database and classified into disease subsamples based on the latest rheumatic diagnosis recorded before/on the day of initiation of the first advanced treatment (index date). The total number of advanced treatments was assessed within the first 5 years following the index date. Treatment patterns and therapeutic sequencing were assessed over the first 2 years. RESULTS: Approximately 20% of patients received ≥2 distinct advanced treatments during the first year following index date - the proportion increased to almost 50% among patients with 5 years of observation. Most patients (RA: 76.8%; PsA: 88.7%) initiated a tumor necrosis factor as the first advanced treatment. Over the first 2 years after the index date, 1/3 of RA and PsA patients switched to another advanced treatment. More than 50% initiated a second treatment with the same mechanism of action (MOA). A small proportion of patients received a biosimilar. CONCLUSION: Despite advent of treatments with different MOA, cycling between treatments with the same MOA was common. Further studies with longer data follow-up would be needed to assess the impact of higher adoption of biosimilars on treatment patterns/sequencing.

Tofacitinib in Patients Hospitalized with Covid-19 Pneumonia.

BACKGROUND: The efficacy and safety of tofacitinib, a Janus kinase inhibitor, in patients who are hospitalized with coronavirus disease 2019 (Covid-19) pneumonia are unclear. METHODS: We randomly assigned, in a 1:1 ratio, hospitalized adults with Covid-19 pneumonia to receive either tofacitinib at a dose of 10 mg or placebo twice daily for up to 14 days or until hospital discharge. The primary outcome was the occurrence of death or respiratory failure through day 28 as assessed with the use of an eight-level ordinal scale (with scores ranging from 1 to 8 and higher scores indicating a worse condition). All-cause mortality and safety were also assessed. RESULTS: A total of 289 patients underwent randomization at 15 sites in Brazil. Overall, 89.3% of the patients received glucocorticoids during hospitalization. The cumulative incidence of death or respiratory failure through day 28 was 18.1% in the tofacitinib group and 29.0% in the placebo group (risk ratio, 0.63; 95% confidence interval [CI], 0.41 to 0.97; P = 0.04). Death from any cause through day 28 occurred in 2.8% of the patients in the tofacitinib group and in 5.5% of those in the placebo group (hazard ratio, 0.49; 95% CI, 0.15 to 1.63). The proportional odds of having a worse score on the eight-level ordinal scale with tofacitinib, as compared with placebo, was 0.60 (95% CI, 0.36 to 1.00) at day 14 and 0.54 (95% CI, 0.27 to 1.06) at day 28. Serious adverse events occurred in 20 patients (14.1%) in the tofacitinib group and in 17 (12.0%) in the placebo group. CONCLUSIONS: Among patients hospitalized with Covid-19 pneumonia, tofacitinib led to a lower risk of death or respiratory failure through day 28 than placebo. (Funded by Pfizer; STOP-COVID ClinicalTrials.gov number, NCT04469114.).

Incidence Rates of Interstitial Lung Disease Events in Tofacitinib-Treated Rheumatoid Arthritis Patients: Post Hoc Analysis From 21 Clinical Trials.

BACKGROUND/OBJECTIVE: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). Interstitial lung disease (ILD) is an extra-articular manifestation of RA. We investigated incidence rates of ILD in patients with RA, receiving tofacitinib 5 or 10 mg twice daily, and identified potential risk factors for ILD. METHODS: This post hoc analysis comprised a pooled analysis of patients receiving tofacitinib 5 or 10 mg twice daily or placebo from 2 phase (P)1, 10 P2, 6 P3, 1 P3b/4, and 2 long-term extension studies. Interstitial lung disease events were adjudicated as "probable" (supportive clinical evidence) or "possible" (no supportive clinical evidence) compatible adverse events. Incidence rates (patients with events per 100 patient-years) were calculated for ILD events. RESULTS: Of 7061 patients (patient-years of exposure = 23,393.7), 42 (0.6%) had an ILD event; median time to ILD event was 1144 days. Incidence rates for ILD with both tofacitinib doses were 0.18 per 100 patient-years. Incidence rates generally remained stable over time. There were 17 of 42 serious adverse events (40.5%) of ILD; for all ILD events (serious and nonserious), 35 of 42 events (83.3%) were mild to moderate in severity. A multivariable Cox regression analysis identified age 65 years or older (hazard ratio 2.43 [95% confidence interval, 1.13-5.21]), current smokers (2.89 [1.33-6.26]), and Disease Activity Score in 28 joints-erythrocyte sedimentation rate score (1.30 [1.04-1.61]) as significant risk factors for ILD events. CONCLUSIONS: Across P1/2/3/4/long-term extension studies, incidence rates for ILD events were 0.18 following tofacitinib treatment, and ILD events were associated with known risk factors for ILD in RA.

Review of the epidemiology and burden of ulcerative colitis in Latin America.

The incidence and prevalence of ulcerative colitis (UC) has been reported to be rising in newly industrialised regions, such as Latin America. Here, we review data from published studies reporting demographics and clinical aspects of UC in Latin America to further understand epidemiology and disease burden. The incidence and prevalence of UC in Latin America varied between regions and studies, ranging between 0.04 to 8.00/100,000 and 0.23 to 76.1/100,000, respectively, and generally increased over the period from 1986 to 2015. The majority of patients with UC were female (53.6-72.6%) and urban residents (77.8-97.4%). Extraintestinal manifestations were reported in approximately 26-89.4% of patients. Use of biologic therapies was generally low (0.8-16.2%), with the exception of Mato Grosso do Sul, Brazil, with a greater proportion of patients tending to receive 5-aminosalicylates, immunosuppressants or corticosteroids; colectomy rates varied between studies (1.5-22%). A high proportion of patients had moderate to severe UC (45.9-73.0%) and, in 11 of 19 studies, the greatest proportion of patients had extensive disease (pancolitis). Colorectal cancer (0-1.7%) and mortality rates (0-7.6%) were low. This evaluation of published studies may influence therapeutic approaches and the development of strategies to improve healthcare access and patient outcomes, although further high-quality studies are required in patients with UC in Latin America.

A comparative study of PF-06438179/GP1111 (an infliximab biosimilar) and reference infliximab in patients with moderate to severe active rheumatoid arthritis: A subgroup analysis.

AIM: PF-06438179/GP1111 (PF-SZ-IFX) is a biosimilar of reference infliximab (Remicade® ). This analysis compared the efficacy of PF-SZ-IFX and reference infliximab sourced from the European Union (IFX-EU) in patient subgroups from a randomized, comparative study of PF-SZ-IFX versus IFX-EU. METHODS: Patients with rheumatoid arthritis were randomized 1:1 to PF-SZ-IFX (n = 324) or IFX-EU (n = 326); study drug (3 mg/kg) was administered intravenously at weeks 0, 2, and 6, then every 8 weeks thereafter. Subgroup analyses of efficacy endpoints such as American College of Rheumatology criteria for ≥20% clinical improvement (ACR20), change in high-sensitivity C-reactive protein (hs-CRP), and change in Disease Activity Score in 28 joints, four components based on hs-CRP (DAS28-CRP) at weeks 14 and 30 were performed by age, gender, race, region, immunogenicity status, and treatment history. RESULTS: Overall, ACR20 response rates as well as changes in DAS28-CRP and hs-CRP at week 14 were similar between PF-SZ-IFX and IFX-EU within the subgroups of age, gender, race, region, treatment history, and immunogenicity status. Results to week 30 support overall similarity in efficacy between the two treatment arms in all subgroups. CONCLUSION: Overall, PF-SZ-IFX and IFX-EU were similar in efficacy within the analyzed subgroups of age, gender, race, region, treatment history, and immunogenicity status. The efficacy results from these subgroup analyses were aligned with the previously described results for the overall population up to week 30.

Treatment Mode Preferences in Rheumatoid Arthritis: Moving Toward Shared Decision-Making.

PURPOSE: Current knowledge of the reasons for patients' preference for rheumatoid arthritis (RA) treatment modes is limited. This study was designed to identify preferences for four treatment modes, and to obtain in-depth information on the reasons for these preferences. PATIENTS AND METHODS: In this multi-national, cross-sectional, qualitative study, in-depth interviews were conducted with adult patients with RA in the United States, France, Germany, Italy, Spain, Switzerland, the United Kingdom, and Brazil. Patients' strength of preference was evaluated using a 100-point allocation task (0-100; 100=strongest) across four treatment modes: oral, self-injection, clinic-injection, and infusion. Qualitative descriptive analysis methods were used to identify, characterize, and summarize patterns found in the interview data relating to reasons for these preferences. RESULTS: 100 patients were interviewed (female, 75.0%; mean age, 53.9 years; mean 11.6 years since diagnosis). Among the four treatment modes, oral administration was allocated the highest mean (standard deviation) preference points (47.3 [33.1]) and was ranked first choice by the greatest percentage of patients (57.0%), followed by self-injection (29.7 [27.7]; 29.0%), infusion (15.4 [24.6]; 16.0%), and clinic-injection (7.5 [14.1]; 2.0%). Overall, 56.0% of patients had a "strong" first-choice preference (ie, point allocation ≥70); most of these patients chose oral (62.5%) vs self-injection (23.2%), infusion (10.7%), or clinic-injection (3.6%). Speed and/or ease of administration were the most commonly reported reasons for patients choosing oral (52.6%) or self-injection (55.2%). The most common reasons for patients not choosing oral or self-injection were not wanting to take another pill (37.2%) and avoiding pain due to needles (46.5%), respectively. CONCLUSION: These data report factors important to patients regarding preferences for RA treatment modes. Patients may benefit from discussions with their healthcare professionals and/or patient support groups, regarding RA treatment modes, to facilitate shared decision-making.

Age Does Not Affect Metoprolol's Effect on Perioperative Outcomes (From the POISE Database).

BACKGROUND: Perioperative ß-blockade reduces the incidence of myocardial infarction but increases that of death, stroke, and hypotension. The elderly may experience few benefits but more harms associated with ß-blockade due to a normal effect of aging, that of a reduced resting heart rate. The tested hypothesis was that the effect of perioperative ß-blockade is more significant with increasing age. METHODS: To determine whether the effect of perioperative ß-blockade on the primary composite event, clinically significant hypotension, myocardial infarction, stroke, and death varies with age, we interrogated data from the perioperative ischemia evaluation (POISE) study. The POISE study randomly assigned 8351 patients, aged ≥45 years, in 23 countries, undergoing major noncardiac surgery to either 200 mg metoprolol CR daily or placebo for 30 days. Odds ratios or hazard ratios for time to events, when available, for each of the adverse effects were measured according to decile of age, and interaction term between age and treatment was calculated. No adjustment was made for multiple outcomes. RESULTS: Age was associated with higher incidences of the major outcomes of clinically significant hypotension, myocardial infarction, and death. Age was associated with a minimal reduction in resting heart rate from 84.2 (standard error, 0.63; ages 45-54 years) to 80.9 (standard error, 0.70; ages >85 years; P < .0001). We found no evidence of any interaction between age and study group regarding any of the major outcomes, although the limited sample size does not exclude any but large interactions. CONCLUSIONS: The effect of perioperative ß-blockade on the major outcomes studied did not vary with age. Resting heart rate decreases slightly with age. Our data do not support a recommendation for the use of perioperative ß-blockade in any age subgroup to achieve benefits but avoid harms. Therefore, current recommendations against the use of ß-blockers in high-risk patients undergoing noncardiac surgery apply across all age groups.

Safety of Tofacitinib in the Treatment of Rheumatoid Arthritis in Latin America Compared With the Rest of the World Population.

OBJECTIVE: Rheumatoid arthritis (RA) is a chronic, autoimmune disease characterized by joint destruction. Tofacitinib is an oral Janus kinase inhibitor for the treatment of RA. This post hoc analysis assessed the safety of tofacitinib in Latin American (LA) patients with RA versus the Rest of World (RoW) population. METHODS: Data were pooled from 14 clinical studies of tofacitinib: six Phase 2, six Phase 3 and two long-term extension studies. Incidence rates (IRs; patients with events/100 patient-years of treatment exposure) were calculated for safety events of special interest combined across tofacitinib doses. 95% confidence intervals (CI) for IRs were calculated using the maximum likelihood method. Descriptive comparisons were made between LA and RoW (excluding LA) populations. RESULTS: This analysis included data from 984 LA patients and 4687 RoW patients. IRs for safety events of special interest were generally similar between LA and RoW populations, with overlapping 95% CIs. IRs for discontinuation due to adverse events, serious infections, tuberculosis, all herpes zoster (HZ), serious HZ, malignancies (excluding non-melanoma skin cancer) and major adverse cardiovascular events were numerically lower for LA versus RoW patients; IR for mortality was numerically higher. No lymphoma was reported in the LA population versus eight cases in the RoW population. Exposure (extent and length) was lower in the LA population (2148.33 patient-years [mean = 2.18 years]) versus RoW (10515.68 patient-years [mean = 2.24 years]). CONCLUSION: This analysis of pooled data from clinical studies of tofacitinib in patients with RA demonstrates that tofacitinib has a consistent safety profile across LA and RoW patient populations.

Latent infection and tuberculosis disease in rheumatoid arthritis patients.

New drug classes, biologics, have been developed over the past 10 years based on human or chimeric antibodies against cytokines or receptors with pivotal roles in the inflammatory pathways of immune-mediated inflammatory disease. Anti-tumor necrosis factor agents carry the largest infection risk of all the biologics, predisposing patients to mycobacterial infections. Patients receiving biologics are at higher risk for developing tuberculosis. New cases of tuberculosis or reactivation of latent tuberculosis infections may occur during the course of treatment, so a high level of vigilance is highly recommended.

Comparison of an interferon-gamma assay with tuberculin skin testing for detection of tuberculosis (TB) infection in patients with rheumatoid arthritis in a TB-endemic population.

OBJECTIVE: Tuberculosis (TB) in patients with rheumatoid arthritis (RA) undergoing treatment with anti-tumor necrosis factor (TNF) agents is commonly the result of reactivation of latent TB infection (LTBI); detection and treatment of LTBI is essential before treatment with anti-TNF agents. We reported previously that the tuberculin skin test (TST) is inaccurate for diagnosis of LTBI in patients with RA. Here, we compare the prevalence of LTBI in RA patients and matched controls according to positive TST and QuantiFeron-TB Gold In-Tube version (QFT) results and determine their agreement. METHODS: A cross-sectional study of 101 RA patients and 93 controls was conducted in Lima, Perú, where the prevalence of LTBI in the general population has been estimated to be 68%. Blood was drawn for QFT assay followed by TST using 2-TU of RT 23 purified protein derivative. TST was deemed positive at >or= 5 mm for RA patients and >or= 10 mm for controls. RESULTS: There were no significant differences between RA patients and controls for age, sex, bacillus Calmette-Guérin vaccination, or history of or contact with TB. 88% of patients had active RA disease and 2 (1.9%) patients had indeterminate QFT results. The number of subjects testing positive with the QuantiFeron assay was comparable between patients and controls (44.6% vs 59.1%, respectively), whereas the TST detected significantly less LTBI among RA patients (26.7%) than controls (65.6%). Thus, the rate of LTBI in RA patients represented 75% and 41% of the rate in their controls using QFT or TST, respectively (p = 0.008). Poor agreement between TST and QFT was seen in RA patients, but in controls, good agreement was observed between these tests. CONCLUSION: In a TB-endemic population, the QuantiFeron-TB Gold In-Tube assay seemed to be a more accurate test for detection of LTBI in RA patients compared with the TST, and may potentially improve the targeting of prophylactic therapy before treatment with anti-TNF agents.