Incidence Rates of Interstitial Lung Disease Events in Tofacitinib-Treated Rheumatoid Arthritis Patients: Post Hoc Analysis From 21 Clinical Trials.
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ABSTRACT: 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.
SUBMITTER: Citera G
PROVIDER: S-EPMC8612919 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:IntroductionTofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA) and psoriatic arthritis (PsA). This post hoc analysis assessed frequency or duration of early select non-serious adverse events (AEs; excluding infections), and their impact on treatment discontinuation, in patients with RA or PsA treated with tofacitinib 5 or 10 mg twice daily, or placebo.MethodsData were pooled from five phase 3 and one phase 3b/4 studies in patients with moderate-to-severe RA, and two phase 3 studies in patients with active PsA. Select all-causality, non-serious AEs, reported to month 3 (placebo-controlled period), were headache, diarrhea, nausea, vomiting, and gastric discomfort (including dyspepsia, gastritis, epigastric discomfort, and abdominal discomfort or pain); incidence rates (unique patients with events per 100 patient-years of follow-up), duration of, and discontinuations due to these non-serious AEs were reported.ResultsWe analyzed 3871 and 710 patients with RA and PsA, respectively. Incidence of non-serious AEs to month 3 was generally similar with tofacitinib and placebo. The most frequent non-serious AEs were headache and diarrhea with tofacitinib, and dyspepsia, nausea, and headache with placebo. Most events were mild or moderate in severity, lasting ≤ 4 weeks. Permanent discontinuations due to non-serious AEs were not observed in patients with PsA, and were < 1.0% in patients with RA across treatment groups. The most frequent cause of temporary discontinuation across all groups was gastric discomfort (0.3-0.8%).ConclusionsNon-serious AE incidence was generally similar in patients with RA or PsA receiving tofacitinib or placebo. Most events were mild or moderate and generally resolved within 4 weeks.Trial registrationClinicalTrials.gov identifiers: NCT00960440; NCT00847613; NCT00814307; NCT00856544; NCT00853385; NCT01877668; NCT01882439; NCT02187055.
| S-EPMC8964869 | biostudies-literature
Project description:ObjectivesTo evaluate the risk of opportunistic infections (OIs) in patients with rheumatoid arthritis (RA) treated with tofacitinib.MethodsPhase II, III and long-term extension clinical trial data (April 2013 data-cut) from the tofacitinib RA programme were reviewed. OIs defined a priori included mycobacterial and fungal infections, multidermatomal herpes zoster and other viral infections associated with immunosuppression. For OIs, we calculated crude incidence rates (IRs; per 100 patient-years (95% CI)); for tuberculosis (TB) specifically, we calculated rates stratified by patient enrolment region according to background TB IR (per 100 patient-years): low (≤0.01), medium (>0.01 to ≤0.05) and high (>0.05).ResultsWe identified 60 OIs among 5671 subjects; all occurred among tofacitinib-treated patients. TB (crude IR 0.21, 95% CI of (0.14 to 0.30)) was the most common OI (n=26); median time between drug start and diagnosis was 64 weeks (range 15-161 weeks). Twenty-one cases (81%) occurred in countries with high background TB IR, and the rate varied with regional background TB IR: low 0.02 (0.003 to 0.15), medium 0.08 (0.03 to 0.21) and high 0.75 (0.49 to 1.15). In Phase III studies, 263 patients diagnosed with latent TB infection were treated with isoniazid and tofacitinib concurrently; none developed TB. For OIs other than TB, 34 events were reported (crude IR 0.25 (95% CI 0.18 to 0.36)).ConclusionsWithin the global tofacitinib RA development programme, TB was the most common OI reported but was rare in regions of low and medium TB incidence. Patients who screen positive for latent TB can be treated with isoniazid during tofacitinib therapy.
| S-EPMC4893093 | biostudies-literature
Project description:Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis. We evaluated the relationship between disease activity, according to Routine Assessment of Patient Index Data 3 (RAPID3) after 6-month treatment with tofacitinib, and long-term outcomes at 24 months. This was a post hoc analysis of two 24-month, phase 3, randomized controlled trials in methotrexate (MTX)-naïve (ORAL Start [NCT01039688]) or MTX-inadequate responder patients (ORAL Scan [NCT00847613]) receiving tofacitinib 5 or 10 mg twice daily (BID) as monotherapy or with background MTX. RAPID3 scores were calculated at baseline, month (M)6, and M24, and defined as remission (≤ 3), low (LDA; > 3-≤ 6), moderate (MDA; > 6-≤ 12), or high disease activity (HDA; > 12). Clinical Disease Activity Index (CDAI), Health Assessment Questionnaire-Disability Index (HAQ-DI) scores, and radiographic non-progression (modified Total Sharp Scores ≤ 0) at M24 were evaluated by M6 RAPID3 response. Among patients receiving tofacitinib 5 or 10 mg BID, respectively, 42.2 and 51.5% (ORAL Start) and 29.8 and 39.0% (ORAL Scan) achieved RAPID3 remission/LDA at M6. Most patients maintained/improved RAPID3 responses at M24. A higher proportion of patients in RAPID3 remission/LDA versus MDA/HDA at M6 achieved CDAI remission, reported normative HAQ-DI scores (< 0.5), and achieved both normative HAQ-DI scores and radiographic non-progression at M24. Patients achieving RAPID3 remission/LDA after 6-month treatment with tofacitinib 5 or 10 mg BID have improved long-term outcomes versus patients with MDA/HDA. These findings support the use of RAPID3 to monitor longer-term disease activity in conjunction with physician-assessed measures.
| S-EPMC6061070 | biostudies-literature
Project description:OBJECTIVES: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:12 410 tofacitinib-treated patients from the development programmes (RA: n=7964; PsO: n=3663; PsA: n=783) were included. IRs (95% CI) of thromboembolic events among the all tofacitinib cohorts' 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)).
| S-EPMC7569391 | biostudies-literature
Project description:INTRODUCTION:Here we examine the relationship between achieving different levels of disease activity with tofacitinib (an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis), long-term structural progression, and patient-reported physical function. METHODS:This was a post hoc analysis of two 24-month, phase III randomized controlled trials in methotrexate (MTX)-naïve (ORAL Start [NCT01039688]) or MTX-inadequate responder (IR) patients (ORAL Scan [NCT00847613]) receiving tofacitinib 5 or 10 mg twice daily as either monotherapy or with background MTX. The modified total Sharp score (mTSS) and Health Assessment Questionnaire-Disability Index (HAQ-DI) were analyzed at month 24 according to disease activity at month 6 defined by the Clinical Disease Activity Index (CDAI) or the Disease Activity Score in 28 joints, C-reactive protein (DAS28CRP). RESULTS:Mean changes from baseline in mTSS at month 24 were less in patients with CDAI remission at month 6 than in those with CDAI moderate/high disease activity (MDA/HDA) at month 6. A DAS28CRP of < 1.9 most closely approximated CDAI remission (≤ 2.8). Tofacitinib appeared to inhibit joint damage in the presence of persistent inflammation compared with MTX. More patients receiving tofacitinib or MTX with CDAI remission or low disease activity (LDA) at month 6 reported normative HAQ-DI scores (< 0.5) at month 24 than did those with CDAI MDA/HDA. CONCLUSION:Regardless of treatment, in both MTX-naïve and MTX-IR patients, remission or LDA at month 6 was associated with successful long-term outcomes: inhibition of structural progression and normative HAQ-DI scores. Long-term outcomes were similar when patients achieved CDAI remission or a DAS28CRP of < 1.9, confirming that this is an appropriate cut-off for remission with DAS28CRP. Tofacitinib potentially inhibits joint damage even with persistent inflammation. FUNDING:Pfizer Inc. TRIAL REGISTRATION:Clinicaltrials.gov identifiers: NCT01039688 and NCT00847613.
| S-EPMC6251846 | biostudies-literature
Project description:Although the rapid onset of effect of glucocorticoids (GCs) allows rapid control of rheumatoid arthritis (RA) symptoms, their chronic use may be associated with several adverse events. The 2022 update of EUALR recommendations for the management of patients with RA suggests to reduce and discontinue oral GCs as quickly as possible. Considering GCs as a "bridging therapy" to promptly reduce symptoms and control inflammation, fast-acting drugs such as tofacitinib could allow faster and safer tapering of GCs. The purpose of this pilot study was to evaluate the steroid-sparing effect of adding tofacitinib in patients with RA inadequately responsive to methotrexate taking concomitant GCs. In this open-label pilot study, we enrolled patients with moderate to severe RA on a stable dose of prednisone (5-12.5 mg/day) who started treatment with tofacitinib. After 1 month, in patients who achieved at least a moderate EULAR response (decrease of > 1.2 in DAS28_CRP), GCs was tapered according to a predetermined schedule until complete discontinuation at week 12. Disease activity was assessed after 4, 12, 24 and 48 weeks of treatment. The primary endpoint was the percentage of patients discontinuing GCs after 12 weeks of tofacitinib treatment. We enrolled 30 patients (26 F: 4 M, mean age 60 ± 13 years, mean disease duration 13.2 ± 7.8 years). The primary endpoint was achieved: 9 patients (30%) discontinued GCs at week-12. At week-24, other 12 patients (46%) withdrew GCs. The median prednisone dose decreased from 5 mg/day (interquartile range 5-10 mg) to 2.5 (0-5) mg/day at week 12 and 48 (p < 0.00001 vs baseline). At week 48, 12 out of 30 patients (40%) had discontinued prednisone. The percentage of patients achieving remission or low disease activity increased throughout the follow-up without any difference between patients who discontinued or not the GC. In this cohort of long-standing RA patients treated with tofacitinib, the discontinuation of glucocorticoids was achievable in up to 30% of patients. These results should encourage rheumatologists to consider GCs tapering and discontinuation of GCs, as suggested by the 2022 EULAR recommendations, an achievable goal.
| S-EPMC10511736 | biostudies-literature
Project description:To analyse malignancy rates in patients with rheumatoid arthritis (RA) treated with tocilizumab.Patients who received tocilizumab or placebo+methotrexate/disease-modifying antirheumatic drugs in the double-blind phases of 5-phase three trials or who received at least 1 dose of tocilizumab in the long-term extension studies were analysed up to the 2 May 2012 cut-off date. Malignancies were monitored throughout the studies, analysed and adjudicated as malignant by medical review. Risk was compared with that in the general population using standardised incidence ratios (SIRs) based on data from the Surveillance Epidemiology and End Results SEER (US general population) and GLOBOCAN (non-US general population) databases.In total, 4009 patients in the tocilizumab all-exposure population were included. Mean treatment duration was 4.0 years (mean 5.1 (range 0.0-6.8); total observation time was 16 120.1 patient-years (PY). The adjudicated malignancy rate (95% CI) was 1.26/100 PY (1.09 to 1.44) and remained constant over time. The SIR (95% CI) for all malignancies combined, excluding non-melanoma skin cancer, was 1.36 (1.01 to 1.80) for US and 1.81 (1.44 to 2.23) for non-US populations, driven primarily by higher rates in lung and bronchus (US/non-US) malignancies and prostate cancer and non-Hodgkin lymphoma (non-US), in contrast to those for the general populations; these higher rates are in line with those expected in patients with RA or in the geographic regions studied.Malignancy rates remained stable with long-term tocilizumab treatment, and malignancy types and rates were consistent with those expected in patients with RA.
| S-EPMC4874056 | biostudies-other
Project description:ImportanceCurrent data are lacking regarding the risk of biologic and targeted synthetic disease-modifying antirheumatic drug (b/tsDMARD) use on the development of interstitial lung disease (ILD) in patients with rheumatoid arthritis (RA).ObjectiveTo determine the risk of developing ILD in patients with RA undergoing treatment with different b/tsDMARDs.Design, setting, and participantsRetrospective cohort study using claims data from the Optum Clinformatics Data Mart between December 2003 and December 2019. Adult patients with RA, 1 year or more of continuous enrollment, treatment with a b/tsDMARD of interest, and without preexisting ILD were included. Data were analyzed from October 2021 to April 2022.ExposuresNew administration of adalimumab, abatacept, rituximab, tocilizumab, or tofacitinib.Main outcomes and measuresCrude incidence rates (IRs) for the development of ILD were calculated. The risk of ILD across different b/tsDMARDs was compared using Cox-regression models. A sensitivity analysis using a prevalent new-user cohort design compared patients treated with tofacitinib and adalimumab.ResultsA total of 28 559 patients with RA (mean [SD] age 55.6 [13.7] years; 22 158 female [78%]) were treated with adalimumab (13 326 patients), abatacept (5676 patients), rituximab (5444 patients), tocilizumab (2548 patients), or tofacitinib (1565 patients). Crude IRs per 1000 person-years for ILD were 3.43 (95% CI 2.85-4.09) for adalimumab, 4.46 (95% CI 3.44-5.70) for abatacept, 6.15 (95% CI 4.76-7.84) for rituximab, 5.05 (95% CI 3.47-7.12) for tocilizumab, and 1.47 (95% CI 0.54-3.27) for tofacitinib. After multiple adjustments, compared with patients treated with adalimumab, patients treated with tofacitinib had a lower risk of ILD (adjusted hazard ratio [aHR] 0.31; 95% CI, 0.12-0.78; P = .009). In a prevalent new-user cohort analysis, patients treated with tofacitinib had 68% reduced risk of ILD compared with adalimumab (aHR 0.32; 95% CI 0.13-0.82; P < .001). In an adjusted model, there was a 69% reduced risk of ILD in patients treated with tofacitinib compared with patients treated with adalimumab.Conclusions and relevanceIn this retrospective cohort of patients with RA, patients treated with tofacitinib had the lowest incidence of ILD compared with patients treated with all bDMARDs evaluated, and patients treated with tofacitinib had a reduced risk of ILD compared with patients treated with adalimumab after adjusting for important covariates. Additional prospective studies are needed to better understand the role tofacitinib may play in preventing ILD in patients with RA. These results, while significant, should be interpreted with caution given the fairly small sample size of the tofacitinib group.
| S-EPMC10028485 | biostudies-literature
Project description:IntroductionThis post hoc analysis evaluated influenza adverse events (AEs) across rheumatoid arthritis (RA), ulcerative colitis (UC), and psoriatic arthritis (PsA) tofacitinib clinical programs.MethodsAvailable data from phase 1, randomized phase 2/3/3b/4 clinical trials (completed by 2018), and long-term extension (LTE) studies (up to May 2019) in patients with RA, UC, and PsA were included [randomized or Overall (phase 1-3b/4 and LTE studies) tofacitinib cohorts]. Incidence rates (IRs; events per 100 patient-years) of combined influenza AEs (seasons 2004/2005 to 2018/2019) were analyzed, including by tofacitinib dose [5 or 10 mg twice daily (BID)] and age (< 65 versus ≥ 65 years). Logistic regression models evaluated risk factors for influenza AEs in the RA Overall tofacitinib cohort.ResultsIn randomized cohorts, combined influenza AE IRs were generally similar across tofacitinib, adalimumab, methotrexate, and placebo groups, across indications. Among Overall tofacitinib cohorts, combined influenza AE IRs with tofacitinib 5/10 mg BID, respectively, were higher in the UC (3.66/5.09) versus RA (2.38/2.19) and PsA (1.74/1.29) cohorts. IRs were generally similar across tofacitinib dose and age groups. Most influenza AEs were nonserious and did not require changes to tofacitinib treatment. Significant risk factors for influenza AEs in patients with RA were geographic region, baseline oral corticosteroid and methotrexate use, and tofacitinib dose.ConclusionsIn the RA, UC, and PsA clinical programs, combined influenza AE IRs were highest in UC, while in each indication they were generally similar across tofacitinib, placebo, and comparator groups. Influenza AEs were predominantly nonserious and not associated with changes to tofacitinib treatment.Trial registration numbersNCT01262118, NCT01484561, NCT00147498, NCT00413660, NCT00550446, NCT00603512, NCT00687193, NCT01164579, NCT00976599, NCT01059864, NCT01359150, NCT02147587, NCT00960440, NCT00847613, NCT00814307, NCT00856544, NCT00853385, NCT01039688, NCT02281552, NCT02187055, NCT02831855, NCT00413699, NCT00661661, NCT00787202, NCT01465763, NCT01458951, NCT01458574, NCT01470612, NCT01877668, NCT01882439, NCT01976364.
| S-EPMC9758022 | biostudies-literature
Project description:ObjectiveTofacitinib is an oral JAK inhibitor that is used for the treatment of rheumatoid arthritis (RA). In previous clinical trials of tofacitinib, a Disease Activity Score in 28 joints (DAS28)-based analysis was used to assess outcomes. In this study, remission rates according to various remission criteria were evaluated across 5 phase III randomized controlled studies.MethodsIn all 5 studies, tofacitinib was administered at a dosage of 5 mg twice daily or 10 mg twice daily, either as monotherapy or with background methotrexate or other conventional synthetic disease-modifying antirheumatic drugs. One of the studies included adalimumab 40 mg once every 2 weeks. In addition to the 4-variable DAS28 using the erythrocyte sedimentation rate (DAS28-4[ESR]), a primary efficacy variable used in the phase III studies, disease activity was assessed post hoc by the 4-variable DAS28 using the C-reactive protein level (DAS28-4[CRP]), the Clinical Disease Activity Index (CDAI), the Simplified Disease Activity Index (SDAI), and Boolean-based assessment.ResultsA total of 3,306 patients were analyzed (1,213 of these patients received tofacitinib 5 mg twice daily, 1,212 received tofacitinib 10 mg twice daily, 679 received placebo, and 202 received adalimumab 40 mg every 2 weeks). Remission rates varied according to the criteria used, with higher rates in the active-treatment groups for the DAS28-4(CRP) than for other scores. At month 3, remission rates with tofacitinib 5 mg twice daily were 18-22% using the DAS28-4(CRP), 5-10% using the DAS28-4(ESR), 4-7% using the SDAI, 5-6% using the CDAI, and 2-7% using the Boolean-based method. In contrast, the remission rates with placebo varied from 0% to 7%, with small differences between the DAS28-4(ESR) and the DAS28-4(CRP).ConclusionAlthough tofacitinib at dosages of 5 mg twice daily and 10 mg twice daily was effective compared with placebo in achieving disease remission, regardless of the disease activity measure, remission rates were substantially higher when the DAS28-4(CRP) was used. The presence or absence and type of acute-phase reactants in remission criteria were significant contributors to remission rates across treatment groups. This finding has important consequences for trial design and clinical practice.
| S-EPMC5396306 | biostudies-literature