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Tofacitinib (CP-690,550) in patients with rheumatoid arthritis receiving methotrexate: Twelve-month data from a twenty-four–month phase III randomized radiographic study†‡
Abstract
Objective
The purpose of this 24-month phase III study was to examine structural preservation with tofacitinib in patients with rheumatoid arthritis (RA) with an inadequate response to methotrexate (MTX). Data from a planned 12-month interim analysis are reported. Methods
In this double-blind, parallel-group, placebo-controlled study, patients receiving background MTX were randomized 4:4:1:1 to tofacitinib at 5 mg twice daily, tofacitinib at 10 mg twice daily, placebo to tofacitinib at 5 mg twice daily, and placebo to tofacitinib at 10 mg twice daily. At month 3, nonresponder placebo-treated patients were advanced in a blinded manner to receive tofacitinib as indicated above; remaining placebo-treated patients were advanced at 6 months. Four primary efficacy end points were all analyzed in a step-down procedure. ResultsAt month 6, response rates according to the American College of Rheumatology 20% improvement criteria for tofacitinib at 5 mg and 10 mg twice daily were higher than those for placebo (51.5% and 61.8%, respectively, versus 25.3%; both P < 0.0001). At month 6, least squares mean (LSM) changes in total modified Sharp/van der Heijde score for tofacitinib at 5 mg and 10 mg twice daily were 0.12 and 0.06, respectively, versus 0.47 for placebo (P = 0.0792 and P ≤ 0.05, respectively). At month 3, LSM changes in the Health Assessment Questionnaire disability index score for tofacitinib at 5 mg and 10 mg twice daily were –0.40 (significance not declared due to step-down procedure) and –0.54 (P < 0.0001), respectively, versus –0.15 for placebo. At month 6, rates of remission (defined as a value
... Randomized controlled trials suggest that TOFA therapy reduces disease activity and improves the patient' s functional status [10][11][12][13][14]. Studies have found different remission rates between 7 and 25% with TOFA [10][11][12][13][14]. ...
... Randomized controlled trials suggest that TOFA therapy reduces disease activity and improves the patient' s functional status [10][11][12][13][14]. Studies have found different remission rates between 7 and 25% with TOFA [10][11][12][13][14]. In the ORAL Sync study, the remission rate at 6 month was 7.2% and it was shown that TOFA reduces the disease activity at 12 months [11]. ...
... Randomized controlled trials suggest that TOFA therapy reduces disease activity and improves the patient' s functional status [10][11][12][13][14]. Studies have found different remission rates between 7 and 25% with TOFA [10][11][12][13][14]. In the ORAL Sync study, the remission rate at 6 month was 7.2% and it was shown that TOFA reduces the disease activity at 12 months [11]. In the ORAL Start study, in which TNF inhibitors resistant patients were recruited, the remission rate was found to be 14.6% in 6 months [13]. ...
Objective:
The present study aims to assess the short- and long-term effects of tofacitinib (TOFA) therapy on efficacy, safety, and drug retention rate patients with rheumatoid arthritis (RA) refractory to conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) and/or biological disease-modifying anti-rheumatic drugs (bDMARDs).
Methods:
Thirty-five patients with RA who received TOFA therapy for at least 3 months in rheumatology outpatient clinic between December 2015 and December 2020 were included in the study. The prospectively follow-up results of the patients obtained on the 6th month and 5th year are presented. Demographic characteristics of the patients, the disease activity score-28 for RA with erythrocyte sedimentation rate (DAS 28-4 [ESR]), change in DAS-28, health assessment questionnaire score, patient visual analog scale score, and laboratory parameters were recorded. The data at 6 months and 5 years of treatment were compared with baseline data. All side effects were recorded at each follow-up visit. Wilcoxon signed-rank tests were used for analysis.
Results:
Of the 35 patients, 23 received TOFA treatment after receiving ≥1 bDMARDs, while the remaining 12 patients received TOFA therapy were biologic naive. On the 6-month follow-up, DAS 28-4 (ESR) score and DAS28 improvement significantly decreased at the 6th months from baseline (p<0.001 and p<0.001, respectively), and moderate disease activity was achieved in 13 patients. High disease activity persisted in four patients. DAS28 improvement according to the EULAR response criteria was good response in 86% of the patients. DAS 28-4 (ESR) score and DAS28 improvement significantly decreased at 5 years from baseline (p<0.01 and p<0.001, respectively), and the moderate disease activity was achieved in 10 patients. High disease activity persisted in two patients. Drug retention rate at 5-year follow-up was 54% and the daily glucocorticoid therapy could be discontinued in 9 patients (47%). Three patients (15%) were tested positive for COVID-19. None of them required hospitalization and no deaths were occurred due to COVID-19.
Conclusion:
TOFA is effective and well-tolerated treatment options that reduce the need for steroids in patients with RA.
... Tofacitinib (TOF) is an oral Janus kinase ( JAK) inhibitor for the treatment of RA. The efficacy and safety of TOF immediate-release 5 and 10 mg BID, administered as monotherapy or in combination with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), predominantly methotrexate (MTX), in patients with moderately to severely active RA, have been previously reported in phase II, 9,10,11,12,13 phase III, [14][15][16][17][18][19][20] and phase IIIb/IV 21 randomized controlled trials (RCTs) of up to 24 months' duration and in long-term extension (LTE) studies with up to 114 months' observation. 22,23,24 The long-term safety of TOF has been reported in an integrated safety analysis of RCTs and LTE studies spanning 114 months' cumulative TOF exposure. ...
... Further, to provide insight into expected disease state outcomes in patients achieving ACR20/50/70 responses in clinical trials, we show the proportions of responders achieving SDAI-and CDAI-defined LDA and remission. 16,17,19,20,21 and are summarized in Table 1. ...
... Each study was conducted in accordance with the Declaration of Helsinki, International Conference on Harmonization Guidelines for Good Clinical Practice, and local country regulations, and was approved by the institutional review board and independent ethics committee at each center. 16,17,19,20,21 Patients provided written informed consent. No further ethical approval was required for this post hoc analysis in accordance with the policies of our institutions. ...
Objective
Evaluate the impact of tofacitinib on American College of Rheumatology (ACR) response criteria components in patients with rheumatoid arthritis (RA).
Methods
This posthoc analysis pooled data from RA phase III randomized controlled trials (RCTs) assessing tofacitinib 5 or 10 mg twice daily (BID), adalimumab, or placebo, with conventional synthetic disease-modifying antirheumatic drugs, and a phase IIIb/IV RCT assessing tofacitinib 5 mg BID monotherapy, tofacitinib 5 mg BID with methotrexate, or adalimumab with methotrexate. Outcomes included: proportions of patients achieving ACR20/50/70 responses and ≥20/50/70% improvement rates in ACR components at Week 2 and Months 1, 3, and 6; mean percent improvement in ACR components and Clinical or Simplified Disease Activity Index (CDAI or SDAI) low disease activity or remission rates, at Month 3, for ACR20/50/70 responders.
Results
Across treatment groups, ≥20/50/70% improvement rates were numerically higher for most physician- versus patient-reported measures. In phase III RCTs, at earlier timepoints, ≥50/70% improvements in Patient Global Assessment of Disease Activity, Pain and Clinician Global Assessment were similar. Among ACR20 responders receiving tofacitinib, mean percent improvements for tender and swollen joint counts were >70% at Month 3. CDAI/SDAI remission was achieved by 27.8–45.0% of ACR70 responders receiving tofacitinib at Month 3.
Conclusion
Among ACR20 responders treated with tofacitinib, physician-reported components particularly exceeded 20% response improvement. At Month 3, disease state generally did not corroborate ACR70 response criteria. Divergences between physician- and patient-reported measures highlight the importance of identifying appropriate patient-reported outcome targets to manage RA symptoms in clinical practice.
... In 40 studies, patients showed an inadequate response to different types of csDMARD and bDMARD therapies , in 5 articles, patients were naïve to csDMARDs [51][52][53][54][55], from which 4 to MTX [51][52][53][54], 1 study did not give restrictions regarding previous medication [56], and 4 studies did not include information about the treatment history [57][58][59]. All JAK inhibitors approved for RA patients were included: tofacitinib appears in 16 [11][12][13][14][15][16][17][18][19][20][21][22][23]51,54,57], baricitinib in 8 [24][25][26][27][28][29][30]55,60], upadacitinib in 9 [31][32][33][34][35][36][37][38]52], filgotinib in 7 [39][40][41][42]53,58], peficitinib in 5 [43][44][45][46]56], decernotinib in 3 articles [47][48][49], and both ritlecitinib [50] and itacitinib [59] were investigated in 1 study. In 14 studies, patients received JAK monotherapy [15,17,20,23,31,41,43,49,[51][52][53][54][55][56], whereas concomitant therapy was applied in 36 studies: one study allowed patients with any type of DMARDs [47], one only nonbiologic DMARDs [13], 10 only csDMARDs [24,25,30,33,34,37,38,40,59,60], 23 specifically MTX [11,12,14,16,18,19,21,22,[27][28][29]32,34,35,39,42,[44][45][46][47]50,58], and in one study [57] data could not be obtained. ...
... All JAK inhibitors approved for RA patients were included: tofacitinib appears in 16 [11][12][13][14][15][16][17][18][19][20][21][22][23]51,54,57], baricitinib in 8 [24][25][26][27][28][29][30]55,60], upadacitinib in 9 [31][32][33][34][35][36][37][38]52], filgotinib in 7 [39][40][41][42]53,58], peficitinib in 5 [43][44][45][46]56], decernotinib in 3 articles [47][48][49], and both ritlecitinib [50] and itacitinib [59] were investigated in 1 study. In 14 studies, patients received JAK monotherapy [15,17,20,23,31,41,43,49,[51][52][53][54][55][56], whereas concomitant therapy was applied in 36 studies: one study allowed patients with any type of DMARDs [47], one only nonbiologic DMARDs [13], 10 only csDMARDs [24,25,30,33,34,37,38,40,59,60], 23 specifically MTX [11,12,14,16,18,19,21,22,[27][28][29]32,34,35,39,42,[44][45][46][47]50,58], and in one study [57] data could not be obtained. Short-term (<6 months) and long-term (>6 months) effects of JAK inhibitors were analyzed separately, however, for most of the outcomes, sufficient data was only present to assess short-term therapy. ...
... A total of 43 articles compared different types of JAK inhibitors to placebo [11][12][13][14][15]17,[19][20][21][22][23][24][25][27][28][29][30][32][33][34][35][36][38][39][40][41][42][43][44][45][46][47][48][49][50][51]53,55,56,[58][59][60]; meta-analysis was possible for 36 different outcomes. Efficacy was monitored via disease activity, inflammatory parameters, and patient-reported questionnaires; in addition, safety information was also collected. ...
Pain, fatigue, and physical activity are major determinants of life quality in rheumatoid arthritis (RA). Janus kinase (JAK) inhibitors have emerged as effective medications in RA and have been reported to exert direct analgesic effect in addition to reducing joint inflammation. This analysis aims to give an extensive summary of JAK inhibitors especially focusing on pain and patient reported outcomes (PRO). MEDLINE, CENTRAL, Embase, Scopus, and Web of Science databases were searched on the 26 October 2020, and 50 randomized controlled trials including 24,135 adult patients with active RA met the inclusion criteria. JAK inhibitors yielded significantly better results in all 36 outcomes compared to placebo. JAK monotherapy proved to be more effective than methotrexate in 9 out of 11 efficacy outcomes. In comparison to biological disease-modifying antirheumatic drugs, JAK inhibitors show statistical superiority in 13 of the 19 efficacy outcomes. Analgesic effect determined using the visual analogue scale and American College of Rheumatology (ACR) 20/50/70 response rates was significantly greater in the JAK group in all comparisons, and no significant difference regarding safety could be explored. This meta-analysis gives a comprehensive overview of JAK inhibitors and provides evidence for their superiority in improving PROs and disease activity indices in RA.
... Five JAK inhibitors (tofacitinib, baricitinib, peficitinib, upadacitinib and filgotinib) are currently approved by different agencies for the treatment of RA, and are categorized as tsDMARDs. In results from clinical trials in patients with RA, tsDMARDs (either as monotherapy or in combination with methotrexate) had multi-target, rapid and robust effects that were equivalent to or superior to those of bDMARDs [16][17][18][19][20][21][22][23] . ...
... Tofacitinib was developed as a small-molecule drug that competitively binds to the ATP-binding site of JAK3. Tofacitinib was initially thought to selectively inhibit phosphorylation of JAK3, but it is now considered to inhibit JAK1, JAK2 and JAK3 to varying degrees in vitro and in vivo 16,17,24 . All of the currently approved JAK inhibitors are competitive antagonists. ...
... • IFNα Phase III clinical trials have demonstrated robust and rapid effects of JAK inhibitors compared with placebo in patients with RA who are methotrexate naive or who have an inadequate response to methotrexate or to bDMARDs [15][16][17][18][19][20][21][22][23] . Baricitinib 4 mg daily dosage, compared with TNF inhibitor adalimumab in a head-to-head phase III trial, achieved superiority in the primary outcome, the ACR20 response rate (20% improvement in the number of tender and the number of swollen joints, along with 20% improvement in three criteria among patient global assessment, physician global assessment, functional ability measure, visual analogue pain scale and erythrocyte sedimentation rate or C-reactive protein) at 12 weeks 18 . ...
The four Janus kinase (JAK) proteins and seven signal transducer and activator of transcription (STAT) transcription factors mediate intracellular signal transduction downstream of cytokine receptors, which are implicated in the pathology of autoimmune, allergic and inflammatory diseases. Development of targeted small-molecule therapies such as JAK inhibitors, which have varied selective inhibitory profiles, has enabled a paradigm shift in the treatment of diverse disorders. JAK inhibitors suppress intracellular signalling mediated by multiple cytokines involved in the pathological processes of rheumatoid arthritis and many other immune and inflammatory diseases, and therefore have the capacity to target multiple aspects of those diseases. In addition to rheumatoid arthritis, JAK inhibition has potential for treatment of autoimmune diseases including systemic lupus erythematosus, spondyloarthritis, inflammatory bowel disease and alopecia areata, in which stimulation of innate immunity activates adaptive immunity, leading to generation of autoreactive T cells and activation and differentiation of B cells. JAK inhibitors are also effective in the treatment of allergic disorders, such as atopic dermatitis, and can even be used for the COVID-19-related cytokine storm. Mechanism-based treatments targeting JAK–STAT pathways have the potential to provide positive outcomes by minimizing the use of glucocorticoids and/or non-specific immunosuppressants in the treatment of systemic immune-mediated inflammatory diseases.
... Keywords: Janus kinase inhibitors, tofacitinib, generic, efficacy, safety монотерапии [20] или в комбинации с MT [21], а также у пациентов, не получавших лечения [23] или рефрактерных к лечению БПВП [21] и ингибиторами ФНО (иФНО) [18]. Было доказано, что ТОФА превосходит метотрексат (МТ) [17,25] и не уступает адалимумабу [19]. Он предотвращает прогрессирование структурных заболеваний суставов с помощью обычной рентгенографии и магнитно-резонанс ной томографии [17,23,25]. ...
... Было доказано, что ТОФА превосходит метотрексат (МТ) [17,25] и не уступает адалимумабу [19]. Он предотвращает прогрессирование структурных заболеваний суставов с помощью обычной рентгенографии и магнитно-резонанс ной томографии [17,23,25]. Наибольшее подавление рентгенологической прогрессии наблюдалось у пациентов с более выраженными исходными структурными повреждениями, но улучшение было отмечено и в других группах [26]. ...
The article presents a review of the basic data on the efficacy and safety of the drug tofacitinib, the place of the drug in the treatment of rheumatoid arthritis (RA) patients according to current international and Russian recommendations. Data on the mechanism of action of Janus kinase inhibitors, the spectrum of cytokines inhibited by tofacitinib is presented. The results of major randomised controlled trials demonstrating high clinical efficacy in patients who have not responded to methotrexate (MT) and other synthetic classical anti-rheumatic drugs (SCARDs), genetically engineered biologic drugs, are presented, with equal efficacy of tofacitinib when given as monotherapy or in combination with MT or other SCARDs, with adalimumab. The safety of tofacitinib with long-term treatment (up to 9.5 years) is analysed. The cardiovascular tolerability of tofacitinib is presented separately, considering the proposals discussed at the last EULAR 2022 Congress. The low incidence of serious cardiovascular adverse events, including venous thrombosis and thromboembolism over the long-term follow-up period, and the risk of these adverse events, which was no higher than on the selective Janus kinase inhibitor baricitinib, are presented. Changes in laboratory parameters (haemoglobin, neutrophil count, aminotransferase concentration) during tofacitinib administration are described. Domestic data on the use of tofacitinib in the treatment of RA patients is demonstrated. An association was shown between early clinical response to tofacitinib (5 mg twice daily) and a reduction in RA activity after 3 and 6 months in RA patients. Tofacitinib in real clinical practice showed early development of effect (by week 12) in the group of patients who did not respond to MT and in 60% of cases to genetically engineered biologic drugs, with respect to indicators of inflammatory activity of RA and functional status of patients. Domestic authors have noted the high safety of tofacitinib. A domestic generic version of the original drug tofacitinib has been reported to be registered for the same indications: RA, psoriatic arthritis, plaque psoriasis, ulcerative colitis.
... The Janus kinase/signal transduction and activator of transcription inhibitors are also being introduced into treatment on a large scale, and their efficacy has been confirmed in many trials [21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38]. All JAKi studied so far in RA are effective: 3 have been approved [21][22][23]. ...
... In 5 studies [28][29][30][31][32] TOFA was administered at a dose of 5 mg twice daily (BID) or 10 mg BID, either as monotherapy or with background MTX treatment or another csDMARD. One of the studies included ADA 40 mg once every 2 weeks. ...
Introduction:
Treatment of severe rheumatoid arthritis (RA) is currently based either on biological agents or Janus kinase/signal transducer and activator of transcription inhibitors, most often in combination with methotrexate (MTX).
Aim of the study:
The aim of the study was to compare the effectiveness and side effects of bio- logic disease-modifying antirheumatic drugs (bDMARDs) and targeted synthetic (ts) DMARDs treatment.
Material and methods:
The analysis included 108 RA patients with active disease treated with MTX 25 mg per week. Eighty patients (group I) were treated with bDMARDs and 28 patients (group II) with JAK-STAT inhibitors. The duration of morning stiffness, pain on Visual Analogue Scale (VAS), 28-joints Disease Activity Score (DAS28) and Simplified Disease Activity Score (SDAI) were assessed. Classical radiographic images of patients' hands and feet using the Larsen and Dale's criteria were evaluated. The effects of treatment with bDMARDs and tsDMARDs were analyzed.
Results:
All studied patients presented at least Larsen and Dale's stage 3 of X-ray changes typical for RA. There were no statistically significant differences in disease duration, ESR, CRP, DAS28 and SDAI values between studied groups. Patients from group II previously used higher numbers of bDMARDs than group I treated with bDMARDs. Low disease activity after treatment was achieved by all patients; therefore patients from group II (treated with tsDMARDs) achieved lower values of patients' global assessment on VAS.
Conclusions:
The results of the present observational study indicated that treatment with JAK inhibitors is very promising. These drugs are not inferior in effectiveness to bDMARDs. It is important to monitor patients for thromboembolic events before and during JAK treatment.
... Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). The efficacy and safety of tofacitinib 5 and 10 mg twice daily administered as monotherapy or in combination with conventional synthetic diseasemodifying antirheumatic drugs (csDMARDs), mainly methotrexate (MTX), in adult patients with moderately to severely active RA, have been demonstrated in phase 2, 1-5 phase 3 [6][7][8][9][10][11] and phase 3b/4 12 13 randomised controlled trials (RCTs) with up to 72 months of follow-up and in long-term extension studies with up to 9.5 years of observation. [14][15][16] ...
... Full eligibility criteria have been reported for each study. [6][7][8][9][10][11] Patients Eligible patients were aged ≥18 years with a diagnosis of RA and met the American College of Rheumatology (ACR) 1987 Revised RA Classification Criteria. Patients were randomised to receive tofacitinib 5 or 10 mg twice daily, placebo (advancing to tofacitinib at months 3 or 6), or the active controls MTX (ORAL Start) or adalimumab (ORAL Standard). ...
Objective:
Tofacitinib is an oral Janus kinase for the treatment of rheumatoid arthritis (RA). This post hoc analysis assessed whether baseline body mass index (BMI) impacts tofacitinib efficacy in patients with RA.
Methods:
Pooled data from six phase 3 studies in patients receiving tofacitinib 5 mg (N=1589) or 10 mg (N=1611) twice daily or placebo (advancing to active treatment at months 3 or 6; N=680), ±conventional synthetic disease-modifying antirheumatic drugs, were stratified by baseline BMI (<25, 25 to <30, ≥30 kg/m2). Endpoints (through to month 6) were assessed descriptively: American College of Rheumatology 20/50/70 response rates; changes from baseline (∆) in Disease Activity Score in 28 joints, erythrocyte sedimentation rate (DAS28-4(ESR)), DAS28-4(C-reactive protein), Clinical Disease Activity Index (CDAI), Health Assessment Questionnaire-Disability Index (HAQ-DI) and pain; and proportions of patients achieving DAS28-4(ESR) ≥1.2 and HAQ-DI ≥0.22 decreases from baseline, low disease activity (DAS28-4(ESR) ≤3.2 or CDAI ≤10) and radiographic non-progression (Δmodified Total Sharp Score ≤0.5; months 12 and 24). Estimates were adjusted using multivariable models for selected outcomes. Univariate/multivariable regression analyses determined predictors of month 6 outcomes.
Results:
Of 3880 patients included, 1690 (43.6%), 1173 (30.2%) and 1017 (26.2%) had baseline BMI <25, 25 to <30 and ≥30 kg/m2, respectively. Tofacitinib showed greater efficacy improvements versus placebo in each BMI category. Differences in efficacy outcomes (adjusted and unadjusted) were generally not clinically meaningful across BMI categories within treatment groups. In regression analyses, BMI was not consistently associated with selected outcomes.
Conclusions:
Baseline BMI did not consistently affect tofacitinib response suggesting that tofacitinib is an effective oral treatment option for adults with moderate to severe RA regardless of baseline BMI, including patients with BMI ≥30 kg/m2.
Trial registration numbers:
NCT00814307, NCT01039688; NCT00960440; NCT00847613; NCT00856544; NCT00853385.
... This was an exploratory post hoc analysis of data pooled from three global Phase 3 randomized controlled trials (ORAL Scan [NCT00847613]; ORAL Standard [NCT00853385]; ORAL Sync [NCT00856544]) of tofacitinib administered in combination with csDMARDs in patients with active RA [23][24][25]. The trials were of 12 (ORAL Standard and ORAL Sync) or 24 months' (ORAL Scan) duration, and the individual study designs have been described in detail previously [23][24][25]. ...
... This was an exploratory post hoc analysis of data pooled from three global Phase 3 randomized controlled trials (ORAL Scan [NCT00847613]; ORAL Standard [NCT00853385]; ORAL Sync [NCT00856544]) of tofacitinib administered in combination with csDMARDs in patients with active RA [23][24][25]. The trials were of 12 (ORAL Standard and ORAL Sync) or 24 months' (ORAL Scan) duration, and the individual study designs have been described in detail previously [23][24][25]. ...
Background
Fatigue, a common symptom of rheumatoid arthritis (RA), is detrimental to health-related quality of life (HRQoL). We evaluated the impact of tofacitinib on fatigue, sleep, and HRQoL and explored associations between fatigue, related patient-reported outcomes (PROs), and disease activity in RA patients.
Methods
This post hoc analysis pooled data from three Phase 3 studies of tofacitinib (ORAL Scan; ORAL Standard; ORAL Sync) in RA patients. Patients received tofacitinib 5 or 10 mg twice daily, placebo, or adalimumab (active control; ORAL Standard only, not powered for superiority) with conventional synthetic disease-modifying antirheumatic drugs. Assessed through Month (M)12 were changes from baseline in disease activity, Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), Medical Outcomes Study Sleep scale (MOS-SS), and Short Form-36 Health Survey (SF-36) composite/domain scores, and proportions of patients reporting improvements from baseline in FACIT-F total and SF-36 domain scores ≥ minimum clinically important differences (MCIDs) or ≥ population normative values. Pearson correlations examined associations among PROs at M6. Treatment comparisons were exploratory, with p < 0.05 considered nominally significant.
Results
Generally, active treatment led to significant improvements from baseline in FACIT-F total, and MOS-SS and SF-36 composite/domain scores vs placebo, observed by M1 and maintained through M6 (last placebo-controlled time point). Through M6, more patients achieved improvements from baseline ≥ MCID and achieved scores ≥ population normative values in FACIT-F total and SF-36 domain scores with tofacitinib vs placebo. Through M12, some nominally significant improvements with tofacitinib vs adalimumab were observed. With active treatment at M6, FACIT-F scores were moderately (0.40–0.59) to highly (≥ 0.60) correlated with SF-36 composite/domain scores (particularly vitality), moderately correlated with most MOS-SS domain scores, and highly correlated with MOS-SS Sleep Problems Index I scores. Disease activity correlations were moderate with FACIT-F scores and low (0.20–0.39) to moderate with SF-36 general health domain/composite scores.
Conclusion
Tofacitinib and adalimumab generally conferred significant, clinically meaningful improvements in fatigue, sleep, and HRQoL (including vitality) vs placebo through M6, with improvements maintained to M12. M6 correlations between FACIT-F, PROs of sleep, HRQoL, and disease activity underscore the interrelatedness of multiple PROs and disease activity in RA.
Trial registration
ClinicalTrials.gov NCT00847613 (registered: February 19, 2009); NCT00853385 (registered: March 2, 2009); NCT00856544 (registered: March 5, 2009).
... Tofacitinib is an oral Janus kinase inhibitor for the treatment of RA and PsA. In patients with moderately to severely active RA, the efficacy and safety of tofacitinib 5 and 10 mg twice daily (BID) administered as monotherapy or in combination with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), mainly methotrexate (MTX), have been demonstrated in phase 2 [5][6][7][8][9], phase 3 [10][11][12][13][14][15], and phase 3b/4 [16] studies of up to 24 months in duration, and in long-term extension studies with up to 114 months of observation [17][18][19]. In patients with active PsA, the efficacy and safety of tofacitinib 5 and 10 mg BID in combination with csDMARDs have been demonstrated in two phase 3 studies of up to 12 months in duration [20,21], and in a long-term extension study (NCT01976364) [22]. ...
... [21]). Patients included in this analysis received tofacitinib 5 or 10 mg BID, or placebo, and had a previous inadequate response to C 1 csDMARD [11,12,[14][15][16]20] or C 1 tumor necrosis factor inhibitor (TNFi) [10,21]. ...
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.Methods
Data 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%).Conclusions
Non-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.
... 6 Biological disease modifying antirheumatic drugs (bDMARDs) and tofacitinib have demonstrated consistent efficacy in reducing the signs and symptoms of RA and have shown improvements in patient-reported outcomes (PROs) with manageable safety profiles. [7][8][9][10][11][12][13] In Latin America, rheumatologists have clinical experience in treating RA patients with bDMARDs 14 or tofacitinib. 15 In contrast to bDMARDs, tofacitinib is orally administered and has been used as a monotherapy more frequently than bDMARDs. ...
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.
... . Studies on the GR isoform expressed by Th2 cells and ILC2s in steroid-resistant asthma are warranted.JAK inhibitors are currently being used to treat various immune-mediated disorders. For example, the JAK1/JAK2 inhibitor Ruxolitinib is used to treat myeloproliferative neoplasms 54 , while the JAK3/JAK1 inhibitor Tofacitinib is approved for patients with methotrexate-resistant rheumatoid arthritis and psoriatic arthritis55, 56 . Moreover, the JAK1 and JAK2 inhibitor Baricitinib has been approved by European regulatory agencies for rheumatoid arthritis57 , and the pan-JAK inhibitor Oclacitinib has been approved for allergic dermatitis in dogs 58 . ...
The standard treatment for allergic-airway inflammation, which is the dominant asthma endotype, is a steroid. However, steroid-refractory asthma is a significant problem. Innate-lymphoid cells (ILCs) produce type-2 cytokines as Th2 cells and play critical roles in asthma pathogenesis. Limited evidence from the asthma-mouse models and human studies suggests that ILC2s may participate in steroid-resistant asthma. Here, we showed that lung ILC2s, but not Th2 cells, can develop steroid resistance that maintains their survival, cytokine production, and pathogenic activities during steroid treatment. Such steroid-resistant ILC2s are associated with the presence of multiple ILC2-stimulating cytokines and the emergence of multipotent IL-5 ⁺ IL-13 ⁺ IL-17A ⁺ ILC2s, and the Janus-kinase (JAK) 3/signal-transducer-and-activator-of-transcription (STAT) 3,5, and 6 pathway participates in the acquisition of steroid-resistant ILC2s. JAK3-inhibitor treatment significantly reduced the survival, proliferation, and cytokine production of multipotent ILC2s in vitro ameliorated ILC2-dependent Alternaria -induced asthma. Moreover, JAK3-inhibitor combined with a steroid strongly inhibited steroid-resistant asthma. Therefore, sustained asthmatic conditions may induce multipotent ILC2s that promote steroid-resistant asthma, and combining JAK3-inhibitor with steroid may be a treatment option for steroid-refractory asthma.
... The improvements presented here were generally greater than the results shown in OPAL Broaden and OPAL Beyond studies. 25 26 The safety of tofacitinib in Chinese patients with PsA was consistent with the established safety profile of tofacitinib in patients with PsA 13-15 27 and in other indications, including RA. [27][28][29][30][31][32][33][34][35][36][37] The most frequently reported AE was upper respiratory tract infection, and up to month 6, the incidence of AEs of special interest was ≤6% for serious infections, ≤1.5% for herpes zoster and ≤0.7% for malignancies excluding NMSC. No adjudicated NMSC, opportunistic infections, MACE, gastrointestinal perforations, thromboembolism or drug-induced liver injury events were reported. ...
Objectives
Efficacy and safety of tofacitinib, an oral Janus kinase inhibitor, were evaluated in a 6-month, double-blind, phase 3 study in Chinese patients with active (polyarthritic) psoriatic arthritis (PsA) and inadequate response to ≥1 conventional synthetic disease-modifying antirheumatic drug.
Methods
Patients were randomised (2:1) to tofacitinib 5 mg twice daily (N=136) or placebo (N=68); switched to tofacitinib 5 mg twice daily after month (M)3 (blinded). Primary endpoint: American College of Rheumatology (ACR50) response at M3. Secondary endpoints (through M6) included: ACR20/50/70 response; change from baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI); ≥75% improvement in Psoriasis Area and Severity Index (PASI75) response, and enthesitis and dactylitis resolution. Safety was assessed throughout.
Results
The primary endpoint was met (tofacitinib 5 mg twice daily, 38.2%; placebo, 5.9%; p<0.0001). M3 ACR20/ACR70/PASI75 responses, and enthesitis and dactylitis resolution rates, were higher and HAQ-DI reduction was greater for tofacitinib 5 mg twice daily versus placebo. Incidence of adverse events (AEs)/serious AEs (M0–3): 68.4%/0%, tofacitinib 5 mg twice daily; 75.0%/4.4%, placebo. One death was reported with placebo→tofacitinib 5 mg twice daily (due to accident). One serious infection, non-serious herpes zoster, and lung cancer case each were reported with tofacitinib 5 mg twice daily; four serious infections and one non-serious herpes zoster case were reported with placebo→tofacitinib 5 mg twice daily (M0–6). No non-melanoma skin cancer, major adverse cardiovascular or thromboembolism events were reported.
Conclusion
In Chinese patients with PsA, tofacitinib efficacy was greater than placebo (primary and secondary endpoints). Tofacitinib was well tolerated; safety outcomes were consistent with the established safety profile in PsA and other indications.
Trial registration number
NCT03486457 .
... JAK3 is activated via stimulation of IL-2, 4, 7, 9, 15, and 21 of the γc family and plays a major role in the immune system. Tofacitinib, which was first approved for the treatment of RA in the USA and Japan in 2012, was developed as a targeted synthetic disease-modifying antirheumatic drug (DMARD) with a molecular weight of approximately 312 Da that competitively binds to the ATP binding site of JAK3 and specifically inhibits signaling of these cytokines [20]. It can be orally administered and has a short half-life of approximately 3 hours and pharmacological properties with rapid in vivo metabolism. ...
Background
In inflamed tissue, immune cells are accumulated, and various intercellular signals are involved in the pathogenesis. Janus kinases (JAKs) are typical tyrosine kinases involved in mediating the signaling of multiple cytokines and growth factors and induce the transcription of molecules related to inflammation or immunity via the transcription factor signal transducers and activators of transcription (STAT). Hence, they have garnered significant interest as a therapeutic target. JAK inhibitors have been evaluated as a major drug for remission induction in the treatment of autoimmune diseases such as rheumatoid arthritis.
Body
Covid-19 infection due to SARS-CoV-2 has caused a pandemic, with approximately 660 million infections and 6.7 million deaths worldwide (January, 2023). The prognosis is poor and the major causes of death are respiratory failure attributed to rapid pneumonia, thromboembolism due to a cytokine storm, and multi-organ failure. As a treatment modality, molecular targeted therapy, such as cytokine-targeting therapy, is attracting attention, in addition to antiviral drugs. Baricitinib, a JAK inhibitor, is used for the treatment of severe pneumonia, in addition to antiviral drugs and glucocorticoids. The mechanism of action of baricitinib includes inhibition of viral receptor-mediated endocytosis, which involves the NF-κB activating kinase (NAK) family, and mediating the anti-cytokine effects via JAK 1/2 inhibition. It improves severe pneumonia and reduces mortality.
Conclusion
Thus, the development of molecular targeted drugs with elucidated pathological mechanisms may aid in controlling Covid-19 infection.
... Тофацитиниб (ТОФА) -иJAK, зарегистрированный для лечения ряда ревматических заболеваний, в том числе РА. Эффективность и безопасность ТОФА в дозе 10 или 20 мг/сут в виде монотерапии или в комбинации с сБПВП, преимущественно метотрексатом (MT), у пациентов с активным РА от умеренной до тяжелой степени были продемонстрированы в многочисленных рандомизированных клинических исследованиях (РКИ) II-IV фазы [5][6][7][8][9][10][11][12][13][14][15][16] продолжительностью до 24 мес, а также в долгосрочных расширенных исследованиях (long-term extension study, LTE) с наблюдением до 114 мес [17][18][19][20]. ...
Evaluation of the reasons for discontinuation of therapy with Janus kinase inhibitors (JAKi) may provide a clue to their more effective use.
Objective : to analyze the survival of tofacitinib (TOFA) therapy and the reasons for its discontinuation in rheumatoid arthritis (RA) in real clinical practice.
Patients and methods . The study included 30 adult patients with RA hospitalized to the V.A. Nasonova Research Institute of Rheumatology from 2018 to 2020 for the biologic disease modifying antirheumatic drugs (bDMARDs) or JAKi treatment. Patients were followed up for 3 years or until treatment with TOFA was discontinued, whichever occurred first.
Results and discussion . TOFA was prescribed as the first line therapy in 3 patients. In all these patients, the drug was discontinued for the following reasons: insufficient efficacy (IE) after 2 full years of treatment; adverse reaction (AR); administrative reasons (AdR), i.e. the inability to continue therapy due to the lack of drug supply at the place of residence. 11 patients received TOFA as the second line therapy, in 8 of them the treatment was interrupted: in 4 due to IE, in 3 due to AR (skin allergy) and in 1 due to AdR one year after its initiation. TOFA was prescribed as a third line therapy in 9 patients, in 2 of them the drug was discontinued due to IE and in 3 due to AR (allergic dermatitis in 2, dyspepsia in 1). Another 1 patient refused treatment due to a planned pregnancy. 6 patients received TOFA as the fourth line therapy, 5 of them (83.3%) continued to receive it for more than 3 years. In 1 patient, TOFA was discontinued after 1 month due to the dry cough and shortness of breath onset. In another 1 patient who was prescribed TOFA as the fifth line therapy, treatment was discontinued due to AR (recurrent Herpes zoster).
Conclusion . As the results of the study show, no relationship was found between the incidence of AR or IE and clinical and demographic indicators, as well as the frequency of TOFA withdrawal and the line of therapy. At the same time, the shortest duration of retention on TOFA therapy was noted when it was prescribed as a first-line drug.
... In the most recent drug development programs of advanced therapies for RA, including biologic agents (bDMARDs) and targeted synthetic DMARDs [tsDMARDs, i.e., Janus kinase (JAK) inhibitors], patients with moderate-tosevere RA who had at least one of the defined PPFs were enrolled for testing both clinical outcomes and radiographic structural endpoints [4][5][6][7]. The Phase 3 clinical program for filgotinib, an oral JAK1-preferential inhibitor, studied populations of RA patients who were naïve to MTX (MTX-naïve, FINCH 3: NCT02886728) or who had inadequate response to MTX (MTX-IR, FINCH 1: NCT02889796) and who had at least one of the major PPFs defined above. ...
Introduction:
We conducted a post hoc analysis of efficacy and safety of filgotinib stratified by estimated radiographic progression rate before baseline (BL) in patients with rheumatoid arthritis (RA) who had inadequate response to methotrexate (MTX; FINCH 1; NCT02889796) or were naïve to it (FINCH 3; NCT02886728).
Methods:
Radiographic progression rate was BL-Modified Total Sharp Score (mTSS) divided by RA duration (BL mTSS/year); estimated rapid radiographic progression (e-RRP) was BL change in mTSS/year ≥ 5; and estimated nonrapid radiographic progression (e-NRRP) was BL mTSS/year < 5. Efficacy and safety were compared between subgroups. All p-values are nominal.
Results:
In FINCH 1 and FINCH 3, 558/1755 (31.8%) and 787/1249 (63.0%) patients, respectively, had BL e-RRP. BL characteristics were generally similar between subgroups within each trial. At week (W) 24, in FINCH 1, proportions achieving a Disease Activity Score 28 for rheumatoid arthritis with C-reactive protein < 2.6 were significantly greater with filgotinib 200 (FIL200) and 100 mg (FIL100) versus placebo among e-RRP and e-NRRP subgroups. In each study, proportions of FIL-treated patients achieving Clinical Disease Activity Index ≤ 2.8 and Simple Disease Activity Index ≤ 3.3 were similar between subgroups. In FINCH 3, disease activity measures were at least numerically improved among patients receiving FIL versus MTX monotherapy. At W24, mTSS changes from BL (CFB) were greater among patients with e-RRP in FINCH 1 and FINCH 3 versus e-NRRP (0.81 versus 0.19, p = 0.001; 0.67 versus 0.25, p = 0.31, respectively). At W52, in FINCH 1, mTSS CFBs were smaller among e-RRP patients treated with FIL200 (0.40; p < 0.001) and FIL100 (0.77; p = 0.024) versus adalimumab (ADA; 1.46). In FINCH 3 at W52, mTSS CFBs were significantly smaller with FIL200 versus MTX among e-RRP patients. Rates of treatment-emergent adverse events (AEs) were comparable between subgroups and across treatment arms.
Conclusions:
Patients with previous e-RRP who received standard care tended to progress radiographically. FIL200 demonstrated persistent, consistent benefit for disease activity control among e-RRP and e-NRRP subgroups, and AE profiles were similar between subgroups. Although filgotinib efficacy was somewhat reduced among patients with e-RRP, filgotinib treatment slowed radiographic progression in both subgroups.
Trial registration:
Clinicaltrials.gov NCT02889796, NCT02886728.
... reduce phosphorylated STAT3 protein levels in the nucleus in RDC synovial fibroblasts, resulting in a decrease in phospho-STAT3-positive cells, especially with high intensity. Efficacy of tofacitinib has been confirmed in the treatment of RA van Vollenhoven et al. 2012;Burmester et al. 2013;Kremer et al. 2013;van der Heijde et al. 2013;Lee et al. 2014). In a sequential synovial biopsy study in RA patients (Boyle et al. 2015), treatment with tofacitinib resulted in decreased expression of MMP-3 gene in synovial biopsies. ...
Interleukin-6 signaling activates signal transducer and activator of transcription 3 (STAT3), resulting in matrix metalloproteinase-3 (MMP-3) production. The hip joints with rapidly destructive coxopathy (RDC) show rapid chondrolysis, probably by increased MMP-3. This study aimed to elucidate STAT3 activation in the synovial tissues with joint destruction in the early stage of RDC. Synovial tissues within 7 months from the disease onset were obtained from four RDC patients with femoral head destruction and high serum levels of MMP-3. RDC synovial tissues demonstrated the synovial lining hyperplasia with an increase of CD68-positive macrophages and CD3-positive T lymphocytes. STAT3 activation was found in the synovial tissues by immunohistochemistry using anti-phospho-STAT3 antibody. The majority of phospho-STAT3-positive cells were the synovial lining cells and exhibited negative expression of the macrophage or T cell marker. Treatment with CP690,550, a Janus Kinase inhibitor, resulted in a decrease in phospho-STAT3-positive cells, especially with high intensity, indicating effective suppression of STAT3 activation in RDC synovial tissues. Inhibitory effect of CP690,550 could work through the Janus Kinase/STAT3 axis in the synovial tissues in the early stage of RDC. Thus, STAT3 may be a potential therapeutic target for prevention of joint structural damage in RDC.
... Compared with MTX, JAKi monotherapy also displayed superiority in RA improvement (20, 21). In terms of combination therapy, several RCTs had suggested that JAKi combined with MTX was preferred over MTX alone for different efficacy endpoints, including ACR response criteria and improvement in physical functioning (4, 5,9,21,34,35). Moreover, long-term extension studies determined that JAKi, in general, showed a consistent safety profile as monotherapy or combination therapy (36,37). ...
Background
We aim to evaluate the efficacy and tolerability of Janus kinase inhibitors (JAKi) as monotherapy and in combination with methotrexate (MTX) in active rheumatoid arthritis (RA).Methods
Medline, EMBASE, and Cochrane Library were systematically searched to identify relevant randomized controlled trials (RCTs). Pooled analysis was conducted using random-effects model, along with the risk difference (RD) and 95% confidence intervals (CIs).ResultsThree RCTs, including 2,290 patients, were included. JAKi (tofacitinib, baricitinib, and filgotinib) plus MTX displayed a higher proportion of patients meeting the American College of Rheumatology (ACR) criteria than JAKi alone at week 52 (ACR20 RD 0.032; 95% CI −0.027 to 0.091; ACR50 RD 0.050; 95% CI 0.003 to 0.097; ACR70 RD 0.056; 95% CI 0.012 to 0.100). Similar results were observed for ACR20/50/70 at week 24. No significant difference was found between two regimens for the proportion of patients achieving Health Assessment Questionnaire disability index (HAQ-DI) improvement ≥ 0.22 at weeks 24 and 52. Regarding low disease activity and remission achievement, JAKi in combination with MTX, contributed higher response rates than JAKi alone at weeks 24 and 52. Compared with JAKi monotherapy, combination therapy had a higher risks of treatment-emergent adverse events (TEAEs) and adverse events (AEs) leading to study discontinuation.ConclusionJAKi combined with MTX demonstrated superiority to JAKi monotherapy in terms of ACR responses, low disease activity and remission achievement. The two regimens presented comparable physical functioning measured by HAQ-DI improvement and similar tolerability, except for high risks of TEAEs and AEs leading to study discontinuation in combination therapy.Systematic Review Registrationhttps://www.crd.york.ac.uk/PROSPERO/, identifier CRD42021288907.
... Similar to SpA, the pathogenesis of inflammation in rheumatoid arthritis (RA) is mediated by a number of effector cytokines (IL-6, IL-7, IL-10, IL-12, IL-15, IL-21, IL-23, IFNα and IFNβ) that signal using JAK [25,26,27]. The efficacy of treatment with Jak inhibitors has been demonstrated in multiple clinical trials in RA [28,29,30,31,32]. In the last year, data from clinical studies, as well as from real clinical practice, confirm the effectiveness of this class of medication in patients with ankylosing spondylitis and psoriatic arthritis [33]. ...
The pathogenesis of spondyloarthritis (SpA) is multifactorial and involves multiple immune cells and cytokines that are signaled by Janus kinase (JAK). Inhibition of JAK signaling pathways has emerged as a new therapeutic option for patients with inflammatory joint diseases. Despite the proven effect of treatment with anti-IL-17, as well as TNFα inhibitors, some patients with ankylosing spondylitis cannot reach minimal disease activity or remission. This necessitated the development of a new class of molecules, and in recent years more and more clinical studies have proven their role in the treatment of both rheumatoid arthritis and ankylosing spondylitis. JAK inhibition is a promising therapeutic strategy for the treatment of SpA and its application has potential in patients with axial, polyarticular, or extraarticular manifestations of the disease in psoriatic arthritis and ankylosing spondylitis. The present literature review aims to highlight the new therapeutic options offered by this class of target synthetic disease-modifying antirheumatic drugs and to summarize the clinical trial data for tofacitinib, upadacitinib and filgotinib reported to date.
... Clinical efficacy and safety of TOF have been extrapolated mainly from patient populations with active RA in phase 2 and phase 3 randomized controlled trials (RCTs), and long-term extension studies. [1][2][3][4][5][6][7][8][9][10][11] RA patients from Latin America (LatAm) differ from patients from the rest of the world in terms of genetic and epidemiologic factors, and in prognosis and so they could potentially elicit different clinical responses to a given mode of action. 12 Across Phase 3 studies and long-term extension studies of TOF, subpopulations from LatAm have been reported to experience similar improvements in efficacy than in patients from the rest of the world. ...
Background: Evidence of effectiveness and safety of tofacitinib (TOF) in the real-world setting in Latin America is currently limited and crucial to complement long-term extension data from randomized controlled trials.
Methods: Patients initiated on TOF between 2014 and 2020 with RA (ACR/EULAR, 2010 criteria) were analyzed. The primary end point at month 3 was remission measured by DAS28-ESR. Secondary end points included prognostic factors for remission at 3 months and of monotherapy at month 12.
Results: Overall, 134 RA patients were analyzed. Remission was achieved in 38.06% at month 3. In univariate analysis, persistent disease activity at 3 months was observed in those patients with longer duration of disease, structural radiological damage, higher baseline DAS28-ESR and greater frequency in previous use of bDMARD. In multivariate analysis, previous use of bDMARD was significantly associated with a decrease in the probability of remission at 3 months. At 12 months, TOF monotherapy group was elderly (p = 0.009) and had a trend for lower frequency of anti-CCP. Treatment persistence was 94.78% at 3 months, 82.84% at 6 months and 66.42% at 12 months.
Conclusions: Clinical remission at 3 months was negatively associated with prior bDMARD and poor prognostic factors. TOF monotherapy at 12 months was more common in elderly patients.
... Clinical efficacy and safety of TOF have been extrapolated mainly from patient populations with active RA in phase 2 and phase 3 randomized controlled trials (RCTs), and long-term extension studies. [1][2][3][4][5][6][7][8][9][10][11] RA patients from Latin America (LatAm) differ from patients from the rest of the world in terms of genetic and epidemiologic factors, and in prognosis and so they could potentially elicit different clinical responses to a given mode of action. 12 Across Phase 3 studies and long-term extension studies of TOF, subpopulations from LatAm have been reported to experience similar improvements in efficacy than in patients from the rest of the world. ...
Background: Evidence of effectiveness and safety of tofacitinib (TOF) in the real-world setting in Latin America is currently limited and crucial to complement long-term extension data from randomized controlled trials. Methods: Patients initiated on TOF between 2014 and 2020 with RA (ACR/EULAR, 2010 criteria) were analyzed. The primary end point at month 3 was remission measured by DAS28-ESR. Secondary end points included prognostic factors for remission at 3 months and of monotherapy at month 12. Results: Overall, 134 RA patients were analyzed. Remission was achieved in 38.06% at month 3. In univariate analysis, persistent disease activity at 3 months was observed in those patients with longer duration of disease, structural radiological damage, higher baseline DAS28-ESR and greater frequency in previous use of bDMARD. In multivariate analysis, previous use of bDMARD was significantly associated with a decrease in the probability of remission at 3 months. At 12 months, TOF monotherapy group was elderly (p = 0.009) and had a trend for lower frequency of anti-CCP. Treatment persistence was 94.78% at 3 months, 82.84% at 6 months and 66.42% at 12 months. Conclusions: Clinical remission at 3 months was negatively associated with prior bDMARD and poor prognostic factors. TOF monotherapy at 12 months was more common in elderly patients.
... In another clinical trial (NCT00853385), tofacitinib showed similar efficacy to adalimumab in patients with rheumatoid arthritis [187]. In patients receiving methotrexate, tofacitinib also stopped the progression of structural damage [188]. By the end of 2012, tofacitinib received the first approval for the treatment of rheumatoid arthritis. ...
Janus kinase (JAK) is a family of cytoplasmic non-receptor tyrosine kinases that includes four members, namely JAK1, JAK2, JAK3, and TYK2. The JAKs transduce cytokine signaling through the JAK-STAT pathway, which regulates the transcription of several genes involved in inflammatory, immune, and cancer conditions. Targeting the JAK family kinases with small-molecule inhibitors has proved to be effective in the treatment of different types of diseases. In the current review, eleven of the JAK inhibitors that received approval for clinical use have been discussed. These drugs are abrocitinib, baricitinib, delgocitinib, fedratinib, filgotinib, oclacitinib, pacritinib, peficitinib, ruxolitinib, tofacitinib, and upadacitinib. The aim of the current review was to provide an integrated overview of the chemical and pharmacological data of the globally approved JAK inhibitors. The synthetic routes of the eleven drugs were described. In addition, their inhibitory activities against different kinases and their pharmacological uses have also been explained. Moreover, their crystal structures with different kinases were summarized, with a primary focus on their binding modes and interactions. The proposed metabolic pathways and metabolites of these drugs were also illustrated. To sum up, the data in the current review could help in the design of new JAK inhibitors with potential therapeutic benefits in inflammatory and autoimmune diseases.
... The efficacy and safety of tofacitinib for the treatment of active RA in adults has been studied through numerous phase II, III, IIIb/IV and IV randomized clinical trials (RCTs) (9). Additionally, two longterm open-label trials have been completed (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23). ...
The purpose of this narrative review is to provide an overview of the real-world data on the use of tofacitinib in patients with active rheumatoid arthritis (RA) in Spain. Sixteen retrospective studies carried out in Spain between 2019 and 2021 have been analyzed, considering patients' characteristics, and treatment patterns, effectiveness, and safety. In those studies, approximately 511 patients received tofacitinib during the study period. They were predominantly women (mean age: 48-61 years). The percentage of patients receiving tofacitinib as monotherapy ranged between 20.0% and 67.9%. Only five studies reported the combined use of corticosteroids (42.0-84.5% of patients), with a mean dose varying from 1.8 to 7.2 mg. A wide range of patients (36.0-85.7%) had failed a previous biological disease-modifying anti-rheumatic drug. The most frequent reason for treatment discontinuation was the lack of efficacy, and the most common adverse event described was herpes zoster infection. Real-world studies complement clinical trials by adding efficacy and safety data in real-world settings to the benefit/risk profile of the drug. The profile of RA patients receiving tofacitinib in Spain has similarities with other real-world studies conducted in other countries.
... Tofacitinib is mainly metabolized in the liver via cytochrome P450 (CYP) 3A4 [5]. Numerous phase III trials have indicated the efficacy of tofacitinib [6][7][8][9]. In contrast, baricitinib is a JAK1/JAK2 inhibitor that inhibits intracellular signaling by numerous inflammatory cytokines such as IL-6, IL-12, and IL-23 [10]. ...
We report a case of rapidly progressing hepatocellular carcinoma after administration of Janus kinase (JAK) inhibitors to treat rheumatoid arthritis. A 76-year-old man was referred to our Department for pain in multiple joints and was diagnosed with rheumatoid arthritis. Blood tests revealed elevated hepatobiliary enzymes, but various tests revealed no signs suggestive of malignancy. He took baricitinib for 2 months followed by tofacitinib for 4 months. After that, he was diagnosed with hepatocellular carcinoma based on imaging findings and elevated tumor markers. This case showed the possibility of a causal relationship between JAK inhibitors and malignancy.
... Baricitinib, tofacitinib, and upadacitinib are JAK inhibitors approved to be used as monotherapy or combination with csDMARD in the USA, Europe, and Japan. These three JAK inhibitors have been shown to improve ACR outcomes and disease activity scores for 28 joints (DAS28) compared to placebo and csDMARDs in randomized controlled trials (RCTs) [12][13][14][15][16][17][18]. These JAK inhibitors have demonstrated varying effects versus adalimumab (ADA) + MTX, suggesting that they may have differential effects [19][20][21][22]. ...
Objective
This study evaluated the effectiveness and cost-effectiveness of baricitinib, tofacitinib and upadacitinib regimens, compared to conventional synthetic disease-modifying antirheumatic drug (csDMARD) alone, among Japanese patients with moderate-to-severe rheumatoid arthritis (RA) inadequately responsive to csDMARD, measured in terms of number needed to treat (NNT) and cost per responder (CPR).
Methods
Efficacy data were derived from two recent network meta-analyses among global and Japanese population. The cost perspective was that of the Japanese Health Service. Both NNT and CPR were based on disease activity score for 28 joints with C-reactive protein (DAS28-CRP) remission and American College of Rheumatology (ACR)20/50/70 at 12 and 24 weeks.
Results
Over 12 weeks, the median NNT and the median CPR to achieve DAS28-CRP remission were 4.3 and JPY 1,799,696 [USD 16,361], respectively, for upadacitinib 15mg + csDMARD. The equivalent results were 6.0 and JPY 2,691,684 [USD 24,470] for baricitinib 4mg + csDMARD and 5.6 and JPY 2,507,152 [USD 22,792] for tofacitinib 5mg + csDMARD. Similar rankings were observed at 24 weeks and for other outcomes.
Conclusions
Upadacitinib 15mg was associated with the lowest NNT and CPR among the three JAK inhibitors used in treatment regimens for Japanese patients with moderate-to-severe RA inadequately responsive to csDMARD.
... Tofacitinib is an oral JAK inhibitor for the treatment of RA. The efficacy and safety of tofacitinib 5 and 10 mg twice daily (BID) administered as monotherapy or with csDMARDs, mainly methotrexate (MTX), in patients with moderately to severely active RA, have been demonstrated in phase 2 [8][9][10][11][12], phase 3 [13][14][15][16][17][18][19], and phase 3b/4 [20] studies of up to 24 months' duration, and in long-term extension (LTE) studies with up to 114 months' observation [21][22][23]. ...
Introduction/objectives
We assess the impact of switching versus staying on the same tofacitinib dose on efficacy and safety in patients with rheumatoid arthritis (RA).
Methods
ORAL Sequel was an open-label, long-term extension study of patients with RA receiving tofacitinib 5 or 10 mg BID for up to 9.5 years. Tofacitinib doses could be switched during the study at investigator discretion. In this post hoc analysis, data from ORAL Sequel were stratified into four groups: 5 → 10 mg BID (Dose-up); 5 mg BID (Stay-on 5); 10 → 5 mg BID (Dose-down); and 10 mg BID (Stay-on 10). Efficacy assessments over 12 months included: change from baseline in 4-component Sisease Activity Score in 28 joints, erythrocyte sedimentation rate (DAS28), and DAS28 minimum clinically important difference, remission, and low disease activity (LDA) rates. Safety was assessed for the study duration.
Results
Generally, DAS28 improvements and minimum clinically important difference rates were significantly greater ( p < 0.05) in Dose-up versus Stay-on 5 up to month 12. DAS28 remission rates were significantly greater in Dose-up versus Stay-on 5 at month 12. Change from baseline in DAS28 was similar in Dose-down and Stay-on 10. No significant differences in DAS28 LDA rates were observed between groups. Safety data were similar overall across the four groups.
Conclusion
In patients with RA receiving open-label tofacitinib, this analysis found that some benefited from increasing dose from 5 to 10 mg BID and did not find that reducing dose from 10 to 5 mg BID affected efficacy or that dose switching in either direction affected safety.
Study registration
ClinicalTrials.gov number NCT00413699. Registered December 20, 2006. https://clinicaltrials.gov/ct2/show/NCT00413699 Key Points • This post hoc analysis of data from the long-term extension study, ORAL Sequel, assessed the impact of dose switching between tofacitinib 5 and 10 mg twice daily (BID), at the investigator’s discretion, on efficacy and safety in patients with rheumatoid arthritis (RA). • Dosing up from tofacitinib 5 to 10 mg BID was associated with improved efficacy up to 12 months versus staying on 5 mg BID, and dosing down from 10 to 5 mg BID was not generally associated with a significant loss of efficacy. • Safety outcomes were generally consistent across dose groups and did not change markedly after switching dose in either direction. • These findings can help to inform physicians on what may be expected in terms of efficacy and safety when adjusting tofacitinib dose according to clinical need. The recommended tofacitinib dosage for the treatment of RA in most jurisdictions is 5 mg BID.
... While in vitro intracellular signalling analyses suggest that the therapies are somewhat distinct, in clinical trials they look reasonably similar and long-term observation in the clinic will tell us whether they differ in practice. Phase III international clinical trials have demonstrated that the clinical and structural effects of these JAK inhibitors were significantly more robust and rapid than the effects of placebo in MTX-naïve patients, as well as in RA patients with inadequate responses to csDMARDs such as MTX or bDMARDs such as TNF-targeting drugs [26][27][28][29][30][31]. Baricitinib and filgotinib are significantly more effective than adalimumab [28,31], whereas upadacitinib is significantly more effective than adalimumab and the selective T cell costimulatory modulator abatacept [30,32]. ...
Through treatment with biological DMARDs (bDMARDs) or targeted synthetic (tsDMARDs) such as Janus kinase (JAK) inhibitors in addition to MTX, clinical remission has become a realistic therapeutic goal for the majority of patients with RA, and sustained remission facilitates prevention of joint damage and physical dysfunction. Long-term safety and sustained inhibition of structural changes and physical dysfunction by bDMARDs have been reported. The development of next-generation bDMARDs and expansion of their indications to various autoimmune diseases are expected. Five JAK inhibitors show comparable efficacy to bDMARDs, and the latest ones are effective for overcoming difficult-to-treat RA regardless of prior medications. Patients treated with JAK inhibitors should be adequately screened and monitored for infection, cardiovascular disorders, thrombosis, malignancies and so on. Advances in therapeutic strategies, including the differential use of therapeutic drugs and de-escalation of treatment after remission induction, are prioritized.
... This is in agreement with previous studies that have demonstrated that earlier disease control is associated with reduced radiographic progression in patients with RA [15][16][17]. Inhibition of radiographic progression has also been observed in other JAK inhibitor studies; however, results have not always been consistent between use as monotherapy or in combination with MTX [18][19][20][21][22][23][24][25]. The results in the SELECT-EARLY study showed consistent structural benefit vs MTX with both upadacitinib doses (15 mg and 30 mg QD) in an MTX-naïve population. ...
Objectives
To evaluate the inhibition of progression of structural joint damage through week 48 in patients with moderately to severely active rheumatoid arthritis (RA) receiving upadacitinib as monotherapy or in combination with methotrexate.
Methods
Radiographic progression was assessed in two phase 3 randomized-controlled trials. Methotrexate–naïve patients were randomized to upadacitinib 15 or 30 mg once daily (QD) or methotrexate monotherapy (SELECT–EARLY, n = 945), while methotrexate inadequate responders (IR) were randomized to upadacitinib 15 mg QD or adalimumab 40 mg every other week or placebo added to background methotrexate (SELECT–COMPARE, n = 1629). Mean changes from baseline in modified Total Sharp Score (mTSS), joint space narrowing (JSN), and erosion scores (ES) were determined. Data were analysed both by linear extrapolation for missing data imputation and treatment switching and as-observed.
Results
In patients naïve or with limited exposure to methotrexate (SELECT-EARLY), mean changes from baseline to week 48 in mTSS were 0.03 for upadacitinib 15 mg, 0.14 for upadacitinib 30 mg, and 1.00 for methotrexate based on linear extrapolation (p < 0.001 for both upadacitinib doses vs methotrexate). Among patients with an inadequate response to methotrexate (SELECT-COMPARE), the mean change from baseline in mTSS was significantly reduced in the upadacitinib 15 mg plus methotrexate group vs placebo plus methotrexate (0.28 vs 1.73; p < 0.001); mean change from baseline in the adalimumab plus methotrexate group was 0.39.
Conclusion
Upadacitinib monotherapy or in combination with background methotrexate was effective in inhibiting the progression of structural joint damage through week 48 in methotrexate-naïve and methotrexate-IR patients with RA.
Trial registration
ClinicalTrials.gov, https://clinicaltrials.gov, NCT02706873 and NCT02629159
... After reading the titles and abstracts, 1581 studies were excluded. The full texts of 77 studies were accessed, of which 19 [20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38] were selected to support this evaluation. (Additional file 2: Appendix 2). ...
Rheumatoid arthritis (RA) is a chronic and autoimmune systemic inflammatory disease that can cause irreversible joint deformities, with increased morbidity and mortality and a significant impact on the quality of life of the affected individual. The main objective of RA treatment is to achieve sustained clinical remission or low disease activity. However, up to 40% of patients do not respond to available treatments, including bDMARDs. New therapeutic targets for RA are emerging, such as Janus kinases (JAKs). These are essential for intracellular signaling (via JAK-STAT) in response to many cytokines involved in RA immunopathogenesis. JAK inhibitors (JAKi) have established themselves as a highly effective treatment, gaining increasing space in the therapeutic arsenal for the treatment of RA. The current recommendations aim to present a review of the main aspects related to the efficacy and safety of JAKis in RA patients, and to update the recommendations and treatment algorithm proposed by the Brazilian Society of Rheumatology in 2017.
Background:
Rheumatoid arthritis (RA), a chronic systemic autoimmune disease, is characterized by synovitis and progressive damage to the bone and cartilage of the joints, leading to disability and reduced quality of life. This study was a randomized clinical trial comparing the outcomes between withdrawal and dose reduction of tofacitinib in patients with RA who achieved sustained disease control.
Methods:
The study was designed as a multicenter, open-label, randomized controlled trial. Eligible patients who were taking tofacitinib (5 mg twice daily) and had achieved sustained RA remission or low disease activity (disease activity score in 28 joints [DAS28] ≤3.2) for at least 3 months were enrolled at six centers in Shanghai, China. Patients were randomly assigned (1:1:1) to one of three treatment groups: continuation of tofacitinib (5 mg twice daily); reduction in tofacitinib dose (5 mg daily); and withdrawal of tofacitinib. Efficacy and safety were assessed up to 6 months.
Results:
Overall, 122 eligible patients were enrolled, with 41 in the continuation group, 42 in the dose-reduction group, and 39 in the withdrawal group. After 6 months, the percentage of patients with a DAS28-erythrocyte sedimentation rate (ESR) of <3.2 was significantly lower in the withdrawal group than that in the reduction and continuation groups (20.5%, 64.3%, and 95.1%, respectively; P < 0.0001 for both comparisons). The average flare-free time was 5.8 months for the continuation group, 4.7 months for the dose reduction group, and 2.4 months for the withdrawal group.
Conclusion:
Withdrawal of tofacitinib in patients with RA with stable disease control resulted in a rapid and significant loss of efficacy, while standard or reduced doses of tofacitinib maintained a favorable state.
Trial registration:
Chictr.org, ChiCTR2000039799.
Collectively known as psoriatic disease, psoriasis and psoriatic arthritis (PsA) are immune-mediated inflammatory diseases in which patients present with cutaneous and musculoskeletal inflammation. Affecting roughly 2-3% of the world's total population, there remains unmet therapeutic needs in both psoriasis and PsA despite the availability of current immunomodulatory treatments. As a result, patients with psoriatic disease often experience reduced quality of life. Recently, a class of small molecules, commonly investigated as anti-cancer agents, called histone deacetylase (HDAC) inhibitors, have been proposed as a new promising anti-inflammatory treatment for immune- and inflammatory-related diseases. In inflammatory diseases, current evidence is derived from studies on diseases like rheumatoid arthritis (RA) and systematic lupus erythematosus (SLE), and while there are some reports studying psoriasis, data on PsA patients are not yet available. In this review, we provide a brief overview of psoriatic disease, psoriasis, and PsA, as well as HDACs, and discuss the rationale behind the potential use of HDAC inhibitors in the management of persistent inflammation to suggest its possible use in psoriatic disease.
Introduction/Objective: The aim of the study is to determine the effectiveness and adverse effects of tofacitinib in patients with rheumatoid arthritis (RA). Methods: 66 Patients who were followed up in rheumatology outpatient clinic of Yıldırım Beyazıt University Faculty of Medicine- Ankara City Hospital, were older than 18 years, used tofacitinib for at least three months were included. Blood count, lipid profile, transaminase levels, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels were determined before and at the third and sixth months of the tofacitinib treatment. Before and after tofacitinib treatment; duration of morning stiffness, DAS 28-ESR, VAS score were determined. Results: The mean age of the patients included in our study was 54.7±12.0 years, and 84.8% were women. The mean duration of tofacitinib use was 19.0±13.5 months. The duration of morning stiffness and DAS 28-ESR and VAS scores of the patients were significantly decreased after tofacitinib treatment (p
Novos alvos terapêuticos para artrite reumatoide (AR) e outras doenças reumáticas imunomediadas (DRIM) vêm sendo elucidados, entre eles a Janus quinases (JAKs). Essas estruturas são essenciais para a sinalização intracelular (via JAK-STAT) em resposta as muitas citocinas envolvidas na imunopatogênese das DRIM. Os inibidores de JAK (iJAK) têm se consolidado como um tratamento altamente eficaz, ganhando cada vez mais espaço no arsenal terapêutico da AR. O presente artigo tem como objetivo apresentar uma atualização dos principais aspectos relacionados ao mecanismo de ação, eficácia e segurança do iJAKs, com ênfase no tratamento de pacientes com AR. Unitermos: Artropatias inflamatórias. Artrite reumatoide. Doenças reumáticas imunomediadas. Inibidores de JAK. Janus quinases. JAK-STAT. Drogas modificadoras do curso da doença sintéticas alvo específicas.
JAK inhibitors (JAKi) are new targeted-synthetic drugs, approved for various immune-mediated inflammatory diseases (IMIDs), including inflammatory arthritides (rheumatoid arthritis—RA, psoriatic arthritis—PsA, ankylosing spondylitis—AS) and ulcerative colitis (UC). JAKi have been associated with increased risk for herpes zoster (HZ), but the relative risk among different JAKi in these IMIDs remains unclear. We aimed to systematically review the incidence of HZ among RA, PsA, AS and UC patients treated with the approved doses of tofacitinib (TOFA), baricitinib (BARI) or upadacitinib (UPA). PubMed, Embase, Scopus, Cochrane and Web-of-Science were searched up to 30 March 2022. Clinical trials and real-world studies (RWS) were included. Outcomes assessed were the incidence rate (/100 patient-years) or/and cumulative incidence of HZ. From 1710 records, 53 clinical trials and 25 RWS were included (RA: 54, PsA: 8, AS: 4, and UC: 12). In clinical trials, the HZ-incidence was higher in TOFA-treated patients with RA (2.2–7.1/100 patient-years) or UC (1.3–7.6/100 patient-years) compared to PsA (1.7/100 patient-years), and with higher doses of TOFA in UC (10 mg/twice daily: 3.2–7.6/100 patient-years vs. 5 mg/twice daily: 1.3–2.3/100 patient-years). Evidence for HZ-risk in JAKi-treated patients with AS and in UPA-treated patients was limited. The HZ-incidence between TOFA and BARI groups in 2 RA RWS did not differ significantly. Concomitant glucocorticoid, but not methotrexate, use in RA increased the HZ-risk. This systematic review showed higher HZ-risk in RA or UC than PsA patients treated with TOFA, in those treated with higher TOFA doses or with concomitant glucocorticoids. Preventive measures and monitoring of JAKi-treated patients with IMIDs are essential in daily practice.
Rheumatoid arthritis (RA) has been linked to an increased risk of osteoporosis as well as fractures. Patients diagnosed with RA had a 25% increased risk of osteoporotic fracture, according to a recent population‐based cohort study that compared them to people without RA. Several studies have found a correlation between osteoporosis and the presence of pro‐inflammatory cytokines, such as tumor necrosis factor (TNF)‐α, interleukin (IL)‐1, and 6. These cytokines play a crucial part in the process of bone resorption by boosting osteoclast activation and encouraging osteoclast differentiation. Based on the correlation between RA, osteoporosis, and inflammation, it is possible that systemic immunosuppression with disease‐modifying antirheumatic drugs (DMARDs) can help individuals with RA have a lower chance of developing osteoporosis and osteoporotic fractures. There is little information on how different DMARDs, biologic or non‐biologic, affect RA patients' bone metabolism. In this study, we present an overview of the influence that targeted therapies, such as biologics, non‐biologics, and small molecule inhibitors, have on bone homeostasis in RA patients.
Objective
We compared the 52-week effectiveness and safety of tofacitinib (TOF) and abatacept (ABT) in patients with RA in a real-world setting and investigated a role of human leucocyte antigens (HLA)-DRB1 shared epitope (SE) in the effectiveness.
Methods
RA patients starting TOF (n = 187) and ABT (n = 183) were enrolled. Effectiveness was compared after reducing the selection bias to a minimum using the inverse probability of treatment weighting (IPTW) based on propensity scores. The influence of SE alleles on effectiveness was compared within each treatment group. A treatment group comparison was also performed within SE-positive and SE-negative groups.
Results
Herpes zoster and some laboratory abnormalities were more frequent in the TOF group than in the ABT group. Patient characteristics did not differ significantly between treatment groups after adjustments with IPTW. The TOF group had a significantly higher proportion of DAS in 28 joints using ESR (DAS28-ESR) remission at week 52 than the ABT group. The DAS28-ESR at week 12 and thereafter was not affected by the copy number of SE alleles in the TOF group, but decreased significantly as the copy number increased in the ABT group. In SE-positive patients, remission and drug retention rates did not differ significantly between the two treatment groups. In SE-negative patients, the TOF group showed significantly higher remission and drug retention rates than the ABT group.
Conclusion
The present results suggest that TOF is more effective with regard to remission at week 52 based on treatment responses in SE-negative RA patients.
Introduction:
Etanercept (ETN) has been shown to slow radiographic progression of rheumatoid arthritis (RA) and psoriatic arthritis (PsA) in clinical trials. This real-world, non-interventional study assessed radiographic progression in patients with RA or PsA treated with ETN for ≤ 36 months in outpatient care in Germany (NCT01623752).
Methods:
Patients with RA or PsA attended ≤ 10 visits across two study phases (phase 1: seven visits, baseline to month 18; phase 2: three visits until month 36). Radiographs were taken at baseline (Rx1), months 12-18 (Rx2), and/or months 30-36 (Rx3). Historic radiographs (Rx0) taken 12-48 months pre-baseline were also evaluated (if available). The primary endpoint was the change in modified total Sharp score (mTSS). The erosion score (ES) and joint space narrowing score (JSN) were also evaluated.
Results:
Overall, 1821 patients were enrolled (RA: n = 1378; PsA: n = 440). In patients with Rx1 and Rx2 (RA: n = 511; PsA: n = 167), the mean mTSS remained stable for both disease groups, and the annualized median change in mTSS was 0. In patients with Rx0, Rx1, and Rx2 (RA: n = 180; PsA: n = 47), annualized radiographic progression in mTSS, ES, and JSN was larger in the pre-ETN treatment phase than during ETN treatment in both disease groups. The percentage of patients with radiographic non-progression was higher during ETN treatment versus pre-ETN. Improvement in clinical disease activity and patient-reported outcomes was also observed.
Conclusions:
This was the first real-world, non-interventional study to report systematically collected radiographic data in a large cohort of patients with RA or PsA under treatment with a biologic. In patients with available radiographic data, mean radiographic progression was lower and the proportion of patients without progression was greater during ETN treatment than in the pre-ETN period.
JAK inhibitors (JAKi) are targeted, small-molecule, disease-modifying therapies that are the newest class of treatments to emerge for the management of rheumatoid arthritis (RA) and the first oral disease-modifying anti-rheumatic drugs (DMARD) to demonstrate comparable clinical efficacy to biological DMARDs (bDMARD). In the UK there are four JAKi licensed for the treatment of RA (baricitinib, tofacitinib, upadacitinib, and filgotinib) and recent years have seen an explosion in their use. Clinical trial evidence supports their efficacy in a range of RA cohorts including DMARD-naïve patients and those with treatment-refractory disease. JAKi are associated with increased risk for infection, particularly herpes zoster virus reactivation, cytopenias, and hyperlipidaemia. In older patients with cardiovascular risk factors, post-marketing data suggest increased risk for malignancy, venous thromboembolism (VTE), and major cardiovascular events (MACE) with JAKi. This review article discusses the mechanism of action of JAKi and the evidence for their efficacy and side effect profile.
Background:
More and more trials have been conducted. We aimed to assess the efficacy and safety of different JAKinibs in RA.
Methods:
A systematic search of randomized controlled trials (RCTs) with JAKinib treatment in RA published in the Medline, Embase, and Cochrane databases up to May 2021 was performed.
Results:
37 trials involving 15,174 patients were identified. Pooled analysis revealed that JAKinibs were associated with significant therapeutic improvement in RA patients as determined by ACR20 (RR = 2.03, 95% CI: 1.85 to 2.28) and HAQ-DI (MD = -0.31, 95% CI: -0.33 to -0.28) over placebo. Compared to placebo, JAKinib treatment was also associated with more adverse events (RR = 1.10, p < 0.001; RR = 1.29, p < 0.001; RR = 1.59, p = 0.02). Baricitinib and upadacitinib were related to more frequent adverse events (RR = 1.10; 95% CI: 1.01, 1.21; RR = 1.19; 95% CI: 1.11, 1.28) and infection (RR = 1.22; 95% CI: 1.09, 1.37; RR = 1.38; 95% CI: 1.22, 1.56), whereas only baricitinib was associated with more herpes zoster (RR = 3.15; 95% CI: 1.19, 8.33).
Conclusions:
JAKinibs were superior to placebo for improving signs, symptoms, and health-related quality of life in RA patients at short term, whereas the overall risk of adverse events and infections were greater with baricitinib and upadacitinib, and a higher risk of herpes zoster was only associated with baricitinib. More trials are needed to investigate the long-term safety.
Purpose:
Tofacitinib is recommended for treatment of rheumatoid arthritis (RA) in patients with moderate to severe disease activity, but there is not enough evidence on its effectiveness after conventional DMARDs vs its use after biologics. The aim was evaluating the effectiveness of tofacitinib in RA as first-line treatment (after conventional DMARDs) in a real-life setting in Colombian (Latin-American) patients.
Patients and methods:
Retrospective cohort study conducted at a specialized center for RA management. A complete statistical analysis was performed to compare the values of the change in the DAS28 at months 3, 6, and 12 in both treatment groups.
Results:
A total of 152 RA patients who received tofacitinib: first-line 85 patients (55.9%) after failure on conventional DMARDs or second-line 67 patients (44.1%) after failure on biologic DMARDs. Comparative analysis of response to treatment showed a reduction in DAS28 at 3, 6, and 12 months in both study groups without statistical differences, but a higher proportion of first-line patients achieved remission (45% vs 23%). Nonresponse at three months were associated with no response at six months of follow-up. Baseline DAS28 was significantly associated with response at 12 months (OR: 1.87, 95%CI: 1.06-3.30, p-value 0.028). In second-line patients, response to tofacitinib was not related to number of biologic DMARDs previously used.
Conclusion:
Tofacitinib is an effective treatment option for patients with RA, maybe better after conventional DMARDs than after biologic therapy failure. Further studies are required to determine the role of tofacitinib in different lines of RA treatment and in other groups of patients.
Purpose
Using data from real-world practice, this analysis compared outcomes in patients with rheumatoid arthritis (RA) initiating treatment with an oral Janus kinase inhibitor, tofacitinib, in combination with persistent, discontinued, or interrupted treatment with oral methotrexate (MTX).
Methods
This retrospective claims analysis (MarketScan® databases) included data from US patients with RA and at least one prescription claim for tofacitinib, dated between January 1, 2013, and April 30, 2017. Eligible patients were continuously enrolled for ≥12 months before and after treatment initiation, and initiated tofacitinib in combination with oral MTX, with at least two prescription claims for each. Patients were grouped according to treatment pattern (MTX-Persistent, MTX-Discontinued, or MTX-Interrupted). Tofacitinib treatment persistence, adherence, and effectiveness, as well as all-cause and RA-related health care costs, were assessed.
Findings
A total of 671 patients were eligible for inclusion; 504 (75.1%) were MTX-Persistent; 131 (19.5%), MTX-Discontinued; and 36 (5.4%), MTX-Interrupted. Rates of tofacitinib treatment persistence, adherence, and effectiveness at 12 months were similar between the MTX-Persistent and MTX-Discontinued cohorts. The percentage of patients switched from tofacitinib to another advanced disease-modifying antirheumatic drug within 12 months of tofacitinib initiation was greater in the MTX-Persistent cohort compared with that in the MTX-Discontinued cohort. RA-related health care costs at 12 months post-initiation were significantly greater in the MTX-Persistent cohort compared with those in the MTX-Discontinued cohort.
Implications
The findings from this analysis of real-world data indicate that patients who initiate tofacitinib in combination with oral MTX may discontinue MTX and still experience outcomes similar to those in patients who persist with MTX, with lesser RA-related health care costs. These results support those from a previous clinical study on methotrexate withdrawal in patients with RA (NCT02831855).
Rheumatoid arthritis is a common chronic inflammatory disease with substantial economic, social, and personal costs. Its pathogenesis is multifactorial and complex. The ultimate goal of rheumatoid arthritis treatment is stopping or slowing down the disease progression. In the past two decades, invention of new medicines, especially biologic agents, revolutionized the management of this disease. These agents have been associated with an improved prognosis and clinical remission, especially in patients who did not respond to traditional disease-modifying anti-rheumatic drugs (DMARDs). Improvement in the understanding of the rheumatoid arthritis pathogenesis leads to the development of novel biologic therapeutic approaches. In the present paper, we summarized the current therapeutics, especially biologic agents, available for the treatment of rheumatoid arthritis.
Rheumatoid arthritis (RA) is a chronic inflammatory disorder that can affect not only joints but also a wide variety of body systems, including lungs, skin, heart, eyes, etc. RA is an autoimmune disorder, which is not deadly in itself. RA appears clinically between the ages of 20 and 40, with women outnumbering men by a 2–3:1 ratio. Because of the long-term medical problems, RA is also associated with a lower life expectancy. The HLA (human leukocyte antigen) region has consistently shown the strongest genetic link with RA, with an estimated genetic contribution to RA pathogenesis of 60%. The role of non-HLA genes within the major histocompatibility complex (MHC) in RA has also been studied. Many genes identified outside the MHC region, such as peptidylarginine deiminase 4, tumor necrosis factor receptor-associated factor 1, protein tyrosin phosphatase nonreceptor 22, are linked to RA. There is a close link between RA and immune cells, which plays a significant role in the disease’s etiology. The immune system’s dendritic cells, natural killer cells, macrophages, neutrophils, and cytokines constitute a strong immunological genetic basis for RA. The many potential treatment choices are determined by the severity of the condition and the individual’s reaction to the specific medications. Recognizing biomarkers to focus the appropriate treatment options to the appropriate patients would bring instant patient benefit. If a reliable biomarker is used to select the best treatment choice for groups or individuals with RA, it may be possible to improve both health and healthcare expenditures. NSAIDs (nonsteroid antiinflammatory drugs) and aspirin were the cornerstones of Rheumatic arthritis treatment until the 1950s. For immediate/short-term RA treatment, corticosteroids and NSAIDs should be exclusively used. Tumor necrosis factor inhibitors, IL-1 and IL-6 antagonists, kinase inhibitors and costimulation signal blockage, and B-cell depleting therapy are some of the interesting areas for RA treatment.
Objective
Cluster of differentiation 81 (CD81) is a tetraspanin membrane protein consisting of 4 transmembrane domains and 2 outer membrane loops. CD81 inhibition is a potential treatment for rheumatoid arthritis (RA). Here, we investigated the therapeutic effects of the cytoplasmic RNA vector expressing anti-CD81 antibodies (the anti-CD81 vector) on the ankle joint synovium in collagen-induced arthritis (CIA) rats.
Methods
Body weight, paw volume, and clinical scores were measured on days 0, 7, and 10 and daily thereafter. On day 28, the ankle joints of the rats were removed and stained with haematoxylin, eosin, and Safranin O. Arthritic changes such as inflammatory cell infiltration, synovial proliferation, articular cartilage destruction, and bone erosion were evaluated by histological scoring.
Results
Symptom onset was delayed in the right lower limbs of the rats administered the cytoplasmic RNA vector (CIA + anti-CD81) compared with that in the control group (CIA + control). The CIA + anti-CD81 rats were heavier than the CIA + control rats. The paw volume and clinical scores were significantly lower in the CIA + anti-CD81 than in the CIA + control. The histological scores indicated significantly milder manifestations of RA in the CIA + anti-CD81 than in the CIA + control.
Conclusions
Administration of the cytoplasmic RNA vector expressing anti-CD81 antibodies suppressed arthritis and joint destruction in CIA rats. Our findings suggest that the cytoplasmic RNA vector can be used to treat RA.
Introduction:
The pathogenesis of systemic lupus erythematosus (SLE) involves abnormalities in both acquired and innate immune system, which is mediated by numerous cytokines. Janus kinase (JAK) plays important roles in the signaling pathways of those cytokines and is an attractive therapeutic target for SLE. Currently, multiple clinical trials using JAK inhibitors with different selectivities for JAK family proteins are being conducted in SLE.
Area covered:
In this article, we provide an overview of the pathological relevance of JAK and the clinical implications of JAK inhibitors in SLE based on recent reports.
Expert opinion:
JAK inhibitors have the potential to modulate various immune networks through a variety of mechanisms, potentially regulating the complex immunopathogenesis in SLE. SLE is a clinically and immunologically heterogeneous disease; therefore, precision medicine is required to maximize the efficacy of JAK inhibitors. Further studies are needed to determine their risk-benefit ratio and selection of the most appropriate patients for JAK inhibitors.
Objectives
To describe the use of baricitinib and tofacitinib by Swedish rheumatoid arthritis (RA) patients and to compare their effectiveness with that of biological disease-modifying anti-rheumatic drugs (bDMARDs).
Methods
RA patients who initiated baricitinib [N = 1420], tofacitinib [N = 316], abatacept [N = 1050], interleukin-6 inhibitors (IL6i) [N = 849], rituximab [N = 1101] or tumour necrosis factor inhibitors (TNFi) [N = 6036] between January 2017 and November 2019 were followed for minimum one year, using data from several linked Swedish national registers. Proportions reaching good-EULAR-DAS28 response, HAQ-DI improvement above 0.2 units and CDAI remission were compared at one year, imputing discontinued treatments as “non-response”. Additionally, we compared drug retention and changes in DAS28, HAQ-DI and CDAI from baseline to three months after treatment initiation.
Results
On average, baricitinib and particularly tofacitinib were initiated as later lines of therapy and more frequently as monotherapy compared with rituximab and TNFi. Adjusted one-year response proportions were consistently lower on TNFi compared with baricitinib, with differences of -4.3 percentage points (95% CI: -8.7–0.1) for good-EULAR response, -9.9 (-14.4 to -5.4) for HAQ-DI improvement, and -6.0 (-9.8 to -2.2) for CDAI remission. Comparisons with non-TNFi bDMARDs also favoured baricitinib, but not consistently. Treatment responses for tofacitinib were only marginally lower than those for baricitinib and generally similar to those of bDMARDs, with precision limited by low power. Comparisons of drug retention and changes in disease activity from baseline to three months supported the one-year findings.
Conclusions
Baricitinib and tofacitinib showed at least equivalent effectiveness compared with bDMARDs after exploring several different effectiveness measures.
Introduction:
Five jakinibs are approved for the treatment of rheumatic diseases. There has been a question of their relative safety to other medications since their approval.
Areas covered:
A literature search was conducted in Pub Med for the integrated safety databases of these molecules in their clinical trial program, registries, and insurance claims data and in a prospective head-to-head study compared to tumor necrosis factor inhibitors in a high-risk population for cardiovascular and malignancy events. There were no differences found in the safety databases, registries or insurance claims data indicating jakinibs are more likely to cause major adverse cardiac events, malignancy, venous thrombotic episodes, infections, and mortality compared to other medications. The head-to-head trial found there were numerically more of these events with the jakinib compared to tumor necrosis factor inhibitors.
Expert opinion:
Cardiac events and malignancy occur more frequently in rheumatoid patients with active disease. Although the safety databases, claims data and registries suggest there is no difference in the risks with a jakinib versus biologics, the prospective safety study showed these events occur numerically higher in patients at the highest risk for these events. In this population, one should consider using a biologic before a jakinib.
Objective:
We aimed to develop recommendations for the management of methotrexate (MTX) when considering the combination with biological (b) or targeted synthetic (ts) disease modifying drugs (DMARDs) in rheumatoid arthritis (RA).
Methods:
Eleven experts on RA were selected. Two coordinators formulated 13 questions about the combination therapy of MTX with bDMARDs or tsDMARDs. A systematic review was conducted to answer the questions. Inclusion and exclusion criteria were established as well as the search strategies (Medline, Embase and the Cochrane Library were searched up to January 2019). Two reviewers selected the articles and collected data. Simultaneously, EULAR and ACR meeting abstracts were evaluated. Based on this evidence, the coordinators proposed preliminary recommendations that the experts discussed and voted in a nominal group meeting. The level of evidence and grade of recommendation was established using the Oxford Center for Evidence Based Medicine and the level of agreement with a Delphi. Agreement was established if at least 80% of the experts voted 'yes' (yes/no).
Results:
The systematic review retrieved 513 citations of which 61 were finally included. A total of 10 recommendations were generated, voted and accepted. The level of agreement was very high in all of them and it was achieved in the first Delphi round. Final recommendations cover aspects such as the optimal MTX dosage, tapering strategy or patients' risk management.
Conclusions:
This document is intended to help clinicians solve usual clinical questions and facilitate decision making when treating RA patients with MTX in combination with bDMARDs or tsDMARDs.
Immunosuppressive therapies are currently indicated for a wide range of diseases. As new agents emerge and indications evolve the landscape grows increasingly complex. Therapies can target pathologic immune system over-activation in rheumatologic or autoimmune disease, or conditioning and graft versus host disease (GVHD) prophylactic regimens may eliminate or inhibit host immune function to improve graft survival and risk of complication in solid organ transplantation (SOT) or hematopoietic stem cell transplantation (HSCT). With immunosuppressive therapy, infections occur. Complex disease states, host factors, and concomitant therapies contribute to a “net state” of immunosuppression that must be considered and may confound perceived increased infection risks in patients receiving treatment.
Introduction
In 2015, the Italian board for the TAilored BIOlogic therapy (ITABIO) proposed evidence-based decisional statements for the first-line tailored biologic therapy in patient with rheumatoid arthritis (RA). Taking in account the new licensed drugs, the aim of present review was to update the previous statements.
Areas covered
A narrative review of the most recent evidence on the efficacy and safety of the old and newly licensed drugs for the treatment of articular and extra-articular RA was performed. In addition, the host-related variables potentially driving the therapy choice, such as the infection risk, the cardiovascular risk, the risk of deep vein thrombosis and thromboembolism, pregnancy, and obesity were analyzed. Consequently, several statements for a personalized therapy were formulated, thus providing a decisional algorithm useful for a proper personalized therapy of RA patients in clinical practice.
Expert opinion
Several clinical variables related to the specific drug and host characteristics may drive the choice towards anti-TNF and non-anti-TNF biologics, or anti-JAKs, thus allowing to personalize the therapy. Consequently, the right therapy for the right patient would ensure a successful therapeutic intervention.
IntroductionRisk of herpes zoster (HZ) is increased with Janus kinase inhibitor use. We evaluated clinical study data relating to HZ management in patients with rheumatoid arthritis (RA) or psoriatic arthritis (PsA) receiving tofacitinib.Methods
This post hoc analysis included data from 21 RA and 3 PsA clinical studies; data were pooled for tofacitinib doses. Outcomes of HZ events (serious and non-serious) and tofacitinib treatment changes were evaluated in response to first and second HZ events. Median time to resolution was stratified by dermatomal involvement, history of HZ prior to tofacitinib, changes to tofacitinib treatment, anti-viral and corticosteroid use, and tofacitinib dose.ResultsSeven hundred eighty-three (11.1%, N = 7061) patients with RA experienced ≥ 1 HZ event, 63 (8.0%) of whom had ≥ 2 HZ events. In patients with PsA, 36 (4.6%, N = 783) experienced ≥ 1 HZ event, 1 (2.8%) of whom had ≥ 2 HZ events. For most HZ events, tofacitinib treatment was unchanged or temporarily discontinued. The majority of patients received anti-viral treatment, most within 3 days of onset. Post-herpetic neuralgia developed in 6.9% and 3.2% of patients with RA with first and second events, respectively, and in 2.8% of patients with PsA with a first event. Most first and second events resolved (RA: 97.6% and 96.8%, respectively; PsA: 94.4% and 100%, respectively). Median time to resolution was 22.0 days for first and 15.0 days for second events for RA and 20.5 days for first and 11.0 days for second events (n = 1) for PsA. Time to resolution of first events for RA and PsA was generally numerically shorter for patients with single dermatomal HZ, history of HZ, or anti-viral use versus those without.Conclusion
Among patients receiving tofacitinib, recurrent events were more common in patients with RA versus PsA; HZ duration was shorter for repeat events.Trial RegistrationNCT01262118, NCT01484561, NCT00147498, NCT00413660, NCT00550446, NCT00603512, NCT00687193, NCT01164579, NCT00976599, NCT01059864, NCT01359150, NCT02147587, NCT00960440, NCT00847613, NCT00814307, NCT00856544, NCT00853385, NCT01039688, NCT02187055, NCT00413699, NCT00661661, NCT01877668, NCT01882439, NCT01976364.
Tofacitinib (CP-690,550) is a novel oral Janus kinase inhibitor that is being investigated for the treatment of rheumatoid arthritis.
In this 12-month, phase 3 trial, 717 patients who were receiving stable doses of methotrexate were randomly assigned to 5 mg of tofacitinib twice daily, 10 mg of tofacitinib twice daily, 40 mg of adalimumab once every 2 weeks, or placebo. At month 3, patients in the placebo group who did not have a 20% reduction from baseline in the number of swollen and tender joints were switched in a blinded fashion to either 5 mg or 10 mg of tofacitinib twice daily; at month 6, all patients still receiving placebo were switched to tofacitinib in a blinded fashion. The three primary outcome measures were a 20% improvement at month 6 in the American College of Rheumatology scale (ACR 20); the change from baseline to month 3 in the score on the Health Assessment Questionnaire-Disability Index (HAQ-DI) (which ranges from 0 to 3, with higher scores indicating greater disability); and the percentage of patients at month 6 who had a Disease Activity Score for 28-joint counts based on the erythrocyte sedimentation rate (DAS28-4[ESR]) of less than 2.6 (with scores ranging from 0 to 9.4 and higher scores indicating greater disease activity).
At month 6, ACR 20 response rates were higher among patients receiving 5 mg or 10 mg of tofacitinib (51.5% and 52.6%, respectively) and among those receiving adalimumab (47.2%) than among those receiving placebo (28.3%) (P<0.001 for all comparisons). There were also greater reductions in the HAQ-DI score at month 3 and higher percentages of patients with a DAS28-4(ESR) below 2.6 at month 6 in the active-treatment groups than in the placebo group. Adverse events occurred more frequently with tofacitinib than with placebo, and pulmonary tuberculosis developed in two patients in the 10-mg tofacitinib group. Tofacitinib was associated with an increase in both low-density and high-density lipoprotein cholesterol levels and with reductions in neutrophil counts.
In patients with rheumatoid arthritis receiving background methotrexate, tofacitinib was significantly superior to placebo and was numerically similar to adalimumab in efficacy. (Funded by Pfizer; ORAL Standard ClinicalTrials.gov number, NCT00853385.).
Tofacitinib (CP-690,550) is a novel oral Janus kinase inhibitor that is being investigated as a targeted immunomodulator and disease-modifying therapy for rheumatoid arthritis.
In this phase 3, double-blind, placebo-controlled, parallel-group, 6-month study, 611 patients were randomly assigned, in a 4:4:1:1 ratio, to 5 mg of tofacitinib twice daily, 10 mg of tofacitinib twice daily, placebo for 3 months followed by 5 mg of tofacitinib twice daily, or placebo for 3 months followed by 10 mg of tofacitinib twice daily. The primary end points, assessed at month 3, were the percentage of patients with at least a 20% improvement in the American College of Rheumatology scale (ACR 20), the change from baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) scores (which range from 0 to 3, with higher scores indicating greater disability), and the percentage of patients with a Disease Activity Score for 28-joint counts based on the erythrocyte sedimentation rate (DAS28-4[ESR]) of less than 2.6 (with scores ranging from 0 to 9.4 and higher scores indicating more disease activity).
At month 3, a higher percentage of patients in the tofacitinib groups than in the placebo groups met the criteria for an ACR 20 response (59.8% in the 5-mg tofacitinib group and 65.7% in the 10-mg tofacitinib group vs. 26.7% in the combined placebo groups, P<0.001 for both comparisons). The reductions from baseline in HAQ-DI scores were greater in the 5-mg and 10-mg tofacitinib groups than in the placebo groups (-0.50 and -0.57 points, respectively, vs. -0.19 points; P<0.001). The percentage of patients with a DAS28-4(ESR) of less than 2.6 was not significantly higher with tofacitinib than with placebo (5.6% and 8.7% in the 5-mg and 10-mg tofacitinib groups, respectively, and 4.4% with placebo; P=0.62 and P=0.10 for the two comparisons). Serious infections developed in six patients who were receiving tofacitinib. Common adverse events were headache and upper respiratory tract infection. Tofacitinib treatment was associated with elevations in low-density lipoprotein cholesterol levels and reductions in neutrophil counts.
In patients with active rheumatoid arthritis, tofacitinib monotherapy was associated with reductions in signs and symptoms of rheumatoid arthritis and improvement in physical function. (Funded by Pfizer; ORAL Solo ClinicalTrials.gov number, NCT00814307.).
Severity of rheumatoid arthritis and progression of radiographic joint damage have decreased over the last decades.
To examine whether this trend is attributable to an underlying trend towards milder disease or to improved treatment.
The study used an inception cohort of patients with early rheumatoid arthritis seen at the Wichita Arthritis Center, Wichita, Kansas, USA, since 1973 and monitored prospectively since their first clinic visit through clinical, radiographic, laboratory, demographic and self-reported data. The radiographic disease progression in patients with disease onset in the 1970s, 1980s and 1990s was compared using a multivariate regression model for longitudinal data. The analysis was adjusted for differences in baseline predictors, type of disease-modifying antirheumatic drugs (DMARDs) and steroid use.
418 patients with rheumatoid arthritis with radiographic follow-up were included. Patients in earlier decades used fewer DMARDs, had longer disease durations and higher tender joint counts at their first visit. Other important predictors of disease progression did not differ significantly between decades of disease onset. The unadjusted rates of radiographic progression differed between decades (analysis of variance, p = 0.01), with a significant trend towards less radiographic progression in more recent times (trend, p<0.001). However, after adjusting for DMARD use, steroid use and baseline predictors, differences between decades vanished (analysis of variance, p = 0.40) and the trend towards less radiographic progression disappeared (trend, p = 0.45).
These results suggest that the observed trend towards milder disease in rheumatoid arthritis is attributable to more effective antirheumatic treatment and not to a secular trend.
To evaluate changes in baseline patient characteristics and entry criteria of randomised, controlled studies of tumour necrosis factor alpha (TNFα) inhibitors in rheumatoid arthritis (RA) patients.
A systematic literature review was performed using predefined inclusion criteria to identify randomised, double-blind, controlled trials that evaluated TNFα inhibitors in adult RA patients. Entry criteria and baseline clinical characteristics were evaluated over time for methotrexate-experienced and methotrexate-naive study populations. Enrolment start date for each trial was the time metric. The anchor time was the study with the earliest identifiable enrolment start date.
44 primary publications (reporting the primary study endpoint) from 1993 to 2008 met the inclusion criteria. Enrolment start dates of August 1993 and May 1997 were identified as time anchors for the 37 methotrexate-experienced studies and the seven methotrexate-naive studies, respectively. In methotrexate-experienced trials, no significant change was observed over the years included in this study in any inclusion criteria (including swollen joint counts and C-reactive protein (CRP)), but a significant decrease over time was observed in the baseline swollen joint count, CRP and total Sharp or van der Heijde modified Sharp score, but not in baseline tender joint counts. In the methotrexate-naive studies, significant decreases over the years were observed in swollen joint and tender joint inclusion criteria, but not in baseline tender joint count, baseline CRP, CRP inclusion criteria or baseline total Sharp or van der Heijde modified Sharp score.
Inclusion criteria and baseline characteristics of RA patients enrolled in studies of TNFα inhibitors have changed, with more recent trials enrolling cohorts with lower disease activity, especially in methotrexate-experienced trials.
Inhibitors of the JAK family of nonreceptor tyrosine kinases have demonstrated clinical efficacy in rheumatoid arthritis and other inflammatory disorders; however, the precise mechanisms by which JAK inhibition improves inflammatory immune responses remain unclear. In this study, we examined the mode of action of tofacitinib (CP-690,550) on JAK/STAT signaling pathways involved in adaptive and innate immune responses. To determine the extent of inhibition of specific JAK/STAT-dependent pathways, we analyzed cytokine stimulation of mouse and human T cells in vitro. We also investigated the consequences of CP-690,550 treatment on Th cell differentiation of naive murine CD4(+) T cells. CP-690,550 inhibited IL-4-dependent Th2 cell differentiation and interestingly also interfered with Th17 cell differentiation. Expression of IL-23 receptor and the Th17 cytokines IL-17A, IL-17F, and IL-22 were blocked when naive Th cells were stimulated with IL-6 and IL-23. In contrast, IL-17A production was enhanced when Th17 cells were differentiated in the presence of TGF-β. Moreover, CP-690,550 also prevented the activation of STAT1, induction of T-bet, and subsequent generation of Th1 cells. In a model of established arthritis, CP-690,550 rapidly improved disease by inhibiting the production of inflammatory mediators and suppressing STAT1-dependent genes in joint tissue. Furthermore, efficacy in this disease model correlated with the inhibition of both JAK1 and JAK3 signaling pathways. CP-690,550 also modulated innate responses to LPS in vivo through a mechanism likely involving the inhibition of STAT1 signaling. Thus, CP-690,550 may improve autoimmune diseases and prevent transplant rejection by suppressing the differentiation of pathogenic Th1 and Th17 cells as well as innate immune cell signaling.
The Janus kinase (JAK) family of tyrosine kinases includes JAK1, JAK2, JAK3 and TYK2, and is required for signaling through Type I and Type II cytokine receptors. CP-690,550 is a potent and selective JAK inhibitor currently in clinical trials for rheumatoid arthritis (RA) and other autoimmune disease indications. In RA trials, dose-dependent decreases in neutrophil counts (PBNC) were observed with CP-690,550 treatment. These studies were undertaken to better understand the relationship between JAK selectivity and PBNC decreases observed with CP-690,550 treatment.
Potency and selectivity of CP-690,550 for mouse, rat and human JAKs was evaluated in a panel of in vitro assays. The effect of CP-690,550 on granulopoiesis from progenitor cells was also assessed in vitro using colony forming assays. In vivo the potency of orally administered CP-690,550 on arthritis (paw edema), plasma cytokines, PBNC and bone marrow differentials were evaluated in the rat adjuvant-induced arthritis (AIA) model.
CP-690,550 potently inhibited signaling through JAK1 and JAK3 with 5-100 fold selectivity over JAK2 in cellular assays, despite inhibiting all four JAK isoforms with nM potency in in vitro enzyme assays. Dose-dependent inhibition of paw edema was observed in vivo with CP-690,550 treatment. Plasma cytokines (IL-6 and IL-17), PBNC, and bone marrow myeloid progenitor cells were elevated in the context of AIA disease. At efficacious exposures, CP-690,550 returned all of these parameters to pre-disease levels. The plasma concentration of CP-690,550 at efficacious doses was above the in vitro whole blood IC50 of JAK1 and JAK3 inhibition, but not that of JAK2.
Results from this investigation suggest that CP-690,550 is a potent inhibitor of JAK1 and JAK3 with potentially reduced cellular potency for JAK2. In rat AIA, as in the case of human RA, PBNC were decreased at efficacious exposures of CP-690,550. Inflammatory end points were similarly reduced, as judged by attenuation of paw edema and cytokines IL-6 and IL-17. Plasma concentration at these exposures was consistent with inhibition of JAK1 and JAK3 but not JAK2. Decreases in PBNC following CP-690,550 treatment may thus be related to attenuation of inflammation and are likely not due to suppression of granulopoiesis through JAK2 inhibition.
Treatment of rheumatoid arthritis (RA) may differ among rheumatologists and currently, clear and consensual international recommendations on RA treatment are not available. In this paper recommendations for the treatment of RA with synthetic and biological disease-modifying antirheumatic drugs (DMARDs) and glucocorticoids (GCs) that also account for strategic algorithms and deal with economic aspects, are described. The recommendations are based on evidence from five systematic literature reviews (SLRs) performed for synthetic DMARDs, biological DMARDs, GCs, treatment strategies and economic issues. The SLR-derived evidence was discussed and summarised as an expert opinion in the course of a Delphi-like process. Levels of evidence, strength of recommendations and levels of agreement were derived. Fifteen recommendations were developed covering an area from general aspects such as remission/low disease activity as treatment aim via the preference for methotrexate monotherapy with or without GCs vis-à-vis combination of synthetic DMARDs to the use of biological agents mainly in patients for whom synthetic DMARDs and tumour necrosis factor inhibitors had failed. Cost effectiveness of the treatments was additionally examined. These recommendations are intended to inform rheumatologists, patients and other stakeholders about a European consensus on the management of RA with DMARDs and GCs as well as strategies to reach optimal outcomes of RA, based on evidence and expert opinion.
Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by inflammation of the articular synovium, resulting in bony erosions, deformity, and, ultimately, joint destruction. With associated comorbid conditions,especially cardiovascular, it can result in significant morbidity as well as early mortality. Patients with RA report impairments in health-related quality of life (HRQOL) in comparison with age- and sex-matched populations without arthritis. These decreases in HRQOL are attributed to the pain, impairment in physical function, and fatigue associated with this disease. The introduction of new disease-modifying antirheumatic drugs has revolutionized the treatment of RA, particularly the biologic agents: etanercept, infliximab,adalimumab, abatacept, and rituximab.Importantly, administration of these agents has resulted in statistically significant and clinically meaningful improvements in physical function and HRQOL. Many clinical studies confirm that with these therapies, RA patients report improvements in HRQOL, reflected by improved physical function, less fatigue, and better emotional and mental function. Maintenance of physical function is no longer the only treatment goal for RA but also to improve, restore, and preserve HRQOL. Results from pivotal clinical trials are analyzed in this article and the relevance of the data derived from the clinical studies to day-to-day clinical practice are also discussed.
Background Tofacitinib (CP-690,550) is a novel, oral Janus kinase inhibitor investigated as a targeted immunomodulator for rheumatoid arthritis (RA).
Objectives This is an analysis of the populations pooled across Phase 2 and 3 RA studies to assess whether there is consistency in the treatment effect of tofacitinib in subgroups of patients.
Methods The demographic and baseline disease characteristics of patients in the Phase 2 and Phase 3 studies were similar, which supports the pooling of these data. Data from patients receiving tofacitinib 5 or 10 mg twice daily (BID) or placebo in all randomised Phase 2 and Phase 3 studies ≥3 months in duration (monotherapy studies NCT00550446, NCT00687193, and NCT00814307; background DMARD Studies NCT00413660, NCT00603512, NCT00960440, NCT00847613, NCT00856544, and NCT00853385) were pooled. ACR20 response rates and rates of improvement from baseline of at least 0.22 in the HAQ-DI at Month 3 were analysed by baseline demographics and disease characteristics and results were expressed as probability ratios (proportion of responders randomised to tofacitinib treatment(s) divided by that of placebo at Month 3) and 95% confidence intervals (CIs). Treatment comparisons included 5 mg BID, 10 mg BID, and 5 and 10 mg BID groups combined, vs placebo. Additionally, ACR20 response rates and change from baseline in the HAQ-DI at Month 3 were analysed by previous treatment experience (traditional DMARDs and TNF inhibitors).
Results In an analysis of 3442 patients in total, tofacitinib demonstrated consistent efficacy in reducing signs and symptoms of RA and improving physical function, as measured by ACR20 and HAQ-DI, respectively, compared to placebo. The probability ratios for all treatment comparisons for ACR20 and HAQ-DI responder rates were ≥1, with the lower boundary of the 95% CIs also ≥1 for all but one subgroup. Efficacy was seen in all subgroups evaluated including: age (18-44, 45-64, and ≥65 years); gender; weight (<60, 60-100, and >100 kg); body mass index (BMI, <18.5, 18.5 to <25, 25 to <30, and ≥30); race (white, black, Asian, other); region (USA, Latin America, Europe plus Canada, and rest of the world); RA duration (<2, 2 to <5, 5 to <10, and ≥10 years); serological status (RF or CCP +), and baseline DAS28-4 (ESR) (≤5.1 and >5.1). The black race group appeared to have lower response rates than the other race groups, although the CI for this group was wide and the sample size relatively small. Tofacitinib also demonstrated consistent efficacy in patients previously treated with traditional DMARDs or TNF inhibitors, irrespective of the number of previous treatments.
Conclusions Tofacitinib was consistently efficacious, as measured by ACR20 and HAQ-DI, across the range of baseline demographics and disease characteristics such as age, gender, weight, BMI, race, geographic region, disease duration, serological status, disease activity and previous treatment experience.
Disclosure of Interest J. Kremer Grant/Research support from: Pfizer Inc, Consultant for: Pfizer Inc, C. Zerbini: None Declared, E. B. Lee Consultant for: Pfizer Inc, D. Gruben Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, S. Krishnaswami Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, S. Zwillich Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, T. Koncz Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, J. Bradley Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, C. Mebus Shareholder of: Pfizer Inc, Employee of: Pfizer Inc
The revised criteria for the classification of rheumatoid arthritis (RA) were formulated from a computerized analysis of 262 contemporary, consecutively studied patients with RA and 262 control subjects with rheumatic diseases other than RA (non-RA). The new criteria are as follows: 1) morning stiffness in and around joints lasting at least 1 hour before maximal improvement; 2) soft tissue swelling (arthritis) of 3 or more joint areas observed by a physician; 3) swelling (arthritis) of the proximal interphalangeal, metacarpophalangeal, or wrist joints; 4) symmetric swelling (arthritis); 5) rheumatoid nodules; 6) the presence of rheumatoid factor; and 7) radiographic erosions and/or periarticular osteopenia in hand and/or wrist joints. Criteria 1 through 4 must have been present for at least 6 weeks. Rheumatoid arthritis is defined by the presence of 4 or more criteria, and no further qualifications (classic, definite, or probable) or list of exclusions are required. In addition, a “classification tree” schema is presented which performs equally as well as the traditional (4 of 7) format. The new criteria demonstrated 91–94% sensitivity and 89% specificity for RA when compared with non-RA rheumatic disease control subjects.
Background:
Rheumatoid arthritis is a heterogeneous chronic disease, and no therapeutic agent has been identified which is universally and persistently effective in all patients. We investigated the effectiveness of tofacitinib (CP-690,550), a novel oral Janus kinase inhibitor, as a targeted immunomodulator and disease-modifying therapy for rheumatoid arthritis.
Methods:
We did a 6-month, double-blind, parallel-group phase 3 study at 82 centres in 13 countries, including North America, Europe, and Latin America. 399 patients aged 18 years or older with moderate-to-severe rheumatoid arthritis and inadequate response to tumour necrosis factor inhibitors (TNFi) were randomly assigned in a 2:2:1:1 ratio with an automated internet or telephone system to receive twice a day treatment with: tofacitinib 5 mg (n=133); tofacitinib 10 mg (n=134); or placebo (n=132), all with methotrexate. At month 3, patients given placebo advanced to either tofacitinib 5 mg twice a day (n=66) or 10 mg twice a day (n=66). Primary endpoints included American College of Rheumatology (ACR)20 response rate, mean change from baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI), and rates of disease activity score (DAS)28-4(ESR) less than 2·6 (referred to as DAS28<2·6), all at month 3. The full analysis set for the primary analysis included all randomised patients who received at least one dose of study medication and had at least one post-baseline assessment. This trial is registered with www.ClinicalTrials.gov, number NCT00960440.
Findings:
At month 3, ACR20 response rates were 41·7% (55 of 132 [95% CI vs placebo 6·06-28·41]; p=0·0024) for tofacitinib 5 mg twice a day and 48·1% (64 of 133; [12·45-34·92]; p<0·0001) for tofacitinib 10 mg twice a day versus 24·4% (32 of 131) for placebo. Improvements from baseline in HAQ-DI were -0·43 ([-0·36 to -0·15]; p<0·0001) for 5 mg twice a day and -0·46 ([-0·38 to -0·17]; p<0·0001) for 10 mg twice a day tofacitinib versus -0·18 for placebo; DAS28<2·6 rates were 6·7% (eight of 119; [0-10·10]; p=0·0496) for 5 mg twice a day tofacitinib and 8·8% (11 of 125 [1·66-12·60]; p=0·0105) for 10 mg twice a day tofacitinib versus 1·7% (two of 120) for placebo. Safety was consistent with phase 2 and 3 studies. The most common adverse events in months 0-3 were diarrhoea (13 of 267; 4·9%), nasopharyngitis (11 of 267; 4·1%), headache (11 of 267; 4·1%), and urinary tract infection (eight of 267; 3·0%) across tofacitinib groups, and nausea (nine of 132; 6·8%) in the placebo group.
Interpretation:
In this treatment-refractory population, tofacitinib with methotrexate had rapid and clinically meaningful improvements in signs and symptoms of rheumatoid arthritis and physical function over 6 months with manageable safety. Tofacitinib could provide an effective treatment option in patients with an inadequate response to TNFi.
Funding:
Pfizer.
Objective. To develop a set of disease activity measures for use in rheumatoid arthritis (RA) clinical trials, as well as to recommend specific methods for assessing each outcome measure. This is not intended to be a restrictive list, but rather, a core set of measures that should be included in all trials.
Methods. We evaluated disease activity measures commonly used in RA trials, to determine which measures best met each of 5 types of validity: construct, face, content, criterion, and discriminant. The evaluation consisted of an initial structured review of the literature on the validity of measures, with an analysis of data obtained from clinical trials to fill in gaps in this literature. A committee of experts in clinical trials, health services research, and biostatistics reviewed the validity data. A nominal group process method was used to reach consensus on a core set of disease activity measures. This set was then reviewed and finalized at an international conference on outcome measures for RA clinical trials. The committee also selected specific ways to assess each outcome.
Results. The core set of disease activity measures consists of a tender joint count, swollen joint count, patient's assessment of pain, patient's and physician's global assessments of disease activity, patient's assessment of physical function, and laboratory evaluation of 1 acute-phase reactant. Together, these measures sample the broad range of improvement in RA (have content validity), and all are at least moderately sensitive to change (have discriminant validity). Many of them predict other important long-term outcomes in RA, including physical disability, radiographic damage, and death. Other disease activity measures frequently used in clinical trials were not chosen for any one of several reasons, including insensitivity to change or duplication of information provided by one of the core measures (e.g., tender joint score and tender joint count) The committee also proposes specific ways of measuring each outcome.
Conclusion. We propose a core set of outcome measures for RA clinical trials. We hope this will decrease the number of outcomes assessed and standardize outcomes assessments. Further, we hope that these measures will be found useful in long-term studies.
BACKGROUND
Although fatigue is a common symptom among cancer patients, it is also a common experience in the general, healthy population. Its universality has made it difficult to appreciate whether the fatigue experienced by patients with cancer is distinguishable from the fatigue experienced by the general population. Because the etiology of fatigue is multifactorial, it also has been difficult to appreciate fully the relative contribution of anemia to cancer-related fatigue.METHODS
To address this issue, responses to a brief, standardized set of 13 questions from the Functional Assessment of Chronic Illness Therapy (FACIT) Measurement System were compared across three groups: anemic cancer patients (n = 2369 patients), nonanemic cancer patients (n = 113 patients), and the general United States population (n = 1010 persons).RESULTSFatigue scores of the anemic cancer patients (at both baseline and upon completion of anemia therapy) were significantly worse compared with the scores of nonanemic cancer patients that, in turn, were worse compared with the scores of the general United States population (P < 0.001). Score distributions were quite distinct for these three groups. Within the group of anemic cancer patients, the degree of anemia (mild, moderate, or severe) also was predictive of the degree of fatigue (P < 0.001), although the distributions were not dramatically distinct.CONCLUSIONS
Although anemia is clearly a factor that contributes to the severity of disease-related fatigue among cancer patients, hemoglobin levels explain only part of the difference compared with fatigue among the general United States population. The distinct distributions of fatigue scores of anemic cancer patients compared with the general United States population and the substantial sample sizes of these two groups enabled a discriminant analysis approach that allowed the differentiation of anemic cancer patients from the general population with high sensitivity (0.92) and reasonable specificity (0.69). Thus, although fatigue is a symptom most anyone can relate to, the fatigue of cancer patients, particularly those who are anemic, is decidedly worse. Interventions targeting this common and life-disrupting symptom likely would be of considerable value to patients with cancer. Cancer 2002;94:528–38. © 2002 American Cancer Society.
Figure 2. 2012 American College of Rheumatology (ACR) recommendations update for the treatment of established rheumatoid arthritis (RA), defined as a disease duration ≥6 months or meeting the 1987 ACR classification criteria. Depending on a patient's current medication regimen, the management algorithm may begin at an appropriate rectangle in the figure, rather than only at the top of the figure. Disease-modifying antirheumatic drugs (DMARDs) include hydroxychloroquine (HCQ), leflunomide (LEF), methotrexate (MTX), minocycline, and sulfasalazine (therapies are listed alphabetically; azathioprine and cyclosporine were considered but not included). DMARD monotherapy refers to treatment in most instances with HCQ, LEF, MTX, or sulfasalazine; in few instances, where appropriate, minocycline may also be used. Anti–tumor necrosis factor (anti-TNF) biologics include adalimumab, certolizumab pegol, etanercept, infliximab, and golimumab. Non-TNF biologics include abatacept, rituximab, or tocilizumab (therapies are listed alphabetically). For the level of evidence supporting each recommendation, please see Supplementary Appendix 7 (available in the online version of this article at http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)2151-4658).* Definitions of disease activity are discussed in Tables 2 and 3 and Supplementary Appendix 4 (available in the online version of this article at http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)2151-4658) and were categorized as low, moderate, or high.† Features of poor prognosis included the presence of 1 or more of the following: functional limitation (e.g., Health Assessment Questionnaire score or similar valid tools), extraarticular disease (e.g., presence of rheumatoid nodules, RA vasculitis, Felty's syndrome), positive rheumatoid factor or anti–cyclic citrullinated peptide antibodies (33–37), and bony erosions by radiograph (38).‡ Combination DMARD therapy with 2 DMARDs, which is most commonly MTX based, with few exceptions (e.g., MTX + HCQ, MTX + LEF, MTX + sulfasalazine, sulfasalazine + HCQ), and triple therapy (MTX + HCQ + sulfasalazine).§ Reassess after 3 months and proceed with escalating therapy if moderate or high disease activity in all instances except after treatment with a non-TNF biologic (rectangle D), where reassessment is recommended at 6 months due to a longer anticipated time for peak effect.¶ LEF can be added in patients with low disease activity after 3–6 months of minocycline, HCQ, MTX, or sulfasalazine.# If after 3 months of intensified DMARD combination therapy or after a second DMARD has failed, the option is to add or switch to an anti-TNF biologic.** Serious adverse events were defined per the US Food and Drug Administration (FDA; see below); all other adverse events were considered nonserious adverse events.†† Reassessment after treatment with a non-TNF biologic is recommended at 6 months due to anticipation that a longer time to peak effect is needed for non-TNF compared to anti-TNF biologics.‡‡ Any adverse event was defined as per the US FDA as any undesirable experience associated with the use of a medical product in a patient. The FDA definition of serious adverse event includes death, life-threatening event, initial or prolonged hospitalization, disability, congenital anomaly, or an adverse event requiring intervention to prevent permanent impairment or damage.Download figure to PowerPoint
Objective. Trials of rheumatoid arthritis (RA) treatments report the average response in multiple outcome measures for treated patients. It is more clinically relevant to test whether individual patients improve with treatment, and this identifies a single primary efficacy measure. Multiple definitions of improvement are currently in use in different trials. The goal of this study was to promulgate a single definition for use in RA trials.
Methods. Using the American College of Rheumatology (ACR) core set of outcome measures for RA trials, we tested 40 different definitions of improvement, using a 3-step process. First, we performed a survey of rheumatologists, using actual patient cases from trials, to evaluate which definitions corresponded best to rheumatologists' impressions of improvement, eliminating most candidate definitions of improvement. Second, we tested 20 remaining definitions to determine which maximally discriminated effective treatment from placebo treatment and also minimized placebo response rates. With 8 candidate definitions of improvement remaining, we tested to see which were easiest to use and were best in accord with rheumatologists' impressions of improvement.
Results. The following definition of improvement was selected: 20% improvement in tender and swollen joint counts and 20% improvement in 3 of the 5 remaining ACR core set measures: patient and physician global assessments, pain, disability, and an acutephase reactant. Additional validation of this definition was carried out in a comparative trial, and the results suggest that the definition is statistically powerful and does not identify a large percentage of placebo-treated patients as being improved.
Conclusion. We present a definition of improvement which we hope will be used widely in RA trials.
To compare the efficacy, safety, and tolerability of 6 dosages of oral tofacitinib (CP-690,550) with placebo for the treatment of active rheumatoid arthritis (RA) in patients receiving a stable background regimen of methotrexate (MTX) who have an inadequate response to MTX monotherapy.
In this 24-week, double-blind, phase IIb study, patients with active RA (n = 507) were randomized to receive placebo or tofacitinib (20 mg/day, 1 mg twice daily, 3 mg twice daily, 5 mg twice daily, 10 mg twice daily, or 15 mg twice daily). All patients continued to receive a stable dosage of MTX. The primary end point was the American College of Rheumatology 20% improvement criteria (ACR20) response rate at week 12.
At week 12, ACR20 response rates for patients receiving all tofacitinib dosages ≥3 mg twice daily (52.9% for 3 mg twice daily, 50.7% for 5 mg twice daily, 58.1% for 10 mg twice daily, 56.0% for 15 mg twice daily, and 53.8% for 20 mg/day) were significantly (P ≤ 0.05) greater than those for placebo (33.3%). Improvements were sustained at week 24 for the ACR20, ACR50, and ACR70 responses, scores for the Health Assessment Questionnaire disability index, the 3-variable Disease Activity Score in 28 joints using the C-reactive protein level (DAS28-CRP), and a 3-variable DAS28-CRP of <2.6. The most common treatment-emergent adverse events occurring in >10% of patients in any tofacitinib group were diarrhea, upper respiratory tract infection, and headache; 21 patients (4.1%) experienced serious adverse events. Sporadic increases in transaminase levels, increases in cholesterol and serum creatinine levels, and decreases in neutrophil and hemoglobin levels were observed.
In patients with active RA in whom the response to MTX has been inadequate, the addition of tofacitinib at a dosage ≥3 mg twice daily showed sustained efficacy and a manageable safety profile over 24 weeks.
To compare the efficacy, safety, and tolerability of 5 doses of oral tofacitinib (CP-690,550) or adalimumab monotherapy with placebo for the treatment of active rheumatoid arthritis (RA) in patients with an inadequate response to disease-modifying antirheumatic drugs.
In this 24-week, double-blind, phase IIb study, patients with RA (n = 384) were randomized to receive placebo, tofacitinib at 1, 3, 5, 10, or 15 mg administered orally twice a day, or adalimumab at 40 mg injected subcutaneously every 2 weeks (total of 6 injections) followed by oral tofacitinib at 5 mg twice a day for 12 weeks. The primary end point was the responder rate according to the American College of Rheumatology 20% improvement criteria (ACR20) at week 12.
Treatment with tofacitinib at a dose of ≥3 mg twice a day resulted in a rapid response with significant efficacy when compared to placebo, as indicated by the primary end point (ACR20 response at week 12), achieved in 39.2% (3 mg; P ≤ 0.05), 59.2% (5 mg; P < 0.0001), 70.5% (10 mg; P < 0.0001), and 71.9% (15 mg; P < 0.0001) in the tofacitinib group and 35.9% of patients in the adalimumab group (P = 0.105), compared with 22.0% of patients receiving placebo. Improvements were sustained at week 24, according to the ACR20, ACR50, and ACR70 response rates as well as classifications of remission according to the 3-variable Disease Activity Score in 28 joints (DAS28) using C-reactive protein and the 4-variable DAS28 using the erythrocyte sedimentation rate. The most common treatment-emergent adverse events (AEs) in patients across all tofacitinib treatment arms (n = 272) were urinary tract infection (7.7%), diarrhea (4.8%), headache (4.8%), and bronchitis (4.8%).
Tofacitinib monotherapy at ≥3 mg twice a day was efficacious in the treatment of patients with active RA over 24 weeks and demonstrated a manageable safety profile.
To compare the efficacy, safety, and tolerability of 4 doses of oral tofacitinib (CP-690,550) with placebo in Japanese patients with active rheumatoid arthritis (RA) receiving stable background methotrexate (MTX) who had an inadequate response to MTX alone.
A total of 140 patients were randomized to receive tofacitinib 1, 3, 5, and 10 mg twice a day or placebo in this 12-week, phase II, double-blind study. All patients remained on background MTX. Efficacy and safety were assessed at weeks 1, 2, 4, 8, and 12. The primary efficacy end point was the American College of Rheumatology 20% improvement criteria (ACR20) response rate at week 12.
ACR20 response rates at week 12 were significant (P < 0.0001) for all tofacitinib treatment groups: 1 mg twice a day, 64.3%; 3 mg twice a day, 77.8%; 5 mg twice a day, 96.3%; and 10 mg twice a day, 80.8% versus placebo, 14.3%. A significant dose-response relationship for the ACR20 was observed (P < 0.0001). Low disease activity was achieved by 72.7% of patients with high baseline disease activity for tofacitinib 10 mg twice a day at week 12 (P < 0.0001). Significant improvements in the ACR50, ACR70, Health Assessment Questionnaire Disability Index, and Disease Activity Score 28-3 (C-reactive protein) were also reported. The most commonly reported adverse events (AEs) were nasopharyngitis (n = 13) and increased alanine aminotransferase (n = 12) and aspartate aminotransferase (n = 9) levels. These AEs were mild or moderate in severity. Serious AEs were reported by 5 patients. No deaths occurred.
In Japanese patients with active RA with an inadequate response to MTX, tofacitinib in combination with MTX over 12 weeks was efficacious and had a manageable safety profile.
The Janus family kinases (Jaks), Jak1, Jak2, Jak3, and Tyk2, form one subgroup of the non-receptor protein tyrosine kinases. They are involved in cell growth, survival, development, and differentiation of a variety of cells but are critically important for immune cells and hematopoietic cells. Data from experimental mice and clinical observations have unraveled multiple signaling events mediated by Jaks in innate and adaptive immunity. Deficiency of Jak3 or Tyk2 results in defined clinical disorders, which are also evident in mouse models. A striking phenotype associated with inactivating Jak3 mutations is severe combined immunodeficiency syndrome, whereas mutation of Tyk2 results in another primary immunodeficiency termed autosomal recessive hyperimmunoglobulin E syndrome. By contrast, complete deletion of Jak1 or Jak2 in the mouse are not compatible with life and, unsurprisingly, do not have counterparts in human disease. However, activating mutations of each of the Jaks are found in association with malignant transformation, the most common being gain-of-function mutations of Jak2 in polycythemia vera and other myeloproliferative disorders. Our existing knowledge on Jak signaling pathways and fundamental work on their biochemical structure and intracellular interactions allow us to develop new strategies for controlling autoimmune diseases or malignancies by developing selective Jak inhibitors, which are now coming into clinical use. Despite the fact that Jaks were discovered only a little more than a decade ago, at the time of writing there are 20 clinical trials underway testing the safety and efficacy of Jak inhibitors.
Trials of rheumatoid arthritis (RA) treatments report the average response in multiple outcome measures for treated patients. It is more clinically relevant to test whether individual patients improve with treatment, and this identifies a single primary efficacy measure. Multiple definitions of improvement are currently in use in different trials. The goal of this study was to promulgate a single definition for use in RA trials.
Using the American College of Rheumatology (ACR) core set of outcome measures for RA trials, we tested 40 different definitions of improvement, using a 3-step process. First, we performed a survey of rheumatologists, using actual patient cases from trials, to evaluate which definitions corresponded best to rheumatologists' impressions of improvement, eliminating most candidate definitions of improvement. Second, we tested 20 remaining definitions to determine which maximally discriminated effective treatment from placebo treatment and also minimized placebo response rates. With 8 candidate definitions of improvement remaining, we tested to see which were easiest to use and were best in accord with rheumatologists' impressions of improvement.
The following definition of improvement was selected: 20% improvement in tender and swollen joint counts and 20% improvement in 3 of the 5 remaining ACR core set measures: patient and physician global assessments, pain, disability, and an acute-phase reactant. Additional validation of this definition was carried out in a comparative trial, and the results suggest that the definition is statistically powerful and does not identify a large percentage of placebo-treated patients as being improved.
We present a definition of improvement which we hope will be used widely in RA trials.
To develop a set of disease activity measures for use in rheumatoid arthritis (RA) clinical trials, as well as to recommend specific methods for assessing each outcome measure. This is not intended to be a restrictive list, but rather, a core set of measures that should be included in all trials.
We evaluated disease activity measures commonly used in RA trials, to determine which measures best met each of 5 types of validity: construct, face, content, criterion, and discriminant. The evaluation consisted of an initial structured review of the literature on the validity of measures, with an analysis of data obtained from clinical trials to fill in gaps in this literature. A committee of experts in clinical trials, health services research, and biostatistics reviewed the validity data. A nominal group process method was used to reach consensus on a core set of disease activity measures. This set was then reviewed and finalized at an international conference on outcome measures for RA clinical trials. The committee also selected specific ways to assess each outcome.
The core set of disease activity measures consists of a tender joint count, swollen joint count, patient's assessment of pain, patient's and physician's global assessments of disease activity, patient's assessment of physical function, and laboratory evaluation of 1 acute-phase reactant. Together, these measures sample the broad range of improvement in RA (have content validity), and all are at least moderately sensitive to change (have discriminant validity). Many of them predict other important long-term outcomes in RA, including physical disability, radiographic damage, and death. Other disease activity measures frequently used in clinical trials were not chosen for any one of several reasons, including insensitivity to change or duplication of information provided by one of the core measures (e.g., tender joint score and tender joint count). The committee also proposes specific ways of measuring each outcome.
We propose a core set of outcome measures for RA clinical trials. We hope this will decrease the number of outcomes assessed and standardize outcomes assessments. Further, we hope that these measures will be found useful in long-term studies.
This article is a short overview of the development of the Sharp/van der Heijde methods for scoring radiographs of hands and feet in rheumatoid arthritis, in addition to a detailed description on how to use the scoring method.
Neutralization of tumor necrosis factor a (TNF-alpha) for three to six months reduces the symptoms and signs of rheumatoid arthritis. However, the capacity of this approach to effect a more sustained benefit and its effect on joint damage are not known.
We treated 428 patients who had active rheumatoid arthritis despite methotrexate therapy with placebo or infliximab, a chimeric monoclonal antibody against TNF-alpha, in intravenous doses of 3 or 10 mg per kilogram of body weight every 4 or 8 weeks in combination with oral methotrexate for 54 weeks. We assessed clinical responses with use of the criteria of the American College of Rheumatology, the quality of life with a health-status questionnaire, and the effect on joint damage radiographically.
The combination of infliximab and methotrexate was well tolerated and resulted in a sustained reduction in the symptoms and signs of rheumatoid arthritis that was significantly greater than the reduction associated with methotrexate therapy alone (clinical response, 51.8 percent vs. 17.0 percent; P<0.001). The quality of life was also significantly better with infliximab plus methotrexate than with methotrexate alone. Radiographic evidence of joint damage increased in the group given methotrexate, but not in the groups given infliximab and methotrexate (mean change in radiographic score, 7.0 vs. 0.6, P<0.001). Radiographic evidence of progression of joint damage was absent in infliximab-treated patients whether or not they had a clinical response.
In patients with persistently active rheumatoid arthritis despite methotrexate therapy, repeated doses of infliximab in combination with methotrexate provided clinical benefit and halted the progression of joint damage.
