tofacitinib and Chronic-Disease

Tofacitinib is an oral Janus kinase (JAK) inhibitor that targets JAK1 and JAK3, and thus regulates immune response. Therefore, tofacitinib is used to treat immune-mediated inflammatory diseases such as chronic plaque psoriasis. The objective of this study was to systematically assess the efficacy and safety of tofacitinib in treating chronic plaque psoriasis.. To systematically review the efficacy and safety of tofacitinib in the treatment of chronic plaque psoriasis, we performed a meta-analysis to evaluate the efficacy and safety of tofacitinib in patients with chronic plaque psoriasis.. Databases including PubMed, Embase, and The Cochrane Library were searched for randomized controlled trials about the efficacy and safety of tofacitinib in treating chronic plaque psoriasis from inception to August 2017 (PROSPERO Code No: CRD42017076587).. Six articles (seven randomized controlled trial studies) involving 3743 patients were included. The meta-analysis results showed that for efficacy, tofacitinib (5 mg or 10 mg) compared with placebo can significantly improve the Physician's Global Assessment response, PASI75, and PASI90 after treatment. For safety, the incidence of adverse reactions was statistically significantly higher for tofacitinib compared with placebo.. Treatment of chronic plaque psoriasis with tofacitinib is effective, but there may be more adverse reactions.

Topics: Chronic Disease; Humans; Piperidines; Protein Kinase Inhibitors; Psoriasis; Pyrimidines; Pyrroles; Treatment Outcome

The outlook for patients with psoriasis has improved significantly over the last 10 years with the introduction of targeted therapies. Cytokines exert their effects by activating intracellular signaling and transcription pathways, among which there are Janus kinases (JAKs) and signal transducers and activators of transcription (STAT) pathways. JAKs are intracellular second messengers that are crucial for transmitting extracellular cytokine signals to the cell. JAK inhibition interrupts intracellular signaling and can suppress immune cell activation and inflammation in T-cell-mediated disorders, such as psoriasis. Consequently, JAKs are the subject of intensive research activity, since they represent possible therapeutic targets. Tofacitinib is an orally available compound belonging to a novel category of nonbiologic drugs, the "JAK inhibitors", which target JAKs. Recently, oral and topical formulations of tofacitinib have been demonstrated to be safe and effective for the treatment of plaque psoriasis in randomized clinical trials. In particular, a 10 mg bid dose of tofacitinib was shown to be noninferior to etanercept 50 mg subcutaneously twice weekly. Questions remain unresolved regarding the safety risk beyond the 5 mg bid dose. This review, assessing the available scientific literature, focuses on the profile of tofacitinib, as investigational compound in the treatment of plaque psoriasis. An overview of the efficacy and safety data from randomized clinical trials is provided. In addition, the authors highlight future potential applications of tofacitinib in other skin diseases, in particular alopecia areata and vitiligo.

Topics: Chronic Disease; Clinical Trials as Topic; Humans; Janus Kinase 3; Piperidines; Protein Kinase Inhibitors; Psoriasis; Pyrimidines; Pyrroles

To analyze lipid changes in patients with rheumatoid arthritis (RA) and patients with spondyloarthritis (SpA) treated with biologic agents or tofacitinib in randomized clinical trials (RCTs).. A systematic literature search was performed, using the Medline, Embase, Cochrane Library, and Web of Knowledge databases. Meta-analyses were performed using random-effects models to assess changes in the percentage of patients with abnormal lipid values or in the mean percentage of increase in the cholesterol and triglycerides levels.. Twenty-five of 4,527 identified articles met the inclusion criteria. Compared with RA patients treated with placebo, those treated with tocilizumab were more likely to have hypercholesterolemia (odds ratio [OR] 4.64; 95% confidence interval [95% CI] 2.71, 7.95 [P < 0.001]), increased levels of high-density lipoprotein (HDL) cholesterol (OR 2.25; 95% CI 1.14, 4.44 [P = 0.020]), and increased levels of low-density lipoprotein (LDL) cholesterol (OR 4.80; 95% CI 3.27, 7.05 [P < 0.001]); this was not observed in patients treated with tumor necrosis factor (TNF) antagonists (OR 1.54; 95% CI 0.90, 2.66 [P = 0.119]) or tofacitinib (OR 3.4; 95% CI 0.62, 18.55 [P = 0.158]). Among patients receiving tofacitinib 5 mg twice daily, the mean percentage of increases in the HDL cholesterol level (weighted mean difference [WMD] 13.00 mg/dl; 95% CI 12.08, 13.93 [P < 0.001]) and the LDL cholesterol level (WMD 11.20 mg/dl; 95% CI 10.08, 12.32 [P < 0.001]) were higher than those in the comparator groups. Among patients treated with tofacitinib 10 mg twice daily, the mean percentage of increases in the HDL cholesterol level (WMD 15.21 mg/dl; 95% CI 13.28, 17.14 [P < 0.001]) and the LDL cholesterol level (WMD 15.42 mg/dl; 95% CI 11.77, 19.06 [P < 0.001]) were also higher than those in the comparator groups. No data were available for RA treated with other biologic agents or for SpA.. In patients with RA treated with tocilizumab or tofacitinib but not with TNF antagonists, moderate changes in lipids are observed. Whether these changes pertain to the control of inflammation or to the mechanism of action of the biologic agents or tofacitinib remains undetermined.

Topics: Adult; Aged; Antibodies, Monoclonal, Humanized; Arthritis, Rheumatoid; Biological Products; Chronic Disease; Female; Humans; Lipids; Male; Middle Aged; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Randomized Controlled Trials as Topic; Spondylarthritis; Treatment Outcome

Tofacitinib is an oral Janus kinase inhibitor being investigated for psoriasis. A Phase 3 withdrawal/re-treatment study (NCT01186744; OPT Retreatment) showed tofacitinib re-treatment was effective in patients with chronic plaque psoriasis.. To describe the effects of tofacitinib withdrawal/re-treatment on health-related quality of life (HRQoL) and disease symptoms measured by patient-reported outcomes (PROs).. The study was divided into initial treatment, treatment withdrawal, and re-treatment periods. Initial treatment: patients were randomized to receive tofacitinib 5 (n = 331) or 10 mg (n = 335) BID for 24 weeks. Treatment withdrawal: patients who achieved both ≥ 75% reduction in Psoriasis Area and Severity Index (PASI) score from baseline and Physician's Global Assessment of 'clear'/'almost clear' at Week (W)24 received placebo (withdrawal) or the previous dose (continuous treatment). Re-treatment: at relapse (> 50% loss of W24 PASI response) or at W40, patients received their initial tofacitinib dose. PROs included: Dermatology Life Quality Index (DLQI), Itch Severity Item (ISI), Short Form-36 (SF-36) and Patient's Global Assessment (PtGA).. After initial treatment with tofacitinib 5 and 10 mg BID, substantial and significant improvements were reported for mean DLQI (baseline: 12.6 and 12.6; W24: 5.1 and 2.6) and ISI (baseline: 6.7 and 6.9; W24: 2.9 and 1.6). Patients continuously treated with tofacitinib 5 and 10 mg BID maintained those improvements through Week 56 (DLQI: 3.0 and 2.1; ISI: 2.3 and 1.4). By W40, patients withdrawn from tofacitinib 5 and 10 mg BID showed worsening in DLQI (5.0 and 6.2) and ISI (3.7 and 4.0) scores; improvements were regained upon re-treatment (W56, DLQI: 3.4 and 2.4; ISI: 2.2 and 1.6). Similar results were reported for PtGA and SF-36.. Continuous tofacitinib treatment provided sustained improvement in HRQoL and disease symptoms. Patients randomized to treatment withdrawal lost initial improvements. Upon re-treatment, improvements were recaptured to levels comparable to those seen with continuous treatment.

Topics: Chronic Disease; Dermatologic Agents; Double-Blind Method; Humans; Piperidines; Psoriasis; Pyrimidines; Pyrroles; Quality of Life; Severity of Illness Index

Tofacitinib is an oral Janus kinase inhibitor that is being investigated for psoriasis. Psoriasis impacts on physical and psychological well-being; improvements in health-related quality of life (HRQoL) with etanercept in psoriasis are well documented.. To evaluate HRQoL with tofacitinib, vs. placebo or etanercept, in the Phase 3, randomized, placebo-controlled, non-inferiority, Oral-treatment Psoriasis Trial (OPT) Compare Study (NCT01241591).. Adults with moderate to severe chronic plaque psoriasis were randomized 3:3:3:1 to tofacitinib 10 or 5 mg twice daily (BID), etanercept 50 mg twice weekly or placebo, for 12 weeks. Patient-reported outcomes (PROs) included Dermatology Life Quality Index (DLQI), Itch Severity Item and Patient Global Assessment of psoriasis.. At baseline, 83.4% (911/1092) of patients had a DLQI score ranging between 6 and 30, indicating a substantial burden of disease. By Week 12, 47.3%, 43.6% and 30.9% of patients in the tofacitinib 10 mg BID, etanercept and tofacitinib 5 mg BID groups, respectively, had a DLQI score of 0 or 1 (no effect of psoriasis on QoL) vs. 7.8% for placebo (all P < 0.0001). Tofacitinib significantly reduced itch vs. placebo (P < 0.05 both doses) and etanercept (P < 0.0001 both doses) within 1 day of starting treatment. Furthermore, reductions in itch were greater with tofacitinib 10 mg BID, vs. etanercept, at Weeks 2-12 (all time points P < 0.05). At Week 2, an Itch Severity Item score of 'little or no itch' was more frequent with tofacitinib 10 mg (68.6%) vs. etanercept (57.4%) and placebo (12.2%), and the PtGA response rate was significantly greater with tofacitinib 10 mg vs. placebo (P < 0.05).. Oral tofacitinib provided significant improvements across multiple PROs by Week 12. Improvements with tofacitinib 10 mg BID were comparable to etanercept, and improvements in itch were greater and more rapid with tofacitinib 10 mg BID.

Topics: Chronic Disease; Dermatologic Agents; Etanercept; Humans; Patient Satisfaction; Piperidines; Placebos; Psoriasis; Pyrimidines; Pyrroles; Treatment Outcome

Tofacitinib is an oral Janus kinase inhibitor being investigated for the treatment of moderate-to-severe plaque psoriasis.. To compare outcomes following tofacitinib withdrawal with outcomes of continuation.. In this phase 3 study (NCT01186744), patients received tofacitinib 5 mg (n = 331) or 10 mg (n = 335) twice daily for 24 weeks. The patients who achieved both ≥ 75% reduction in Psoriasis Area and Severity Index (PASI 75) score from baseline and Physician's Global Assessment (PGA) of 'clear' or 'almost clear' (PGA response) received a placebo (withdrawal) or the previous dose. At relapse (> 50% reduction in the PASI improvement during initial treatment) or week 40, the patients received the initial dose.. Initial treatment: 33·5% and 55·2% achieved both PASI 75 and PGA responses with tofacitinib 5 and 10 mg twice daily, respectively, making them eligible for the treatment-withdrawal period. Withdrawal: 56·2%, 62·3%, 23·3% and 26·1% maintained PASI 75 responses with tofacitinib 5, 10 mg, placebo (5 mg) and placebo (10 mg) twice daily, respectively; 49·9%, 63·9%, 22·9% and 18·0% maintained PGA responses; and 92·3%, 93·0%, 32·8% and 42·9% did not relapse. Elevations in low-density lipoprotein-cholesterol levels following initial treatment (mean increase: 8·71 mg dL(-1) with 5 mg twice daily, 10·26 mg dL(-1) with 10 mg twice daily) were reversed upon withdrawal. Retreatment: 36·8% and 61·0% of patients who relapsed achieved PASI 75 responses with tofacitinib 5 or 10 mg after 16 weeks; 44·8% and 57·1% regained PGA responses.. Patients who received continuous treatment maintained a response more effectively when compared with placebo recipients. Safety profiles were comparable in both the continuous treatment group and retreatment group. Of those patients who relapsed, up to 60% recaptured a response with tofacitinib.

Topics: Adolescent; Adult; Aged; Chronic Disease; Dermatologic Agents; Double-Blind Method; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Patient Outcome Assessment; Piperidines; Protein Kinase Inhibitors; Psoriasis; Pyrimidines; Pyrroles; Quality of Life; Retreatment; Treatment Outcome; Young Adult

New therapeutic options are needed for patients with psoriasis. Tofacitinib, an oral Janus kinase inhibitor, is being investigated as a treatment for moderate-to-severe chronic plaque psoriasis. In this study, we aimed to compare two tofacitinib doses with high-dose etanercept or placebo in this patient population.. In this phase 3, randomised, multicentre, double-dummy, placebo-controlled, 12-week, non-inferiority trial, adult patients with chronic stable plaque psoriasis (for ≥12 months) who were candidates for systemic or phototherapy and had a Psoriasis Area and Severity Index (PASI) score of 12 or higher and a Physician's Global Assessment (PGA) of moderate or severe, and had failed to respond to, had a contraindication to, or were intolerant to at least one conventional systemic therapy, were enrolled from 122 investigational dermatology centres worldwide. Eligible patients were randomly assigned in a 3:3:3:1 ratio to receive tofacitinib 5 mg or 10 mg twice daily at about 12 h intervals, etanercept 50 mg subcutaneously twice weekly at about 3-4 day intervals, or placebo. Randomisation was done by a computer-generated randomisation schedule, and all patients and study personnel were masked to treatment assignment. The co-primary endpoints were the proportion of patients at week 12 with at least a 75% reduction in the PASI score from baseline (PASI75 response) and the proportion of patients achieving a PGA score of "clear" or "almost clear" (PGA response), analysed in the full analysis set (all patients who were randomised and received at least one dose of study drug). This study is registered with ClinicalTrials.gov, number NCT01241591.. Between Nov 29, 2010, and Sept 13, 2012, we enrolled 1106 eligible adult patients with chronic plaque psoriasis and randomly assigned them to the four treatment groups (330 to tofacitinib 5 mg twice daily, 332 to tofacitinib 10 mg twice daily, 336 to etanercept 50 mg twice weekly, and 108 to placebo). Of these patients, 1101 actually received their assigned study medication (329 in the tofactinib 5 mg group, 330 in the tofacitinib 10 mg group, 335 in the etanercept group, and 107 in the placebo group). At week 12, PASI75 responses were recorded in 130 (39·5%) of 329 patients in the tofacitinib 5 mg group, 210 (63·6%) of 330 in the tofacitinib 10 mg group, 197 (58·8%) of 335 in the etanercept group, and six (5·6%) of 107 in the placebo group. A PGA response was achieved by 155 (47·1%) of 329 patients in the tofacitinib 5 mg group, 225 (68·2%) of 330 in the tofacitinib 10 mg group, 222 (66·3%) of 335 in the etanercept group, and 16 (15·0%) of 107 in the placebo group. The rate of adverse events was similar across the four groups, with serious adverse events occurring in seven (2%) of 329 patients in the tofacitinib 5 mg group, five (2%) of 330 in the tofacitinib 10 mg group, seven (2%) of 335 in the etanercept group, and two (2%) of 107 in the placebo group. Three (1%) of 329 patients in the tofacitinib 5 mg group, ten (3%) of 330 in the tofacitinib 10 mg group, 11 (3%) of 335 in the etanercept group, and four (4%) of 107 patients in the placebo group discontinued their assigned treatment because of adverse events.. In patients with moderate-to-severe plaque psoriasis, the 10 mg twice daily dose of tofacitinib was non-inferior to etanercept 50 mg twice weekly and was superior to placebo, but the 5 mg twice daily dose did not show non-inferiority to etanercept 50 mg twice weekly. The adverse event rates over 12 weeks were similar for tofacitinib and etanercept. This study indicates that in the future tofacitinib could provide a convenient and well-tolerated therapeutic option for patients with moderate-to-severe plaque psoriasis.. Pfizer Inc.

Topics: Adult; Anti-Inflammatory Agents, Non-Steroidal; Chronic Disease; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Etanercept; Female; Humans; Immunoglobulin G; Male; Middle Aged; Piperidines; Protein Kinase Inhibitors; Psoriasis; Pyrimidines; Pyrroles; Receptors, Tumor Necrosis Factor; Treatment Outcome

Tofacitinib is an oral Janus kinase inhibitor being investigated for psoriasis.. To determine the 16-week efficacy and safety of two oral tofacitinib doses vs. placebo in patients with moderate-to-severe chronic plaque psoriasis.. Patients in two similarly designed phase III studies (OPT Pivotal 1, NCT01276639, n = 901; OPT Pivotal 2, NCT01309737, n = 960) were initially randomized 2 : 2 : 1 to tofacitinib 10 or 5 mg or placebo, twice daily. Coprimary efficacy end points (week 16) included the proportion of patients achieving Physician's Global Assessment (PGA) of 'clear' or 'almost clear' (PGA response) and the proportion achieving ≥ 75% reduction in Psoriasis Area and Severity Index (PASI 75).. Across OPT Pivotal 1 and OPT Pivotal 2, 745 patients received tofacitinib 5 mg, 741 received tofacitinib 10 mg and 373 received placebo. At week 16, a greater proportion of patients achieved PGA responses with tofacitinib 5 and 10 mg twice daily vs. placebo (OPT Pivotal 1, 41·9% and 59·2% vs. 9·0%; OPT Pivotal 2, 46·0% and 59·1% vs. 10·9%; all P < 0·001). Higher PASI 75 rates were observed with tofacitinib vs. placebo (OPT Pivotal 1, 39·9%, 59·2% and 6·2%, respectively, for tofacitinib 5 and 10 mg twice daily and placebo; OPT Pivotal 2, 46·0%, 59·6% and 11·4%; all P < 0·001 vs. placebo). Adverse event (AE) rates appeared generally similar across groups; rates of serious AEs, infections, malignancies and discontinuations due to AEs were low. Twelve patients reported herpes zoster across the tofacitinib treatment groups in both studies vs. none in the respective placebo groups. The most common AE across groups was nasopharyngitis.. Oral tofacitinib demonstrated significant efficacy vs. placebo during the initial 16 weeks of treatment in patients with moderate-to-severe psoriasis. Safety findings were consistent with prior studies.

Topics: Administration, Oral; Adolescent; Adult; Aged; Chronic Disease; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Piperidines; Protein Kinase Inhibitors; Psoriasis; Pyrimidines; Pyrroles; Treatment Outcome; Young Adult

The Janus kinase (JAK) inhibitor, tofacitinib, has shown efficacy for the treatment of psoriasis in a phase IIb trial (A3921047; NCT00678210).. To report haematology data from the phase IIb trial, given the importance of JAK-dependent signalling in haematopoiesis.. Patients with moderate-to-severe chronic plaque psoriasis were randomized to receive tofacitinib 2, 5 or 15 mg, or placebo, twice daily over 12 weeks. Blood samples were collected at screening, baseline, weeks 2, 4, 8 and 12 during treatment, and weeks 14 and 16 during off-treatment follow-up.. Baseline haematology was similar across patients receiving tofacitinib 2 mg (n = 49), 5 mg (n = 49) or 15 mg (n = 49), or placebo (n = 50). Tofacitinib conferred dose-dependent decreases in haemoglobin, haematocrit and red blood cell counts, while reticulocyte counts initially declined, before recovering by week 8, and exceeding baseline levels after treatment cessation. With regard to white blood cells, tofacitinib had no clear dose-dependent effects on basophils or monocytes, but appeared to be associated with transient or reversible dose-dependent decreases in neutrophil and eosinophil counts and transient increases in lymphocyte counts, which were primarily attributable to increases in B-cell counts. Natural killer cell counts declined with tofacitinib.. Tofacitinib conferred tolerable, dose-dependent changes in haematological parameters during short-term administration in patients with psoriasis. The effects did not appear to be progressive, and were often transient or reversible.

Topics: Adolescent; Adult; Aged; Basophils; Blood Cell Count; Chronic Disease; Dermatologic Agents; Dose-Response Relationship, Drug; Female; Hematocrit; Hemoglobins; Humans; Killer Cells, Natural; Leukocytes; Male; Middle Aged; Monocytes; Piperidines; Protein Kinase Inhibitors; Psoriasis; Pyrimidines; Pyrroles; Young Adult

Tofacitinib (CP-690,550) is a novel Janus kinase inhibitor in development as an oral formulation for the treatment of several inflammatory diseases including psoriasis.. This phase 2a study aimed to assess the efficacy, systemic safety, local tolerability and systemic pharmacokinetics of topical tofacitinib in mild-to-moderate plaque psoriasis.. Two tofacitinib ointment formulations were evaluated in this multicentre, double-blind, vehicle-controlled trial (NCT01246583). Seventy-one patients were randomized 2 : 1 : 2 : 1 to 2% tofacitinib ointment 1, vehicle 1, 2% tofacitinib ointment 2 and vehicle 2, each administered twice daily for 4 weeks to a single fixed 300 cm(2) treatment area containing a target plaque with or without one or more nontarget plaques and normal skin.. The primary endpoint of percentage change from baseline in the Target Plaque Severity Score at week 4 demonstrated statistically significant improvement for ointment 1 [least squares mean (LSM) -54.4%] vs. vehicle 1 (LSM -41.5%), but not ointment 2 (LSM -24.2%) vs. vehicle 2 (LSM -17.2%). Secondary endpoints (target plaque area and Itch Severity Item) improved similarly for tofacitinib ointment vs. corresponding vehicle. Adverse event (AE) occurrence was similar across treatment groups. All AEs were mild or moderate and none were serious or led to subject discontinuation. One application-site AE (erythema) was reported. Tofacitinib mean systemic exposure was minimal and was greater for ointment 1 than for ointment 2.. Tofacitinib ointment 1 was well tolerated and efficacious compared with vehicle for the treatment of plaque psoriasis. Further study of topical tofacitinib for psoriasis treatment is warranted.

Topics: Administration, Cutaneous; Adult; Aged; Chronic Disease; Dermatologic Agents; Double-Blind Method; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Ointments; Piperidines; Protein Kinase Inhibitors; Psoriasis; Pyrimidines; Pyrroles; Treatment Outcome; Young Adult

Tofacitinib is a novel, oral Janus kinase inhibitor under investigation as a potential treatment for plaque psoriasis.. This Phase 2b, 12-week, dose-ranging study (A3921047, NCT00678210) aimed to characterize the exposure-response, efficacy and safety of tofacitinib vs. placebo in patients with moderate-to-severe chronic plaque psoriasis.. One hundred and ninety-seven patients were randomized. The primary endpoint was the proportion of patients achieving a ≥ 75% reduction in the Psoriasis Area and Severity Index (PASI 75) score at week 12.. At week 12, PASI 75 response rates were significantly higher for all tofacitinib twice-daily groups: 25·0% (2 mg; P < 0·001), 40·8% (5 mg; P < 0·0001) and 66·7% (15 mg; P < 0·0001), compared with placebo (2·0%). Significant increases in the proportion of PASI 75 responses were seen by week 4 and were maintained at week 12. Exposure-response over the 0-15 mg tofacitinib twice-daily dose range was successfully characterized. PASI 50, PASI 90 and Physician's Global Assessment response rates were also higher for tofacitinib vs. placebo. The most frequently reported adverse events (AEs) were infections and infestations: 22·4% (2 mg twice daily), 20·4% (5 mg twice daily), 36·7% (15 mg twice daily) and 32·0% (placebo). Discontinuations due to AEs were 6·0%, 2·0%, 4·1% and 6·1% of patients in the placebo, and 2, 5 and 15 mg twice-daily tofacitinib groups, respectively. Dose-dependent increases from baseline in mean serum high-density lipoprotein, low-density lipoprotein and total cholesterol, and decreases in haemoglobin and neutrophils were observed.. Short-term treatment with oral tofacitinib results in significant clinical improvement in patients with moderate-to-severe plaque psoriasis and is generally well tolerated.

Topics: Administration, Oral; Adult; Chronic Disease; Dermatologic Agents; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Janus Kinase 3; Male; Piperidines; Psoriasis; Pyrimidines; Pyrroles; Treatment Outcome

Anti-melanoma differentiation-associated gene 5 (MDA5) antibody is associated with clinically amyopathic dermatomyositis (CADM) with rapidly progressive interstitial lung disease (RP-ILD). Recently, several studies have reported that tofacitinib (TOF), a Janus kinase inhibitor, might be effective for cases of new or refractory RP-ILD in anti-MDA5 antibody-positive CADM; however, it is unknown whether TOF can also be effective for relapsed cases. We herein report a relapsed case of RP-ILD in anti-MDA5 antibody-positive CADM, which was successfully treated by combination therapy with TOF (5 mg twice daily). Our case suggests that TOF may also be a potential treatment option for relapsed cases of this disease.

Topics: Autoantibodies; Chronic Disease; Humans; Interferon-Induced Helicase, IFIH1; Lung Diseases, Interstitial; Recurrence

Topics: Chronic Disease; Humans; Osteomyelitis; Piperidines; Pyrimidines; Recurrence

There are limited real-world data on the change in total work impairment (TWI) in biological-treated patients with inflammatory bowel disease (IBD). This study aimed to evaluate the real-world effects of initiating biological therapy or tofacitinib on change in TWI in IBD patients.. This multicenter prospective cohort study enrolled IBD patients who started treatment with biological therapy or tofacitinib. Subjects completed the work productivity and activity impairment (WPAI) questionnaire and short inflammatory bowel disease questionnaire at therapy initiation and at week 26. Total work impairment comprises working hours missed due to sick leave and impact of disease during working hours (range 0%-100%). Clinical disease activity was assessed using the Harvey-Bradshaw Index and Simple Clinical Colitis Activity Index (SCCAI).. We included 137 IBD patients for analyses (median age 38 years, 58% Crohn's disease [CD]). The median baseline TWI was 50% and decreased by a median of 10%-points of points after 26 weeks. Patients with continued biological therapy or tofacitinib use, clinical disease activity at baseline, and clinical response or remission at week 26 showed a greater median TWI reduction (22%-points) than the remaining study patients (7%-points; P = .014). Ulcerative colitis (UC) and IBD-unclassified (IBD-U) patients showed a greater median TWI reduction (26%-points) than CD patients (6%-points); P = .041. Correlations were observed between decrease in TWI and decrease in SCCAI, decrease in fatigue and increase in quality of life.. Work impairment in IBD patients decreased following biological therapy or tofacitinib initiation. Patients achieving clinical remission or response showed the greatest improvement, especially UC and IBD-U patients.

Topics: Adult; Biological Therapy; Chronic Disease; Colitis, Ulcerative; Crohn Disease; Humans; Inflammatory Bowel Diseases; Prospective Studies; Quality of Life

Topics: Chronic Disease; Humans; Photosensitivity Disorders; Piperidines; Pyrimidines

Vitiligo is a chronic treatment-resistant autoimmune disorder characterized by circumscribed depigmented maculae. This study was conducted to evaluate the efficacy and safety of tofacitinib combined with narrowband ultraviolet B (NB-UVB) phototherapy for refractory nonsegmental vitiligo. Fifteen patients with nonsegmental vitiligo resistant to conventional therapies were administered oral tofacitinib at 5 mg twice daily plus topical halometasone cream, tacrolimus 0.1% ointment, or pimecrolimus cream twice daily and NB-UVB three times per week for 16 weeks. The control group comprised 19 patients with nonsegmental vitiligo treated with topical drugs plus NB-UVB same as the combination group. Treatment efficacy was measured by the percentage of repigmentation of vitiligo lesions at 4th, 8th, 12th, and 16th week after beginning treatment. From 8th week, the repigmentation level was significantly higher in the combination group than in the controls. From fourth week, the response rate was significantly higher in the combination group than in the controls. Only one patient in the combination group reported mild pain in the hand and foot joints, but the pain subsided with cessation of therapy. No other severe adverse effects occurred. So, tofacitinib in combination with NB-UVB phototherapy may be an effective and safe alternative modality for refractory vitiligo.

Topics: Chronic Disease; Combined Modality Therapy; Emollients; Humans; Pain; Phototherapy; Prospective Studies; Treatment Outcome; Ultraviolet Therapy; Vitiligo

The Janus kinase/signal transducer and activator of transcription (JAK-STAT) pathway play a key role in immune modulation, especially in the polarization of T helper cells. JAK inhibitors reduce inflammation by inhibiting the phosphorylation of STAT. We investigated whether a JAK inhibitor, tofacitinib, can reduce inflammation in a mouse model of chronic rhinosinusitis with nasal polyps (CRSwNP).. An eosinophilic CRSwNP model was induced using 4-week-old BALB/c mice. The therapeutic effects of topical tofacitinib were compared with the effects of triamcinolone acetonide (TAC). Polyp formation and eosinophilic infiltration were assessed by histology. Levels of phosphorylated STAT (pSTAT), eosinophil cationic protein, and eotaxin were measured by immunohistochemistry. Gene expression levels of GATA-3 was measured using quantitative PCR. The production of cytokines in sinonasal tissues, including interleukin IL-4, IL-5, IL-12, and interferon-γ, were measured using enzyme-linked immunosorbent assays (ELISA).. Topical tofacitinib administration significantly reduced the number of polyp-like lesions and the degree of eosinophilic infiltration, with an efficacy comparable with that of systemic TAC administration. Similarly, the levels of pSTAT6, eosinophil cationic protein, and eotaxin decreased with tofacitinib treatment. Tofacitinib decreased the gene expression level of GATA-3. Lastly, tofacitinib significantly decreased IL-4 and IL-5 production to a similar extent as that by systemic or topical TAC administration. Tofacitinib, but not TAC, significantly increased the production of interferon-γ.. Topical tofacitinib administration may be an effective treatment for eosinophilic CRSwNP by inhibiting phosphorylation of STATs.. N/A. Laryngoscope, 131:E1400-E1407, 2021.

Topics: Adjuvants, Immunologic; Administration, Intranasal; Animals; Chronic Disease; Cytokines; Disease Models, Animal; Eosinophilia; Eosinophils; Humans; Janus Kinases; Male; Mice; Nasal Mucosa; Nasal Polyps; Piperidines; Pyrimidines; Rhinitis; Signal Transduction; Sinusitis; STAT Transcription Factors; Triamcinolone Acetonide

The Janus kinases (JAKs) are intracellular tyrosine kinases involved in a broad variety of inflammatory cascades participating in the pathogenesis of systemic lupus erythematosus (SLE). Diffuse non-scarring alopecia is one of the most frequent cutaneous manifestations in SLE, resulting in devastating psychosocial consequences. Although recent studies have shown promising outcomes of the JAK inhibitors in SLE treatment, the efficacy of tofacitinib in diffuse non-scarring alopecia due to SLE has never been reported. Here we present a 29-year-old SLE patient with a 10-year history of refractory severe diffuse non-scarring alopecia who experienced dramatic hair regrowth with tofacitinib. Furthermore, we have made a systematic review regarding the potential effectiveness of tofacitinib in systemic and cutaneous lupus erythematosus. To the best of our knowledge, this is the first case study depicting an SLE patient with refractory alopecia who experienced impressive hair regrowth with the JAK1/3 inhibitor tofacitinib therapy, which contributes to expanding the field of possible uses of tofacitinib in SLE patients with difficult-to-treat cutaneous involvement, including severe alopecia.

Topics: Adult; Alopecia Areata; Chronic Disease; Female; Humans; Lupus Erythematosus, Systemic; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Recurrence; Treatment Outcome

Topics: Aged; Arthritis, Rheumatoid; Chronic Disease; Female; Follow-Up Studies; Humans; Male; Middle Aged; Piperidines; Protein Kinase Inhibitors; Pruritus; Pyrimidines; Severity of Illness Index; Treatment Outcome

Although existing psoriasis treatments are effective and well tolerated in many patients, there is still a need for new effective targeted treatment options. Tofacitinib is an oral Janus kinase inhibitor that has been investigated in patients with moderate-to-severe chronic plaque psoriasis.. To consider the benefits and risks of tofacitinib in patients with moderate-to-severe psoriasis.. Data were pooled from one phase II, four phase III and one long-term extension study comprising 5204 patient-years of tofacitinib treatment. Efficacy end points included patients achieving Physician's Global Assessments of 'clear' or 'almost clear', ≥ 75% and ≥ 90% reduction in Psoriasis Area and Severity Index (coprimary end points) and improvements in Dermatology Life Quality Index score, Hospital Anxiety and Depression Scale depression score and Itch Severity Item score, at weeks 16 and 52. Safety data were summarized for 3 years of tofacitinib exposure.. Tofacitinib 5 and 10 mg twice daily (BID) showed superiority over placebo for all efficacy end points at week 16, with response maintained for 52 weeks of continued treatment. Tofacitinib improved patients' quality of life and was well tolerated. Rates of safety events of interest (except herpes zoster) were similar to those in the published literature and healthcare databases for other systemic psoriasis therapies. Tofacitinib 10 mg BID demonstrated greater efficacy than 5 mg BID.. Tofacitinib has a benefit-risk profile in moderate-to-severe psoriasis consistent with that of other systemic treatments.

Topics: Administration, Oral; Adolescent; Adult; Aged; Aged, 80 and over; Chronic Disease; Dose-Response Relationship, Drug; Female; Humans; Male; Middle Aged; Piperidines; Protein Kinase Inhibitors; Psoriasis; Pyrimidines; Pyrroles; Quality of Life; Randomized Controlled Trials as Topic; Risk Assessment; Severity of Illness Index; Young Adult

Tofacitinib is a targeted inhibitor of janus kinase (JAK), currently approved for the treatment of rheumatoid arthritis. We present a patient on treatment withtofacitinib who had an episode of classic dermatomal herpes zoster followed months later by atypical chronic cutaneous ulcers also caused by herpes zoster.

Topics: Arthritis, Rheumatoid; Chronic Disease; Female; Herpes Zoster; Humans; Middle Aged; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Skin; Skin Ulcer

The progression from acute to chronic antibody-mediated rejection in kidney transplant recipients is usually not prevented by current therapeutic options. Here, we investigated whether the use of tofacitinib (TOFA), a Janus kinase 3 inhibitor, was capable of preventing the progression of allograft dysfunction in a Fisher-to-Lewis rat model of kidney transplantation.. Rats were treated from the third week after transplantation to allow the development of rejection. Treatment was based on cyclosporin A, rapamycin or TOFA. Renal function was assessed at 1, 4, 8, and 12 weeks after transplantation, whereas rat survival, histological lesions, and infiltrating lymphocytes were analyzed at 12 weeks.. Tofacitinib prolonged graft survival, preserved tubular and glomerular structures and reduced humoral damage characterized by C4d deposition. Tofacitinib was able to reduce donor-specific antibodies. In addition, T and natural killer cell graft infiltration was reduced in TOFA-treated rats. Although rapamycin-treated rats also showed prolonged graft survival, glomerular structures were more affected. Moreover, only TOFA treatment reduced the presence of T, B and natural killer cells in splenic parenchyma.. Tofacitinib is able to reduce the immune response generated in a rat model of kidney graft rejection, providing prolonged graft and recipient survival, better graft function, and less histological lesions.

Topics: Animals; Chronic Disease; Complement C4b; Disease Models, Animal; Disease Progression; Graft Rejection; Graft Survival; Humans; Immunity, Cellular; Immunity, Humoral; Immunosuppressive Agents; Janus Kinase 3; Kidney; Kidney Transplantation; Male; Peptide Fragments; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Rats; Rats, Inbred F344; Rats, Inbred Lew; Signal Transduction; Treatment Outcome

Tofacitinib is an oral Janus kinase inhibitor being investigated for psoriasis.. We sought to report longer-term tofacitinib efficacy and safety in patients with moderate to severe psoriasis.. Data from 2 identical phase-III studies, Oral-treatment Psoriasis Trial Pivotal 1 and 2, were pooled with data from these patients in an ongoing open-label long-term extension study. Patients (n = 1861) were randomized 2:2:1 to tofacitinib 5 mg, 10 mg, or placebo twice daily (BID). At week 16, placebo patients were rerandomized to tofacitinib. Pivotal study participants could enroll into the long-term extension where they received tofacitinib at 10 mg BID for 3 months, after which dosing could be 5 or 10 mg BID.. At week 28, the proportions of patients randomized to tofacitinib 5 and 10 mg BID achieving 75% or greater reduction in Psoriasis Area and Severity Index score from baseline were 55.6% and 68.8%, and achieving Physician Global Assessment of clear or almost clear were 54.7% and 65.9%. Efficacy was maintained in most patients through 24 months. Serious adverse events and discontinuations because of adverse events were reported in less than 11% of patients over 33 months of tofacitinib exposure.. There was no dose comparison beyond week 52.. Oral tofacitinib demonstrated sustained efficacy in patients with psoriasis through 2 years, with 10 mg BID providing greater efficacy than 5 mg BID. No unexpected safety findings were observed.

Topics: Administration, Oral; Adult; Aged; Chronic Disease; Clinical Trials, Phase III as Topic; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Janus Kinases; Male; Middle Aged; Patient Safety; Piperidines; Protein Kinase Inhibitors; Psoriasis; Pyrimidines; Pyrroles; Quality of Life; Randomized Controlled Trials as Topic; Severity of Illness Index; Time Factors; Treatment Outcome; Young Adult

The studies reported herein are the first to document the effect of the in vivo administration of a JAK3 inhibitor for defining the potential role of NK cells during acute SIV infection of a group of 15 rhesus macaques (RM). An additional group of 16 MHC/KIR typed RM was included as controls. The previously optimized in vivo dose regimen (20 mg/kg daily for 35 days) led to a marked depletion of each of the major NK cell subsets both in the blood and gastro-intestinal tissues (GIT) during acute infection. While such depletion had no detectable effects on plasma viral loads during acute infection, there was a significant sustained increase in plasma viral loads during chronic infection. While the potential mechanisms that lead to such increased plasma viral loads during chronic infection remain unclear, several correlates were documented. Thus, during acute infection, the administration of the JAK3 inhibitor besides depleting all NK cell subsets also decreased some CD8⁺ T cells and inhibited the mobilization of the plasmacytoid dendritic cells in the blood and their localization to the GIT. Of interest is the finding that the administration of the JAK3 inhibitor during acute infection also resulted in the sustained maintenance during chronic infection of a high number of naïve and central memory CD4⁺ T cells, increases in B cells in the blood, but decreases in the frequencies and function of NKG2a⁺ NK cells within the GIT and blood, respectively. These data identify a unique role for JAK3 inhibitor sensitive cells, that includes NK cells during acute infection that in concert lead to high viral loads in SIV infected RM during chronic infection without affecting detectable changes in antiviral humoral/cellular responses. Identifying the precise mechanisms by which JAK3 sensitive cells exert their influence is critical with important implications for vaccine design against lentiviruses.

Topics: Animals; B-Lymphocytes; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Chronic Disease; Enzyme Inhibitors; Enzyme-Linked Immunosorbent Assay; Flow Cytometry; Janus Kinase 3; Killer Cells, Natural; Macaca mulatta; Piperidines; Pyrimidines; Pyrroles; Simian Acquired Immunodeficiency Syndrome; Viral Load

In the last 15 years, the therapeutical options for the treatment of chronic inflammatory diseases in rheumatology have increased a lot. Nevertheless, some patients do not respond or respond partially to the current therapies--including to the biologics therapy. Tofacitinib (Xeljanz) is now on the Swiss market. It inhibits the JAK pathway. Tofacitinib--as monotherapy or with methotrexate--improves the control of rheumatoid arthritis (RA). In a comparative study, tofacitinib was as effective as adalimumab. Further, tofacitinib reduced structural damages in RA and is considered as an alternative, in case of non-response, to anti-TNF and probably to other biologics therapy. The side effects are upper respiratory tract and opportunist infections and tuberculosis. Blood count, lipids, kidney function, liver tests, CK and blood pressure have to be monitored.

Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Chronic Disease; Drug Approval; Humans; Inflammation; Janus Kinases; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Rheumatic Diseases; Switzerland

A Bayesian nonlinear longitudinal Emax model for a binary endpoint was used to characterize the dose-response relationship for a new treatment of rheumatoid arthritis. The model includes prespecified parametric functions for the dependence of response on dose level and time. It was selected based on pharmacometric input about likely dose and time trends. The longitudinal model was useful for combining data collected at different doses and times from two different studies. The example illustrates the utility of more substantive parametric models to guide selection of doses outside the initial dosing range when designing an additional phase 2 study and for extrapolating shorter-term phase 2 dose response to longer-term phase 3 studies, as is often required for dosing decisions in drug development for chronic diseases. Comparison of the estimated dose response from the longitudinal model with a corresponding logistic regression model applied at a single time point also demonstrated improved precision. Specification of an informative prior distribution based on numerous sources of prior information is described. This was the most difficult step in the analysis and one that has limited the use of Bayesian methods in similar applications. Model fit was evaluated and the potential impact of some model deficiencies on the dosing decision was assessed. Analyses of the combined studies identified doses likely to achieve a targeted effect in larger and longer confirmatory trials.

Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Bayes Theorem; Chronic Disease; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Dose-Response Relationship, Drug; Humans; Longitudinal Studies; Nonlinear Dynamics; Piperidines; Pyrimidines; Pyrroles

Rheumatoid arthritis (RA) is a chronic inflammatory disease that causes irreversible joint damage and significant disability. However, the fundamental mechanisms underlying how inflammation and joint destruction in RA develop and are sustained chronically remain largely unknown. Here, we show that signal transducer and activator of transcription 3 (STAT3) is the key mediator of both chronic inflammation and joint destruction in RA. We found that inflammatory cytokines highly expressed in RA patients, such as IL-1β, tumor necrosis factor alpha and IL-6, activated STAT3 either directly or indirectly and in turn induced expression of IL-6 family cytokines, further activating STAT3 in murine osteoblastic and fibroblastic cells. STAT3 activation also induced expression of receptor activator of nuclear factor kappa B ligand (RANKL), a cytokine essential for osteoclastogenesis, and STAT3 deficiency or pharmacological inhibition promoted significant reduction in expression of both IL-6 family cytokines and RANKL in vitro. STAT3 inhibition was also effective in treating an RA model, collagen-induced arthritis, in vivo through significant reduction in expression of IL-6 family cytokines and RANKL, inhibiting both inflammation and joint destruction. Leukemia inhibitory factor expression and STAT3 activation by IL-1β were mainly promoted by IL-6 but still induced in IL-6-deficient cells. Thus, our data provide new insight into RA pathogenesis and provide evidence that inflammatory cytokines trigger a cytokine amplification loop via IL-6-STAT3 that promotes sustained inflammation and joint destruction.

Topics: Animals; Arthritis, Experimental; Arthritis, Rheumatoid; Chronic Disease; Enzyme Inhibitors; Fibroblasts; Gene Expression; Humans; Inflammation; Interleukin-1beta; Interleukin-6; Joints; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Osteoclasts; Piperidines; Pyrimidines; Pyrroles; RANK Ligand; Signal Transduction; STAT3 Transcription Factor; Tumor Necrosis Factor-alpha