ABSTRACT
Cytokine storm syndromes (CSSs) comprise a group of severe and often fatal hyperinflammatory conditions driven by the overproduction of pro-inflammatory cytokines by activated cells of the immune system. Many of the CSS-associated cytokines mediate their downstream effects by signaling through the Janus kinases (JAKs) and signal transducers and activators of transcription (STATs). In addition, several of these cytokines are produced downstream of JAK/STAT pathway activation. Therefore, targeting JAK/STAT signaling using small molecule JAK inhibitors has become an increasingly appealing therapeutic option to dampen hyperinflammation in patients with CSSs. Application of JAK inhibitors in preclinical CSS models has shown improvements in multiple sequelae of hyperinflammation, and there is growing clinical evidence supporting the efficacy of JAK inhibition in patients with these conditions. Although generally well tolerated, JAK inhibitor use is not without potential for toxicity, especially in settings like CSSs where end-organ dysfunction is common. More prospective clinical trials incorporating JAK inhibitors, alone or in combination with other immunomodulatory therapies, are necessary to determine the optimal dosing, schedule, efficacy, and tolerability of these agents for patients experiencing CSSs.
Subject(s)
Cytokine Release Syndrome , Janus Kinase Inhibitors , Janus Kinases , Humans , Janus Kinase Inhibitors/therapeutic use , Janus Kinase Inhibitors/adverse effects , Cytokine Release Syndrome/drug therapy , Cytokine Release Syndrome/immunology , Janus Kinases/antagonists & inhibitors , Janus Kinases/metabolism , Signal Transduction/drug effects , Cytokines/metabolism , Animals , STAT Transcription Factors/metabolism , STAT Transcription Factors/antagonists & inhibitorsABSTRACT
Vitiligo, an autoimmune condition characterized by depigmented skin patches due to the loss of functional melanocytes, has been linked to dysregulation in the JAK-STAT signaling pathway, particularly in IFN-g signaling. The use of JAK inhibitors, such as ruxolitinib cream, a JAK1 and JAK2 inhibitor, presents a promising approach for vitiligo treatment. This study aims to systematically assess the effectiveness and safety of ruxolitinib cream in patients with vitiligo. We conducted a systematic review and meta-analysis following PRISMA guidelines to evaluate the efficacy and safety of ruxolitinib cream for the treatment of vitiligo. A comprehensive search of PubMed, Google Scholar, and Cochrane Library databases for randomized controlled trials (RCTs). Data selection, screening, extraction, and risk of bias assessment were meticulously performed. Statistical analysis was conducted using Review Manager Software, version 5.4, with significant heterogeneity addressed through appropriate methods. Our meta-analysis included 3 studies with 830 vitiligo patients. Significant improvements were observed in F-VASI, T-VASI, F-BSA, and T-BSA scores, with greater efficacy at 24 weeks compared to 12 weeks [MD -24.17, 95% CI (-31.78 to -16.56), P < 0.00001], [MD -14.12, 95% CI (-20.54 to -7.70); P < 0.0000], [MD -16.25, 95% CI (-22.20 to -10.31), P < 0.00001], [MD -9.19, 95% CI (-13.47 to -4.92); P < 0.00001]. Ruxolitinib showed increased risk ratios for F-VASI75, F-VASI90, and F-VASI50, indicating better outcomes with longer treatment durations [MD 2.9, 95% CI 1.88-4.49; P < 0.00001], [MD 4.66, 95% CI 2.09-10.39; P = 0.0002], [MD 2.53, 95% CI 1.84-3.46; P < 0.00001]. No significant differences were found in mild and moderate adverse events, while severe cases favored ruxolitinib. Placebo had a significant advantage in any adverse events, with no significant difference in drug-related adverse events. Serious adverse events did not significantly differ between groups. The findings strongly support the efficacy of ruxolitinib therapy in improving various parameters over time for treating vitiligo. However, thorough consideration of its safety profile, particularly concerning adverse events and potential side effects, is warranted. Further studies with larger sample sizes are needed to confirm these conclusions.
Subject(s)
Nitriles , Pyrazoles , Pyrimidines , Vitiligo , Vitiligo/drug therapy , Humans , Pyrimidines/administration & dosage , Pyrimidines/therapeutic use , Pyrazoles/administration & dosage , Pyrazoles/adverse effects , Pyrazoles/therapeutic use , Treatment Outcome , Skin Cream/administration & dosage , Janus Kinase Inhibitors/therapeutic use , Janus Kinase Inhibitors/administration & dosage , Janus Kinase Inhibitors/adverse effects , Randomized Controlled Trials as TopicABSTRACT
BACKGROUND: Tofacitinib is an oral Janus kinase inhibitor for the treatment of ulcerative colitis (UC). We aimed to identify the safety and effectiveness of tofacitinib in patients with UC in routine clinical settings in Korea. METHODS: This open-label, observational, prospective, post-marketing surveillance study was conducted at 22 hospitals in the Republic of Korea. Patients with moderate to severe active UC who received tofacitinib were included and followed up for up to 52 weeks. Tofacitinib was administered at a dosage of 10 mg twice daily for at least 8 weeks, followed by 5 or 10 mg twice daily at the investigator's discretion based on clinical evaluation according to the approved Korean label. Safety including adverse events (AEs) and effectiveness including clinical remission, clinical response, and endoscopic mucosal healing were evaluated. Safety analysis set was defined as all patients registered for this study who received at least one dose of tofacitinib according to the approved Korean label and followed up for safety data. Effectiveness analysis set included patients in the safety analysis set who were evaluated for overall effectiveness assessment and excluded patients who had received tofacitinib less than 8 weeks. RESULTS: A total of 110 patients were enrolled, of whom 106 patients were included in the safety population. The median duration of treatment was 370 days and the treatment duration ranged from 16 to 684 days for the safety population. AEs occurred in 42 patients (39.6%). Serious AEs (SAEs) occurred in 7 patients (6.6%) and of them, there were 2 cases of serious infections. These serious infections were reported as Adverse Event of Special Interest (AESI) in this study and no other AESI were reported. There were no cases of death during the study period. Clinical remission rates were 40.0%, 46.7%, 57.6%, and 55.1% at 8, 16, 24, and 52 weeks, and clinical response rates were 77.8%, 87.9%, 56.6%, and 81.4% at each visit, respectively. Endoscopic mucosal healing rates were 58.7% at 16 weeks and 46.2% at 52 weeks. CONCLUSION: Tofacitinib was effective in Korean patients with moderate to severe active UC and the safety findings were consistent with the known safety profile of tofacitinib. This study confirmed the safety and effectiveness of tofacitinib in Korean patients with moderate to severe active UC in routine clinical settings. TRIAL REGISTRATION: This study is registered in the ClinicalTrials.gov under the identifier NCT04071405, registered on 28 August 2019.
Subject(s)
Colitis, Ulcerative , Piperidines , Product Surveillance, Postmarketing , Pyrimidines , Humans , Pyrimidines/adverse effects , Pyrimidines/therapeutic use , Pyrimidines/administration & dosage , Piperidines/adverse effects , Piperidines/therapeutic use , Piperidines/administration & dosage , Colitis, Ulcerative/drug therapy , Male , Female , Adult , Prospective Studies , Middle Aged , Republic of Korea , Pyrroles/adverse effects , Pyrroles/therapeutic use , Pyrroles/administration & dosage , Treatment Outcome , Janus Kinase Inhibitors/adverse effects , Janus Kinase Inhibitors/therapeutic use , Janus Kinase Inhibitors/administration & dosage , Aged , Protein Kinase Inhibitors/adverse effects , Protein Kinase Inhibitors/therapeutic use , Protein Kinase Inhibitors/administration & dosage , Young Adult , Remission InductionSubject(s)
Arthritis, Rheumatoid , Herpes Zoster , Janus Kinase Inhibitors , Humans , Antirheumatic Agents/therapeutic use , Antirheumatic Agents/adverse effects , Arthritis, Rheumatoid/drug therapy , Arthritis, Rheumatoid/complications , Janus Kinase Inhibitors/adverse effects , Janus Kinase Inhibitors/therapeutic use , Risk FactorsABSTRACT
Patients with rheumatoid arthritis (RA) who receive immunosuppressive medications have a heightened risk of infection. The goal of our study was to calculate the pooled cumulative incidence and risk of infection in patients with RA treated with Janus kinase inhibitors (JAKi). The PubMed and EMBASE databases were queried for randomized controlled trials comparing patients with RA treated with JAKi (upadacitinib, baricitinib, tofacitinib, peficitinib, or filgotinib), defined as the treatment group, compared with control subjects, defined as participants receiving placebo or treatment regimen that was similar to that of participants in the treatment group, with the exception of JAKi. The primary study endpoint was the relative risk (RR) of any-grade and severe infection. The secondary endpoints were RR and cumulative incidence of opportunistic infections, herpes zoster, and pneumonia. The Stata v17 software was used for all data analysis. Results showed that treatment with baricitinib was associated with an increased risk of any-grade (RR 1.34; 95% CI: 1.19-1.52) and opportunistic (RR 2.69; 95% CI: 1.22-5.94) infection, whereas treatment with filgotinib (RR 1.21; 95% CI: 1.05-1.39), peficitinib (RR 1.40; 95% CI: 1.05-1.86) and upadacitinib (RR 1.30; 95% CI: 1.09-1.56) was associated with increased risk of any-grade infection only. Analysis based on type of infection showed a pooled cumulative incidence of 32.44% for any-grade infections, 2.02% for severe infections, 1.74% for opportunistic infections, 1.56% for herpes zoster, and 0.49% for pneumonia in patients treated with any JAKi during the follow-up period. Treatment with specific JAKi in patients with RA is associated with an increased risk of any-grade and opportunistic infections but not severe infection. Close clinical monitoring of patients with RA treated with JAKi is required to establish the long-term infection risk profile of these agents.
Subject(s)
Arthritis, Rheumatoid , Azetidines , Janus Kinase Inhibitors , Piperidines , Purines , Pyrazoles , Pyrimidines , Sulfonamides , Arthritis, Rheumatoid/drug therapy , Arthritis, Rheumatoid/complications , Humans , Janus Kinase Inhibitors/adverse effects , Janus Kinase Inhibitors/therapeutic use , Azetidines/adverse effects , Azetidines/therapeutic use , Incidence , Purines/adverse effects , Purines/therapeutic use , Pyrazoles/adverse effects , Pyrazoles/therapeutic use , Pyrimidines/adverse effects , Pyrimidines/therapeutic use , Piperidines/adverse effects , Piperidines/therapeutic use , Sulfonamides/adverse effects , Sulfonamides/therapeutic use , Herpes Zoster/epidemiology , Herpes Zoster/chemically induced , Opportunistic Infections/epidemiology , Opportunistic Infections/chemically induced , Pyrroles/adverse effects , Pyrroles/therapeutic use , Niacinamide/analogs & derivatives , Niacinamide/adverse effects , Niacinamide/therapeutic use , Infections/epidemiology , Infections/chemically induced , Randomized Controlled Trials as Topic , Heterocyclic Compounds, 3-Ring/adverse effects , Heterocyclic Compounds, 3-Ring/therapeutic use , Antirheumatic Agents/adverse effects , Antirheumatic Agents/therapeutic use , Triazoles/adverse effects , Triazoles/therapeutic use , Adamantane/analogs & derivatives , PyridinesABSTRACT
Severe alopecia areata (AA) is a nonscarring hair loss for immune disorder and SALT score ≥ 50%. The guidelines for managing patients with severe AA suggest treatments: systemic steroids, JAK inhibitors, and contact immunotherapy. However, there is a lack of evidence indicating the superiority of one treatment over another. Therefore, this study aimed to identify the most effective treatment for severe AA through network meta-analysis. Following the PRISMA guidelines, we conducted a network meta-analysis. The literature search was retrieved across four databases. The Cochrane 5.1 risk of bias assessment tool and ROBINS-I tool assessed quality of the included studies. Subsequently, efficacy and safety comparisons among the three treatments were conducted using Stata 14.0 on account of the frequency method. The SUCRA rank indicated that oral dexamethasone (95.9%) > diphenylcyclopropenone(DPCP) (74.5%) > oral ritlecitinib (62.6%) > oral baricitinib (46.9%) > squaric acid dibutyl ester(SADBE) (20.1%) > placebo (0.0%) from high to low in the aspect of improving efficacy. As for safety, placebo(88.4%) > oral ritlecitinib (86.5%) > oral baricitinib (62.1%) > SADBE (37.0%) > oral dexamethasone(22.3%) > DPCP(3.8%) in the aspect of decreasing adverse events. Oral dexamethasone and DPCP showed superior efficacy compared to oral ritlecitinib and oral baricitinib. However, in terms of safety, oral ritlecitinib was preferable. Some adverse events associated with oral dexamethasone and DPCP were intolerable to patients, whereas those related to oral ritlecitinib and oral baricitinib were more manageable. Overall, ritlecitinib and baricitinib remain promising drugs in the future treatment of severe AA.
Subject(s)
Alopecia Areata , Janus Kinase Inhibitors , Network Meta-Analysis , Humans , Alopecia Areata/drug therapy , Alopecia Areata/immunology , Janus Kinase Inhibitors/adverse effects , Janus Kinase Inhibitors/therapeutic use , Janus Kinase Inhibitors/administration & dosage , Treatment Outcome , Administration, Oral , Purines/administration & dosage , Purines/adverse effects , Azetidines/administration & dosage , Azetidines/adverse effects , Azetidines/therapeutic use , Dexamethasone/administration & dosage , Dexamethasone/adverse effects , Dexamethasone/therapeutic use , Sulfonamides/administration & dosage , Sulfonamides/adverse effects , Sulfonamides/therapeutic use , Immunotherapy/methods , Immunotherapy/adverse effects , Cyclopropanes/administration & dosage , Cyclopropanes/adverse effects , Cyclopropanes/therapeutic use , Severity of Illness Index , PyrazolesSubject(s)
Herpes Zoster , Janus Kinase Inhibitors , Humans , Herpes Zoster/drug therapy , Herpes Zoster/diagnosis , Janus Kinase Inhibitors/therapeutic use , Janus Kinase Inhibitors/adverse effects , Janus Kinase Inhibitors/administration & dosage , Male , Female , Middle Aged , Pyrimidines/adverse effects , Pyrimidines/administration & dosage , Aged , Antiviral Agents/administration & dosage , Antiviral Agents/therapeutic use , Antiviral Agents/adverse effects , Pyrazoles/adverse effects , Pyrazoles/administration & dosage , Administration, Oral , PiperidinesSubject(s)
Janus Kinase Inhibitors , Humans , Janus Kinase Inhibitors/therapeutic use , Janus Kinase Inhibitors/adverse effects , Psoriasis/drug therapy , Pyrimidines/adverse effects , Pyrimidines/therapeutic use , Pyrazoles/adverse effects , Pyrazoles/therapeutic use , Piperidines/adverse effects , Piperidines/therapeutic use , NitrilesABSTRACT
BACKGROUND: Janus kinase (JAK) inhibitors (JAKis) are effective therapeutic agents against rheumatoid arthritis (RA). However, patients having RA with particular risk factors may have a higher incidence of adverse effects (AEs), including major cardiovascular events (MACE) and infections. In this multicenter cohort study, we aimed to clarify the risk factors affecting the drug retention of JAKis in patients with RA. METHODS: We retrospectively evaluated patients with RA who received their first JAKi (tofacitinib, baricitinib, upadacitinib, or filgotinib) at our institute. The clinical outcomes, including AEs, were recorded, particularly MACE and serious infections. The drug retention rates were analyzed using the Kaplan-Meier method, and risk factors affecting drug retention rates were determined using a multivariable Cox regression hazards model. RESULTS: Overall 184 patients with RA receiving their first use of baricitinib (57.6%), tofacitinib (23.9%), upadacitinib (12.0%), or filgotinib (6.5%) were included in this study. Fifty-six (30.4%) patients discontinued JAKi treatment owing to ineffectiveness (9.2%) or AEs, including infections (21.2%). The overall drug retention rates were significantly lower in patients treated with pan-JAKi than in those treated with JAK1 inhibitors (p = 0.03). In the Cox regression model, the presence of baseline high RA disease activity, use of glucocorticoid and treatments with pan-JAKis were associated with reduced drug retention rates of JAKis (p < 0.001, p = 0.01 and 0.04, respectively). Pan-JAKi treated patients with high disease activity had significantly lower drug retention rates (p < 0.001). CONCLUSIONS: In a real-world setting, the drug retention rates of JAKis were reduced mainly by treatment discontinuation owing to AEs. Treatment with pan-JAKis and high baseline RA disease activity were identified as predictive factors for the discontinuation of JAKis. Lower drug retention rates were found in patients receiving pan-JAKis with high disease activity than in those without high disease activity.
Subject(s)
Arthritis, Rheumatoid , Azetidines , Janus Kinase Inhibitors , Piperidines , Purines , Pyrazoles , Sulfonamides , Humans , Arthritis, Rheumatoid/drug therapy , Male , Female , Middle Aged , Janus Kinase Inhibitors/therapeutic use , Janus Kinase Inhibitors/adverse effects , Azetidines/therapeutic use , Azetidines/adverse effects , Retrospective Studies , Aged , Pyrazoles/therapeutic use , Pyrazoles/adverse effects , Purines/therapeutic use , Purines/adverse effects , Sulfonamides/therapeutic use , Sulfonamides/adverse effects , Piperidines/therapeutic use , Piperidines/adverse effects , Pyrimidines/therapeutic use , Pyrimidines/adverse effects , Heterocyclic Compounds, 3-Ring/therapeutic use , Heterocyclic Compounds, 3-Ring/adverse effects , Antirheumatic Agents/therapeutic use , Antirheumatic Agents/adverse effects , Triazoles/therapeutic use , Triazoles/adverse effects , Risk Factors , Adult , PyridinesABSTRACT
Herpes zoster (HZ) risk is increased in rheumatoid arthritis (RA) patients receiving Janus kinase inhibitors (JAKi) therapy. Identifying and evaluating the risk factors of HZ development in patients receiving JAKi therapy would be clinically helpful. We investigated HZ's incidence rates (IR), identified the risk factors, and further assessed their influence on HZ development in RA patients undergoing JAKi therapy. We retrospectively evaluated 249 RA patients who received JAKi therapy between 2015 and 2023. Data regarding clinical characteristics, HZ reactivation, HZ vaccination status, and concomitant medication use were collected. Among 249 JAKi-treated patients, 44 developed new-onset HZ (tofacitinib, 28/142; baricitinib, 6/35; upadacitinib,10/72), with an IR of 5.11/100patient-years. Multivariate analysis revealed significant predictors of HZ development: a long JAKi exposure period, prior HZ or COVID-19 history, and concomitant high-dose corticosteroids use. The interval between JAKi initiation and HZ development was significantly shorter in patients with prior HZ history than in those without (median, 6.5 months versus 33.5 months, p < 0.001), suggesting "biphasic" emergence of HZ. Only one patient who had experienced an HZ episode while receiving JAKi developed recurrent HZ. None of the seventeen patients immunized with the non-live recombinant zoster vaccine developed HZ. Our JAKi-treated patients had elevated HZ risks, a class effect across different JAKi. A long exposure period, prior history of HZ or COVID-19, and concomitant high-dose corticosteroid treatment may further increase the risk. The emergence of HZ shows a biphasic pattern: early HZ development in patients with prior HZ and late development in those without. Key Points ⢠An increased risk of HZ was observed in Taiwanese RA patients treated with JAKi, presenting as a class effect. ⢠Patients with a long JAKi exposure period, prior history of HZ or COVID-19, and concomitant use of high-dose corticosteroids were at high risk of HZ while receiving JAKi therapy. ⢠The interval between JAKi initiation and HZ occurrence was shorter in patients with prior HZ than in those without, showing "biphasic" emergence.
Subject(s)
Adrenal Cortex Hormones , Arthritis, Rheumatoid , Azetidines , Herpes Zoster , Janus Kinase Inhibitors , Humans , Arthritis, Rheumatoid/drug therapy , Herpes Zoster/chemically induced , Herpes Zoster/prevention & control , Herpes Zoster/epidemiology , Retrospective Studies , Male , Female , Middle Aged , Aged , Janus Kinase Inhibitors/adverse effects , Janus Kinase Inhibitors/therapeutic use , Risk Factors , Adrenal Cortex Hormones/administration & dosage , Adrenal Cortex Hormones/adverse effects , Adrenal Cortex Hormones/therapeutic use , Azetidines/adverse effects , Azetidines/therapeutic use , Sulfonamides/adverse effects , Sulfonamides/administration & dosage , Sulfonamides/therapeutic use , Piperidines/adverse effects , Piperidines/therapeutic use , Piperidines/administration & dosage , Incidence , Pyrazoles/adverse effects , Purines/adverse effects , Pyrimidines/adverse effects , Heterocyclic Compounds, 3-Ring/adverse effects , Heterocyclic Compounds, 3-Ring/therapeutic use , Heterocyclic Compounds, 3-Ring/administration & dosage , COVID-19/epidemiology , Adult , SARS-CoV-2 , Antirheumatic Agents/adverse effects , Antirheumatic Agents/therapeutic useABSTRACT
OBJECTIVE: To evaluate the efficacy and safety of Janus kinases inhibitors (JAKi) for adult-onset Still's disease (AOSD) patients. METHODS: We searched the Embase, PubMed, the Cochrane Central Register of Controlled Trials (CENTRAL), and the China National Knowledge Infrastructure (CNKI) from inception up to 22 October 2023. The results were supplemented by a backward search of relevant publications. Two authors independently selected trials. The available studies were comprehensively reviewed and analysed. RESULTS: A total of 9 studies with a total of 35 patients were included in the review. Of these patients, 17 (48.6%) patients were treated with tofacitinib, 14 (40%) with baricitinib, 4 (11.4%) with ruxolitinib and 1 (2.9%) with upadacitinib. After treatment with JAKi, 17 (48.6%) patients showed complete remission, 12 (34.3%) patients showed partial remission, and 7 (20%) patients showed loss of efficacy or relapse. The use of ruxolitinib showed a remission rate of 100% in AOSD patients with macrophage activation syndrome (MAS). The incidence of adverse events (AEs) reported were mild and rare overall. Most AEs were abnormal lipid parameters (9.7%), bacterial pneumonia (3.2%), organised pneumonia (3.2%), diarrhoea (3.2%), increased heart rate (3.2%), menometrorrhagia (3.2%) and leukopenia (3.2%). One patient died from bacterial pneumonia. CONCLUSION: JAKi therapy may be an option for patients with AOSD, especially for refractory AOSD. For patients with AOSD complicated by MAS, ruxolitinib seems to be a better choice than other JAKi agents. Although our study shows that JAKi are well tolerated in AOSD patients, we still need to be on the lookout for fatal infections.
Subject(s)
Janus Kinase Inhibitors , Still's Disease, Adult-Onset , Humans , Still's Disease, Adult-Onset/drug therapy , Janus Kinase Inhibitors/therapeutic use , Janus Kinase Inhibitors/adverse effects , Treatment Outcome , AdultABSTRACT
The safety profile of baricitinib (BARI), a Janus kinase inhibitor broadly used for the treatment of rheumatoid arthritis (RA), includes asymptomatic laboratory abnormalities, such as an increase in creatine kinase (CK). Data from randomized controlled trials suggest that concomitant myalgia is rare in RA and does not lead to drug discontinuation. We describe the case of a 68-year-old Caucasian female with longstanding, multi-failure RA who started BARI and achieved disease remission. However, she developed a symptomatic CK increase, as well as a parallel increase in total cholesterol, low-density lipoprotein, and triglycerides. Dechallenge-rechallenge demonstrated a plausible relationship between the clinical/laboratory abnormalities and BARI. In fact, when the drug was withdrawn, CK returned to normal and myalgia disappeared, whereas symptoms returned and CK levels increased when BARI was restarted. BARI may be rarely associated with symptomatic CK elevation, and this may pose clinical challenges, particularly for patients with multi-failure RA who achieved good disease control with BARI but required drug discontinuation due to intolerance.
Subject(s)
Arthritis, Rheumatoid , Azetidines , Creatine Kinase , Purines , Pyrazoles , Sulfonamides , Humans , Arthritis, Rheumatoid/drug therapy , Arthritis, Rheumatoid/complications , Female , Purines/adverse effects , Purines/therapeutic use , Aged , Azetidines/therapeutic use , Azetidines/adverse effects , Pyrazoles/therapeutic use , Pyrazoles/adverse effects , Sulfonamides/adverse effects , Sulfonamides/therapeutic use , Creatine Kinase/blood , Myalgia/chemically induced , Antirheumatic Agents/therapeutic use , Antirheumatic Agents/adverse effects , Janus Kinase Inhibitors/therapeutic use , Janus Kinase Inhibitors/adverse effectsABSTRACT
OBJECTIVE: This study aims to evaluate the efficacy and safety of JAK inhibitors in the treatment of patients with RA. METHODS: The databases CNKI, VIP, Wanfang, CBM, and PubMed, Embase, Cochrane Library and Web of Science were searched to identify relevant randomized controlled trials (RCTs), all from the time of database creation to April 2024. Screening, data extraction, and risk of bias assessment (using Review Manager-5.3 software) were independently performed by at least two authors. The network meta-analysis was conducted using R 4.1.3 software. PROSPERO registration number: CRD42022370444. RESULTS: Thirty-three RCTs included 15,961 patients The experimental groups involved six JAK inhibitors (filgotinib, tofacitinib, decernotinib, baricitinib, upadacitinib and peficitinib) and 12 interventions (different doses of the six JAK inhibitors), and the control group involved adalimumab (ADA) and placebo. Compared with placebo, all JAK inhibitors showed a significant increase in efficacy measures (ACR20/50/70). Compared with ADA, only tofacitinib, low-dose decernotinib, and high-dose peficitinib showed a significant increase in ACR20/50/70. Decernotinib ranked first in the SUCRA ranking of ACR20/50/70. In terms of safety indicators, only those differences between low-dose filgotinib and high-dose upadacitinib, low-dose tofacitinib and high-dose upadacitinib were statistically significant. Low-dose filgotinib ranked first in the SUCRA ranking with adverse events as safety indicators. Only the efficacy and safety of tofacitinib ranked higher among different SUCRA rankings. CONCLUSION: Six JAK inhibitors have better efficacy than placebo. The superior efficacy of decernotinib and safety of low-dose filgotinib can be found in the SUCRA. However, there are no significant differences in safety between the different JAK inhibitors. Head-to-head trials, directly comparing one against each other, are required to provide more certain evidence.
Subject(s)
Arthritis, Rheumatoid , Azetidines , Bayes Theorem , Janus Kinase Inhibitors , Network Meta-Analysis , Piperidines , Pyrimidines , Humans , Arthritis, Rheumatoid/drug therapy , Janus Kinase Inhibitors/therapeutic use , Janus Kinase Inhibitors/adverse effects , Pyrimidines/therapeutic use , Pyrimidines/adverse effects , Piperidines/therapeutic use , Piperidines/adverse effects , Azetidines/therapeutic use , Azetidines/adverse effects , Purines/therapeutic use , Purines/adverse effects , Pyrroles/therapeutic use , Pyrroles/adverse effects , Pyrazoles/therapeutic use , Pyrazoles/adverse effects , Sulfonamides/therapeutic use , Sulfonamides/adverse effects , Randomized Controlled Trials as Topic , Treatment Outcome , Heterocyclic Compounds, 2-Ring/therapeutic use , Heterocyclic Compounds, 2-Ring/adverse effects , Niacinamide/analogs & derivatives , Niacinamide/therapeutic use , Niacinamide/adverse effects , Benzamides/therapeutic use , Benzamides/adverse effects , Heterocyclic Compounds, 3-Ring/therapeutic use , Heterocyclic Compounds, 3-Ring/adverse effects , Antirheumatic Agents/therapeutic use , Antirheumatic Agents/adverse effects , Triazoles/therapeutic use , Triazoles/adverse effects , Triazoles/administration & dosage , Adamantane/analogs & derivatives , Pyridines , Valine/analogs & derivativesABSTRACT
BACKGROUND: Abrocitinib, an oral, once-daily, Janus kinase 1-selective inhibitor, is efficacious in moderate-to-severe atopic dermatitis with a manageable long-term safety profile. OBJECTIVE: We aimed to provide updated integrated long-term safety results for abrocitinib from available data accrued up to a maximum of almost 4 years in patients with moderate-to-severe atopic dermatitis from the JADE clinical development program. METHODS: Analysis included 3802 patients (exposure: 5213.9 patient-years) from the phase II monotherapy study (NCT02780167) and the phase III studies JADE MONO-1 (NCT03349060), JADE MONO-2 (NCT03575871), JADE TEEN (NCT03796676), JADE COMPARE (NCT03720470), JADE DARE (NCT04345367; 200 mg only), JADE REGIMEN (NCT03627767), and JADE EXTEND (NCT03422822; data cutoff 25 September, 2021). Data from patients receiving one or more doses of abrocitinib 200 mg or 100 mg were pooled in a consistent-dose cohort (patients were allocated to receive the same abrocitinib dose throughout exposure in the qualifying parent study and/or long-term study) or a variable-dose cohort (patients received open-label abrocitinib 200 mg; responders were randomized to abrocitinib 200 mg, 100 mg, or placebo, and could then receive abrocitinib 200 mg plus topical corticosteroids as rescue therapy). Incidence rates of adverse events of special interest were assessed. Cox regression analysis of risk factors for herpes zoster and serious infections was performed. RESULTS: Overall, this safety analysis of long-term data up to a maximum of ~ 4 years of abrocitinib exposure does not indicate any changes from the previously reported risk profile. The most frequent serious infections (per Medical Dictionary for Regulatory Activities preferred term) with consistent-dose abrocitinib 200 mg and 100 mg were herpes zoster (0.5% and 0.2%), pneumonia (0.2% with either dose), and herpes simplex (0.1% with either dose). Risk factors for herpes zoster were a history of herpes zoster, abrocitinib 200-mg dose, age ≥ 65 years, absolute lymphocyte count < 1 × 103/mm3 before the event, and residing in Asia. For serious infections, > 100 kg body weight was a risk factor. Incidence rate/100 patient-years (95% confidence interval) with the consistent abrocitinib 200-mg and 100-mg dose combined was higher in older (aged ≥ 65 years) patients versus younger (aged 18 to < 65 years) patients for serious adverse events (17.6 [11.7â25.4] vs 6.7 [5.8â7.8]), malignancy excluding non-melanoma skin cancer (2.4 [0.6â6.0] vs 0.1 [0.0â0.4]), non-melanoma skin cancer (2.4 [0.6â6.1] vs 0.2 [0.1â0.4]), lymphopenia (3.5 [1.3â7.6] vs 0.1 [0.0â0.3]), and venous thromboembolism (1.7 [0.4â5.1] vs 0.1 [0.0â0.3]). Incident rate/100 patient-years (95% confidence interval) of non-melanoma skin cancer with the consistent abrocitinib 200-mg and 100-mg dose combined was higher in current/former smokers (0.9 [0.4â1.6]) vs never-smokers (0.0 [0.0â0.1]). CONCLUSIONS: This safety update showed a consistent profile for abrocitinib with no new safety signals and continues to support that abrocitinib has a manageable long-term safety profile in patients with moderate-to-severe atopic dermatitis. Risk of specific adverse events was higher in certain patient populations, especially those aged ≥ 65 years. [Video abstract available.] CLINICAL TRIAL REGISTRATION: NCT02780167; study start date: April, 2016; primary completion date: March, 2017; study completion date: April, 2017. NCT03349060; study start date: 7 December, 2017; study completion date: 26 March, 2019. NCT03575871; study start date: 29 June, 2018; study completion date: 13 August, 2019. NCT03720470; study start date: 29 October, 2018; primary completion date: 27 December, 2019; study completion date: 6 March, 2020. NCT03796676; study start date: 18 February, 2019; study completion date: 8 April, 2020. NCT03627767; study start date: 11 June, 2018; primary completion date: 2 September, 2020; study completion date: 7 October, 2020. NCT04345367; study start date: 11 June, 2020; primary completion date: 16 December, 2020; study completion date: 13 July, 2021. NCT03422822; study start date: 8 March, 2018; study completion date: ongoing (estimated completion date: 31 January, 2026).
Abrocitinib is an approved treatment for people with moderate or severe atopic dermatitis, also known as AD or atopic eczema. Abrocitinib is a tablet that is taken by mouth once a day. This safety analysis looked at the side effects of treatment in a large group of adults and adolescents with moderate or severe AD who took abrocitinib up to a maximum of almost 4 years. This analysis also looked at which people were more likely to have certain side effects after taking abrocitinib. The results from this analysis were similar to those of previous safety analyses with abrocitinib, with no new side effects. Infections such as shingles, pneumonia, or herpes simplex can occur during treatment with abrocitinib. Shingles was more likely to occur in people who previously had shingles before taking abrocitinib, or who took the higher dose of abrocitinib (200 mg), or were 65 years of age or older, or had certain blood test results, or lived in Asia. People who are 65 years of age or older and took abrocitinib were more likely to develop some types of cancer, have certain abnormal blood test results, or develop blood clots in the veins than people with AD who were younger and took abrocitinib. Current or former smokers with AD who took abrocitinib were more likely to develop skin cancer (but not melanoma) than people with AD who took abrocitinib but have never smoked. This analysis further shows that abrocitinib had manageable safety in patients with moderate-to-severe AD. Video abstract: Integrated safety update of abrocitinib in 3802 patients with moderate-to-severe atopic dermatitis: data from more than 5200 patient-years with up to 4 years of exposure (MP4 63720 KB).
Subject(s)
Dermatitis, Atopic , Severity of Illness Index , Adolescent , Adult , Aged , Female , Humans , Male , Middle Aged , Young Adult , Administration, Oral , Boron Compounds/administration & dosage , Boron Compounds/adverse effects , Boron Compounds/therapeutic use , Dermatitis, Atopic/drug therapy , Herpes Zoster/chemically induced , Herpes Zoster/epidemiology , Janus Kinase Inhibitors/adverse effects , Janus Kinase Inhibitors/administration & dosage , Janus Kinase Inhibitors/therapeutic use , Pyrimidines/adverse effects , Pyrimidines/administration & dosage , Sulfonamides , Treatment OutcomeABSTRACT
OBJECTIVES: To compare the risk of cardiovascular events among Janus kinase inhibitors (JAKIs), biological disease-modifying antirheumatic drugs (bDMARDs) (tumour necrosis factor inhibitors (TNFIs) and non-TNFIs) and methotrexate (MTX) in Japanese patients with rheumatoid arthritis (RA). METHODS: Using Japanese claims data, patients with RA were enrolled in this study if they had at least one ICD-10 code (M05 or M06), were new users of JAKIs, bDMARDs or MTX between July 2013 and July 2020 and being 18 years old or older. The incidence rate (IR), IR ratio and adjusted hazard ratio (aHR (95% CI)) of cardiovascular events including venous thromboembolism, arterial thrombosis, acute myocardial infarction and stroke were calculated. A time-dependent Cox regression model adjusted for patient characteristics at baseline was used to calculate aHR. RESULTS: In 53 448 cases, IRs/1000 patient-years of the overall cardiovascular events were 10.1, 6.8, 5.4, 9.1 and 11.3 under the treatments with JAKIs, bDMARDs, TNFIs, non-TNFIs and MTX, respectively. The adjusted HRs of JAKIs for overall cardiovascular events were 1.7 (1.1 to 2.5) versus TNFIs without MTX and 1.7 (1.1 to 2.7) versus TNFIs with MTX. CONCLUSIONS: Among patients with RA, individuals using JAKIs had a significantly higher risk of overall cardiovascular events than TNFIs users, which was attributed to the difference in the risk between JAKIs and TNFIs versus MTX. These data should be interpreted with caution because of the limitations associated with the claims database.
Subject(s)
Antirheumatic Agents , Arthritis, Rheumatoid , Cardiovascular Diseases , Janus Kinase Inhibitors , Methotrexate , Humans , Arthritis, Rheumatoid/drug therapy , Arthritis, Rheumatoid/complications , Female , Male , Antirheumatic Agents/therapeutic use , Antirheumatic Agents/adverse effects , Middle Aged , Cardiovascular Diseases/epidemiology , Cardiovascular Diseases/etiology , Janus Kinase Inhibitors/therapeutic use , Janus Kinase Inhibitors/adverse effects , Japan/epidemiology , Aged , Retrospective Studies , Longitudinal Studies , Methotrexate/therapeutic use , Methotrexate/adverse effects , Adult , Incidence , Databases, Factual , Risk Factors , Insurance, Health , East Asian PeopleABSTRACT
OBJECTIVES: - Janus Kinase inhibitors (JAKi) are a new class of drugs available for pediatric rheumatic diseases. This study aimed to describe the safety and effectiveness of JAKi in these diseases, with a focus on longitudinal interferon-stimulated genes (ISG) assessment. METHODS: - We present a single-center retrospective study of children with refractory pediatric rheumatic diseases including connective tissue diseases, monogenic type I interferonopathies or juvenile idiopathic arthritis, receiving JAKi. According to physicians' assessment, treatment effectiveness was classified at 12 months as a complete response in the total absence of disease activity, partial response in case of significant (>50%) but incomplete improvement or no response in the case of non-response or improvement of less than 50% of the clinical and biological parameters. ISG were monitored longitudinally using Nanostring technology. RESULTS: - 22 children were retrospectively included in this study, treated either by baricitinib or ruxolitinib. Complete response was achieved at 12 months in 9/22 (41%) patients. 6/22 (27%) patients were non-responders and treatment had been discontinued in five of them. Within the interferon (IFN)-related diseases group, ISG-score was significantly reduced 12 months after JAKi onset (p = 0.0068). At 12 months, daily glucocorticoid doses had been reduced with a median dose of 0.16 mg/kg/day (IQR 0.11; 0.33) (p = 0.0425). 7/22 (32%) patients had experienced side effects, infections being the most common. Increase of the body mass index was also recorded in children in the first 6 months of treatment. CONCLUSION: - JAKi represent a promising treatment of immune-mediated pediatric diseases, enabling to decrease type-I IFN transcriptomic signature in responding patients, especially in the context of juvenile dermatomyositis. JAKi represent steroid-sparing drugs but they induce metabolic changes linked to weight gain, posing a concern in the treatment of young patients and teenagers. More data are required to define the efficacy and safety of JAKi in the management of refractory pediatric rheumatic diseases.
Subject(s)
Interferon Type I , Janus Kinase Inhibitors , Humans , Retrospective Studies , Child , Male , Female , Janus Kinase Inhibitors/therapeutic use , Janus Kinase Inhibitors/adverse effects , Adolescent , Treatment Outcome , Interferon Type I/metabolism , Child, Preschool , Pyrazoles/therapeutic use , Pyrazoles/adverse effects , Purines/therapeutic use , Pyrimidines/therapeutic use , Azetidines/therapeutic use , Arthritis, Juvenile/drug therapy , Sulfonamides/therapeutic use , Rheumatic Diseases/drug therapy , Nitriles/therapeutic useABSTRACT
INTRODUCTION: Rheumatoid arthritis (RA) is usually treated with disease modifying antirheumatic drugs (DMARDs), including biological DMARDs (bDMARDs) and more recently, Janus kinase inhibitors (JAKi). Randomized trials suggest similar infection risks for JAKi and bDMARDs, but real-world data are scarce. METHODS: From a nationally representative prescription database, adult RA patients starting a new JAKi or bDMARD between August 1st, 2018, and January 31st, 2021, were included. Prescriptions of antibiotic, antiviral or antifungal medication were used as proxy for infections. Infection incidence rates (IR) were compared between JAKi and bDMARDs and infection risks were estimated using multilevel Poisson regression adjusted for follow-up time and potential confounders and stratified for age < 65 and ≥ 65 years. RESULTS: In 14,989 patients, we identified 20,050 treatment episodes with either JAKi or bDMARDs. The infection IR was significantly higher in JAKi (48/100 patient years) compared bDMARDs (35/100 patient years, adjusted incidence rate ratio (IRR) 1.22, 95% CI 1.12-1.33). More herpes zoster infections were seen in JAKi compared to bDMARDs (adjusted IRR 2.65, 95% CI 1.94-3.60). No significant differences in infection IRs were found comparing JAKi baricitinib and tofacitinib. In older patients, infection IRs were higher, but IRRs were similar between age groups. CONCLUSION: In comparison to bDMARDs, JAKi are associated with a slightly higher infection risk and a higher risk of herpes zoster specifically. In older patients, infection IRs are higher but similar infection risks for JAKi and bDMARDs are observed. No differences in infection risk between tofacitinib and baricitinib were found. Key Points ⢠Compared to bDMARDs, JAKi are associated with a slightly higher infection risk for all ages ⢠An increased risk of herpes zoster in patients who use JAK inhibitors was confirmed ⢠No significant differences in infection incidence were found between tofacitinib and baricitinib.
Subject(s)
Antirheumatic Agents , Arthritis, Rheumatoid , Azetidines , Janus Kinase Inhibitors , Piperidines , Purines , Pyrazoles , Pyrimidines , Sulfonamides , Humans , Male , Janus Kinase Inhibitors/therapeutic use , Janus Kinase Inhibitors/adverse effects , Female , Middle Aged , Arthritis, Rheumatoid/drug therapy , Purines/therapeutic use , Purines/adverse effects , Antirheumatic Agents/adverse effects , Antirheumatic Agents/therapeutic use , Piperidines/therapeutic use , Piperidines/adverse effects , Aged , Pyrimidines/therapeutic use , Pyrimidines/adverse effects , Sulfonamides/therapeutic use , Sulfonamides/adverse effects , Azetidines/therapeutic use , Azetidines/adverse effects , Pyrazoles/adverse effects , Pyrazoles/therapeutic use , Incidence , Herpes Zoster/epidemiology , Herpes Zoster/chemically induced , Adult , Infections/epidemiology , Infections/chemically inducedSubject(s)
Inflammatory Bowel Diseases , Piperidines , Protein Kinase Inhibitors , Pyrimidines , Pyrroles , Humans , Piperidines/adverse effects , Piperidines/therapeutic use , Pyrimidines/adverse effects , Pyrimidines/therapeutic use , Pyrroles/adverse effects , Pyrroles/therapeutic use , Pyrroles/administration & dosage , Inflammatory Bowel Diseases/drug therapy , Protein Kinase Inhibitors/adverse effects , Protein Kinase Inhibitors/therapeutic use , Janus Kinase Inhibitors/therapeutic use , Janus Kinase Inhibitors/adverse effectsABSTRACT
BACKGROUND AND AIMS: Tofacitinib is an oral Janus kinase inhibitor for the treatment of ulcerative colitis (UC). We report an integrated summary of tofacitinib safety from the completed global UC clinical program (9.2 years maximum tofacitinib exposure). METHODS: This analysis included patients receiving tofacitinib 5 or 10 mg twice daily (b.i.d.) from completed phase 2/3 placebo-controlled studies, an open-label, long-term extension study and a randomized phase 3b/4 study. Proportions and incidence rates (IRs; unique patients with events/100 patient-years [PY] of exposure) were evaluated for deaths and adverse events (AEs) of special interest (AESI). RESULTS: Overall, 1157 patients received ≥1 dose of tofacitinib 5 or 10 mg b.i.d.; 938 (81.1%) were in the predominant dose tofacitinib 10 mg b.i.d. group; 552 (47.7%) received tofacitinib for ≥2 years; total exposure: 3202.0 PY; 994 (85.9%) experienced AEs; 254 (22.0%) experienced serious AEs. Median treatment duration: 1.7 (range 0.0-9.2) years. IRs (95% CI) for combined tofacitinib doses: deaths 0.24 (0.10-0.48); serious infections (SIs) 1.80 (1.37-2.32); herpes zoster (HZ; non-serious and serious) 3.24 (2.63-3.94); serious HZ 0.24 (0.10-0.48); opportunistic infections 0.96 (0.65-1.36); malignancies (excluding non-melanoma skin cancer [NMSC]) 0.88 (0.59-1.26); NMSC 0.71 (0.45-1.07); major adverse cardiovascular events 0.27 (0.12-0.52); deep vein thrombosis 0.06 (0.01-0.22); pulmonary embolism 0.18 (0.07-0.40); and gastrointestinal perforations 0.09 (0.02-0.27). CONCLUSIONS: Except for HZ and SIs, IRs for AESI were <1 case/100 PY. Safety was consistent with previous analyses of shorter exposure and tofacitinib's known safety profile, including real-world data. CLINICALTRIALS: GOV: NCT00787202; NCT01465763; NCT01458951; NCT01458574; NCT01470612; NCT03281304.
Subject(s)
Colitis, Ulcerative , Piperidines , Pyrimidines , Pyrroles , Piperidines/adverse effects , Piperidines/administration & dosage , Piperidines/therapeutic use , Humans , Pyrimidines/adverse effects , Pyrimidines/administration & dosage , Colitis, Ulcerative/drug therapy , Pyrroles/adverse effects , Pyrroles/administration & dosage , Female , Male , Adult , Middle Aged , Protein Kinase Inhibitors/adverse effects , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/therapeutic use , Aged , Herpes Zoster/epidemiology , Herpes Zoster/chemically induced , Janus Kinase Inhibitors/adverse effects , Janus Kinase Inhibitors/administration & dosage , Janus Kinase Inhibitors/therapeutic use , Young AdultABSTRACT
BACKGROUND: Atopic dermatitis (AD), a highly pruritic, inflammatory skin disease, affects approximately 7% of adolescents globally. A topical formulation of ruxolitinib, a Janus kinase (JAK) 1/JAK2 inhibitor, demonstrated safety and efficacy among adolescents/adults in two phase 3 studies (TRuE-AD1/TRuE-AD2). OBJECTIVE: To describe safety and efficacy of 1.5% ruxolitinib cream versus vehicle and long-term disease control of ruxolitinib cream among adolescents aged 12-17 years from pooled phase 3 study data. METHODS: Patients [≥ 12 years old with AD for ≥ 2 years, Investigator's Global Assessment score (IGA) 2/3, and 3-20% affected body surface area (BSA) at baseline] were randomized 2:2:1 to ruxolitinib cream (0.75%/1.5%) or vehicle for 8 weeks of continuous use followed by a long-term safety (LTS) period up to 52 weeks with as-needed use. Patients originally applying vehicle were rerandomized 1:1 to 0.75%/1.5% ruxolitinib cream. Efficacy measures at week 8 included IGA treatment success (IGA-TS; i.e., score of 0/1 with ≥ 2 grade improvement from baseline), ≥ 75% improvement in Eczema Area and Severity Index (EASI-75), and ≥ 4-point improvement in itch numerical rating scale (NRS4). Measures of disease control during the LTS period included IGA score of 0 (clear) or 1 (almost clear) and percentage affected BSA. Safety was assessed throughout the study. RESULTS: Of 1249 randomized patients, 245 (19.6%) were aged 12-17 years. Of these, 45 patients were randomized to vehicle and 92 patients to 1.5% ruxolitinib cream. A total of 104/137 (75.9%) patients continued on 1.5% ruxolitinib cream in the LTS period [82/92 (89.1%) continued on 1.5% ruxolitinib cream; 22/45 (48.9%) patients on vehicle were reassigned to 1.5% ruxolitinib cream], and 83/104 (79.8%) of these patients completed the LTS period. At week 8, substantially more patients who applied 1.5% ruxolitinib cream versus vehicle achieved IGA-TS (50.6% versus 14.0%), EASI-75 (60.9% versus 34.9%), and NRS4 (52.1% versus 17.4%; P = 0.009). The mean (SD) reduction in itch NRS scores was significantly greater in patients applying 1.5% ruxolitinib cream versus vehicle from day 2 [- 0.9 (1.9) versus -0.2 (1.4); P = 0.03]. During the LTS period, mean (SD) trough steady-state ruxolitinib plasma concentrations at weeks 12/52 were 27.2 (55.7)/15.5 (31.5) nM. The percentage of patients achieving IGA score of 0 or 1 was sustained or further increased with 1.5% ruxolitinib cream; mean affected BSA was generally low (< 3%; i.e., mild disease). Through 52 weeks, application site reactions occurred in 1.8% of adolescent patients applying 1.5% ruxolitinib cream at any time; no patients had serious adverse events. There were no serious infections, malignancies, major adverse cardiovascular events, or thromboembolic events. CONCLUSIONS: Meaningful anti-inflammatory and antipruritic effects were demonstrated with 1.5% ruxolitinib cream in the subset of adolescent patients with AD, comparable with those observed in the overall study population; long-term, as-needed use maintained disease control and was well tolerated. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifiers NCT03745638 (registered 19 November 2018) and NCT03745651 (registered 19 November 2018).