Comparison of efficacy and safety of tofacitinib and azathioprine in patients with alopecia areata and variants: a double-blind, randomized controlled trial.

BACKGROUND: Alopecia areata (AA) is an autoimmune pathology manifested by loss of hair. OBJECTIVE: To evaluate and compare the efficacy and safety of tofacitinib and azathioprine in patients with AA and variants. METHODS: In this double-blind randomized controlled trail (RCT) carried out at the Department of Dermatology, Medical Teaching Institute-Lady Reading Hospital (MTI-LRH), Peshawar, Pakistan, patients aged ≥ 12 years diagnosed with AA, alopecia totalis (AT) or alopecia universalis (AU) with minimum 50% scalp hair loss for a period ≥ 06 years were included. Patients were randomly assigned to receive oral tofacitinib 5 mg twice daily (Group I) or oral azathioprine 2 mg/kg body weight once daily (Group II). The primary endpoint was Severity of Alopecia Tool (SALT) score, evaluated at baseline and 06 months follow-up. Safety was consistently assessed during the study. RESULTS: A total of 104 patients underwent random allocation into either the tofacitinib group (n = 52) or the azathioprine group (n = 52). The mean (SD) age of patients was 20.23 (7.14) years and 22.26 (8.07) years, while the mean (SD) disease duration was 6.59 (4.01) years and 7.98 (4.40) years in in Group I and II, respectively. Overall, 40 (38.5%) patients were adolescents while 70 (67.3%) were male. 52 (50%) had AA, 37 (35.5%) had AT and 15 (14.5%) had AU. Mean baseline SALT score in tofacitinib group was 91.02 ± 10.21 and azathioprine group was 91.02 ± 10.63, which at 06 months follow-up improved to 14.1 ± 24.6 and 63.9 ± 33.9, respectively (difference, 11.5 points; 95% confidence interval, 38.3-61.3, p < 0.0001). Overall, no major adverse effects and no difference among the minor adverse effects in the two groups (04 adverse events for tofacitinib group and 08 for azathioprine group: p = 0.23) was observed. CONCLUSIONS: Efficacy of tofacitinib was significantly higher than azathioprine, whilst both drugs were well-tolerated in patients with AA and variants.

Baricitinib as a treatment for myasthenia gravis: A case report.

Myasthenia gravis (MG) is an autoimmune disease that targets neuromuscular junctions. While immunotherapy remains the cornerstone of treatment, the effects of Janus kinase (JAK) inhibitors on MG remain underexplored. In this report, we describe the case of a 58-year-old woman with ocular myasthenia gravis who received treatment with the JAK inhibitor, baricitinib for alopecia areata. The patient presented with left eyelid ptosis and an inadequate response to steroids and pyridostigmine, along with symptoms of alopecia areata. Following diagnosis, we initiated a treatment regimen consisting of baricitinib for six months. After initiation of baricitinib, we observed a complete resolution of the patient's MG symptoms, accompanied by hair regrowth, even when steroids were tapered and pyridostigmine was discontinued. Furthermore, the titer of the anti-acetylcholine receptor antibody was decreased. This report represents the first reported case of anti-acetylcholine receptor antibody-positive MG that was successfully treated through the inhibition of JAK activity.

Effect of JAK Inhibitors on the Risk of Death in Patients with Moderate to Severe COVID-19: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Background: The pathophysiology of COVID-19 involves a signalling pathway based on the Janus kinases (JAKs) and the signal transducer and activator of transcription (STAT) family of proteins. As such, there has been growing interest in exploring JAK inhibitors as potential therapeutic agents for this disease. Objective: To provide a comprehensive summary of the efficacy of JAK inhibitors in the treatment of COVID-19 through a systematic review and meta-analysis. Data Sources: A systematic literature search was conducted in multiple electronic databases (PubMed, Scopus, and the Cochrane Central Register of Controlled Trials) and preprint repositories, without language restrictions, to identify relevant studies published up to December 31, 2023. Study Selection and Data Extraction: The primary outcome of interest was all-cause mortality. Randomized controlled trials (RCTs) investigating the administration of JAK inhibitors in patients with COVID-19 were included. Data Synthesis: Through the systematic literature search, a total of 20 RCTs meeting the inclusion criteria were identified. A random-effects model was employed to estimate the pooled odds ratio for death with administration of a JAK inhibitor relative to non-administration of such an agent, with 95% confidence interval. Meta-analysis of these trials revealed a significant reduction in mortality among patients with COVID-19 who received JAK inhibitors relative to those who did not receive these agents (pooled odds ratio 0.70, 95% confidence interval 0.58-0.84). Conclusions: The results of this systematic review and meta-analysis suggest that JAK inhibitors, specifically baricitinib, may address the urgent need for effective treatments in the ongoing COVID-19 pandemic by reducing the risk of death among affected patients. However, further research, including larger-scale RCTs, is needed to establish the efficacy and safety of other JAK inhibitors in the treatment of COVID-19 and to generate more robust evidence regarding their use in this specific patient population.

Contexte: La physiopathologie de la COVID-19 implique une voie de signalisation basée sur les Janus kinases (JAK) et les protéines STAT (pour signal transducer and activator of transcription en anglais, soit, les protéines transductrices de signal et activatrices de transcription). C'est pourquoi l'étude des inhibiteurs de JAK en tant qu'agents thérapeutiques potentiels pour cette maladie suscite un intérêt croissant. Objectif: Fournir un résumé complet de l'efficacité des inhibiteurs de JAK dans le traitement de la COVID-19 grâce à une revue systématique et une méta-analyse. Sources des données: Une recherche systématique de la littérature a été menée dans plusieurs bases de données électroniques (PubMed, Scopus et le Cochrane Central Register of Controlled Trials) et dans les référentiels de prépublications, sans restrictions linguistiques, pour identifier les études pertinentes publiées jusqu'au 31 décembre 2023. Sélection des études et extraction des données: Le principal résultat d'intérêt était la mortalité, toutes causes confondues. Des essais contrôlés randomisés (ECR) portant sur l'administration d'inhibiteurs de JAK chez des patients atteints de COVID-19 ont été inclus. Synthèse des données: Grâce à la recherche documentaire systématique, un total de 20 ECR répondant aux critères d'inclusion ont été identifiés. Un modèle à effets aléatoires a été utilisé pour estimer le rapport de cotes groupé de décès avec l'administration d'un inhibiteur de JAK par rapport à la non-administration d'un tel agent, avec un intervalle de confiance de 95 %. La méta-analyse de ces essais a révélé une réduction significative de la mortalité chez les patients atteints de COVID-19 ayant reçu des inhibiteurs de JAK par rapport à ceux n'ayant pas reçu ces agents (rapport de cotes groupé 0,70, intervalle de confiance à 95 % 0,58­0,84). Conclusions: Les résultats de cette revue systématique et méta-analyse indiquent que les inhibiteurs de JAK, en particulier le baricitinib, pourraient répondre au besoin urgent de traitements efficaces dans le cadre de la pandémie de COVID-19 en cours en réduisant le risque de décès parmi les patients touchés. Cependant, des recherches supplémentaires, y compris des ECR à plus grande échelle, sont nécessaires pour établir l'efficacité et l'innocuité d'autres inhibiteurs de JAK dans le traitement de la COVID-19 et pour générer des éléments probants plus solides concernant leur utilisation dans cette population de patients en particulier.

Successful treatment of severe atopic dermatitis and alopecia universalis with upadacitinib in a 29-year-old male patient.

A 29-year-old male patient had severe atopic dermatitis (AD) and alopecia universalis (AU) that could not be controlled by using classic therapy. He started taking upadacitinib and achieved an excellent response for both his AD and AU. Thus, upadacitinib represents a promising therapeutic approach for patients with severe AD and alopecia areata.

LACC1 deficiency leading to juvenile arthritis and anemia.

OBJECTIVE: Juvenile arthritis caused by loss-of-function LACC1 mutations is characterized by early onset of symmetric and chronic arthritis, associated with an elevation of inflammatory markers. We aimed to describe serum cytokine levels, explore the type I interferon pathway, and evaluate the efficacy of treatment in a patient presenting with polyarthritis and anemia caused by novel compound heterozygous variations in LACC1. METHODS: Clinical data of a patient with compound heterozygous variations in LACC1 was collected. Serum cytokine levels and IFN-stimulated cytokine genes were analyzed at diagnosis, at disease flare, and after treatment. Full-length cDNA of LACC1 was checked by RNA analysis. Single-cell RNA sequencing was performed in PBMCs. RESULTS: Two novel variants in the LACC1 gene were identified in a patient presenting with polyarthritis and anemia. LACC1-cDNA was normally expressed in the healthy control, the target production at 1384 bp was not observed in the patient. Compared to nine patient controls with non-systemic juvenile idiopathic arthritis, serum interleukin(IL)-6 level was significantly elevated in the affected patient. The median IFN score for the patient, her mother, and controls were 118, 8, and 4.9, respectively. The combined treatment of JAK inhibitors with prednisone or tocilizumab led to a complete response, including remission of joint symptoms, resolution of anemia, reduced expression of IFN-stimulated cytokine genes, and normalized levels of inflammatory markers, including CRP, ESR, SAA, and serum IL-6. CONCLUSION: LACC1 may play a crucial role in multiple inflammatory signaling pathways. The combination therapy of JAK inhibitors and tocilizumab may be effective for a subset of refractory patients.

Rapid resolution of erythrodermic atopic dermatitis with upadacitinib: A case report.

Atopic dermatitis is a chronic inflammatory skin disease that may progress to erythroderma in severe cases. Biologic agents such as dupilumab have recently become the mainstay of systemic treatment for moderate-to-severe cases, yet many patients remain refractory to therapy. Here, we present a case of erythrodermic atopic dermatitis, resistant to prednisone and dupilumab, with remarkably rapid achievement of remission following treatment with upadacitinib, an oral selective Janus kinase 1 inhibitor.

CXCR6+CD69+ CD8+ T cells in ascites are associated with disease severity in patients with cirrhosis.

Background & Aims: Patients with advanced cirrhosis often develop hepatic decompensation, which is accompanied by systemic inflammation and may eventually lead to acute-on-chronic liver failure. One important cause of systemic hyperinflammation is a dysregulated overshooting immune response in ascites in the abdominal cavity. In this study, we analyzed the role of CD8+ T cells in the ascites immune compartment. Methods: Peripheral blood and ascites fluid were collected from 50 patients with decompensated cirrhosis. Phenotype and functional responses of CD8+ T cells were analyzed, and obtained data were compared with each other as well as with healthy controls and patients with compensated cirrhosis. Results: High-dimensional flow cytometry revealed that CD8+ T cells are abundant in the ascites of patients with cirrhosis and exhibit a chronically activated bystander phenotype with innate-like functions. Indeed, we identified distinct CXCR6+CD69+ clusters of late effector memory CD8+ T cells that were rarely found in blood and correlated with clinical parameters of disease severity. Moreover, this CD8+ T-cell population was hyperresponsive to innate cytokines and exhibited cytokine-mediated bystander activation. Interestingly, the Janus kinase (JAK) inhibitor tofacitinib was able to effectively block bystander-activated CXCR6+CD69+ CD8+ T cells and significantly suppress effector molecule production. Conclusions: The results indicate that CXCR6+CD69+ CD8+ T cells in ascites are associated with disease severity and may contribute to inflammation in patients with decompensated cirrhosis, suggesting that targeted inhibition of this immune cell subset may be a viable therapeutic option. Impact and Implications: Patients with advanced cirrhosis often develop hepatic decompensation, which is accompanied by systemic inflammation and eventually leads to acute-on-chronic liver failure. One important cause of systemic hyperinflammation is a dysregulated overshooting immune response in ascites in the abdominal cavity. In this study, we demonstrate that CXCR6+CD69+ CD8+ T cells are abundant in the ascites of patients with cirrhosis, exhibit a chronically activated bystander phenotype, and correlate with clinical parameters of disease severity. Moreover, we show that the Janus kinase (JAK) inhibitor tofacitinib can effectively block these bystander-activated CXCR6+CD69+ CD8+ T cells, suggesting that targeted inhibition of this immune cell subset may be a potential therapeutic strategy. Clinical trial number: Prospective registry: INFEKTA (DRKS00010664).

The Dilemma of Balancing Anti-Tumor Necrosis Factor-Alpha (Anti-TNF-α) Biologics for Psoriatic Arthritis Control With the Risk of Severe Systemic Infection.

The treatment landscape for psoriatic arthritis (PsA) has evolved significantly with the introduction of biologic therapies, such as adalimumab, which effectively inhibits tumor necrosis factor-alpha (TNF-α) activity. However, despite their efficacy in controlling inflammation, biologic therapies are associated with heightened risks of infectious complications and malignancies. We present a case of a 66-year-old female with PsA treated with adalimumab who presented with recurrent systemic bacterial infections. Despite attempts to adjust dosing intervals to minimize infection risks, the patient experienced severe complications, including urosepsis, endocarditis, and liver abscesses. The dilemma arises in balancing PsA control with anti-TNFα therapy while minimizing infection risks. Current evidence supporting prophylactic antibiotics in such cases is limited, and determining the next steps for treatment involves challenging decisions such as withholding TNF inhibitors or switching to alternative immunomodulators. This case underscores the need for further research into prophylactic treatment and monitoring protocols to manage recurrent infections during anti-TNF-α therapy effectively.

Tofacitinib Monotherapy in Rheumatoid Arthritis: Clinical Trials and Real-World Data Contextualization of Patients, Efficacy, and Treatment Retention.

Purpose: To evaluate the characteristics, efficacy, and retention of tofacitinib monotherapy in patients with rheumatoid arthritis using data from randomized controlled trials (RCTs) and real-world data (RWD). Patients and Methods: Three patient groups receiving tofacitinib 5 mg twice daily (BID) monotherapy were defined for post hoc RCT/long-term extension (LTE) analyses: (1) disease-modifying antirheumatic drug (DMARD)-inadequate responder patients from phase 3/3b/4 RCTs; (2) methotrexate-naïve patients from a phase 3 RCT; and (3) index study patients continuing in an LTE study. Outcomes included low disease activity (LDA)/remission rates defined by Clinical Disease Activity Index (CDAI); Disease Activity Score in 28 joints (DAS28-4), erythrocyte sedimentation rate; DAS28-4, C-reactive protein (DAS28-4[CRP]); and rates of/time to discontinuation due to lack of efficacy/adverse events. RWD were identified by non-systematic literature searches of PubMed, Embase, and American College of Rheumatology/European Alliance of Associations for Rheumatology congress abstracts (2012-2022). Results: RCT/LTE analyses included 1000/498 patients receiving tofacitinib 5 mg BID monotherapy. Baseline disease activity was high; patients tended to receive concomitant glucocorticoids; most were biologic DMARD-naïve. CDAI LDA rates were 32.2-62.2% for Groups 1/2 (months 3-12) and 64.0-70.7% for Group 3 (months 12-72). In Groups 1, 2, and 3, 4.0%, 15.6%, and 27.7% of patients, respectively, discontinued tofacitinib monotherapy due to lack of efficacy/adverse events. From 11 RWD publications, 16.6-66.1% received tofacitinib monotherapy. Consistent with clinical data, tofacitinib monotherapy effectiveness (month 6 CDAI LDA, 30.2%; month 3 DAS28-4[CRP] remission, 53.4%) and persistence were observed in RWD, with retention comparable to tofacitinib combination therapy. Conclusion: Tofacitinib monotherapy demonstrated clinically significant responses/persistence in RCT/LTE analyses, with effectiveness observed and persistence comparable to combination therapy in RWD. Trial Registration: NCT00814307, NCT02187055, NCT01039688, NCT00413699, NCT00661661 (ClinicalTrials.gov).

Comparison of anti-IL-6 receptor and JAK inhibitors in patients with rheumatoid arthritis from the real-world practice FIRST study.

OBJECTIVES: A molecular-targeted drug that is suitable as the second choice for patients with rheumatoid arthritis (RA) who show an inadequate response to the first biological disease-modifying antirheumatic drug (bDMARD) is unknown. This study aimed to analyze the efficacy and safety of interleukin-6 receptor (IL-6Ri) and Janus kinase inhibitors (JAKis), often selected as molecular-targeted drugs for second or subsequent treatments. METHODS: The efficacy and safety of JAKis and IL-6Ri were compared using propensity score-based inverse probability of treatment weighting (PS-IPTW) using propensity scores after 26 weeks of therapy in patients with RA. RESULTS: The remission rate at week 26, determined by the clinical disease activity index (CDAI), and the incidence of infection were higher in the JAKis than in the IL-6Ri group. The CDAI trajectories were divided into four according to the growth mixture modeling. IL-6Ri demonstrated greater efficacy in RA patients with ineffective to single bDMARD therapy compared with those with multiple ineffective bDMARDs. In patients who failed to respond to one bDMARD, there was no significant difference in the CDAI remission rate at week 26 between the JAKis (29.1%) and IL-6Ri (21.8%) groups (p= 0.21). However, for patients who did not respond to at least two bDMARDs, the CDAI remission rate at week 26 was higher in the JAKis than in the IL-6Ri group. CONCLUSIONS: IL-6Ri offers a superior balance of efficacy and safety compared with JAKis for RA patients unresponsive to one bDMARD. However, JAKis may suit patients who do not respond to multiple bDMARDs.

Potential impact of European Medicines Agency measures to minimise risk of serious side effects on JAKi prescribing and utilisation in the UK.

OBJECTIVE: Janus kinase inhibitors (JAKi) or targeted synthetic (ts) disease-modifying antirheumatic drugs (DMARDs) effectively treat rheumatoid arthritis (RA). However, due to safety concerns, the European Medicines Agency (EMA) published risk minimisation measures limiting JAKi prescription to certain at-risk patients unless no suitable alternative is available. This analysis included patients who had started their first-ever JAKi before EMA measures were published in a large national cohort study to investigate the potential impact of these measures on JAKi prescribing and utilisation in UK. METHOD: RA patients starting first-ever JAK inhibitor therapy in BSRBR-RA between 13-February-2017 and 31-May-2022 were included. Percentages of patients meeting EMA risk criteria were presented. For at-risk patients, previous number of distinct biological (b) DMARD classes were described. RESULT: A total of 1341 patients were included, and 80% (N = 1075) met ≥1 EMA risk criterion. Of those who met ≥1 risk criterion, 529 patients (49%) had received JAKi as their first or second b/tsDMARD class, whereas 299 (28%) had received ≥3 prior bDMARD classes. CONCLUSION: Four-in-five RA patients commencing JAKi before the EMA advisory were considered 'at-risk' with prescribing only advised if there was no suitable alternative. Almost a third of those patients had already received ≥3 bDMARDs classes, and alternative therapies would be very limited for them; meanwhile, suitable alternatives might have existed for the remaining proportion, especially for those who received JAKi as their first or second b/tsDMARD, and re-evaluation of the suitability of their treatment may be needed.

Short-Term Use of Upadacitinib in Combination With Biologic Therapy for Inducing Clinical Remission in Patients With Active Inflammatory Bowel Disease.

We report that upadacitinib intended for short-term use in combination with biologic therapy appeared to be effective in inducing steroid-free clinical remission in patients with active inflammatory bowel disease, but a substantial proportion of patients required extended use.

Ruxolitinib in steroid-refractory acute graft-vs-host disease: Japanese subgroup analysis of the randomized REACH2 trial.

Acute graft-versus-host disease (aGvHD) is a major complication after allogeneic hematopoietic stem cell transplantation in Japan and other countries. Nearly one-third of patients do not respond to standard systemic steroid therapy and no standard second-line treatment has been established in Japan. We report efficacy and safety findings of ruxolitinib versus best available therapy (BAT) from a subgroup analysis of the international, phase 3 REACH2 study in Japanese patients with steroid-refractory aGvHD. The primary endpoint was overall response rate (ORR) at day 28. Overall, 9 patients received ruxolitinib and 21 received BAT. The ORR at day 28 (88.9% vs 52.4%) and durable ORR at day 56 (66.7% vs 28.6%) were higher with ruxolitinib versus BAT. The estimated cumulative incidence of loss of response at 6 months was 12.5% with ruxolitinib and 18.2% with BAT. The median failure-free survival was longer with ruxolitinib versus BAT (2.73 vs 1.25 months). The most common adverse events up to day 28 in the ruxolitinib and BAT groups were anemia (55.6% vs 19.0%) and thrombocytopenia (44.4% vs 4.8%, respectively). Ruxolitinib showed better efficacy outcomes and a consistent safety profile compared with BAT in the Japanese subgroup, and the findings were consistent with overall study results.

The Real-World Effectiveness, Persistence, Adherence, and Safety of Janus Kinase Inhibitor Baricitinib in Rheumatoid Arthritis: A Long-Term Study.

Background/Aim: Baricitinib (BAR) is the first oral selective Janus kinase inhibitor approved in Europe for rheumatoid arthritis (RA). Real-world data are still needed to clarify its long-term benefits/risk profile. This study aimed to evaluate the effectiveness, persistence, adherence, and safety of BAR in a real-world setting. Methods: An ambispective study was conducted between October 2017 and December 2021 in RA patients starting BAR. The effectiveness was evaluated, assessing changes from the baseline of the Disease Activity Score using 28-joint counts-C reactive protein (DAS28CRP), and the achievement of low disease activity/remission. Drug persistence was evaluated using Kaplan-Meier analysis. Adherence was estimated using the medication possession ratio (MPR) and the 5-item Compliance Questionnaire for Rheumatology. Safety was assessed determining global incidence proportion and adverse event adjusted incidence rates. Results: In total, 61/64 recruited patients were finally analyzed, 83.6% were female, 78.7% were seropositive, the mean age was 58.1 (15.4) years, and the disease duration was 13.9 (8.3) years. A total of 32.8% of patients were naïve to biologics and 16.4% received BAR as monotherapy. The median exposure to BAR was 12.4 (6.6-31.2) months (range 3.1-51.4). A significant change in DAS28CRP was observed after treatment (difference -1.2, p = 0.000). 70.5% and 60.7% of patients achieved low disease activity or remission, respectively, and 50.8% (31/61) remained on BAR throughout the follow-up, with a median persistence of 31.2 (9.3-53.1) months. The average MPR was 0.96 (0.08) and all patients exhibited "good adherence" according to the questionnaire. In total, 21.3% of patients discontinued baricitinib due to toxicity. Conclusions: In our real-world practice, BAR demonstrated effectiveness, large persistence, high adherence to treatment, and an acceptable safety profile.

Post-marketing safety concerns with abrocitinib: a real-world pharmacovigilance analysis of the FDA adverse event reporting system.

BACKGROUND: Abrocitinib was newly approved for treatment of moderate-to-severe atopic dermatitis. The present study was to assess abrocitinib-related adverse events (AEs) using the Food and Drug Administration Adverse Event Reporting System (FAERS). METHODS: Disproportionality analyses, including the reporting odds ratio (ROR), the proportional reporting ratio (PRR), the Bayesian confidence propagation neural network (BCPNN), and the multi-item gamma Poisson shrinker (MGPS) algorithms, were employed to quantify the signals of abrocitinib-related AEs. RESULTS: A total of 3,177,744 reports of AEs were collected from the FAERS database, of which 1370 reports were identified with abrocitinib as the primary suspect drug. Abrocitinib-induced adverse events (AEs) occurred across 27 system organ classes (SOCs). A total of 68 preferred terms (PTs) with significant disproportionality, meeting the criteria of all four algorithms simultaneously, were identified. Unexpected significant AEs, such as increased blood cholesterol, venous embolism, hypoacusis, cellulitis, and tuberculosis, might also occur. The median onset time for abrocitinib-associated AEs was 182 days (interquartile range [IQR] 47-527 days). CONCLUSIONS: The results of this study were consistent with clinical observations. Additionally, unexpected safety signals for abrocitinib were identified, which provided supportive information for the safety profile of abrocitinib. Prospective clinical studies are warranted to validate these findings.