Safety Of Janus Kinase Inhibitors Research Articles

Janus kinase inhibitors versus tumor necrosis factor inhibitors in rheumatoid arthritis: meta-analytical comparison of efficacy and safety.

Rheumatoid arthritis (RA) is a chronic systemic autoimmune disorder characterized by persistent inflammation leading to progressively worse disability. Janus kinase (JAK) inhibitors and tumor necrosis factor (TNF) inhibitors are pivotal in RA treatment, yet their comparative efficacy remains underexplored. This study aimed to compare the efficacy and safety of JAK inhibitors and TNF inhibitors in treating RA using data from randomized controlled trials (RCTs). A meta-analysis and outcomes analysis were based on results of the Health Assessment Questionnaire Disability Index (HAQ-DI), Clinical Disease Activity Index (CDAI), Visual Analogue Scale (VAS), and Patient Global Assessment Scale (PtGA) and other indices as incidences of venous thromboembolism (VTE) and malignancy. The JAK inhibitors caused a statistically significant improvement in the HAQ-DI score [MD = 0.08, 95% CI (0.03, 0.12), p = 0.0008] compared with the TNF inhibitors. However, no significant difference was observed between the two drug classes in the CDAI score [MD = -2.03, 95% CI (-9.27, 5.22), p = 0.58]. JAK inhibitors were associated with an increase in the VAS score [MD = 3.62, 95% CI (0.86, 6.38), p = 0.01], but there was no significant difference in the PtGA score [MD = 1.91, 95% CI (-3.25, 7.08), p = 0.47]. JAK inhibitors demonstrated superior efficacy in improving the functional status and reducing the disease activity in RA patients compared with TNF inhibitors. Both drug classes exhibited comparable safety profiles for VTE and malignancies, though JAK inhibitors had a higher risk for thromboembolism.

Efficacy and safety of Janus kinase inhibitors in patients with difficult-to-treat rheumatoid arthritis.

This study evaluated the effectiveness of Janus kinase inhibitors (JAKi) in patients with difficult-to-treat rheumatoid arthritis (D2T RA). This study included 220 patients with RA who were treated with JAKi. Sixty-two patients were naïve to biological disease-modifying anti-rheumatic drugs (bDMARDs)/JAKi (1st group), 57 patients were failure to one bDMARDs/JAKi (2nd group), and 101 patients were failure to ≥ 2 bDMARDs/JAKi. Of these 101 patients, 25 did not meet the D2T RA criteria (non-D2T RA group) and 76 met the D2T RA criteria (D2T RA group). : DAS28-ESR was improved in all groups at 24 weeks (1st: p<0.01, 2nd: p<0.01, non-D2T RA: p=0.01, D2TRA: p=0.02), and improvement ratio of DAS28-ESR was not different between DT2RA group and 2nd (p=0.73) or non-D2T RA group (p=0.68). Glucocorticoid use (odds ratios: 8.67; 95% CI: 1.23-60.90; P=0.03) and number of past bDMARD/JAKi uses ≥ 3 (odds ratios: 10.55; 95% CI: 1.39-80.30; P=0.02) were risk factors for DAS28-ESR ≥ 3.2 at 24 weeks in the D2T RA group. Clinical efficacy of JAKi in D2T RA group did not differ from that in 2nd and non-D2T RA groups. Glucocorticoid use and multiple bDMARD/JAKi failure were poor prognostic factors for D2T RA.

Janus kinase inhibitors and tumour necrosis factor inhibitors show a favourable safety profile and similar persistence in rheumatoid arthritis, psoriatic arthritis and spondyloarthritis: real-world data from the BIOBADASER registry

ObjectivesTo compare the safety of Janus kinase inhibitors (JAKi) with that of tumour necrosis factor inhibitors (TNFi) and determine drug persistence among patients with rheumatoid arthritis (RA) and spondyloarthritis (SpA).MethodsWe...

Navigating treatment resistance: Janus kinase inhibitors for ulcerative colitis

The management of refractory ulcerative colitis (UC) and acute severe UC (ASUC) is challenging due to the lack of standardized approaches in cases resistant to multiple treatments. In this editorial, I investigate the efficacy and safety of Janus kinase inhibitors, particularly upadacitinib and tofacitinib, in controlling severe and refractory disease. I highlight a notable case report by Xu et al , which explores the case of a patient with primary nonresponse to two classes of biologics and two fecal microbiota transplants who exhibited a remarkable response to upadacitinib. Furthermore, I discuss the use of tofacitinib in refractory UC and ASUC, either as monotherapy or in combination with biologics, which has shown promising response rates. Additionally, emerging evidence of upadacitinib efficacy in ASUC is presented. Overall, these cases emphasize the complex nature of managing refractory ASUC and the potential of small-molecule therapies to achieve remission. Further research is needed to refine treatment strategies for patients with treatment-resistant UC.

Oral Janus Kinase Inhibitors in Pediatric Atopic Dermatitis.

To analyze the efficacy and safety of Janus kinase inhibitors (JAKi) in the treatment of pediatric AD. Adolescents with moderate and severe atopic dermatitis (AD) need systemic therapies, as stated several recent practice guidelines. (JAKi) have shown their efficacy in the treatment of adult AD, however, there is a lack of information concerning efficacy and safety of their use in pediatric AD. We found that the JAKi'sabrocitinib (ABRO),baricitinib(BARI), andupadacitinib (UPA),are all an effective treatment option with a very fast onset of action for adolescents with moderate-to-severe AD. BARI was not effective in children between 2 and 10years with moderate-to-severe AD. Fortunately,majorsafety issues with JAKi in adolescents with AD have not been documented in the trials, so far, contrasting with the reports in adults with AD, where these events have very rarely occurred.There are some reports of herpes zoster (HZ) infection in adolescents on JAKi, but it is not a major safety concern. Acne is a relatively common AE with UPA in adolescents; however, it is responsive to standard treatment. This review will help the clinician to choose among the JAKi according to the needs and clinical features of patients with moderate and severe AD. In the following years, with the advent of new biologicals and JAKi, these therapies will fall into place in each phase of the evolution of patients with AD.

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

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. 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. 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. 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.

The Retention Rate and Safety of JAK Inhibitors in Rheumatoid Arthritis: Real Word Data from a Monocentric Cohort.

Background/Objectives: To date, the literature concerning real-world data on the retention rate and safety of Janus kinase inhibitors (JAKis) is limited. To retrospectively evaluate the overall drug retention rate (DRR) of different JAKis in a monocentric cohort of patients with rheumatoid arthritis (RA). Methods: Patients diagnosed with RA and treated with JAKis who were evaluated at our outpatient clinic from March 2017 to December 2023 were included in the study. Demographic, clinical characteristics, and comorbidities were recorded. The DRR was evaluated as the time to drug discontinuation, and baseline predictors of drug discontinuation were investigated through Cox regression after adjusting for baseline confounders. Results: The global DRR for JAKis was 51.3%. The DRR was 37.5% for tofacitinib, 46.6% for baricitinib, 69.4% for upadacitinib, and 53.5% for filgotinib. Considering all JAKis, the only significant predictor of drug discontinuation was the use of JAKis as a first-line treatment (HR 95% CI [0.25 (0.13-0.46)]. When considering each JAKi individually, a longer disease duration predicted TOF discontinuation (HR95% CI [1.05 (1.01-1.09)], while seropositivity protected against TOF being withdrawn (HR95% CI [0.41 (0.17-0.97)]. No independent predictors emerged for other JAKis. Conclusions: the use of JAKis as a first-line treatment as well as disease duration and serology may impact the DRR of JAKis, which may inform tailored treatment strategies in clinical practice.

Janus kinase inhibition (JAKi) therapy in refractory anti-synthetase syndrome: A retrospective cohort study

ObjectivesTo evaluate the efficacy and safety of Janus kinase inhibitors (JAKi) in the treatment of refractory anti-synthetase syndrome (ASS) in real-world clinical settings. MethodsThe medical records of all refractory ASS patients who were treated with JAKi from October 2020 to June 2023 were retrospectively reviewed. ResultsTwenty patients were included, and all (100 %) patients had interstitial lung disease (ILD). After treatment with JAKi, 14 (70 %) of the refractory ASS patients showed significant improvement in clinical manifestations, including arthritis (56.3 % vs. 6.3 %, p = 0.002), rash (77.8 % vs. 27.8 %, p = 0.012), shortness of breath (55.6 % vs. 16.7 %, p = 0.039), cough (61.1 % vs. 11.1 %, p = 0.012). Improvement was noted for myalgia (50 % vs. 11.1 %, p = 0.016) and muscular weakness (61.1 % vs. 11.1 %, p = 0.012), while creatine kinase (CK) levels, which were abnormally elevated in five patients prior treatment, were significantly lowered (1096 ± 1042.98 IU/L vs. 199.2 ± 144.66 IU/L, p = 0.043). A decrease in levels of inflammatory markers, including erythrocyte sedimentation rate (ESR) (p = 0.001) and C-reactive protein (CRP) (p = 0.023) was observed in the patients. In ASS-ILD, the CT score reduced (188.75 ± 69.67 vs. 156.35 ± 74.62, p = 0.001). Furthermore, the glucocorticoid dose significantly reduced (21.42 ± 13.26 mg vs. 11.32 ± 8.59 mg; p = 0.001). ConclusionsJAKi were effective in most refractory ASS patients as evidenced by improved skin rash, myositis, and ILD. However, larger prospective controlled studies are required to evaluate its efficacy.

JAK inhibitors in refractory juvenile rheumatic diseases: Efficacy, tolerance and type-I interferon profiling, a single center retrospective study

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.

Safety of Janus kinase inhibitors compared to biological DMARDs in patients with rheumatoid arthritis and renal impairment: the ANSWER cohort study

Data on the safety of Janus kinase inhibitors (JAKis) in patients with renal impairment are lacking. This study aimed to investigate the safety of JAKis compared to biological (b) DMARDs in patients with rheumatoid arthritis (RA) and renal impairment. We used a multi-centre observational registry of patients with RA in Japan (the ANSWER cohort). We assessed the drug retention rates of b/targeted synthetic DMARDs with different modes of action (tumour necrosis factor inhibitors (TNFis), immunoglobulins fused with cytotoxic T-lymphocyte antigen (CTLA-4-Ig), interleukin-6 receptor inhibitors (IL-6Ris), and JAKis) in patients with RA stratified by pre-treatment estimated glomerular filtration rate (eGFR) levels. The time to discontinuation of bDMARDs or JAKis was analysed using a multivariate Cox proportional hazards model This study included 3775 patients, who were classified into three groups (the normal group (eGFR ≥ 60 mL/min/1.73 m2): 2893 patients; CKDa group (eGFR 45–60 mL/min/1.73 m2): 551; and CKDb group (eGFR < 45 mL/min/1.73 m2): 331). In the CKDb group, the 12-month drug retention rate due to adverse events (AE) was the lowest in patients treated with JAKi (TNFi: 93.1%; IL-6Ri: 94.1%; CTLA-4-Ig: 92.3%; JAKi: 75.1%). In the normal and CKDa groups, drug retention rates due to AE were similar among patients treated with bDMARDs and JAKi. In contrast, drug retention rates due to inefficacy were similar between bDMARDs and JAKis in all groups. In the Cox-proportional model, in the CKDb group, TNFi, IL-6Ri, and CTLA-4-Ig showed lower incidence of drug discontinuation due to AE than JAKis (TNFi: hazard ratio = 0.23 (95% confidence interval 0.09–0.61), IL-6Ri: 0.34 (0.14–0.81), CTLA-4-Ig: 0.36 (0.15–0.89)). JAKis showed the lowest drug retention due to AE in patients with moderate-to-severe and severe renal impairment (eGFR < 45 mL/min/1.73 m2). Physicians should pay more attention to renal function when using JAKis than when using bDMARDs.

Real-World Experience of Tofacitinib and Baricitinib Use in Alopecia Areata in Greek Population: A Retrospective Analysis With Focus on Safety.

The introduction of Janus Kinase inhibitors (JAKi) seems to revolutionize the field of alopecia areata (AA) therapeutics. However, real-world data are still missing. To provide evidence about effectiveness and safety of tofacitinib and baricitinib in AA in real-world settings and describe baseline disease characteristics and patients profiles that are considered good candidates for JAKi in the daily practice. Furthermore, we intended to investigate potential correlations between baseline characteristics and treatment outcomes. We retrospectively reviewed the databases of two tertiary Hospitals in Greece, to identify individuals of any age currently being treated with systemic JAKi for severe AA. We identified 42 individuals, including 3 adolescents. In our cohort, 52.3% (22/42) were under tofacitinib and 47.6% (20/42) under baricitinib treatment. Efficacy analysis was performed on the subgroup of 30 patients that had completed at least a 3-month follow-up on treatment. In the latter group, mean time on treatment was 10 months. Mean Severity of Alopecia Tool and mean Dermatology Life Quality Index scores decreased from 84.46% and 12.86 at baseline, to 43.26% and 6.63, respectively. Complete response (CR) was recorded in 4 (13.33%), partial in 12 (40%) and no response in 14 patients (46.66%), correspondingly. Seventeen out of 42 (40.5%) individuals in total, reported at least 1 adverse event. No patient required hospitalization. Among 15 patients (35.7%) who got COVID-19, one suffered from serious infection. The 3 adolescents achieved CR with no significant adverse events. Real-world data suggest efficacy and safety of JAKi in severe forms of AA. Tolerability is optimal in younger individuals.

Tofacitinib in Pregnancy: Assessing Pregnancy and Infant Outcomes, Cord Blood, and Breast Milk Concentrations

Janus kinase (JAK) inhibitors are effective anti-inflammatory agents for treatment of ulcerative colitis (UC).1 According to drug regulatory agencies and international guidelines, JAK inhibitors should be avoided during pregnancy and lactation.2-4 The existing evidence on safety of JAK inhibitors during pregnancy is scarce and almost exclusively limited to tofacitinib.4-7.

P718 Observational real-world evidence on the efficacy and safety of Janus Kinase inhibitors (JAKi) in the treatment of moderate to severe Active Ulcerative Colitis (UC)

Abstract Background Janus kinase inhibitors (JAKi) are the first orally administered treatment for Ulcerative Colitis (UC). The JAK family comprises of four intracellular tyrosine kinases inhibitors (JAK1, JAK2, JAK3 and Tyrosine Kinase 2). Inhibition of the JAK kinases lead to dampening of the inflammatory cytokines which drive Inflammatory Bowel Disease (IBD). Tofacitinib was the first generation pan-JAKi. This was followed by second generation JAKi: Filgotinib and Upadacinib which preferentially inhibit JAK1. We report on the real-world evidence on the efficacy and safety of JAKi in the treatment of UC in a tertiary IBD treatment centre. Methods Patients attending the IBD clinic at weeks 8-12 of initiation of therapy were included. Baseline demographics, disease activity and previous therapies were recorded. Clinical response was measured using the SCCAI and biochemical response was measured using calprotectin and CRP. We defined clinical response as ≥3 points reduction from baseline SCCAI, and clinical remission as SCCAI Score of &amp;lt;2.5, and / or biochemical remission as a CRP of less than 5 mg/L and a calprotectin level of &amp;lt; 250 mg/g. We also assessed treatment persistence, and the reasons for treatment cessation. Results The UC populations are shown in Table 1. 52 patients were included and an additional 24 patients who discontinued therapy early on were assessed to review secondary outcomes. Table 1 summarises the comparative outcomes of the JAKi. 81% and 63% of patients achieved clinical and biochemical remission respectively. Overall, 31% discontinued treatment due to lack of efficacy or adverse events. 60% of patients reported adverse events (AEs), 25 % of patients discontinued treatment due to AEs and 84% of patients continued treatment despite reporting AEs. The most common AEs were hypercholesteremia and cold and flu like symptoms and the most common AEs related with treatment discontinuation were recurrent infection or persistent deranged liver functions contributed to patients’ history of primary sclerosing cholangitis. No Serious Adverse Events were reported. 60% of patients on tofacitinib developed side effects and persisted with therapy, which included hypercholesteremia (67%), shingles (11%), flu like symptom (11%) and hair loss (11%). 53% had side effects with Filgotinib; hypercholesteremia (25%), cold like symptoms (25%), chest infection (13%), shingles (13%), acne (13%). 68% developed side effects with Upadacitinib; reports of acne (20%), cold and flu (33%), shingles and mood swings (7%) and high cholesterol (67%). Conclusion In this real-world cohort of UC patients, JAKi was effective in inducing remission and had an acceptable safety profile. The observed safety profile was as expected compared to clinical data results.

Efficacy and safety of JAK inhibitors in rheumatoid arthritis: update for the practising clinician.

Janus kinase (JAK) inhibitors, including tofacitinib, baricitinib, upadacitinib and filgotinib, are increasingly used in the treatment of rheumatoid arthritis (RA). There has been debate about their safety, particularly following the issuance of guidance by regulatory agencies advising caution in their use in certain patients. The registrational clinical trials and registry data of JAK inhibitors did not identify a difference in therisk of major adverse cardiovascular events (MACEs), venous thromboembolism, malignancies or infections (other than herpes zoster) with a JAK inhibitor versus abiologicDMARD. In the ORAL Surveillance trial, which enrolled patients >50 yearsof age with ≥1 cardiovascular risk factor, tofacitinib was statistically inferior to TNF inhibitors for the occurrence of MACEs and malignancy. Further post hoc analysis of the data revealed that anageof ≥65 years, ahigh baseline cardiovascular risk, ahistory of smoking, sustained inflammation, disease activity and suboptimal treatment of cardiovascular comorbidities all increase the risk of these outcomes. The guidance issued by regulatory agencies should be carefully considered to ensure appropriate and safe treatment of patients with RA without undertreatment of patients who might benefit from JAK inhibitor, as well as biologic, treatment. As always, the risks associated with the use of these agents, treatment goals, costs and patient preferences should be discussed with the patient.

Efficacy and safety of Janus kinase inhibitors in non-infectious inflammatory ocular diseases: a prospective cohort study from the international AIDA network registries.

Non-infectious inflammatory ocular diseases pose significant challenges in diagnosis and management, often requiring systemic immunosuppressive therapy. Since Janus kinase (JAK) inhibitors may represent a novel therapeutic option for these disorders, the present study aimed to expand current knowledge about their efficacy and safety in patients with these conditions. This prospective cohort study included 12 adult patients from the international AutoInflammatory Disease Alliance (AIDA) Network registries dedicated to non-infectious ocular inflammatory conditions. We assessed ocular flares, visual acuity, disease course, and complications before and after initiating JAK inhibitor therapy. Ocular inflammation was related to a systemic disease in 8 (66.7%) patients as follows: spondyloarthritis (n = 3), peripheral psoriatic arthritis (n = 1), rheumatoid arthritis (n = 1), antinuclear antibodies (ANA) positive juvenile idiopathic arthritis (n = 1), Behçet's syndrome (n = 1), Vogt-Koyanagi-Harada syndrome (n = 1). In total, 4 patients received baricitinib, 1 patient received tofacitinib, and 7 patients underwent upadacitinib treatment. The overall average duration of JAK inhibitors treatment was 8.6 ± 5.5 months (ranging from 3 to 20 months). At the last assessment, ocular disease control was complete in 12/12 patients. One patient discontinued baricitinib due to poor compliance after a 12-month relapse-free period. The incidence of ocular flares was 125 episodes/1.000 person-months prior to the initiation of JAK inhibitors and 28.6 episodes/1.000 person-months thereafter. The incidence rate ratio for experiencing a relapse before starting a JAK inhibitor compared to the following period was 4.37 (95% CI 1.3-14.7, p-value: 0.02). JAK inhibitors demonstrate efficacy and safety in controlling ocular inflammatory relapses, confirming that they represent a valuable treatment option for patients with non-infectious inflammatory ocular diseases resistant to conventional treatments.

Janus Kinase Inhibitors and Interstitial Lung Disease Associated With Pediatric Rheumatic Diseases: An Unexplored Field.

Rheumatic diseases are often complicated by lung disease, commonly presenting as interstitial lung disease (ILD), with potentially detrimental consequences for patient survival. Although less frequent in pediatric patients, pulmonary involvement may be observed in almost all childhood-onset rheumatic conditions. The development of biological disease-modifying anti-rheumatic drugs has significantly improved clinical outcomes. However, disease remission is not always complete or long-lasting, and treatment may need to be discontinued due to adverse effects. A novel class of drugs, namely Janus kinase inhibitors (JAKis), has been proposed to provide a significant survival benefit for patients with rheumatic diseases. Despite the ample literature on the efficacy and safety of JAKis in rheumatic disease, only a few studies have investigated the effectiveness of these drugs in patients with pulmonary involvement, and only two case reports have presented results in pediatric patients. We provide an overview of the rationale for using JAKis in ILDs associated with rheumatic disease and summarize the main studies evaluating their efficacy in both adult and pediatric patients. The present review highlights the need for controlled long-term studies to assess the efficacy and safety of JAKis in pediatric rheumatic disease complicated by lung disease.

JAK Inhibitors in Solid Organ Transplantation.

Janus kinase (JAK) inhibitors are a novel group of immunosuppressive drugs approved to treat certain rheumatic and allergic disorders; however, their efficacy in the regulation of alloimmune responses after solid organ transplantation has not yet been elucidated. In the present review, we have summarized the results of invitro, invivo, experimental, and clinical trial studies about the efficacy and safety of JAK inhibitors in improving allograft survival in solid organ transplantations, including kidney, heart, lung, and liver transplants. Moreover, reports on administering JAK inhibitors to steroid-resistant patients with graft versus host disease (GvHD) after solid organ transplantation have been reviewed. Overall findings are suggestive of a beneficial role for JAK inhibitors in organ transplantation: for example, they have been shown to improve allograft function, reduce the rate and score of acute rejection, downregulate the expression of proinflammatory cytokines and adhesion molecules, and decrease oxidative stress. However, the adverse effects of these drugs, in particular bone marrow suppression and infection, remain an obstacle.

Safety of Janus Kinase Inhibitors: A Real-World Multicenter Retrospective Cohort Study.

Oral Janus kinase inhibitors (JAKis) represent an effective strategy for rheumatoid arthritis (RA) treatment. A previous study supported that tofacitinib (TOF) is associated with higher incidence of cardiovascular (CV) and neoplastic events compared to tumor necrosis factor inhibitors. Given the apparent discrepancy between these data and real-world experience, we aimed to investigate the safety and efficacy of the available JAKis in a multicenter cohort. We retrospectively evaluated patients with RA who ever received 1 JAKi (TOF, baricitinib [BAR], upadactinib [UPA], filgotinib [FIL]) from 4 tertiary care centers in Milan, Italy. Outcomes related to JAKi safety were recorded, particularly major CV events as well as adverse events of special interest (AESIs), which included serious infections, opportunistic infections, venous thromboembolism, herpes zoster infections, liver injury, malignancies, and deaths; retention rates were also calculated. Further analyses included patients fulfilling the risk factors suggested to influence TOF safety. Six hundred eighty-five patients were included and received BAR (48%), TOF (31%), UPA (14%), or FIL (7%) as first-line innovative treatment prior to a biologic. Of a total of 1137 patient-years of observation, we recorded 1 stroke and 123 (18%) AESIs, including 3 deaths, all a result of severe infections. Among patients with a higher CV risk, we observed a higher frequency of AESIs (23%). Our real-world data confirm that JAKis are effective and carry a low risk of AESIs, especially in patients who do not display CV risk factors at baseline. Our study could not identify differences between JAKis. Different safety profiles should be defined in larger prospective cohorts.

Drug Retention Rates and the Safety of Janus Kinase Inhibitors in Elderly Patients with Rheumatoid Arthritis.

We examined the real-world drug retention rate and safety data of Janus kinase inhibitors (JAKis) in elderly patients with rheumatoid arthritis (RA). This study enrolled 133 RA patients (≥65 years) with sufficient clinical data who were initiated with JAKis during the study period. These patients were divided into two groups: the very elderly group (≥ 75 years) and the elderly group (65 ≤ years < 75). The drug retention rates of JAKis were compared using Kaplan-Meier curves. The discontinuation rates of JAKis were as follows: lack of effectiveness 27 (20.3%), adverse events (AEs) 29 (21.8%), and remission 2 (1.5%). There was no significant difference in the overall drug retention rate between the very elderly group (≥75 years) and the elderly group. Furthermore, the overall drug retention rates of JAKis were not affected by gender, methotrexate use, and anti-citrullinated protein/peptide antibody (ACPA) status. The discontinuation rates of JAKis due to AEs were comparable both in the very elderly group (≥75 years) and the elderly group (65 ≤ years < 75). Whereas chronic lung disease and hypoalbuminemia were independently associated with discontinuation rates due to AEs, the overall drug retention rates were significantly lower in patients treated with the approved dose of JAKis than in those treated with a reduced or tapered dose. Our results suggest that the overall drug retention rate of JAKis in very elderly patients (≥75 years) was comparable with that in elderly patients (65 ≤ years < 75). The discontinuation rates of JAKis due to AEs were also comparable both in very elderly group patients and elderly patients.

Recommendations for risk minimization when using Janus kinase inhibitors for the treatment of chronic inflammatory skin diseases.

In accordance with article 20 of Regulation (EC) No 726/2004, the Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicines Agency (EMA) has re-evaluated the safety of Janus kinase inhibitors for the treatment of inflammatory diseases and formulated safety information deviating from the previous indications in the respective summary of product characteristics of the products concerned. These refer to the consideration of a possibly increased risk of venous thromboembolic or severe cardiovascular events, an increased infection rate and an increase in the prevalence of skin cancer across drugs and indications. Therefore, in patients with independent risk factors (age 65 years and older, smokers or former smokers, patients with oral contraception or hormone replacement therapy and other risk factors), it is recommended to use Janus kinase inhibitors therapeutically only if there are no suitable treatment alternatives. To facilitate a pragmatic and thorough detection of high-risk patients in everyday clinical practice, an interdisciplinary checklist was developed that is suitable as a working tool from the perspective of the dermatologist.