Tofacitinib Treatment Research Articles

CD206+ macrophages are relevant non-invasive imaging biomarkers and therapeutic targets in experimental lung fibrosis

BackgroundInterstitial lung diseases (ILDs) include a large number of diseases associated with progressive pulmonary fibrosis (PPF), including idiopathic pulmonary fibrosis (IPF). Despite the rarity of each of the fibrotic ILDs...

Treatment with tofacitinib attenuates muscle loss through myogenin activation in the collagen-induced arthritis.

Sarcopenia is a muscle disease characterized by reduction of muscle strength and muscle mass. In RA, 25.9 to 43.3% of the patients present sarcopenia. The loss of muscle mass observed in RA patients occurs either by activation of catabolic pathways or by inhibition of anabolic pathways. Despite having a list of drugs capable of treating RA inflammation, their effect on muscle is unclear. Our objective was to evaluate the tofacitinib effect on the muscle mass of collagen-induced arthritis (CIA) mice. CIA was induced in male DBA/1J mice by subcutaneous injection of Type 2 Collagen plus Freund Adjuvant. Animals were randomized into 3 groups: CIA + tofacitinib; CIA + vehicle; and healthy controls. Treatment was administered twice a day, between days 18 and 45 after induction. Clinical score, edema, and body weight were evaluated during the experimental period. After euthanasia, tibiotarsal joints were collected for assessment of disease histopathological score, and tibialis anterior (TA) and gastrocnemius (GA) muscles were weighed to assess muscle mass. Muscle atrophy was evaluated by measurement of TA myofiber cross-sectional area (CSA). Protein expression was evaluated by western blot using GA homogenates. Serum inflammatory markers were evaluated by ELISA. Statistical analysis included ANOVA followed by Tukey's or with Kruskal-Wallis. The statistical difference was assumed for p < 0.05. Tofacitinib treatment decreased arthritis severity by reducing clinical score, and hind paw edema in comparison with the vehicle group. Tofacitinib showed weight gain, higher TA and GA weights, and increased CSA compared to the vehicle group. On day 45, Tofacitinib presented increased muscle strength compared to the vehicle group, however, no difference was found in muscle fatigue. Pax7 expression was unchanged, while MyoD expression showed an increasing trend, and myogenin expression was significantly increased in Tofacitinib compared to vehicle and control groups. The treatment didn't modify Murf-1 expression. Tofacitinib mice showed decreased serum levels of TNF and increased IL-6 serum levels. Tofacitinib attenuated muscle loss in arthritic mice, increased muscle weight and muscle CSA. Activation of satellite cell regeneration, based on the increased expression of myogenin, is a potential mechanism involved in tofacitinib action against muscle loss.

Transcriptional Profiling of Tofacitinib Treatment in Juvenile Idiopathic Arthritis: Implications for Treatment Response Prediction.

To assess changes in gene expression following tofacitinib treatment and investigate transcription patterns as potential predictors of treatment response in patients with active juvenile idiopathic arthritis (JIA). Whole blood samples were collected from JIA patients at baseline and after 18 weeks of open-label tofacitinib treatment (clinical trial NCT02592434). Patients who achieved a JIA-American College of Rheumatology (ACR) response of 70 or above at week 18 were classified as treatment-responders (TR) while those with at most a JIA-ACR30 response were classified as poor-responders (PR). Differential gene expression and gene ontology (GO) over-representation analyses were performed to compare RNA expression between week 18 and baseline samples, as well as between PR and TR samples at baseline. Samples from 67 patients at baseline and 60 at week 18 were analyzed. Following 18 weeks of tofacitinib treatment across all JIA subjects, 883 genes showed significant differential expression (week 18 - baseline). The most strongly downregulated genes were over-represented within IL-7, type I, and type II interferon pathways, while upregulated genes were enriched in ontologies related to neuronal cell processes and cell signaling. Comparing PR and TR at baseline, 663 genes showed differential expression. Upregulated genes were over-represented within ontologies including activation of MAPK activity (p=9.40x10-5), myeloid cell development (p=8.13 x10-5), activation of GTPase activity (p=0.00015), and organelle transport along microtubules (p=0.00021). Tofacitinib treatment in JIA downregulated genes in interferon and IL-7 signaling pathways regardless of effectiveness. Furthermore, baseline upregulation of MAPK signaling may predict poor response to tofacitinib treatment in JIA.

Evaluating the effects of 5-aminosalicylic acid on tofacitinib treatment in ulcerative colitis.

Tofacitinib and aminosalicylic acid (5-ASA) are commonly used to treat ulcerative colitis (UC). However, evidence on the effect of concomitant 5-ASA use in patients receiving tofacitinib is limited. This study investigated the effects of 5-ASA combined with tofacitinib in UC patients. This retrospective cohort study used data from the Medical Data Vision database, including patients with UC treated with tofacitinib from May 2018 to April 2022. Patients were grouped according to tofacitinib dosage and assessed for the efficacy of concomitant 5-ASA use. The primary endpoint was clinical relapse. A total of 1213 patients with UC were included in the analysis, with 416 in the 5mg BID group and 797 in the 10mg BID group. In the 5mg BID group, the cumulative relapse-free rate was significantly higher in patients receiving concomitant 5-ASA (P<0.0001). Multivariate Cox regression analysis confirmed that concomitant 5-ASA use significantly reduced the risk of clinical relapse (adjusted hazard ratio [HR], 0.47; 95% confidence interval [CI], 0.31-0.70). In the 10mg BID group, no significant difference was noted in the cumulative relapse-free rate between patients treated with and without 5-ASA (P=0.445). Similarly, multivariate Cox regression analysis indicated that concomitant 5-ASA use did not significantly affect relapse risk (adjusted HR, 0.97; 95% CI, 0.71-1.32). Concomitant 5-ASA use reduced the risk of relapse in patients on 5mg tofacitinib BID, suggesting benefits at lower doses. However, no significant benefit was observed with 5-ASA use in those 10mg tofacitinib BID.

Optimal timing of recombinant herpes zoster virus vaccination for a JAK inhibitor treatment in rheumatoid arthritis: a multicentre, open-label, randomised comparative study (STOP-HZ study): study protocol

IntroductionJanus kinase (JAK) inhibitors are an important therapeutic option in the treatment of rheumatoid arthritis, but increase the risk of developing herpes zoster. Although a dry recombinant zoster vaccine (RZV) that can be used under immunosuppressive conditions has recently been developed, its optimal use and appropriate timing in patients scheduled to start JAK inhibitors is still unclear. The present study is designed to clarify the appropriate timing of JAK inhibitor initiation to measure varicella zoster virus (VZV)-specific IgG titers and VZV-specific T cell response in patients with rheumatoid arthritis who start tofacitinib at the first RZV vaccination or at the second one.Methods and analysisSTOP HZ (Effectiveness andSafeTyOfProphylactic RecombinantHerpesZoster Virus Vaccination for Rheumatoid Arthritis Patients with Tofacitinib Treatment) study is a multicentre, open-label, randomised, comparative study in patients with rheumatoid arthritis who are scheduled to start tofacitinib. This study enrols 60 study subjects in 12 sites. Enrolled subjects receive RZV two times on day 1 and week 8 and initiate tofacitinib 5 mg two times a day at the time of their first RZV (day 1, group A) or second RZV (week 8, group B) based on randomisation. The random assignment is performed centrally in a 1:1 ratio. Patients in Group B continue the same treatment until the start of tofacitinib treatment. Primary endpoint is VZV-specific IgG antibody titers at week 12 compared with those at baseline in each group. Secondary endpoints include comparison of VZV-specific IgG antibody between the groups, changes in disease activity of rheumatoid arthritis, VZV-specific T cell response and adverse events.Ethics and disseminationThe study has been approved by the Certified Review Board of Keio (No. 2022008), and conforms to the Declaration of Helsinki and good clinical practice guidelines. Written informed consent is obtained from participants prior to enrolment. The results of this study are planned to be submitted for publishment in relevant peer-review journals.Trial registration numberjRCTs031230329.

Safety outcomes of tocilizumab and tofacitinib treatment for rheumatoid arthritis: Target trial emulation.

Biological disease-modifying antirheumatic drugs have been the primary treatment option for moderate to severe rheumatoid arthritis (RA) in Taiwan since 2010. Tocilizumab is an interleukin-6 receptor inhibitor, whereas tofacitinib is a Janus kinase inhibitor. The two medications were indicated to treat RA by direct and indirect inhibition of interleukin-6 cytokine. We compared the safety outcomes of tocilizumab and tofacitinib in patients with RA in real-world clinical settings, following the 7 key components of target trial emulation (TTE). The data source was the Taiwan National Health Insurance Research Database. Patients with RA between 2010 and 2018 were eligible and assigned to either tocilizumab or tofacitinib based on their first prescription of these two medications. The index date was set as the first prescription date of either study medication. Propensity score stabilized weighting (PSSW) was used to balance the characteristics between the two medication groups. The incidences of safety outcomes were all-cause mortality, cancer, coronary heart disease, stroke, venous thrombosis events, tuberculosis, joint replacement events, and herpes zoster infection. The intention-to-treat (ITT) effect was commenced from the index date until the study outcomes, independently, 3 years, withdrawal, or December 31, 2021, whichever occurred first. For the per-protocol (PP) effect, patients were required to maintain the same medical group during the entire follow-up period. A total of 2125 patients with RA who were prescribed tocilizumab (n = 844) or tofacitinib (n = 1281) were included in this study. The mean follow-up duration was 2.78 years in the tocilizumab group and 2.83 years in the tofacitinib group. For ITT, the sample sizes were 721 and 1196 for the tocilizumab and tofacitinib, respectively, after PSSW. A substantially lower incidence rate of herpes zoster infection (per 100 patient-years) was observed in the tocilizumab group (3.67) than in the tofacitinib group (7.61), with a hazard ratio of 0.48 (95%CI =0.37-0.63; p < .0001). All-cause mortality, cancer, coronary heart disease, stroke, total hip replacement, and tuberculosis were similar between the two medication groups. For PP, the sample sizes were 619 and 1085 for the tocilizumab and tofacitinib, respectively, after PSSW. The results of the PP analysis were similar to those of the ITT analysis. Tocilizumab and tofacitinib act along the same inflammatory pathway. A lower herpes zoster incident rate was observed in the tocilizumab group than in the tofacitinib group. The incidence rates of other safety concerns and mortality rates were comparable in both groups of patients with RA treated in real-world settings.

JAK inhibition with tofacitinib rapidly increases contractile force in human skeletal muscle.

Reduction in muscle contractile force associated with many clinical conditions incurs serious morbidity and increased mortality. Here, we report the first evidence that JAK inhibition impacts contractile force in normal human muscle. Muscle biopsies were taken from patients who were randomized to receive tofacitinib (n = 16) or placebo (n = 17) for 48 h. Single-fiber contractile force and molecular studies were carried out. The contractile force of individual diaphragm myofibers pooled from the tofacitinib group (n = 248 fibers) was significantly higher than those from the placebo group (n = 238 fibers), with a 15.7% greater mean maximum specific force (P = 0.0016). Tofacitinib treatment similarly increased fiber force in the serratus anterior muscle. The increased force was associated with reduced muscle protein oxidation and FoxO-ubiquitination-proteasome signaling, and increased levels of smooth muscle MYLK. Inhibition of MYLK attenuated the tofacitinib-dependent increase in fiber force. These data demonstrate that tofacitinib increases the contractile force of skeletal muscle and offers several underlying mechanisms. Inhibition of the JAK-STAT pathway is thus a potential new therapy for the muscle dysfunction that occurs in many clinical conditions.

Therapeutic potential of oral tofacitinib in alopecia areata: a retrospective study

Background: Alopecia areata (AA), a prevalent autoimmune disorder, poses challenges in management, particularly in severe cases. Recent advancements highlight janus kinase (JAK) inhibitors-tofacitinib demonstrating promise. However, the literature reports conflicting information on its safety profile, especially at higher doses, necessitating a comprehensive evaluation. Methods: This retrospective analysis investigates the long-term efficacy and safety of oral tofacitinib in AA patients from January 2017 to October 2022. The study included 69 patients diagnosed with patchy multifocal AA (mfAA), alopecia totalis (AT), alopecia universalis (AU) or alopecia sub-totalis (AS). Data analysis incorporated demographic details, treatment history, autoimmune comorbidities, tofacitinib dosages, prior investigations, recurrence rates, and adverse effects. Efficacy was assessed using severity of alopecia tool (SALT) scores, with a grading system for percentage of hair regrowth. Results: The study comprising of 58% males and 42% females, exhibited varied alopecia types. Treatment response analyzed through percent change in SALT score revealed 46.5% showed very good response to tofacitinib treatment, while 4.3% had excellent response (100% change in SALT score). 44.9% of patients showed no recurrence. Adverse effects were minimal, including acneiform eruptions and upper respiratory tract infections. Pearson correlations revealed age negatively correlated with hair regrowth percentage, suggesting older individuals exhibited lower regrowth responses. Conclusions: Our findings endorse tofacitinib as a promising therapeutic option for the management of AA, with no serious side effects observed even during longer treatment durations. It can be regarded as the primary choice of treatment modality for moderate to severe forms of AA.

Assessing the Efficacy and Challenges of Tofacitinib in the Management of COVID-19: A Systematic Review and Meta-analysis of Cohort Studies

Objectives: Global healthcare faces challenges in combating COVID-19, with rising cases despite widespread vaccination. Severe COVID-19 cases, marked by acute respiratory distress and cytokine release syndrome, highlight the importance of managing cytokine storms. Janus kinase (JAK) inhibitors, such as tofacitinib, show promise in this regard. While tofacitinib is recommended for severe cases, challenges include adverse effects, conflicting studies, and the need for further investigation of new virus strains. Overcoming these hurdles is crucial for developing an effective treatment protocol and reducing COVID-19 mortality. Methods: This study conducted a comprehensive search across PubMed, Scopus, and ISI Web of Science for observational studies on tofacitinib treatment in human adults with COVID-19. The search covered a specified period up to 2024. Data extraction, including study characteristics and quality assessment, employed the Newcastle Ottawa Scale and a modified Cochrane tool. Statistical analysis, conducted with Comprehensive Meta-Analysis Software, assessed heterogeneity and significance levels. Results: The meta-analysis of the three studies showed a significant reduction in mortality (Risk Ratio: 0.372, 95% CI: 0.213–0.649, P-value = 0.001) with low heterogeneity (Cochrane P-value = 0.793), while no significant reduction in the need for mechanical ventilation was observed (Cochrane P-value = 0.194). Conclusion: Tofacitinib administration shows a significant reduction in COVID-19 mortality. However, the limited studies on its efficacy highlight the need for cautious interpretation in clinical assessments.

Tofacitinib for child-onset systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that can cause diverse clinical manifestations in multiple organ systems. Child-onset SLE (cSLE) is associated with significantly higher morbidity and mortality than adult-onset SLE. The traditional treatments for SLE (glucocorticoids, antimalarials, conventional and biological disease-modifying antirheumatic drugs) often have significant adverse effects and may not fully control disease activity. Tofacitinib is an oral Janus kinase (JAK) inhibitor that inhibits the JAK-STAT pathway and has the potential to reduce SLE severity. cSLE patients who received tofacitinib and had at least one follow-up visit were retrospectively examined. Case histories, laboratory test results, and treatment regimens were analyzed at disease onset, initiation of tofacitinib treatment, and 1, 3, 6, 9, 12, 18, and 24 months after starting tofacitinib. We examined 9 patients with refractory cSLE. All patients were female and the average age at diagnosis was 10.67 years. At initiation of tofacitinib, the average age was 13.28 years and the average disease duration was 2.62 years. Four patients experienced alleviation of symptoms and reduced their daily prednisone dosages; one of them also discontinued cyclosporine A and two of them also discontinued belimumab. The other 5 patients experienced no apparent benefit. Tofacitinib may provide clinical benefits for some patients with refractory cSLE, and can also allow reduction in the glucocorticoid dosage. Tofacitinib has the potential as an adjunctive treatment for some patients with cSLE.

Tofacitinib treatment for plaque psoriasis and psoriatic arthritis: A meta-analysis of randomised controlled trials.

Objectives Tofacitinib is used as an oral Janus-associated kinase (JAK) inhibitor acting on JAK1 and JAK3, in treating psoriatic disease. However, there is still no consensus on the optimal dosage and duration of tofacitinib. In this study, we aimed to evaluate the effects of tofacitinib in treating psoriatic disease. Methods and Materials A literature search was done utilising Cochrane library, Medline, EMBASE, Wiley Online library, Web of Science and BIOSIS Previews through December 18, 2022. We performed a meta-analysis of published original studies to assess the impact of tofacitinib in plaque psoriasis or psoriatic arthritis therapy based on seven randomised controlled trials (RCTs) involving 2,672 patients (receiving tofacitinib) and 853 controls (receiving placebo). Results Compared with placebo, the treatment of 5 mg twice-daily (BID) tofacitinib for 12 weeks is sufficient to significantly alleviate the main clinical manifestations of psoriasis [≥75% decrease in Psoriasis Area and Severity Index score (PASI 75): Risk ratio (RR)=4.38 (95% Confidence interval (CI) 2.51 to 7.64); ≥90% decrease in PASI score (PASI 90): RR=21.68 (95% CI 4.20 to 111.85); Physician's Global Assessment of 'clear' or 'almost clear' (PGA 0/1): RR=3.93 (95%CI 3.03 to 5.09)]. Interestingly, there was no significant difference in improvement in PGA 0/1 with 5 mg BID tofacitinib given for 16 weeks when compared with 5 mg BID tofacitinib for 12 weeks [RR=1.11 (95%CI 0.98 to 1.25)]. Additionally, the 5 mg BID tofacitinib for 16 weeks treatment schedule significantly increased the incidence of upper respiratory tract infection (URTI) [RR=1.89 (95%CI 1.06 to 3.38)] as compared to 5 mg BID tofacitinib for 12 weeks treatment schedule [RR=1.15 (95%CI 0.60 to 2.20)]. Conclusion The 5 mg BID tofacitinib for 12 weeks treatment significantly improved psoriasis without causing too many specific adverse events. This indicated that tofacitinib is an effective treatment plan for psoriatic disease by reasonably controlling dosage and dosing time.

Biomarker Changes in Response to Tofacitinib Treatment in Patients with Polyarticular Course Juvenile Idiopathic Arthritis.

Examine levels of candidate blood-based biomarkers (CBB) in juvenile idiopathic arthritis (JIA) treated with tofacitinib. JIA patients who participated in clinical trial NCT02592434 received tofacitinib from baseline to week 18. Serial serum samples were assayed for CBB (S100A8/9, S100A12, IL-18, SAA, resistin, VEGF, Angiopoietin-1, Angiopoietin-2, MMP8, MMP2, TIMP1, Leptin, CXCL9, sIL2R, ICAM-1, sTNFr, IL-6, IL-23, MCP1, CCL18, and CCL20). Association of CBB with JIA response to treatment from baseline to week 18 were assessed. This study included 166 patients with polyarticular-course JIA. Paired serum samples from 143 patients were available at both baseline and week 18. There were 35% (50/143) of patients with a JIA-American College of Rheumatology 90 (JIA-ACR90) level improvement while 90/121/137 (63%/85%/96%) achieved JIA-ACR70/50/30 improvement at wk18. Despite small numerical differences by JIA category, there were no baseline CBB values that independently predicted a decrease in JADAS-27 or JIA-ACR90 response by week 18. Decrease in resistin level (baseline to week 18) was significantly associated with wk18 improvement in JADAS-27 and JIA-ACR90 response, after adjusting for age, sex, JIA disease duration and baseline resistin [(r2 0.79, SE, 0.070, p<0.01 and OR(95%CI) = 1.134(1.018,1.264)]. HLA-B27 positivity was significantly associated with not achieving a JIA-ACR90 response at week 18 (p=0.0097). Among the CBB included, only resistin was significantly associated with treatment response, and no CBB was identified that forecasts JIA improvement after initiation of tofacitinib. The association of HLA-B27 positivity with lower response to tofacitinib in JIA is intriguing and merits further study.

Tofacitinib for the treatment of immune-related adverse events in cancer immunotherapy: a multi-center observational study

BackgroundTreatment strategy against immune-related adverse events (irAEs) induced by immune checkpoint inhibitors (ICIs) frequently requires other immunosuppressive agents. Tofacitinib is a rapidly acting JAK-STAT inhibitor with proven efficacy in multiple autoimmune diseases. We aimed to evaluate the efficacy and safety of tofacitinib in the management of irAEs in cancer patients.MethodsCancer patients who received ICIs and were treated with tofacitinib for the management of irAEs at 6 institutions were retrospectively included in this study. Demographic and clinical characteristics were obtained from electronic medical records. Longitudinal assessment of cardiac troponin T (cTnT) with clinical assessment was utilized to evaluate the benefit of tofacitinib treatment in patients with ICI myocarditis. Overall survival (OS) was also assessed.ResultsFifty-three patients were included in this study. The median time from irAE onset to tofacitinib therapy was 17 (range, 2–186) days and the median duration of tofacitinib treatment was 52.5 (range, 3–277) days. Enrolled patients were subdivided into 3 groups based on clinical severity and steroid responsiveness including 11 life-threatening cases, 30 steroid-resistant cases, and 12 cases with steroid taper failure. Clinical remission rate in each group was 54.5%, 96.7%, and 100%, respectively (P < 0.01). Tofacitinib was well-tolerated with 4 patients (7.5%) developing infectious events. From the ICI initiation, the overall median OS was 16.1 (95% CI 7.8–26.9) months.ConclusionTofacitinib showed promising clinical efficacy in patients experiencing irAEs, particularly in patients who failed to respond to steroids or experienced relapse during steroid tapering. Moreover, and most importantly, tofacitinib exhibited a favorable safety profile in cancer patients developing irAEs in terms of both toxicity and anti-tumor activity. Future prospective studies are warranted.

Real-world risk factors for herpes zoster in patients with rheumatoid arthritis undergoing tofacitinib treatment.

This study sought to assess the risk factors of herpes zoster (HZ) in rheumatoid arthritis (RA) patients treated with tofacitinib (TOFA). This retrospective study reviewed RA patients receiving TOFA. We compared clinical characteristics, laboratory profiles, concomitant medication use, and HZ incidence in patients with and without recent biologic synthetic disease-modifying antirheumatic drugs (bDMARDs) treatment, which is defined as their administration ≤180 days before the initiation of TOFA treatment. We used univariate Cox proportional hazards models and Kaplan-Meier analysis to assess risk factors. Among 304 RA patients, 97 had recent bDMARDs use and 207 did not. Patients with recent bDMARDs use typically had lower weekly doses of methotrexate, less hydroxychloroquine use, and shorter follow-up. In the recent bDMARDs group, 64 (66.0%) used tumor necrosis factor inhibitors (TNFi), 19 (19.6%) used tocilizumab, and 14 (14.4%) used abatacept. The overall incidence rate (IR) of HZ was 5.62 per 100 person-years. Patients with recent bDMARDs use exhibited a higher HZ risk compared to those without recent bDMARDs use (IR ratio: 2.34, 95% CI, 1.04-5.19, p = 0.028). Recent bDMARDs use (hazard ratio: 2.4, 95% CI, 1.12-4.95, p = 0.024) was an independent risk factor for HZ among multivariable analysis. Kaplan-Meier analysis confirmed increased HZ risk in RA patients on TOFA with recent bDMARDs use (log-rank p = 0.015). HZ is common in RA patients treated with TOFA, and recent bDMARDs (TNFi, tocilizumab, and abatacept) use is a risk factor for HZ. HZ vaccination, therefore, should be recommended for this group.

The treatment of Tofacitinib for rosacea through the inhibition of the JAK/STAT signaling pathway.

Rosacea is a chronic inflammatory skin disease characterized by facial erythema and telangiectasia. Despite ongoing research, the pathogenesis of rosacea remains incompletely understood, and current therapies are not entirely satisfactory. The JAK/STAT signaling pathway plays an essential role in immunoregulation, inflammation, and neurovascular regulation. Inhibition of the JAK/STAT pathway appears to hold promise as a potential therapy for rosacea. This study aimed to investigate the effects of the JAK inhibitor tofacitinib on rosacea and to preliminarily explore its therapeutic mechanism. To this end, a rosacea-like mouse model was induced using LL37 and treated with a 2% tofacitinib emulsion. The results demonstrated that topical application of tofacitinib significantly ameliorated rosacea-like phenotype, reduced the infiltration of CD4+ T cells and mast cells, and suppressed dermal angiogenesis. RT-qPCR analysis revealed a reduction in mRNA expression levels of STAT1, STAT4, and STAT5a in skin lesions following topical tofacitinib treatment. Additionally, three patients diagnosed with erythematotelangiectatic rosacea (ETR) were included in the study and treated with oral tofacitinib, leading to a significant improvement in erythema and flushing symptoms. These findings collectively suggest that tofacitinib alleviates LL37-induced rosacea-like skin inflammation in mice and rosacea skin lesions by inhibiting the JAK/STAT signaling pathway.

Comparative characteristics of the effectiveness of drugs for the treatment of alopecia areata in childhood

Alopecia areata (АА) is an autoimmune inflammatory disease with an established genetic predisposition, which is based on the lesion of hair follicles, leading to persistent or temporary hair loss. To date, treatment of АA in children, is limited to the use in most cases of external hormonal therapy in the form сream or the prescription of intradermal injections of GCS in outpatient conditions. However, data on the effectiveness of this group of drugs in severe forms of AA flow are not fully studied. There is an open question of the choice of the most preferred drug in patients simultaneously with a severe flow of AA and a severe form of atopic dermatitis. Another interesting variant of treatment of AA is the drug Dupilumab. (blocker IL-4 and IL-13). The mechanism of action of dupilumab at АA remains unknown, and its effect on TH-type 2 is assumed.Purpose of the study. To conduct a comparative performance characterization of: external GCS (Clobetazole) and injectable GCS (Betamethazone) for treatment of AA in children; Tofacitinib treatment for children with alopecia and the presence or absence of atopic dermatitis in the form of a concomitant disease; use of Dupilumaba to treat children with AA.Materials and methods. The research sample includes 420 patients. By the nature of the lesion, we considered three types of alopecia: spotted, total and universal. Patient data is taken from the register of AA patients in children. [13]. The effectiveness of the treatment was assessed on the scale SALT [14]. Patients were monitored for six months.Results. Use of intradermal injections GKS (Betamethazone), more effective than outdoor GKS (Clobetazole). In patients with atopic dermatitis, the efficacy of Tofacitinib for AA treatment is reliably higher than in patients without atopic dermatitis. Dupilumab may be a drug of choice for treating patients with a total and universal form of AA.Conclusion. Additional randomized controlled trials are needed to assess the long-term efficacy of drugs such as Tofacitinib and Dupilumab.

Tofacitinib Treatment Suppresses CD4+ T-Cell Activation and Th1 Response, Contributing to Protection against Staphylococcal Toxic Shock.

Staphylococcal toxic shock syndrome (STSS) is a rare, yet potentially fatal disease caused by Staphylococcus aureus (S. aureus) enterotoxins, known as superantigens, which trigger an intense immune response. Our previous study demonstrated the protective effect of tofacitinib against murine toxin-induced shock and a beneficial effect against S. aureus sepsis. In the current study, we examined the effects of tofacitinib on T-cell response in peripheral blood using a mouse model of enterotoxin-induced shock. Our data revealed that tofacitinib suppresses the activation of both CD4+ and CD8+ T cells in peripheral blood. Furthermore, both gene and protein levels of Th1 cytokines were downregulated by tofacitinib treatment in mice with enterotoxin-induced shock. Importantly, we demonstrated that CD4+ cells, but not CD8+ cells, are pathogenic in mice with enterotoxin-induced shock. In conclusion, our findings suggest that tofacitinib treatment suppresses CD4+ T-cell activation and Th1 response, thereby aiding in protection against staphylococcal toxic shock in mice. This insight may guide the future development of novel therapies for STSS.

Tofacitinib Regulates Endostatin via Effects on CD147 and Cathepsin S.

Angiogenesis is critical for rheumatoid arthritis (RA) progression. The effects of tofacitinib, a JAK-STAT inhibitor used for RA treatment, on angiogenesis in RA are unclear. We, therefore, evaluated the levels of angiogenic factors in two systems of a human co-culture of fibroblast (HT1080) and monocytic (U937) cell lines treated with tofacitinib and in serum samples from RA patients before and after six months of tofacitinib treatment. Tofacitinib reduced CD147 levels, matrix metalloproteinase-9 (MMP-9) activity, and angiogenic potential but increased endostatin levels and secreted proteasome 20S activity. In vitro, tofacitinib did not change CD147 mRNA but increased miR-146a-5p expression and reduced STAT3 phosphorylation. We recently showed that CD147 regulates the ability of MMP-9 and secreted proteasome 20S to cleave collagen XVIIIA into endostatin. We show here that tofacitinib-enhanced endostatin levels are mediated by CD147, as CD147-siRNA or an anti-CD147 antibody blocked proteasome 20S activity. The correlation between CD147 and different disease severity scores supported this role. Lastly, tofacitinib reduced endostatin' s degradation by inhibiting cathepsin S activity and recombinant cathepsin S reversed this in both systems. Thus, tofacitinib inhibits angiogenesis by reducing pro-angiogenic factors and enhancing the anti-angiogenic factor endostatin in a dual effect mediated partly through CD147 and partly through cathepsin S.

A hierarchical cluster analysis for clinical profiling of tofacitinib treatment response in patients with rheumatoid arthritis.

Tofacitinib is the first oral JAK inhibitor approved for treating rheumatoid arthritis (RA). To enhance our understanding of tofacitinib drug response, we used hierarchical clustering to analyse the profiles of patient who responded to the treatment in a real-world setting. Patients who commenced on tofacitinib treatment were selected from 12 major rheumatology centres in Malaysia. The aim was to assess their response to tofacitinib defined as achieving DAS28-CRP/ESR ≤ 3.2 and DAS28 improvement > 1.2 at 12weeks. A hierarchical clustering analysis was performed using sociodemographic and clinical parameters at baseline. All 163 RA patients were divided into three clusters (Clusters 1, 2 and 3) based on specific clinical factors at baseline including bone erosion, antibody positivity, disease activity and anaemia status. Cluster 1 consisted of RA patients without bone erosion, antibody negative, low baseline disease activity measure and absence of anaemia. Cluster 2 comprised of patients without bone erosion, RF positivity, anti-CCP negativity, moderate to high baseline disease activity score and absence of anaemia. Cluster 3 patients had bone erosion, antibody positivity, high baseline disease activity and anaemia. The response rates to tofacitinib varied among the clusters: Cluster 1 had a 79% response rate, Cluster 2 had a 66% response rate, and Cluster 3 had a 36% response rate. The differences in response rates between the three clusters were found to be statistically significant. This cluster analysis study indicates that patients who are seronegative and have low disease activity, absence of bone erosion and no signs of anaemia may have a higher likelihood of benefiting from tofacitinib therapy. By identifying clinical profiles that respond to tofacitinib treatment, we can improve treatment stratification yielding significant benefits and better health outcomes for individuals with RA.

Early and Sustained Symptom Control with Mirikizumab in Patients with Ulcerative Colitis in the Phase 3 LUCENT Programme.

Ulcerative colitis [UC], a chronic inflammatory bowel disease, may manifest with symptoms of increased stool frequency [SF], rectal bleeding [RB], bowel urgency [BU], abdominal pain [AP], and fatigue. Mirikizumab, an anti-IL-23p19 antibody, demonstrated efficacy and safety in patients with moderately to severely active UC in the LUCENT Phase 3 trials. We evaluated mirikizumab's efficacy in achieving symptom control and time to symptom improvement during induction, maintenance of sustained symptom control, 'comprehensive symptom control', defined according to a combination of individual patient-reported outcomes, and prognostic baseline indicators of early symptomatic remission at Week 4. The results of LUCENT-1/-2 have previously been reported. Treatment differences for symptomatic endpoints were compared over 52 weeks versus placebo [PBO] and comprehensive symptomatic endpoints at 12 and 52 weeks of continuous treatment. Subgroup analyses were conducted for prior biologic or tofacitinib treatment failure. Prognostic analyses were run using regression analysis. By Week [W] 2, mirikizumab-treated patients achieved greater reductions in SF, RB, BU, and fatigue versus PBO. At W4, there was a higher rate of AP improvement. At W12, a greater proportion of mirikizumab-treated patients achieved symptomatic remission, RB remission, SF remission, and BU remission/clinically meaningful improvement. Mirikizumab-treated patients sustained symptom control versus placebo patients in maintenance until W52. This treatment effect was shown in patients regardless of prior biologic or tofacitinib failure. Additionally, mirikizumab achieved comprehensive symptom control versus PBO at W12 and W52. Mirikizumab demonstrated efficacy in achieving and sustaining symptom control and comprehensive symptom control over 52 weeks [NCT03518086; NCT03524092].