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INTRODUCTION: Obese rheumatoid arthritis (RA) patients often show reduced responses to traditional treatments, including TNF inhibitors (TNFi). Considering the different mechanisms of action it is important to evaluate the efficacy of tofacitinib in obese patients. This study aims to explore the impact of obesity on the drug survival of tofacitinib in RA patients. MATERIAL AND METHODS: This retrospective cohort study included RA patients treated with tofacitinib. Patients were categorized into obese (BMI ≥ 30 kg/m2) and non-obese (BMI < 30 kg/m2) groups. The primary outcome was drug survival, assessed using Kaplan-Meier and logistic regression analyses. RESULTS: The study comprised 80 RA patients, with 31 (39%) classified as obese. At the 12-month mark, the drug survival rate for tofacitinib was higher in the obese group (81%) compared to the non-obese group (59%). Contrary to univariable analysis, multivariate analysis did not identify obesity as a significant predictor of drug survival. Other variables including sex, hypertension, diabetes mellitus, and anti-cyclic citrullinated peptide (anti-CCP) positivity also showed no significant association with tofacitinib drug survival. CONCLUSION: The findings indicate that obesity does not alter the drug survival rate for tofacitinib among RA patients. Univariate analysis reported a potentially higher drug survival rate in obese patients; however, the lack of statistical significance in multivariate analysis and the study's retrospective nature necessitate further research to validate these observations and guide personalized therapeutic strategies for this population.

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Purpose: At present, we have entered the era of using biological agents and small molecule targeted drugs to treat diseases. Although there have been many reports of biological agents treating pityriasis rubra pilaris recently, the clinical application of the JAK inhibitors in the treatment of pityriasis rubra pilaris has been rarely reported, and there is a lack of evidence on the safety and efficacy of these drugs. We explore the use of the JAK inhibitor tofacitinib in the treatment of pityriasis rubra pilaris with significant efficacy and no significant side effects, providing new ideas for the clinical treatment of pityriasis rubra pilaris. Methods: We cover a case of pityriasis rubra pilaris treated with the JAK inhibitor tofacitinib, which showed significant efficacy without any adverse effects. Results: This case report showed that the JAK inhibitor tofacitinib had significant clinical efficacy in the treatment of pityriasis rubra pilaris. We speculated that the treatment of pityriasis rubra pilaris with the JAK inhibitors may be related to blocking the activation of the JAK/STAT pathway, thereby blocking the high expression of cytokines IL-17, IL-12/IL-23, IL-23, TNF-α. Conclusion: The JAK inhibitor tofacitinib can become a new option for treating pityriasis rubra pilaris.

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BACKGROUND: 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. AIM: 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). METHODS: 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. RESULTS: 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]. CONCLUSION: 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.

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Objective: The signal transducer and activator of transcription 3 (STAT3) gain-of-function (GOF) syndrome (STAT3-GOF) is an inborn error of immunity (IEI) characterized by diverse manifestations of immune dysregulation that necessitate systemic immunomodulatory treatment. The blockade of the interleukin-6 receptor and/or the inhibition of the Janus kinases has been commonly employed to treat diverse STAT3-GOF-associated manifestations. However, evidence on long-term treatment outcome, especially in the case of adult patients, is scarce. Methods: Clinical data, including laboratory findings and medical imaging, were collected from all seven patients, diagnosed with STAT3-GOF, who have been treated at the Hannover University School, focusing on those who received a Janus kinase (JAK) inhibitor (JAKi). Previously published cases of STAT3-GOF patients who received a JAKi were evaluated, focusing on reported treatment efficacy with respect to diverse STAT3-GOF-associated manifestations of immune dysregulation and safety. Results: Five out of seven patients diagnosed with STAT3-GOF were treated with a JAKi, each for a different indication. Including these patients, outcomes of JAKi treatment have been reported for a total of 41 patients. Treatment with a JAKi led to improvement of diverse autoimmune, inflammatory, or lymphoproliferative manifestations of STAT3-GOF and a therapeutic benefit could be documented for all except two patients. Considering all reported manifestations of immune dysregulation in each patient, complete remission was achieved in 10/41 (24.4%) treated patients. Conclusions: JAKi treatment improved diverse manifestations of immune dysregulation in the majority of STAT3-GOF patients, representing a promising therapeutic approach. Long-term follow-up data are needed to evaluate possible risks of prolonged treatment with a JAKi.

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The JAK2 V617F mutation is the most common driver gene in myeloproliferative neoplasm (MPN), which means that the JAK/STAT signaling pathway is persistently activated independent of cytokines, and plays an important part in the onset and development of MPN. The JAK inhibitors, although widely used in the clinical practice, are unable to eradicate MPN. Therefore, the unavoidable long-term treatment poses a serious burden for patients with MPN. It is established that the JAK2 V617F mutation, in addition its role in the JAK/STAT pathway, can promote cell proliferation, differentiation, anti-apoptosis, DNA damage accumulation, and other key biologic processes through multiple pathways. Other than that, the JAK2 V617F mutation affects the cardiovascular system through multiple mechanisms. Although JAK inhibitors cannot eradicate MPN cells, the combined use of JAK inhibitors and other drugs may have surprising effects. This requires an in-depth understanding of the mechanism of action of the JAK2 V617F mutation. In this review, the authors explored the role of the JAK2 V617F mutation in MPN from multiple aspects, including the mechanisms of non-JAK/STAT pathways, the regulation of cellular methylation, the induction of cellular DNA damage accumulation, and effects on the cardiovascular system, with the objective of providing valuable insights into multidrug combination therapy for MPN.

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Hidradenitis suppurativa (HS) is a chronic inflammatory disease characterised by recurrent painful nodules, abscesses, fistulas and scarring. The primary distinguishing factor in the complex, yet still not fully understood, pathogenesis is an inflammation occurring within the hair follicle, followed by an immune response leading to further development of the skin lesions seen in HS. The treatment of patients with HS is very difficult due to the complexity of the lesions and the frequent tendency to recurrence, which also has a negative impact on the psychological state of patients and directly translates into a reduced quality of life. This review article addresses the pathogenesis, clinical presentation of HS and, in particular, explores the new therapeutic options available.

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The use of medications which target the JAK-STAT signaling pathway, also known as janus kinase (JAK) inhibitors, has rapidly increased in recent years. Patient perceptions, opinions, and concerns regarding the use of JAK inhibitors are largely uninvestigated. Our objective is to better understand patient concerns, reported side effects, and sentiments regarding the use of JAK inhibitors for dermatologic disease. The authors performed a cross-sectional analysis of the most frequented subreddits for dermatologic disease in which JAK inhibitors have obtained FDA approval (r/atopic dermatitis, r/psoriasis, r/alopecia areata, r/vitiligo, and r/eczeJAKS). The sentiment, central theme, and engagement level of each post was evaluated using previously utilized methods. Nine hundred twenty-three posts were analyzed, with the majority focusing on efficacy (433, 47%) and medication-related side effects (150, 16%). Other themes of interest to patients were Payment/Insurance (84, 9%), Study Results/News (69, 7%), Administration/Dosage (33, 4%), and Medication Interactions (31, 3%). The most frequently reported side effects were acne/folliculitis (24, 22%), nausea/gastrointestinal disturbance (11,10%), and fatigue/muscle aches (10, 9%). At the same time, the medication interactions garnering the most concern were sunscreens/facial moisturizers (5, 16%), topical calcineurin inhibitors (4, 13%), and Marijuana/THC (3, 9.%). This analysis highlights that patients are most concerned about the efficacy and side effects of JAK inhibitors in addition to issues regarding access to JAK inhibitors. Providers can use the insights gained from this study to address hesitancy better and guide comprehensive, patient-centered discussions with patients regarding JAK inhibitor use.

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Spondyloarthritis (SpA) is a term to describe a group of chronic inflammatory rheumatic diseases, which have common pathophysiological, genetic, and clinical features. Under the umbrella term SpA, two main groups are subsumed: axial SpA (radiographic axSpA and non-radiographic axSpA) and peripheral SpA (with the leading representative being psoriatic arthritis (PsA) but also arthritis associated with inflammatory bowel disease (IBD), reactive arthritis, and undifferentiated pSpA). The key clinical symptom in axSpA is chronic back pain, typically with inflammatory characteristics, which starts in early adulthood, while the leading clinical manifestations of peripheral SpA (pSpA) are arthritis, enthesitis, and/or dactylitis. Furthermore, extra-musculoskeletal manifestations (EMMs) (acute anterior uveitis, psoriasis, and IBD) can accompany axial or peripheral symptoms. All these factors need to be taken into account when making treatment decisions in SpA patients. Despite the major advances in the treatment landscape over the past two decades with the introduction of biological disease-modifying anti-rheumatic drugs (bDMARDs) and most recently targeted synthetic DMARDs (tsDMARDs), a relevant proportion of patients still does not achieve the desired state of remission (=absence of disease activity). With this implementation of new treatment modalities, clinicians now have more choices to make in the treatment algorithms. However, despite generalized treatment recommendations, all factors need to be carefully considered when deciding on the optimal treatment strategy for an individual patient in clinical practice, aiming at an important first step towards personalized treatment strategies in SpA. In this narrative review, we focus on the efficacy of approved and emerging treatment options in axSpA and PsA as the main representative of pSpA and discuss their selective effect on the different manifestations associated with SpA to provide guidance on drivers of treatment decisions in specific situations.

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Approximately one-third of patients with myeloid disorders like myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML) exhibit inflammatory and autoimmune disorders (IADs). These IADs often include atypical and incomplete forms of common autoimmune conditions, and exhibit resistance to conventional immunosuppressive therapies. There is growing interest in molecular relationships between IADs and MDS/CMML to find potential targeted therapies. Recently, patients with somatic mutations in the UBA1 gene were identified as having VEXAS syndrome. Herein, we present a concise case-series illustrating concurrent elderly-onset inflammatory manifestations and myeloid disorders (MDS, CMML, and idiopathic cytopenia of undetermined significance). These patients manifested inflammatory or autoimmune symptoms, including erythema nodosum, Raynaud's phenomenon, Sjogren syndrome, and refractory pruritus, having onset after 60-years of age. The inflammatory manifestations were largely refractory to traditional immunosuppressive regimens. Remarkably, treatment with a JAK-1 inhibitor, upadacitinib, in two cases yielded marked resolution of inflammatory symptoms, facilitating the gradual tapering of corticosteroids, improvement of hemoglobin levels, and reduction in serum C-reactive protein levels. Upon loss of response to upadacitinib, JAK-2 inhibitor ruxolitinib provided clinical benefit in one of the cases, facilitating further tapering of glucocorticoids. This arena warrants further exploration through prospective studies of larger cohorts to delineate optimal management strategies.

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The horror autoinflammaticus derived from aberrant type I interferon secretion determines a special group of autoinflammatory diseases named interferonopathies. Diverse mechanisms involved in nucleic acids sensing, metabolizing or the lack of interferon signaling retro-control are responsible for the phenotypes associated to Aicardi-Goutières Syndrome (AGS), Proteasome-Associated Autoinflammatory Diseases (PRAAS), STING-Associated Vasculopathy with Infancy Onset (SAVI) and certain forms of monogenic Systemic lupus erythematosus (SLE). This review approaches interferonopathies from the basic immunogenetic concept to diagnosis and treatment.

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Psoriasis is a common chronic, immune-mediated inflammatory skin disease associated with various comorbidities. Managing psoriasis is often challenging as the therapy is decided based on the area of the disease, associated comorbidities and impairment in quality of life, besides the patient's preference. Making progress in the development of new molecules that can be used topically or orally, effectively controlling the disease with minimal side effects and providing long-lasting remissions are the needs of the hour. Recent developments in understanding the complexities of the pathogenesis of psoriasis have resulted in the reinforcement of treatment modalities, leading to the evolution of various biologics and small-molecule inhibitors. In comparison with biologics, both patients and treating physicians prefer small molecules for various reasons such as avoiding injections and side effects that are associated with biologics biologics. Moreover small molecules are economical than biologics. Newer small molecules, both topical and oral, are promising additions to the therapeutic arsenal in the management of psoriasis in the future.

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BACKGROUND: In 2021, an EULAR task force published a definition of difficult-to-treat rheumatoid arthritis (D2T RA). Our current knowledge of D2T RA with the EULAR definition is based on European and Asian cohorts, and no North American cohort has yet to be published. The aim of this study was to compare D2T RA patients to non-D2T RA who are good responders to advanced therapy, and to describe their evolution in an university health center patient cohort. METHODS: This is a retrospective single centre study of the medical records of all adults with RA on at least one biologic or target synthetic DMARD (b/tsDMARD). D2T RA group was defined according to the EULAR definition of D2T RA. The non-D2T RA group was defined as a b/tsDMARD good responder who had low-disease activity or remission for at least one year on 1 or 2 b/tsDMARD mechanism of action. We compared the patients' comorbidities, and history of b/tsDMARD use. Descriptive statistics and proportions were calculated. Kaplan-Meier analysis with log-rank test was used to estimate and compare median survival. RESULTS: Among the 417 patients, 101 (24%) were D2T RA and 316 (76%) were non-D2T RA. D2T RA group was slightly younger (63 ± 9 years versus 65 ± 12 years, p = 0.045), more likely to have concomitant non-inflammatory pain (28% versus 8%, p < 0.0001) and to discontinue at least one b/tsDMARD due to intolerance (39% versus 10%, p < 0.0001). In the D2T RA group, JAK inhibitors were associated with longer drug continuation when used as the third b/tsDMARD. Fewer patients were using corticosteroid at their most recent follow-up in this Canadian cohort compared to others (16% versus from 29 to 74%). CONCLUSION: Concomitant non-inflammatory pain was more prevalent in D2T RA patients compared to b/tsDMARD good responder non-D2T RA patients. Steroid-sparing strategies is possible even in D2T RA patients. Future prospective research may compare JAK inhibitors with other mechanisms of action in D2T RA.

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INTRODUCTION: Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by persistent itching. Conventional treatments for AD include topical corticosteroids and calcineurin inhibitors, but there are emerging therapies targeting the JAK-TYK2 pathway that are promising for the treatment of AD. AREAS COVERED: This review comprehensively explores the pathogenesis, triggers, clinical manifestations, and conventional treatment options for AD. In addition, we discuss novel therapeutic agents targeting alternative signaling pathways, with a focus on clinical trials evaluating tyrosine kinase 2 (TYK2) inhibitors, including systemic and topical agents. We also provide a detailed assessment of ICP-332 efficacy, safety, and potential adverse effects in moderate-to-severe AD. EXPERT OPINION: Janus kinase inhibitors that have been recently approved have shown promise for the treatment of AD, especially for patients with severe phenotypes. Preliminary findings from randomized controlled trials suggest that TYK2 inhibitors exhibit rapid efficacy and acceptable safety in the management of AD; however, additional investigations, including long-term trials, are warranted to fully understand their efficacy and safety profile.

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OBJECTIVES: Hepatitis B reactivation (HBVr) constitutes a side effect of the treatment of autoimmune rheumatic diseases. Even though HBVr risk of conventional synthetic disease modifying anti-rheumatic drugs (csDMARDs) and anti-tumor necrosis factor (anti-TNF) agents has long been established, the risk of targeted synthetic (ts)DMARDs and anti-interleukin (anti-IL) agents remains largely unknown. METHODS: We conducted a SLR (PubMed, Scopus and EMBASE) and metanalysis to examine the HBVr risk for the following: anti-IL17, anti-IL12/23, anti-IL23 and JAK-inhibitors in patients with chronic HBV infection (HBsAg presence or detectable HBV-DNA) and in patients with prior HBV infection (HBcAb-positive and HBsAg-negative). Meta-analysis was performed using both the fixed and random effects method and was conducted using the R computing language. RESULTS: Overall, our study revealed a low HBVr risk of < 6% in all agents; the risk was significantly higher for people having chronic compared with those with resolved HBV (14,4% vs 5.1%, respectively p< 0.01). There was no difference among different drugs in the HBVr rates [anti-IL-17: 4% (95% CI: 1-9%), anti-IL-12/IL-23: 2% (95% CI: 0-5%), JAK-inhibitors: 4% (95% CI: 1-8%), anti-IL23: 0%]. Of note, HBVr rate reached 28% in patients with chronic HBV who did not receive anti-viral treatment. For patients with resolved hepatitis the respective percentage was 4.7%. CONCLUSION: Overall, our meta-analysis shows that patients with chronic HBV receiving anti-IL-17, anti-IL-12/23, anti-IL-23 and JAK-inhibitors have significant risk for HBVr, especially if they are not under anti-viral treatment. In contrast, resolved HBV seems to offer minor risk for HBVr even without anti-viral treatment.

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IBD (inflammatory bowel disease) is a chronic inflammatory disease of the gastrointestinal tract with increasing incidence worldwide. Multiple factors, such as genetic background, environmental and luminal factors, and mucosal immune dysregulation, have been implicated in the cause of IBD, although the cause of the disease remains unknown. IL-12 and IL-23 and their downstream signaling pathways participate in the pathogenesis of inflammatory bowel disease. Early and aggressive treatment with biologic therapies or novel small molecules is needed to decrease complications and the need for hospitalization and surgery. The landscape of inflammatory bowel disease (IBD) treatment has tremendously improved with the development of biologics and small molecule drugs. Several novel biologics and small molecule drugs targeting IL-12 and IL-23 and their downstream targets have shown positive efficacy and safety data in clinical trials, and several drugs have been approved for the treatment of IBD. In the future, numerous potential emerging therapeutic options for IBD treatment are believed to come to the fore, achieving disease cure.

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Background/Objectives: Janus kinase inhibitors (JAKis) belong to a new class of targeted oral drugs that have been added to the therapeutic arsenal for rheumatoid arthritis (RA). The aim of this study was to evaluate the efficacy and safety profiles of these four available molecules (tofacitinib, baricitinib, filgotinib, and upadacitinib) in real life. Methods: A retrospective, single-center observational study including all patients treated with JAKis for RA from 1 October 2017 to 1 December 2023. We assessed the maintenance rate at 24 months, which is an indirect reflection of the clinical and biological safety and efficacy profiles. Results: The 76 patients in our study were thus treated for the first time with anti-JAK, including 55 patients with baricitinib (BAR), 9 patients with tofacitinib (TOF), 4 patients with upadacitinib (UPA), and 8 patients with filgotinib (FIL). The majority of our patients had BAR introduced as the first intention. The therapeutic maintenance at 2 years for all our patients was 50%. The average maintenance duration was 8.6 months and was similar in all the groups. Of the 76 patients included in this study treated with Baricitinib (72.3%), 38 (50%) discontinued their treatment after two years of follow-up. Conclusions: Although this retrospective study is subject to various biases, it shows that the persistence rates of the four JAKi molecules in daily practice did not differ significantly, thus confirming the long-term efficacy of these drugs.

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The management of inflammatory bowel diseases (IBD) requires weighing an individual patient's therapeutic benefits and therapy-related complication risks. The immunomodulators that have been commonly used so far in IBD therapy are thiopurines, including 6-mercaptopurine and azathioprine. As our understanding of the IBD pathomechanisms is widening, new therapeutic approaches are being introduced, including the Janus kinase (JAK) inhibitors and Sphingosine 1-phosphate receptor (S1PR) modulators' development. Non-selective JAK inhibitors are represented by tofacitinib, while selective JAK inhibitors comprise filgotinib and upadacitinib. As for the S1PR modulators, ozanimod and etrasimod are approved for UC therapy. The number of elderly patients with IBD is growing; therefore, this review aimed to evaluate the effectiveness and safety of the oral immunomodulators among the subjects aged ≥60. Possible complications limit the use of thiopurines in senior patients. Likewise, the promising effectiveness of new drugs in IBD therapy in those with additional risk factors might be confined by the risk of serious adverse events. However, the data regarding this issue are limited.

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INTRODUCTION: Clinical remission is the main target in the management of patients with rheumatoid arthritis (RA). However, several authors found synovitis in patients with RA in clinical remission at ultrasonography (US). Upadacitinib is a selective Janus kinase 1 inhibitor that achieved significantly higher remission rates than adalimumab and abatacept in patients with RA. Here we present the 24-week data of the UPAdacitinib Rheumatoid Arthritis REmission UltraSonography (UPARAREMUS) study. METHODS: This is a longitudinal multicenter observational study, enrolling bio-naïve and bio-inadequate responder patients affected by RA. The primary endpoint was the proportion of patients achieving both clinical and US remission at week 24. The proportion of patients achieving clinical remission with different composite indexes at week 12 and 24 was also evaluated. US of four target joints (wrists and second metacarpophalangeal bilaterally) was performed at baseline and weeks 12/24, and US remission was defined as the absence of power Doppler (PD) signal ≥ 2 in one target joint, or PD ≥ 1 in two target joints. RESULTS: After 12 weeks and 24 weeks, 40% and 63.6% of patients achieved US plus clinical remission. The following parameters were associated with US plus clinical remission: being bio-naïve and having a shorter disease duration, although at multivariate analysis significant odds ratio (OR) was found only for being bio-naïve. CONCLUSIONS: UPARAREMUS is the first study evaluating the efficacy of upadacitinib in reaching both clinical and US remission in patients with RA. At 24 weeks, 63.6% of patients reached the primary endpoint, the only baseline associated parameter was being bio-naïve.

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PURPOSE: Heterozygous STAT1 Gain-of-Function (GOF) mutations are the most common cause of chronic mucocutaneous candidiasis (CMC) among Inborn Errors of Immunity. Clinically, these mutations manifest as a broad spectrum of immune dysregulation, including autoimmune diseases, vascular disorders, and malignancies. The pathogenic mechanisms of immune dysregulation and its impact on immune cells are not yet fully understood. In treatment, JAK inhibitors have shown therapeutic effectiveness in some patients. METHODS: We analyzed clinical presentations, cellular phenotypes, and functional impacts in five Taiwanese patients with STAT1 GOF. RESULTS: We identified two novel GOF mutations in 5 patients from 2 Taiwanese families, presenting with symptoms of CMC, late-onset rosacea, and autoimmunity. The enhanced phosphorylation and delayed dephosphorylation were displayed by the patients' cells. There are alterations in both innate and adaptive immune cells, including expansion of CD38+HLADR +CD8+ T cells, a skewed activated Tfh cells toward Th1, reduction of memory, marginal zone and anergic B cells, all main functional dendritic cell lineages, and a reduction in classical monocyte. Baricitinib showed therapeutic effectiveness without side effects. CONCLUSION: Our study provides the first comprehensive clinical and molecular characteristics in STAT1 GOF patient in Taiwan and highlights the dysregulated T and B cells subsets which may hinge the autoimmunity in STAT1 GOF patients. It also demonstrated the therapeutic safety and efficacy of baricitinib in pediatric patient. Further research is needed to delineate how the aberrant STAT1 signaling lead to the changes in cellular populations as well as to better link to the clinical manifestations of the disease.

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