Ulcerative colitis (UC) is an inflammatory disorder of the gastrointestinal tract. Although Tofacitinib, which inhibits the JAK1 and JAK3 signalling pathway, is approved to treat patients with UC, its specific mechanism of action remain elusive. Given the central role that conventional dendritic cells (cDC) elicit in gut homeostasis, we hypothesised that Tofacitinib acts modulating cDC function in UC.

Human biopsies were obtained from colon of controls, and patients with UC (active and quiescent). Lamina propria mononuclear cells (LPMC) were ex-vivo cultured in the presence/absence of Tofacitinib. The specific effect elicited over human intestinal cDC, monocytes and macrophages was assessed by flow cytometry. cDC were also enriched following Tofacitinib conditioning in order to assess its effect over naïve T-cells.

Several human intestinal cDC, monocyte and macrophage subsets can be found in the human colon, with these cells being more similar between controls and patients with qUC referred to patients with aUC. Following ex-vivo culture, Tofacitinib downregulated JAK1 expression on intestinal monocytes from patients with both active and quiescent UC. As for macrophages, JAK1 was decreased on patients with active UC while JAK was downregulated on macrophages from patients with quiescent disease. Tofacitinib did not modulate the phenotype or function of human intestinal cDC.

Tofacitinib does not modulate the phenotype and function of human intestinal cDC in UC. On the contrary, it displays a differential capacity to modulate intestinal monocyte and macrophage phenotype. Future studies should address whether it also translates into a differential function of these cells.

Tofacitinib, a small molecule pan-JAK inhibitor, targets key inflammatory pathways that play a pivotal role in the pathophysiology of uveitis. Its ability to inhibit multiple cytokine signaling pathways makes it a promising candidate for the treatment of ocular inflammation. This study aimed to investigate the effect of oral tofacitinib on peptide-derived S-antigen (PDSAg)-induced chronic experimental autoimmune uveitis (EAU) in rats.

Nineteen albino Wistar rats were divided into five groups. Groups 1-3 (5 rats each) were immunized with 15 micrograms PDSAg to induce EAU; Group 2 received tofacitinib (5 mg/kg) by gavage twice daily. Group 3 received saline in the same manner as Group 2. Group 4 (2 rats) was a healthy control group. Group 5 (2 rats) received only tofacitinib. Uveitis development and treatment efficacy were evaluated using clinical scoring based on the the signs of anterior segment inflammation and histological scoring based on the deterioration of the retinal architectural structure.

Uveitis confirmed based on histological evidence was observed in all EAU groups (Groups 1-3) compared to the healthy control group (Group 4) (p < 0.001, Mann-Whitney U test). Tofacitinib significantly delayed the onset of uveitis in Group 2 when compared with Groups 1 and 3, which did not receive tofacitinib (p < 0.001, Mann-Whitney U test). Histological scores also showed a trend toward reduction (p = 0.393, Mann-Whitney U test).

Oral tofacitinib delayed uveitis onset and reduced clinical and histological findings, suggesting its potential as an alternative treatment for uveitis.

Dissecting cellulitis of the scalp (DCS) is a type of neutrophilic scarring alopecia identified by the development of folliculitis with clusters of perifollicular pustules and then progresses to abscesses and intercommunicating sinus formation. In the absence of evidence-based guidelines, the treatment of DCS remains a therapeutic challenge. Our study aimed to assess the safety and efficacy of biologics, including tumor necrosis factor-α (TNF-α) blockers, anti-interleukins (ILs), and small molecule inhibitors, including Janus kinase (JAK) inhibitors and phosphodiesterase inhibitors in treating DCS.

PubMed/Medline, Scopus, and Ovid Embase databases were systematically searched until February 4th, 2024. Study selection was restricted to case reports, case series, cohort studies, and clinical trials published in English-language. NIH and Murad et al.'s quality assessment tools were utilized for critical appraisal.

A total of 34 articles involving 81 patients met the inclusion criteria. The immunomodulators studied for the treatment of DCS include adalimumab, infliximab, certolizumab pegol, ustekinumab, secukinumab, guselkumab, risankizumab, tildrakizumab, apremilast, upadacitinib, and baricitinib. Our findings implied that TNF-α blockers and IL inhibitors were associated with clinical improvement in most individuals with moderate-to-severe DCS, especially in those who had failed earlier treatments. Moreover, certolizumab pegol could be a safe option for DCS in pregnancy. In addition, the prescription of small molecule inhibitors, including JAK inhibitors and apremilast in DCS patients, demonstrated a significant amelioration in DCS symptoms with a desirable safety profile. Nevertheless, the available data was limited, warranting further investigation. Besides, all aforementioned immunomodulators are still debated for their effectiveness on hair regrowth and reversing the scarring process.

The application of immunomodulators in treating DCS was associated with satisfactory outcomes, although there is still a need to assess the long-term safety and effectiveness of these therapeutic agents in preventing disease progression and new flare-ups.

Cutaneous leishmaniasis is a disease caused by protozoan parasites of the genus Leishmania, and although parasites influence disease severity, cytotoxic CD8 T cell responses mediate damage to the infected skin. We found that the cytotoxic protein perforin was expressed in CD8 T cells only upon recruitment to Leishmania-infected skin, suggesting that lesional inflammatory cues induced perforin. Here, using a mouse model of Leishmania major infection, we demonstrated that the expression of perforin was driven by a combination of hypoxia and IL-15, both of which are microenvironmental signals present within Leishmania-infected skin. We also demonstrated that the major sources of Il15 mRNA in cutaneous leishmaniasis lesions are neutrophils and macrophages and that macrophages exposed to hypoxia in vitro produce more Il15. Since perforin is only present in lesions, we reformulated a small molecule perforin inhibitor for topical application and found that local inhibition of perforin is sufficient to ameliorate disease in established cutaneous leishmaniasis. Thus, topical perforin inhibition may be considered a therapeutic strategy for patients with cutaneous leishmaniasis and other inflammatory skin diseases where cytotoxic CD8 T cells contribute to disease pathogenesis.

Janus kinase inhibitors (JAKis) effectively treat chronic inflammatory diseases but are associated with cardiovascular side effects through unknown mechanisms. This study aimed to investigate the impact of JAKis on prothrombotic thromboxane (TX)A2 production in human whole blood (WB) as a possible mechanism.

We evaluated the effects of 4 JAKis- tofacitinib, baricitinib, filgotinib, and upadacitinib (0.04-20.0 μM)-on TXB2 biosynthesis in clotting WB from healthy subjects, serving as a marker for platelet TXA2 generation. Additionally, we assessed the impact of these JAKis on TXB2 production in WB from healthy subjects, patients with systemic lupus erythematosus (SLE), and treatment-naïve patients with axial spondyloarthritis (axSpA) after 24-hour lipopolysaccharide (LPS) stimulation, as a marker of platelet and leukocyte prostanoid biosynthesis.

All JAKis increased serum TXB2 production in clotting WB, although not in a concentration-dependent manner. In LPS-stimulated WB, tofacitinib (1 μM) significantly increased TXB2 production in healthy subjects (HSs) (42% ± 33%, n = 17), patients with SLE (57% ± 39%, n = 12), and patients with axSpA (31% ± 23%, n = 15). Baricitinib (1 μM) also increased TXB2 in HSs (30% ± 22%, n = 10). Upadacitinib showed a trend towards increased TXB2 (46% ± 40%, n = 7), while filgotinib did not (21% ± 19%, n = 7). Aspirin (100 μM) almost completely reduced serum TXB2 in the presence of all JAKis.

The enhanced biosynthesis of TXA2 in platelets, with a minor contribution from leukocytes, may contribute to the increased cardiovascular risk associated with JAKis. Low-dose aspirin may offer a protective effect, warranting further investigations.

Patients with immune-mediated rheumatic diseases (IMRDs) face an elevated risk of varicella-zoster virus infection (VZV) and herpes zoster (HZ). Treatment with immunosuppressors further increases the risk. A new recently approved adjuvant recombinant inactive vaccine offers safe protection against HZ. However, limited data exist on the efficacy of this new vaccine in patients with IMRDs treated with JAK inhibitors (JAK-i). We aimed to characterize B- and T-cell immune responses elicited by the HZ recombinant subunit vaccine in patients with IMRDs under treatment with JAK-i, and to identify factors that might be associated with reduced immunogenicity, and therefore reduced protection.

We investigated humoral and cellular CD4 and CD8 immune responses following a two-dose regimen of the recombinant inactive vaccine in 43 patients with rheumatic diseases treated with different JAK-i. The responses were compared with age, gender and disease-matched healthy controls.

Patients with IMRDs treated with JAK-i showed reduced seroconversion rate (63% vs. 100% and lower VZV IgG titres (1222 ± 411 vs. 3048 ± 556, P < 0.0001) as compared with healthy controls. Functional T CD4 (IL-2 plus IFN-γ secretion) and T CD8 (granzyme A and/or granzyme B secretion) immune responses were also significantly diminished in IMRD patients. Negative correlation was found between VZV antibody titres and age, specific treatments (baricitinib, tofacitinib, upadacitinib), cumulative MTX and glucocorticoid doses, history of multiple DMARDs and treatment duration with JAK-i. Functional T-CD4 responses but not functional T-CD8 responses also showed similar negative correlations. Positive associations were observed between functional T-CD4 and T-CD8 responses.

Our study provides valuable insights into the immune responses elicited by the recombinant inactive vaccine in patients with IMRDs treated with JAK-i. In these patients we have observed a broad impact on the adaptive humoral and cellular immune responses, suggesting a potential reduction in protection against HZ infection and VZV reactivation.

Acute rejection is the main contributor to early allograft failure. Current immunosuppressive regimens have shortcomings, such as toxicity and minimal inhibitory effects on B cells. Hence, developing novel, effective, and selective anti-acute rejection drugs is crucial. Therefore, this study aimed to investigate the inhibitory effect of ritlecitinib (PF-06651600), a new janus kinase 3 inhibitor, on T and B cells, as well its preventive effects on acute allograft rejection. A murine cardiac transplantation model coupled with cell culture- and immunohistochemistry-based techniques was used. In vitro assays demonstrated that ritlecitinib inhibits naïve CD4+ T cell differentiation into T helper (Th)1 and Th17 cells, reduces relative inflammatory cytokines, and suppresses CD4+ and CD8+ T cell proliferation. Furthermore, ritlecitinib inhibited B cell activation and differentiation and antibody production. In vivo experiments revealed that ritlecitinib significantly prolongs allograft survival, decreases serum donor-specific antibody immunoglobulin G levels, alleviats allograft damage, and reduces C4d deposition and T, B, and plasma cell infiltration in allografts. Moreover, B and plasma cell percentages and counts were significantly decreased in recipient spleen, lymph nodes, bone marrow, and blood. Overall, ritlecitinib prevented acute rejection in cardiac transplantation by inhibiting T and B cells, suggesting its potential as a novel clinical immunosuppressant.

Janus kinase inhibitors (JAKis) represent a relatively new class of immunomodulatory drugs with potent effects on various cytokine signalling pathways. They have revolutionized the treatment landscape for autoimmune diseases such as rheumatoid arthritis, psoriatic arthritis, and ulcerative colitis. However, their ability to modulate immune responses presents a dual-edged nature, influencing both protective immunity and pathological inflammation. This review explores the complex role of JAKis in infectious settings, highlighting both beneficial and detrimental effects. On the one hand, experimental models suggest that JAK inhibition can impair host defence mechanisms, increasing susceptibility to certain bacterial and viral infections. For example, tofacitinib-treated mice exhibited more severe joint erosions in Staphylococcus aureus (S. aureus) septic arthritis and showed impaired viral clearance in herpes simplex encephalitis. Additionally, clinical data confirm an increased risk of herpes zoster in patients receiving JAKis, underscoring the need for rigorous monitoring. On the other hand, JAK inhibition has demonstrated protective effects in certain infectious and hyperinflammatory conditions. In sepsis models, including cecal ligation and puncture (CLP) and S. aureus bacteraemia, tofacitinib improved survival by attenuating excessive inflammation. Furthermore, JAKis, particularly baricitinib, have shown substantial efficacy in mitigating cytokine storms during severe COVID-19 infections, leading to improved clinical outcomes and reduced mortality. These observations suggest that JAKis have a role in modulating hyperinflammatory responses in select infectious contexts. In conclusion, JAKis present a complex interplay between immunosuppression and immunomodulation. While they increase the risk of certain infections, they also show potential in managing hyperinflammatory conditions such as cytokine storms. The key challenge is determining which patients and situations benefit most from JAKis while minimizing risks, requiring a careful and personalized treatment approach.

Tofacitinib, a first-generation Janus kinase (JAK) 1/3 inhibitor, is commonly used for treating ulcerative colitis and rheumatoid arthritis. However, its role in myasthenia gravis (MG) remains unclear. This study aimed to evaluate the immunomodulatory effects of tofacitinib on experimental autoimmune myasthenia gravis (EAMG) and peripheral blood mononuclear cells (PBMCs) from patients with MG.

Flow cytometry, enzyme-linked immunosorbent assay (ELISA), quantitative reverse transcription polymerase chain reaction (qRT-PCR), and Western blot were used to evaluate the effects of tofacitinib on T helper (Th) cell profiles, humoral immune responses, and the JAK-signal transducer and activator of transcription (STAT) pathway proteins.

In vivo, tofacitinib significantly ameliorated EAMG severity in rats, reducing the proportions of Th1, Th17 and memory B cells, and anti-acetylcholine receptor (AChR) antibodies levels, while increasing the proportions of regulatory T (Treg) cells. In vitro, tofacitinib administration resulted in a significant decrease in the proportions of Th1 and IgG-secreting B cell, and a significant upregulation of Treg cells in mononuclear cells (MNCs) from EAMG rats, which was consistent with findings in PBMCs from MG patients. Further analysis revealed that tofacitinib inhibited CD4+ T cell differentiation into Th1 by decreasing phosphorylated STAT1 levels, while promoting Treg differentiation via increased phosphorylated STAT5 levels in MNCs from EAMG rats.

Tofacitinib modulates Th cell profiles and humoral immune responses by targeting the JAK-STAT pathway, suggesting its potential as a therapeutic candidate for MG. Further clinical studies are warranted to evaluate the efficacy and safety of tofacitinib in MG patients.

Tofacitinib, a Janus kinase (JAK) inhibitor, has emerged as a primary therapeutic agent for managing autoimmune diseases such as rheumatoid arthritis, psoriatic arthritis, dermatitis and ulcerative colitis. By inhibiting the phosphorylation of JAK enzymes, tofacitinib prevents their activation within the JAK-STAT signaling pathway, which is vital for inflammatory responses. However, the tofacitinib delivery presents significant challenges, including pH-dependent solubility, poor permeability and susceptibility to oral degradation. This review provides an in-depth analysis of current and emerging formulations to enhance the delivery and efficiency of tofacitinib. This review highlights the physicochemical, pharmacodynamic and pharmacokinetic properties of tofacitinib. Additionally, it discusses various strategies, including oral modified release formulations, topical/transdermal delivery utilizing lipid-based and polymeric systems, and parenteral delivery systems. Recent advancements in nanotechnology, such as liposomes, micelles, keratinocyte exosomes, proposomes, proglycosomes, transethosomes, squalenyl nanoparticles and lyotropic liquid crystalline nanoparticles, are explored as potential nanocarriers to existing delivery constraints. The development of advanced tofacitinib delivery systems can address the challenges in its delivery and improve therapeutic outcomes and patient compliance, paving the way for enhanced treatment strategies in autoimmune and inflammatory conditions.

The incidence of ulcerative colitis (UC) is on the rise also in Japan. Simultaneously, therapeutic options, including biologics and Janus kinase (JAK) inhibitors, have significantly expanded over the past decade. Although tofacitinib (TOF), one of JAK inhibitors, is a viable option for patients with moderate to severe UC, there is insufficient data to predict responsiveness of TOF treatment. The present study aimed to determine whether the infiltration of IL-17 A-positive mononuclear cells into the colonic mucosa can predict responsiveness to TOF treatment. Patients with UC who underwent TOF treatment were divided into responder and failure groups. Subsequently, we conducted a comparative analysis to identify differences in the infiltration of IL-17 A-positive cells into the colonic mucosa through immunohistochemical examination of colon biopsy samples. The proportion of IL-17 A positive mononuclear cells in colon biopsy samples was significantly higher in the failure group than among responders (38.2% vs. 21.2%). Consistent with this finding, our re-analysis of RNA sequence datasets available in the Gene Expression Omnibus (GEO) database suggested that TOF exerts a more pronounced influence on Th1 cells compared with IL-17-producing Th17 cells. In summary, an abundance of IL-17 A-positive mononuclear cells in the colonic mucosa has the potential to predict the responsiveness to TOF treatment.

Juvenile Idiopathic arthritis (JIA) is one of the most common chronic diseases in children. It still remains a challenge to treat refractory poly-articular course JIA patients, especially in Bangladesh, where patients from low socio-economic backgrounds are unable to manage biological agents. Tofacitinib is one of the alternative options to biological agents, which can be taken orally and is cost effective. The purpose of this prospective observational study was to evaluate the efficacy of tofacitinib in the treatment of refractory poly-articular course JIA cases.

This study was carried out in the Department of Pediatrics, Bangabandhu Sheikh Mujib Medical University (BSMMU). A total number of 50 refractory polyarticular course JIA patients received JAK-2 inhibitor, tofacitinib along with other drugs according to the recommended doses. The disease activity level was measured by Juvenile Arthritis Disease Activity Score-27 (JADAS-27). All the cases were assessed at baseline, 6th, 12th and52nd week of tofacitinib therapy. The relevant statistical tests were applied for data analysis.

After treating the refractory cases with tofacitinib, arthritis subsided, and laboratory parameters improved in all the cases. Overall JADAS-27 score improvement was 40.67%, 56.38% and 96% at 6th, 12th and 52nd week of follow-up respectively. It was also possible to taper the dose of steroid gradually and stopped it by 24 weeks. Tofacitinib was well tolerated with minimum side effects.

Tofacitinib was effective to all the children with poly-articular course JIA. It was well tolerated and had very few tolerable adverse effects.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by multiple joints lesions. Tolerogenic dendritic cells (tolDCs) play crucial roles in maintaining immune homeostasis. The immunomodulatory activity of plant-derived arabinogalactan (AGs) has been well investigated, however, whether AGs could suppress autoimmune responses by inducing tolDCs is remain unclear.

Collagen-induced arthritis (CIA, a mouse model of RA) mice were utilized to ascertain the role of AGs (obtained from Cynanchum atratum) in autoimmune responses. An antibiotic cocktail was administered to eliminate gut microbiota. Germ-free (GF) and Toll-like receptor 2 (TLR2) knockout mice were used to determine the function of AGs in intestinal immune cells.

The oral administration of dietary AGs substantially reduced the severity of CIA and rebalanced the ratio of regulatory T cells (Tregs) to T helper 17 (Th17) cells. Although the antibiotic cocktail depleted the mice's gut microbiota, AGs had a therapeutic effect on their CIA. AGs restored Treg/Th17 homeostasis by inducing CD103+ tolDCs, regardless of the gut microbiota of the GF mice. Coculture experiments confirmed that AGs induced tolDCs and transforming growth factor β (TGF-β) secretion, leading to Treg amplification. RNA sequencing and TLR2 knockout experiments revealed that AGs induced tolDCs through a TLR2-mediated mechanism. Preventive interventions with AGs established a tolerogenic intestinal immune microenvironment, which delayed the onset and progression of CIA. AGs functioned synergistically with tofacitinib, a JAK inhibitor, to effectively restore Treg/Th17 balance and alleviate CIA.

This study introduces a novel microbiota-independent mechanism through which soluble dietary AGs inhibit systemic autoimmune responses. Our findings provide insights into the supplementation of dietary AGs in patients with preclinical or progressive RA.

Hidradenitis suppurativa (HS) is an autoinflammatory condition characterized by abscesses, inflammatory nodules, and tunnels in intertriginous sites of the body. The pathogenesis of HS involves follicular occlusion in combination with environmental, genetic, hormonal, and metabolic factors. HS lesions are characterized by an influx of neutrophils, histiocytes, B and T cells, and upregulation of proinflammatory cytokines such as tumor necrosis factor-α, interleukin-1, interleukin-17, and interferons. Selective small molecule inhibitors (SMIs) are organic compounds that bind to active sites on target proteins involved in inflammatory signaling pathways, most commonly blocking enzymes, ion channels and receptors. SMIs are divided into conventional and selective SMIs. Selective SMIs are further subdivided into kinase and nonkinase SMIs. Currently there are five selective SMIs available in the United States with demonstrated efficacy for HS in clinical studies including apremilast, topical ruxolitinib, upadacitinib, fostamatinib, and sirolimus. These selective SMIs target four pathways hypothesized to be important to HS pathogenesis including phosphodiestase 4, Janus kinases, spleen tyrosine kinase, and mammalian target of rapamycin. Several new SMIs are currently in the clinical trial pipeline targeting Bruton's tyrosine kinase, aryl hydrocarbon receptors, heat shock protein 90 as well as interleukin-1 and -17 signaling pathways.

Janus kinase (JAK) inhibitors have gathered interest as treatments for several inflammatory and autoimmune diseases. The four first marketed inhibitors target JAK1, with varying selectivity towards other JAK family members, but none inhibit tyrosine kinase-2 (TYK2) at clinically relevant doses. TYK2 is required for the signaling of the interleukin (IL)-12 and IL-23 cytokines, which are key to the polarization of TH1 and TH17 cells, respectively; two cell subtypes that play major roles in inflammatory diseases. Herein, we report our effort towards the optimization of a potent and selective dual JAK1/TYK2 inhibitor series starting from a HTS hit. Structural information revealed vectors required to improve both JAK1 and TYK2 potency as well as selectivity towards JAK2. The potent inhibition of both JAK1 (3.5 nM) and TYK2 (5.7 nM) in biochemical assays by our optimized lead compound, as well as its notable selectivity against JAK2, were confirmed in cellular and whole blood assays. Inhibition of TYK2 by the lead compound was demonstrated by dose-dependent efficacy in an IL-23-induced psoriasis-like inflammation mouse model.

Janus kinase inhibitors (JAKi) are drugs that block tyrosine kinases responsible for transducing cytokine signals. The first JAKi was approved by the US Food and Drug Administration (FDA) in 2011 to treat rheumatoid arthritis in adults. A pediatric indication was not approved until 8 years later, for acute graft-versus-host disease. Since then, topical and oral formulations have gained FDA approval for pediatric patients with dermatologic diseases. While increasing evidence supports the safety of these medications in adults, data are limited in children. We sought to determine whether JAKi adverse events (AEs) as reported in clinical trials and via postapproval pharmacovigilance services are comparable in adult and pediatric patients. Pharmacovigilance data were extracted from the FDA's Adverse Event Reporting System and the Canada Vigilance Adverse Reaction Online Database for baricitinib, upadacitinib, abrocitinib, ruxolitinib, and tofacitinib. The pooled data were analyzed to detect the most common AEs for specific JAKi and for the drug class. We assessed 399,649 AEs from 133,216 adults and 2883 AEs from 955 patients under 18 years old and identified slightly different AE profiles for the two age groups. Both populations had increased risk for infections and gastrointestinal AEs. However, pediatric patients reported a higher proportion of blood and lymphatic disorders, while reports of nervous system and musculoskeletal/connective tissue disorders were more common in adults. The spectrum of AEs extracted from pharmacovigilance reports was similar to clinical trials. The JAKi AE profiles we observed may prove helpful in counseling patients and their parents before starting therapy and for monitoring once patients are on therapy.

Leprosy is a chronic, infectious, and debilitating disorder that primarily affects the skin and peripheral nerves. The disease course may be complicated by immune-mediated reactions during or after therapy, which may further worsen nerve damage. Type II lepra reaction (T2LR) is a painful inflammatory condition with systemic features, such as fever, tender erythematous nodules, arthritis, neuritis, orchitis, lymphadenitis, and iritis. Erythema nodosum leprosum (ENL), the hallmark of type II lepra reactions, results in hospitalization and consequent impairment in quality of life. The treatment options include long-term high-dose systemic corticosteroids, thalidomide, and/or clofazimine. However, the prognosis is often complicated by the adverse effects of the drugs; therefore, there is a need for alternative and safer therapies. Herein, we present the case of a 31-year-old male with recurrent lepra reactions who did not respond adequately to steroids. Therefore, we initiated therapy with tofacitinib, a non-selective inhibitor of the Janus kinase/signal transduction and transcription activation (JAK/STAT) pathway. The results included complete resolution of abnormalities on blood laboratory investigations and symptomatic resolution of symptoms. In this article, we delve into the possible role of tofacitinib in T2LR and other inflammatory conditions.

Curcumin (Cur), with diverse pharmacological properties, shows anti-obesity, immunomodulatory, and anti-inflammatory effects. Its role in ulcerative colitis complicated by obesity remains unclear.

Here, colitis is induced in obese mice using dextran sulfate sodium (DSS), followed by administration of Cur at a dosage of 100 mg kg-1 for 14 days. Cur effectively alleviates DSS-induced colitis in obese mice, accompanied by an increase in body weight and survival rate, reduction in disease activity index, elongation of the colon, decrease in colonic weight, and improvements in ulcer formation and inflammatory cell infiltration in colonic tissues. Additionally, Cur effectively improves lipid metabolism and the composition of the gut microbiota, and enhances mucosal integrity and boosts anti-oxidative stress capacity in obese mice with colitis. Importantly, Cur is effective in improving the homeostasis of memory T cells in obese mice with colitis. Furthermore, Cur regulates inflammatory cytokines expression and inhibits activation of the JAK2/STAT signaling pathway in colonic tissues of obese mice with colitis.

Cur alleviates colitis in obese mice through a comprehensive mechanism that improves lipid metabolism, modulates gut microbiota composition, enhances mucosal integrity and anti-oxidative stress, balances memory T cell populations, regulates inflammatory cytokines, and suppresses the JAK2/STAT signaling pathway.

Cytokines function as communication tools of the immune system, serving critical functions in many biological responses and shaping the immune response. When cytokine production or their biological activity goes awry, the homeostatic balance of the immune response is altered, leading to the development of several pathologies such as autoimmune and inflammatory disorders. Cytokines bind to specific receptors on cells, triggering the activation of intracellular enzymes known as Janus kinases (JAKs). The JAK family comprises four members, JAK1, JAK2, JAK3 and tyrosine kinase 2, which are critical for intracellular cytokine signalling. Since the mid-2010s multiple JAK inhibitors have been approved for inflammatory and haematological indications. Currently, approved JAK inhibitors have demonstrated clinical efficacy; however, improved selectivity for specific JAKs is likely to enhance safety profiles, and different strategies have been used to accomplish enhanced JAK selectivity. In this update, we discuss the background of JAK inhibitors, current approved indications and adverse effects, along with new developments in this field. We address the issue of JAK selectivity and its relevance in terms of efficacy, and describe new modalities of JAK targeting, as well as new aspects of JAK inhibitor action.

Immune factors such as interferon‑ɣ and interleukin 4 belong to the group of cytokines that are dependent on type I/II receptors for their signal transmission. Upon activation, these receptors transmit their signal to the cell nucleus and, thus, modulate gene transcription via a signaling cascade consisting of Janus kinases (JAK). This family of four kinases (JAK 1, JAK 2, JAK 3, and tyrosine kinase 2 (TYK2)) subsequently activate members of the signal transducer and activator of transcription (STAT). This finding turned the JAK/STAT signaling pathway into a pharmacological target for the treatment of inflammatory diseases in which cytokines using type I/II receptors play a pathogenic role. In 2018, the European Medicines Agency (EMA) approved tofacitinib for the treatment of psoriatic arthritis. This was the first approval of a JAK/STAT pathway inhibitor for patients treated by dermatologists and rheumatologists. Since then, several new JAK inhibitors have been approved for dermatologic diseases such as atopic dermatitis, alopecia areata, vitiligo, and plaque-type psoriasis. In addition, JAK inhibitors are being investigated for the treatment of many other skin diseases. Thus, systemic JAK inhibitors complete the spectrum of immunotherapeutics with a broader immunological approach compared to monoclonal antibodies. The low molecular weight of JAK inhibitors enables the preparation of these drugs for both systemic and topical administration. Their utilization could represent a valuable alternative to topical steroids. The safety profile of JAK inhibitors must be taken into account. Possible long-term effects may become apparent in the next few years. This article describes both approved JAK inhibitors and relevant new JAK inhibitors that are promising candidates for approval as therapeutics in dermatology.

Metabolic dysfunction-associated steatotic liver disease (MASLD) comprises a spectrum of liver diseases that span simple steatosis, metabolic dysfunction-associated steatohepatitis (MASH) and fibrosis and may progress to cirrhosis and cancer. The pathogenesis of MASLD is multifactorial and is driven by environmental, genetic, metabolic and immune factors. This review will focus on the role of the type 3 cytokines IL-17 and IL-22 in MASLD pathogenesis and progression. IL-17 and IL-22 are produced by similar adaptive and innate immune cells such as Th17 and innate lymphoid cells, respectively. IL-17-related signaling is upregulated during MASLD resulting in increased chemokines and proinflammatory cytokines in the liver microenvironment, enhanced recruitment of myeloid cells and T cells leading to exacerbation of inflammation and liver disease progression. IL-17 may also act directly by activating hepatic stellate cells resulting in increased fibrosis. In contrast, IL-22 is a pleiotropic cytokine with a dominantly protective signature in MASLD and is currently being tested as a therapeutic strategy. IL-22 also exhibits beneficial metabolic effects and abrogates MASH-related inflammation and fibrosis development via inducing the production of anti-oxidants and anti-apoptotic factors. A sex-dependent effect has been attributed to both cytokines, most importantly to IL-22 in MASLD or related conditions. Altogether, IL-17 and IL-22 are key effectors in MASLD pathogenesis and progression. We will review the role of these two cytokines and cells that produce them in the development of MASLD, their interaction with host factors driving MASLD including sexual dimorphism, and their potential therapeutic benefits.

Rheumatoid arthritis (RA) is a highly prevalent autoimmune disorder. The pathogenesis of the disease is complex and involves various cellular populations, including fibroblast-like synoviocytes, macrophages, and T cells, among others. Identification of signalling pathways and molecules that actively contribute to the development of the disease is crucial to understanding the mechanisms involved in the chronic inflammatory environment present in affected joints. Recent studies have demonstrated that the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway regulates the behaviour of immune cells and contributes to the progression of RA. Several JAK inhibitors, such as tofacitinib, baricitinib, upadacitinib, and filgocitinib, have been developed, and their efficacy and safety in patients with RA have been comprehensively investigated in a number of clinical trials. Consequently, JAK inhibitors have been approved and registered as a treatment for patients with RA. In this review, we discuss the involvement of JAK/STAT signalling in the pathogenesis of RA and summarise the potential beneficial effects of JAK inhibitors in cells implicated in the pathogenesis of the disease. Moreover, we present the most important phase 3 clinical trials that evaluated the use of these agents in patients.

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.

Dendritic cells (DCs) are professional antigen-presenting cells (APCs), including heterogenous populations with phenotypic and functional diversity that coordinate bridging innate and adaptive immunity. Signal transducer and activator of transcriptions (STAT) factors as key proteins in cytokine signaling were shown to play distinct roles in the maturation and antigen presentation of DCs and play a pivotal role in modulating immune responses mediated by DCs such as differentiation of T cells to T helper (Th) 1, Th2 or regulatory T (Treg) cells. This review sheds light on the importance of STAT transcription factors' signaling pathways in different subtypes of DCs and highlights their targeting potential usages for improving DC-based immunotherapies for patients who suffer from cancer or diverse autoimmune conditions according to the type of the STAT transcription factor and its specific activating or inhibitory agent.

Psoriasis is a highly prevalent dermatological disease associated with an increased systemic inflammatory response. In addition, joint involvement is also present in around 20% of patients. Therefore, treatment modalities used in this condition should be simultaneously effective at improving skin manifestations, reducing inflammation, and addressing psoriatic arthritis when present. Twenty years ago, the introduction of biologic treatments for psoriasis was a turning point in the management of this condition, offering an effective and reasonably safe option for patients whose disease could not be adequately controlled with conventional therapies. At the moment, Janus Kinase inhibitors (JAKis) are a new class of promising molecules in the management of psoriasis. They are orally administered and can show benefits in patients who failed biologic therapy. We conducted a scoping review in order to identify randomized-controlled trials that investigated different JAKis in patients with plaque psoriasis and psoriatic arthritis, with an emphasis on molecules that have been approved by the European Medicines Agency and the Food and Drug Administration. The added value of this study is that it collected information about JAKis approved for two different indications, plaque psoriasis and psoriatic arthritis, in order to provide an integrated understanding of the range of effects that JAKis have on the whole spectrum of psoriasis manifestations.

LMB-100 is a mesothelin (MSLN)-targeting recombinant immunotoxin (iTox) carrying a Pseudomonas exotoxin A payload that has shown promise against solid tumors, however, efficacy is limited by the development of neutralizing anti-drug antibodies (ADAs). Tofacitinib is an oral Janus Kinase (JAK) inhibitor that prevented ADA formation against iTox in preclinical studies.

A phase 1 trial testing LMB-100 and tofacitinib in patients with MSLN-expressing cancers (pancreatic adenocarcinoma, n=13; cholangiocarcinoma, n=1; appendiceal carcinoma, n=1; cystadenocarcinoma, n=1) was performed to assess safety and to determine if tofacitinib impacted ADA formation. Participants were treated for up to 3 cycles with LMB-100 as a 30-minute infusion on days 4, 6, and 8 at two dose levels (100 and 140 µg/kg) while oral tofacitinib was administered for the first 10 days of the cycle (10 mg BID). Peripheral blood was collected for analysis of ADA levels, serum cytokines and circulating immune subsets.

The study was closed early due to occurrence of drug-induced pericarditis in 2 patients. Pericarditis with the combination was not reproducible in a transgenic murine model containing human MSLN. Two of 4 patients receiving all 3 cycles of treatment maintained effective LMB-100 levels, an unusual occurrence. Sustained increases in systemic IL-10 and TNF-α were seen, a phenomenon not observed in prior LMB-100 studies. A decrease in activated T cell subsets and an increase in circulating immunosuppressive myeloid populations occurred. No radiologic decreases in tumor volume were observed.

Further testing of tofacitinib to prevent ADA formation is recommended in applicable non-malignant disease settings.

https://www.clinicaltrials.gov/study/NCT04034238.

Accumulating evidence reveals an association between circulating cytokine levels and vitiligo. However, the causal association between circulating cytokine levels and vitiligo remains unrevealed.

We performed a two-sample Mendelian randomization (MR) analysis using a genome-wide association study of the 41 cytokines dataset, which was conducted with 3 Finnish cohorts (n = 8,293). Vitiligo data were acquired from strictly defined vitiligo data collected by FinnGenbiobank analysis, which included 207,613 European ancestors (131 vitiligo patients, 207,482 controls). The inverse-variance weighted (IVW) method, weighted median (WME), simple model, weighted model, and MR-Egger were used to determine the changes in vitiligo pathogenic cytokine taxa, followed by sensitivity analysis, including horizontal pleiotropy analysis. The MR Steiger test evaluated the strength of a causal association, and the leave-one-out method was used to assess the reliability of the results. The possibility of reverse causality was also investigated using a reverse MR study.

We observed that rising IL-4 levels generated an enhanced probability of vitiligo in IVW (OR 2.72, 95%CI 1.19-6.22, p = 0.018). According to the results of the MR analysis, there were causal links between IL-4 and vitiligo. Results were steady after sensitivity and heterogeneity analyses.

Our research reveals that a genetically determined increased level of circulating IL-4 may be linked to a higher risk of developing vitiligo. The development of innovative treatment approaches (such as tofacitinib or dupilumab) that focus on blocking IL-4 as a novel way of preventing and treating vitiligo is significantly impacted by our findings.

Autoimmune bullous diseases, connective tissue diseases, and vasculitis represent a group of severe rare skin diseases. While glucocorticoids and immunosuppressive agents serve as standard treatments for these diseases, their efficacy is limited due to adverse side effects, indicating the need for alternative approaches. Biologics have been used in the management of some rare skin diseases. However, the use of biologics is associated with concerns, such as infection risk and high costs, prompting the quest for efficacious and cost-effective alternatives. This study discusses the safety issues associated with tofacitinib and its potential in treating rare skin diseases.

This narrative review focuses on the pharmacodynamic properties of tofacitinib and its impact on the JAK/STAT pathway. In addition, we present a comprehensive discussion of the effects and mechanism of action of tofacitinib for each severe rare skin disease.

This role of tofacitinib in treating severe rare skin diseases has been discussed, shedding light on its promising prospects as a treatment modality. Few reports of serious adverse events are available in patients treated with tofacitinib.

We explored the mechanism of action, efficacy, and safety considerations of tofacitinib and found that it can be used as a treatment option for rare skin diseases. However, multicenter clinical studies are needed to confirm the efficacy and safety of JAK inhibitors.

Psoriasis is a chronic inflammatory immune condition. Treatments for psoriasis vary with disease severity, ranging from topicals to systemic biologic agents. The pharmacokinetic (PK) and pharmacodynamic (PD) properties of these therapies establish drug efficacy, toxicity, and optimal dosing to ensure therapeutic drug levels are sustained and adverse effects are minimized.

A literature search was performed on PubMed, Google Scholar, and Ovid MEDLINE for PK and PD, efficacy, and safety data regarding oral systemic nonbiologic therapies utilized for moderate-to-severe plaque psoriasis. The findings were organized into sections for each drug: oral acitretin, methotrexate, cyclosporine, apremilast, tofacitinib, and deucravacitinib.

Some psoriasis patients may not respond to initial therapy. Ongoing research is evaluating genetic polymorphisms that may predict an improved response to specific medications. However, financial and insurance barriers, as well as limited genetic polymorphisms correlated with treatment response, may restrict the implementation of genetic testing necessary to personalize treatments. How well psoriasis patients adhere to treatment may contribute greatly to variation in response. Therapeutic drug monitoring may help patients adhere to treatment, improve clinical response, and sustain disease control.

Tofacitinib is contraindicated in pregnancy. We present a patient with ulcerative colitis on tofacitinib who had an unplanned pregnancy. Tofacitinib was ceased, switched to vedolizumab, and she gave birth to a healthy newborn at term. Case reports of reassuring outcomes provide real-world data that assists decision-making for future patients.

Exosomes are extracellular vesicles in the range of 40-150 nm released from the cell membrane. Exosomes secreted by keratinocytes can communicate with other keratinocytes and immune cells with specific biomarkers at their surface, which may be effective on inflammation of psoriasis and its pathogenesis.

The present study aimed to formulate and study effectiveness of an exosomal delivery system of tofacitinib (TFC).

TFC was loaded by different methods in exosomes and then characterized for particle size, zeta potential, drug loading efficiency, and release efficiency. By comparing these parameters, the probe sonication method was chosen to load TFC into exosomes. The MTT assay was used to compare the cytotoxicity of the free drug with the TFC-loaded exosomes (TFC-Exo), and Real-time PCR was used to determine the expression levels of several genes involved in psoriasis expressed in the A-431 keratinocyte and their suppression after treatment. Animal model of psoriasis was induced in BALB/c mice by imiquimod and the efficacy of free TFC, and TFC-Exo were studies on macroscopic appearance and histopathological symptoms.

Exosomes encapsulating TFC showed lower cytotoxicity in MTT assay, higher suppression the expression of TNF-a, IL-23, IL-6, and IL-15 genes in real-time PCR and better therapeutic effect on animal models compered to free TFC.

This method of drug delivery for TFC may be effective on enhancing its therapeutic effects and reduction its side effects favorably in chronic administration.

Personalised medicine and the identification of predictors of the efficacy of specific drugs represent the ultimate goal for the treatment of ulcerative colitis (UC) in order to break the current therapeutic ceiling. JAK inhibitors are a new class of advanced therapies, orally administered, showing a good profile of efficacy and safety in both randomised controlled trials (RCTs) and real-world studies. Unfortunately, to date, it is not possible to draw the ideal profile of a patient maximally benefiting from this class of drugs to guide clinicians' therapeutic choices. Baseline clinical activities and inflammatory biomarkers, as well as their early variation after treatment initiation, emerged as the main predictors of efficacy from post hoc analyses of RCTs with tofacitinib. Similar findings were also observed in the real-life studies including mainly patients with a history of pluri-refractoriness to biological therapies. At last, a few new biomarkers have been explored, even though they have not been validated in large cohorts. This paper provides a review of the current knowledge on clinical variables and biomarkers predicting response to JAK inhibitors in UC.

Fundamental insight gained over the last decades led to the discovery of cytokines as pivotal drivers of inflammatory diseases such as rheumatoid arthritis, psoriasis/psoriasis arthritis, inflammatory bowel diseases, atopic dermatitis and spondylarthritis. A deeper understanding of the pro-inflammatory and anti-inflammatory effects of various cytokines has prompted new cytokine-targeting therapies, which revolutionised the treatment options in the last years for patients with inflammatory disorders. Disease-associated immune responses typically involve a complex interplay of multiple cytokines. Therefore, blockade of one single cytokine does not necessarily lead to a persistent remission in all patients with inflammatory disorders and fostered new therapeutic strategies targeting intracellular pathways shared by multiple cytokines. By inhibiting JAK-STAT signalling pathways common to families of cytokines, JAK-inhibitors (JAKinibs) have created a new paradigm for the treatment of inflammatory diseases. Multiple agents have been approved for various disorders and more are being investigated for several new indications. Second-generation selective JAKinibs have been devised with the aim to achieve an increased selectivity and a possible reduced risk of side effects. In the current review, we will summarise the current body of evidence of pan versus selective JAKinibs and the most recent insights on new side effects and indications, including COVID-19.

Noninfectious uveitis (NIU) in children and adolescents is a rare but treatable cause of visual impairment in children. Treatments for pediatric NIU and their side effects, along with the risks of vision loss and the need for long-term disease monitoring, pose significant challenges for young patients and their families. Treatment includes local and systemic approaches and this review will focus on systemic therapies that encompass corticosteroids, conventional synthetic disease-modifying antirheumatic drugs (csDMARD), and biological disease-modifying antirheumatic drugs (bDMARD). Treatment is generally planned in a stepwise approach. Methotrexate is well-established as the preferential csDMARD in pediatric NIU. Adalimumab, an antitumor necrosis factor (TNF) agent, is the only bDMARD formally approved for pediatric NIU and has a good safety and efficacy profile. Biosimilars are gaining increasing visibility in the treatment of pediatric NIU. Other bDMARD with some evidence in literature for the treatment of pediatric NIU include infliximab, tocilizumab, abatacept, rituximab and, more recently, Janus kinase inhibitors. Important aspects of managing children on these systemic therapies include vaccination issues, risk of infection, and psychological distress. Also, strategies need to address regarding primary nonresponse/secondary loss of response to anti-TNF treatment, biological switching, and monitoring regimens for these drugs. Optimal management of pediatric uveitis involves a multidisciplinary team, including specialist pediatric uveitis and rheumatology nurses, pediatric rheumatologists, psychological support, orthoptic and optometry support, and play specialists.

Antidepressants are widely used for the pharmacological treatment of anxiety and mood disorders. Since the eruption of the SARS-COV-2 pandemic and the later development of targeted treatments against COVID-19, inevitably many patients receive antidepressants as well as targeted treatments against COVID-19 against COVID-19. Co-administration of antidepressants with COVID-19 therapeutics has the potential of drug-drug interactions, of varying severity and clinical significance.

This is a curated narrative review of the current state of the art regarding drug-drug interactions between COVID-19 therapeutics and medications licensed for the pharmacotherapy of depression. A systematic search of electronic databases, using as keywords the international nonproprietaty names of currently approved COVID-19 therapeutics and antidepressants was performed, and additionally online interaction checker tools were consulted. Derived data were synthesized for each COVID-19 therapeutic and presented with up-to-date guidance.

Several COVID-19 therapeutics have potential for drug-drug interactions with antidepressants. Remdesivir and Nirmatrelvir-Ritonavir have the higher risk, whereas several monoclonal antibodies appear safer. The most serious drug-drug interactions (serotonin syndrome and QTc prolongation) require close monitoring; however, DDI toward reducing the efficacy of antidepressants may be difficult to recognize. As COVID-19 treatment protocols take precedence, psychiatrists should exert flexibility in antidepressant use and proactively monitor treatment progress.

Protein kinases play a major role in cellular activation processes, including signal transduction by diverse immunoreceptors. Given their roles in cell growth and death and in the production of inflammatory mediators, targeting kinases has proven to be an effective treatment strategy, initially as anticancer therapies, but shortly thereafter in immune-mediated diseases. Herein, we provide an overview of the status of small molecule inhibitors specifically generated to target protein kinases relevant to immune cell function, with an emphasis on those approved for the treatment of immune-mediated diseases. The development of inhibitors of Janus kinases that target cytokine receptor signalling has been a particularly active area, with Janus kinase inhibitors being approved for the treatment of multiple autoimmune and allergic diseases as well as COVID-19. In addition, TEC family kinase inhibitors (including Bruton's tyrosine kinase inhibitors) targeting antigen receptor signalling have been approved for haematological malignancies and graft versus host disease. This experience provides multiple important lessons regarding the importance (or not) of selectivity and the limits to which genetic information informs efficacy and safety. Many new agents are being generated, along with new approaches for targeting kinases.

Interstitial lung disease (ILD) is one of the most serious extra-articular complications of rheumatoid arthritis (RA), which increases the mortality of RA. Because the pathogenesis of RA-ILD remains poorly understood, appropriate therapeutic strategies and biomarkers have not yet been identified. Thus, the goal of this review was to summarize and analyze the reported data on the etiology and pathogenesis of RA-ILD. The incidence of RA-ILD increases with age, and is also generally higher in men than in women and in patients with specific genetic variations and ethnicity. Lifestyle factors associated with an increased risk of RA-ILD include smoking and exposure to pollutants. The presence of an anti-cyclic citrullinated peptide antibody, high RA disease activity, and rheumatoid factor positivity also increase the risk of RA-ILD. We also explored the roles of biological processes (e.g., fibroblast-myofibroblast transition, epithelial-mesenchymal transition, and immunological processes), signaling pathways (e.g., JAK/STAT and PI3K/Akt), and the histopathology of RA involved in RA-ILD pathogenesis based on published preclinical and clinical models of RA-ILD in animal and human studies.