To evaluate the efficacy of Janus kinase inhibitor (JAKi) therapy in managing cicatrizing conjunctivitis associated with ocular cicatricial pemphigoid (OCP) and mucous membrane pemphigoid with ocular involvement (ocMMP).

Retrospective chart review of patients with cicatrizing conjunctivitis secondary to OCP or ocMMP who underwent treatment with JAKi at a tertiary academic medical center from August 2015 to November 2024 for minimum follow-up of six months. Collected data included demographics, Foster stage of cicatrization, and treatment course.

Thirty-two patients met inclusion criteria: 23 (71.9 %) with OCP and 9 (28.1 %) with ocMMP. 96.9 % of patients demonstrated clinical improvement within twelve months of treatment initiation. Best response achieved were as follows: 1 (3.1 %) no response, 17 (53.1 %) partial response, 14 (43.8 %) complete remission, and 12 (37.5 %) steroid-free complete remission. The mean time to partial response, complete remission, steroid-free complete remission was 3.1 ± 1.8 (range, 0.9-8.3), 7.8 ± 3.3 months (range, 2.3-14.7 months), and 10.3 ± 7.4 months, (range, 2.3-31.4 months), respectively. Relapse in disease activity occurred in 8/32 (25.0 %) of patients. Side effects occurred in 8/32 (25.0 %) of patients. Four patients (12.5 %) discontinued therapy due to severe adverse events, including transient ischemic attack, pulmonary embolism, pyelonephritis, and cholecystitis. There was a significant association between lower Foster cicatrization stages and achieving remission (U = 630.0, p = 0.0036), with a rank-biserial correlation of 0.72.

JAK inhibitor therapy demonstrates efficacy in the management of recalcitrant cicatrizing conjunctivitis associated with pemphigoid. These findings highlight JAK inhibitors as a promising therapeutic option for refractory cases.

Background: Atopic dermatitis (AD) is a chronic pruritic inflammatory disease affecting children and adults. Upadacitinib and abrocitinib are selective Janus kinase 1 inhibitors approved for the treatment of moderate-to-severe AD. Although their efficacy and safety are described in phase 3 clinical trials, real-world data are limited. Objectives: We aimed to evaluate the effectiveness and safety of upadacitinib and abrocitinib treatment in a real-life adult population with moderate-to-severe AD throughout an extended observation period. Methods: This retrospective observational study was conducted by analyzing data from the electronic records of IRCCS Humanitas Research Hospital from January 2023 to December 2024. Patients were administered either upadacitinib (15 or 30 mg) or abrocitinib (100 or 200 mg). Effectiveness was evaluated by using clinician-reported scores (Investigator Global Assessment [IGA] and Eczema Area and Severity Index [EASI]) and patient-reported outcomes (peak pruritus numerical rating scale [PP-NRS]) at weeks 8, 16, 32 and 52. Statistical significance was set at a probability value (p-value) < 0.05. Adverse events were also collected. Results: In total, 129 patients were included in the study, and 84 of them reached 52 weeks. At week 52, the EASI 75, 90, and 100 responses were 88.9%, 70.8%, and 54.2% for upadacitinib, and 100%, 91.7%, and 75% for abrocitinib. An IGA score equal to 0 or 1 at 52 weeks was achieved by 84.7% of patients treated with upadacitinib and 100% of those receiving abrocitinib. A four-point reduction from baseline PP-NRS was reported by 86.1% for upadacitinib and by 83.3% of patients for abrocitinib after one year of follow-up. Conclusions: Our study showed comparable or even higher effectiveness outcomes in terms of EASI 75, EASI 90, and EASI 100 at week 52 compared to phase-3 clinical trials, with no new safety concerns, supporting the real-world effectiveness of abrocitinib and upadacitinib in moderate-to-severe AD.

Autoimmune Bullous Diseases (AIBDs), characterized by the formation of blisters due to autoantibodies targeting structural proteins, pose significant therapeutic challenges. Current treatments, often involving glucocorticoids or traditional immunosuppressants, are limited by their non-specificity and side effects. Cytokines play a pivotal role in AIBDs pathogenesis by driving inflammation and immune responses. The JAK-STAT pathway is central to the biological effects of various type I and II cytokines, making it an attractive therapeutic target. Preliminary reports suggest that JAK inhibitors may be a promising approach in PV and BP, but further clinical validation is required. In AIBDs, particularly bullous pemphigoid (BP) and pemphigus vulgaris (PV), JAK inhibitors have shown promise in modulating pathogenic cytokine signaling. However, the safety and selectivity of JAK inhibitors remain critical considerations, with the potential for adverse effects and the need for tailored treatment strategies. This review explores the role of cytokines and the JAK-STAT pathway in BP and PV, evaluating the therapeutic potential and challenges associated with JAK inhibitors in managing these complex disorders.

The clinical efficacy of Janus kinase inhibitors (JAKinibs) is highly variable and their safety profiles are poorly understood.

We established two flow cytometry panels for the assessment of two promising leukocyte biomarkers: signal transducer and activator of transcription (STAT) phosphorylation and cytokine receptor expression. We evaluated the first panel, which assesses phosphorylation levels for STAT1, STAT3, and STAT5 after cytokine stimulation, with or without in vitro pretreatment with JAKinibs, in 10 healthy donors. We then evaluated the second panel, which assesses cytokine receptor expression on T cells and B cells, in five healthy donors.

Stimulation with interleukin (IL)-2 or IL-7 increased STAT5 phosphorylation in T cells but not in B cells or monocytes. IL-6 stimulation induced STAT3 phosphorylation in monocytes and CD4 T cells and, to a lesser extent, in CD8 T cells, but not in B cells. IL-21 stimulation led to STAT3 phosphorylation in T cells and, to a lesser extent, in B cells, but not in monocytes. Interferon-α stimulation increased STAT1 phosphorylation in all cell types. STAT phosphorylation levels were lower after pretreatment with JAKinibs. A dose-response curve was plotted, confirming the correlation between JAKinib concentration and STAT phosphorylation inhibition. The second panel showed that each cell type displayed a distinct pattern of cytokine receptors expression, and that this pattern might be modified by in vitro treatment with JAKinibs.

This preliminary study confirms the utility of flow cytometry for monitoring the biological effects of JAKinibs. Further studies on treated patients are now required to evaluate the clinical value of these two flow cytometry panels.

Axial spondyloarthritis (axSpA) is a chronic inflammatory disease that predominantly affects the sacroiliac joints and spine. Tumor necrosis factor (TNF) and interleukin (IL)-17A are key cytokines in disease pathogenesis and are established axSpA treatment targets. Recently, axSpA treatment options have been complemented by Janus kinase inhibitors (JAKi), which inhibit various cytokines without directly impacting TNF or IL-17 signaling. The effect of JAKi on axSpA remains under investigation: besides a JAK2-mediated (and potentially tyrosine kinase 2 [TYK2]-mediated) effect on the IL-23/IL-17 axis, emerging evidence suggests γδ T cells, type 3 innate lymphoid cells, and mucosa-associated invariant T cells, which are dependent on IL-7 and/or IL-15 and thus on JAK1, are strongly inhibited by JAKi used to treat axSpA. This review summarizes potential effects of JAKi on axSpA and shows evidence from pre-clinical/clinical studies. Greater understanding of the mechanisms of action of available treatments may improve knowledge of axSpA and pave the road for future therapies.

B cells play a crucial role in autoimmune diseases, as evidenced by autoantibody responses and the effectiveness of B cell-targeted therapies. Janus kinase inhibitors (JAKi), which target downstream signaling of cytokine receptors, are potent rheumatic disease-modifying drugs. However, besides reducing inflammation, JAKi may impact the adaptive immune system. In this study, we examined the effects of JAKi on B-cell function using in vitro cultures and multiparameter flow cytometry. The results show a JAKi-mediated reduction in plasma cell differentiation, primarily by inhibition of memory B-cell stimulation and proliferation. JAKi exposure resulted in stalling R848, IL-2, and IL-21 stimulated B cells in an intermediate activated state with elevated naïve cells displaying increased expression of CXCR5, CD71, CD22, and CD20. In addition, the data demonstrate a moderate JAKi-mediated reduction of B cell TNF and IL-8 cytokine expression following stimulation. Importantly, the efficacy varied greatly between drugs; tofacitinib and upadacitinib (pan JAKi; JAK1i) exhibited the strongest impact, while baricitinib (JAK1/JAK2i) showed donor-dependent variation, and filgotinib (JAK1i) had no effect. All JAKi, except filgotinib, inhibited IL-2 or IL-21-induced STAT3 phosphorylation. Still, filgotinib demonstrated similar inhibition of phospho-STAT5 as other JAKi following IL-21. These findings underscore the therapeutic impact of JAKi through the modulation of B-cell functions.

Tuberculosis (TB) is the leading cause of death in the world from an infectious disease. Its etiologic agent, the Mycobacterium tuberculosis (Mtb), is a slow-growing bacterium that has coexisted in humans for thousands of years. According to the World Health Organization, 10.6 million new cases of TB and over 1 million deaths were reported in 2022. It is widely recognized that patients affected by chronic autoimmune arthritis such as rheumatoid arthritis (RA), psoriatic arthritis (PsA), and ankylosing spondylitis (AS) have an increased incidence rate of TB disease compared to the general population. As conceivable, the risk is associated with age ≥65 years and is higher in endemic regions, but immunosuppressive therapy plays a pivotal role. Several systematic reviews have analysed the impact of anti-TNF-α agents on the risk of TB in patients with chronic autoimmune arthritis, as well as for other biologic disease-modifying immunosuppressive anti-rheumatic drugs (bDMARDs) such as rituximab, abatacept, tocilizumab, ustekinumab, and secukinumab. However, the data are less robust compared to those available with TNF-α inhibitors. Conversely, data on anti-IL23 agents and JAK inhibitors (JAK-i), which have been more recently introduced for the treatment of RA and PsA/AS, are limited. TB screening and preventive therapy are recommended in Mtb-infected patients undergoing bDMARDs and targeted synthetic (ts)DMARDs. In this review, we evaluate the current evidence from randomized clinical trials, long-term extension studies, and real-life studies regarding the risk of TB in patients with RA, PsA, and AS treated with bDMARDs and tsDMARDs. According to the current evidence, TNF-α inhibitors carry the greatest risk of TB progression among bDMARDs and tsDMARDs, such as JAK inhibitors and anti-IL-6R agents. The management of TB screening and the updated preventive therapy are reported.

As a drug-induced hypersensitivity syndrome, drug reaction with eosinophilia and systemic symptoms (DRESS) is potentially fatal. Most patients with DRESS recover within a few weeks; however, some patients may suffer from a prolonged disease course and develop autoimmune sequelae.

To investigate the immune mechanism and therapeutic targets of patients with recalcitrant DRESS with a prolonged disease course.

Thirty-two patients with recalcitrant DRESS with a prolonged treatment course (≥ 8 weeks; 'prolonged DRESS'), 28 patients with DRESS with a short treatment course (< 2 weeks; 'short-duration DRESS') and 26 healthy donors (HDs) were enrolled.

Bulk transcriptome results showed that the mRNA expression levels of CCR8 and CXCR3 were significantly increased in blood samples from patients in the acute stage of prolonged DRESS [Padj = 1.50 × 10-9 (CCR8) and Padj = 2.60 × 10-4 (CXCR3), patients with prolonged DRESS compared with the HD group]. Serum and skin lesion concentrations of CCL1 and CXCL10 (ligands of CCR8 and CXCR3, respectively) were significantly increased in patients with prolonged DRESS compared with patients with short-duration DRESS. The results from high-parameter flow cytometry and autoantibody screening also identified significant increases in CD8+ GNLY+ CXCR3+ effector memory T cells, CD8+ central memory T cells, CD4+ CCR8+ T helper 2 cells and IgG anti-HES-6 autoantibodies in patients with prolonged DRESS. Furthermore, in vitro blocking assays revealed that Janus kinase inhibitors (JAKi; mainly tofacitinib and upadacitinib) significantly decreased the release of CCL1 and CXCL10. Some patients with prolonged DRESS were successfully treated with JAKi.

JAKi (tofacitinib and upadacitinib) were associated with decreased concentrations of CCL1 and CXCL10, suggesting that they may attenuate CCR8/CCL1 and CXCR3/CXCL10 axis-mediated memory T-cell activation, which contributes to disease pathogenesis in patients with recalcitrant DRESS and a long-term treatment course.

Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disease marked by inflammation of synovium and generation of autoantibodies. Bone and cartilage are frequently damaged along with weakening of tendons and ligaments resulting in disability. An effective RA treatment needs a multi-disciplinary approach which relies upon pathophysiology that is still partially understood. In RA patients, inflammation was induced by pro-inflammatory cytokines including IL-1, IL-6 & IL-10. The conventional dosage regimens for treating RA have drawbacks such as ineffectiveness, greater doses, frequent dosing, relatively expensive and serious adverse effects. To formulate an effective treatment plan for RA, research teams have recently focused on producing several nanoformulations containing anti-inflammatory APIs with an aim to target the inflamed area. Nanomedicines have recently gained popularity in the treatment of RA. Interestingly, unbelievable improvements have been observed in current years in diagnosis and management of RA utilizing nanotechnology. Various patents and clinical trial data have been reported in relevance to RA treatment.

Although efficacy and safety of Upadacitinib and Dupilumab in moderate to severe atopic dermatitis (AD) have been shown in clinical trials, real world data are still limited. The aim of this retrospective study is to indirectly compare the efficacy and safety of Upadacitinib and Dupilumab in patients with moderate to severe AD in real world practice.

A single-center retrospective cohort study was conducted. The study included patients with moderate to severe AD, who were enrolled from May 2022 to March 2024, to indirectly compare the efficacy and safety of Upadacitinib and Dupilumab over 12 weeks duration.

Eighty-seven patients were included (46 received Upadacitinib and 41 Dupilumab). Compared with week 0, there was a significant decrease in EASI score, ADCT score and NRS score in patients of both groups in weeks 4, 8, and 12. In week 4, the reduction in EASI score, ADCT score and NRS score was significantly greater in patients of Upadacitinib group compared to those in Dupilumab group. Compared to baseline, in week 12, the decrease in IL-4, IL-13, and IL-31 level in the serum of patients in Upadacitinib group was significantly greater than that of patients in Dupilumab group. The total IgE of patients in Dupilumab group decreased significantly, while there was no significant change in patients of Upadacitinib group. Although Upadacitinib group reported more adverse events than Dupilumab group, no serious adverse events were observed.

Both Upadacitinib and Dupilumab groups showed effective trend in patients with moderate to severe AD. Upadacitinib has better efficacy and rapid onset in the treatment of patients with moderate to severe AD.

Rheumatoid arthritis is a complex disease marked by joint pain, stiffness, swelling, and chronic synovitis, arising from the dysregulated interaction between synoviocytes and immune cells. Its unclear etiology makes finding a cure challenging. The concept of digital twins, used in engineering, can be applied to healthcare to improve diagnosis and treatment for complex diseases like rheumatoid arthritis. In this work, we pave the path towards a digital twin of the arthritic joint by building a large, modular biochemical reaction map of intra- and intercellular interactions. This network, featuring over 1000 biomolecules, is then converted to one of the largest executable Boolean models for biological systems to date. Validated through existing knowledge and gene expression data, our model is used to explore current treatments and identify new therapeutic targets for rheumatoid arthritis.

This study aimed to compare the efficacy and safety of baricitinib in patients with rheumatoid arthritis (RA) receiving different doses based on renal function.

We conducted a retrospective study within the JAK Study Group, involving 23 facilities in Fukuoka Prefecture, examining patients treated with baricitinib for RA. Patients were categorized into two dose groups: 4 mg with normal/mild renal dysfunction and 2 mg with moderate renal dysfunction. Baricitinib's efficacy, retention rate, and safety were compared between the groups after propensity score matching.

After propensity score matching, disease duration, methotrexate dosage, and anti-cyclic citrullinated peptide antibody positivity rate were balanced across 33 patients in both groups. No significant differences were observed between the groups in tender/swollen joint counts, changes in evaluator/patient global assessments, achievement rate of low disease activity, remission rate on clinical/simplified disease activity indices, or retention rate. Additionally, the incidence of adverse events aligned with previous reports, indicating similar drug safety profiles.

Baricitinib 2 mg in RA patients with moderate renal dysfunction showed comparable efficacy and retention rate to 4 mg in patients with normal/mild renal dysfunction. The incidence and types of adverse events were consistent with previous studies, indicating the safety of the drug at these dosages.

Fibrosis drives end-organ damage in many diseases. However, clinical trials targeting individual upstream activators of fibroblasts, such as TGFβ, have largely failed. Here, we target the leukemia inhibitory factor receptor (LIFR) as an "autocrine master amplifier" of multiple upstream activators of lung fibroblasts. In idiopathic pulmonary fibrosis (IPF), the most common fibrotic lung disease, we found that lung myofibroblasts had high LIF expression, and the fibroblasts in fibroblastic foci coexpressed LIF and LIFR. In IPF, fibroblastic foci are the "leading edge" of fibrosis and a key site of disease pathogenesis. TGFβ1, one of the principal drivers of fibrosis, up-regulated LIF expression in IPF fibroblasts. We found that TGFβ1, IL-4, and IL-13 stimulations of fibroblasts require the LIF-LIFR axis to evoke a strong fibrogenic effector response in fibroblasts. In vitro antibody blockade of LIFR on IPF lung fibroblasts reduced the induction of profibrotic genes after TGFβ1 stimulation. Silencing LIF and LIFR reduced profibrotic fibroblast activation following TGFβ1, IL-4, and IL-13 stimulations. We also demonstrated that LIFR amplified profibrotic stimuli in precision-cut lung slices from IPF patients. These LIFR signals were transduced via JAK2, and STAT1 in IPF lung fibroblasts. Together, we find that LIFR drives an autocrine circuit that amplifies and sustains pathogenic activation of IPF fibroblasts. Targeting a single, downstream master amplifier on fibroblasts, like LIFR, is an alternative therapeutic strategy that simultaneously attenuates the profibrotic effects of multiple upstream stimuli.

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.

Axial spondyloarthritis (axSpA) is a chronic illness with limited treatment options. The role of Janus kinase (JAK) inhibition as a therapeutic option has increasingly become a focus of research in recent years as they have brought a new mode of action to the clinical armamentarium. This review assesses the efficacy and safety profile of these drugs in axSpA. The current phase 2 and 3 clinical trials data are summarized across tofacitinib, upadacitinib and filgotinib. Moreover, the safety profiles of these drugs, in the context of emerging safety signals such as during the ORAL surveillance study, are reviewed. In summary, JAK inhibitors offer a novel therapeutic target for axSpA and appear to address some of the unmet needs for patients who have either failed to respond to current treatment options or in whom they are contraindicated. There is a relative lack of evidence in non-radiographic axSpA and longer-term trials are needed to establish true efficacy and safety profile in radiographic axSpA.

Alopecia universalis (AU), an advanced form of alopecia areata (AA), is a condition characterized by the complete loss of hair over the entire skin surface. Recent progress has significantly enhanced our understanding of the pathogenesis of AU. In particular, interferon-γ (IFN-γ) and interleukin (IL)-15 seem to play a pivotal role in the pathogenesis of the disease. Nonetheless, a variety of medications has been used to treat the disease with frequently inconsistent results. Given the broad modulation of the immune system and inhibition of key molecules, including IFN-γ and IL-15, oral janus kinase (JAK) inhibitors represent a treatment option for moderate to severe cases of AA, as demonstrated in case reports supporting their efficacy and tolerability. We present the case of a patient suffering from psoriatic arthritis and AU who experienced a sudden improvement in peripheral arthritis and AU while receiving JAK1 selective treatment with upadacitinib. So far, there are very limited case reports of successful upadacitinib treatment for patients with AA, mostly in patients also suffering from atopic dermatitis. Thus, we provide evidence for the efficacy of upadacitinib in managing AU in adults, as well as in the context of inflammatory arthritis such as psoriatic arthritis.

Leucine-rich alpha-2 glycoprotein (LRG) is a useful serum biomarker for monitoring disease activity during remission in ulcerative colitis (UC). Because LRG levels differ among patients, it is necessary to assess them after profiling patients, especially in patients with refractory UC undergoing treatment with molecular-targeted drugs. This study aimed to analyze LRG levels that indicate mucosal healing according to clinical characteristics and molecular-targeted drugs.

Among 214 patients with UC treated with biologics or Janus kinase (JAK) inhibitors, this study evaluated 111 patients (174 measurements) who achieved mucosal healing based on colonoscopy performed within 2 months before and after LRG measurement and experienced no changes in disease status or treatment during the same period. We analyzed the relationship of LRG with clinical characteristics (including sex, age, body mass index, and disease type and duration) and molecular-targeted drugs.

Compared with men, women had significantly higher LRG levels (9.5 μg/mL vs. 11.3 μg/mL, p < 0.001). In addition, LRG levels were significantly higher in older patients (12.0 μg/mL vs. 9.8 μg/mL, p < 0.01). LRG levels were the highest in patients treated with vedolizumab and lower in patients treated with JAK inhibitors (vedolizumab: 12.7 μg/mL; tofacitinib: 8.9 μg/mL; upadacitinib: 8.5 μg/mL; and filgotinib: 9.1 μg/mL; p < 0.0001).

Among the patients who achieved mucosal healing, LRG levels were significantly higher in women and older patients. LRG levels differed according to the molecular-targeted drug used and were higher with vedolizumab and lower with JAK inhibitors.

Bullous pemphigoid (BP) is a rare, life-threatening autoimmune blistering disease with pruritus and tension blisters/bullous as the main clinical manifestations. Glucocorticosteroids are the main therapeutic agents for it, but their efficacy is poor in some patients. Tofacitinib, a small molecule agent that inhibits JAK1/3, has shown incredible efficacy in a wide range of autoimmune diseases and maybe a new valuable treatment option for refractory BP.

To report a case of refractory BP successfully treated with tofacitinib, then explore the underlying mechanism behind the treatment, and finally review similarities to other cases reported in the literature.

Case report and literature review of published cases of successful BP treatment with JAK inhibitors. The case report describes a 73-year-old male with refractory BP that was successfully managed with the combination therapy of tofacitinib and low-dose glucocorticoids for 28 weeks. Immunohistochemistry and RNA sequencing were performed to analyze the underlying mechanism of tofacitinib therapy. A systematic literature search was conducted to identify other cases of treatment with JAK inhibitors.

Throughout the 28-week treatment period, the patient experienced clinical, autoantibody and histologic resolution. Immunohistochemical analysis showed tofacitinib significantly decreased the pSTAT3 and pSTAT6 levels in the skin lesions of this patient. RNA sequencing and immunohistochemical testing of lesion samples from other BP patients identified activation of the JAK-STAT signaling pathway. Literature review revealed 17 previously reported cases of BP treated with four kinds of JAK inhibitors successfully, including tofacitinib (10), baricitinib (1), upadacitinib (3) and abrocitinib (3).

Our findings support the potential of tofacitinib as a safe and effective treatment option for BP. Larger studies are underway to better understand this efficacy and safety.

The COVID-19 pandemic caused by the SARS-CoV-2 virus infected more than 775,686,716 humans and was responsible for the death of more than 7,054,093 individuals. COVID-19 has taught us that the development of vaccines, repurposing of drugs, and understanding the mechanism of a disease can be done within a short time. The COVID-19 proteomics and metabolomics has contributed to its diagnosis, understanding of its progression, host-virus interaction, disease mechanism, and also in the search of suitable anti-COVID therapeutics. Mass spectrometry based proteomics was used to find the potential biomarkers of different stages of COVID-19 including severe and nonsevere cases in the blood serum. Notably, protein-protein interaction techniques to understand host-virus interactions were also significantly useful. The single-cell proteomics studies were carried out to ascertain the changes in immune cell composition and its activation in mild COVID-19 patients versus severe COVID-19 patients using whole-blood and peripheral-blood mononuclear cells. Modern technologies were helpful to deal with the pandemic; however, there is still scope for further development. Further, attempts were made to understand the protein-protein, metabolite-metabolite, and protein-metabolite interactomes, derived from proteins and metabolite fingerprints of COVID-19 patients by reanalysis of COVID-19 public mass spectrometry based proteomics and metabolomics studies. Further, some of these interactions were supported by the literature as validations in the COVID-19 studies.

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.

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.

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.

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.

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.

Crohn's disease (CD) is a chronic inflammatory bowel disease that significantly impacts patient quality of life. This systematic review evaluates the safety and efficacy of upadacitinib, a selective Janus kinase (JAK) inhibitor, in the treatment of CD. A comprehensive literature search was conducted across multiple databases, yielding seven studies published between 2020 and 2024, encompassing 1,481 patients. The review includes randomized controlled trials, post hoc analyses of phase 3 trials, and observational studies. Findings consistently demonstrate upadacitinib's superiority over placebo in inducing and maintaining clinical remission, achieving endoscopic response, and normalizing inflammatory markers. Notably, upadacitinib showed rapid symptom relief, with clinical remission observed as early as five to six days after treatment initiation. Efficacy was observed across various patient populations, including those with prior biologic failure. Long-term studies indicated sustained clinical and endoscopic improvements, with remission rates maintained for up to 30 months. Upadacitinib also demonstrated effectiveness in real-world, treatment-refractory cohorts. Safety profiles were generally consistent with those of other JAK inhibitors. Common adverse events included infections, particularly herpes zoster, and laboratory abnormalities such as neutropenia and elevated creatine kinase. Serious adverse events were infrequent, although careful monitoring is warranted. This review suggests that upadacitinib is a promising treatment option for moderate to severe CD, offering rapid and sustained efficacy with an acceptable safety profile.

Tofacitinib is an oral Janus kinase inhibitor for the treatment of ulcerative colitis (UC). We aimed to identify the safety and effectiveness of tofacitinib in patients with UC in routine clinical settings in Korea.

This open-label, observational, prospective, post-marketing surveillance study was conducted at 22 hospitals in the Republic of Korea. Patients with moderate to severe active UC who received tofacitinib were included and followed up for up to 52 weeks. Tofacitinib was administered at a dosage of 10 mg twice daily for at least 8 weeks, followed by 5 or 10 mg twice daily at the investigator's discretion based on clinical evaluation according to the approved Korean label. Safety including adverse events (AEs) and effectiveness including clinical remission, clinical response, and endoscopic mucosal healing were evaluated. Safety analysis set was defined as all patients registered for this study who received at least one dose of tofacitinib according to the approved Korean label and followed up for safety data. Effectiveness analysis set included patients in the safety analysis set who were evaluated for overall effectiveness assessment and excluded patients who had received tofacitinib less than 8 weeks.

A total of 110 patients were enrolled, of whom 106 patients were included in the safety population. The median duration of treatment was 370 days and the treatment duration ranged from 16 to 684 days for the safety population. AEs occurred in 42 patients (39.6%). Serious AEs (SAEs) occurred in 7 patients (6.6%) and of them, there were 2 cases of serious infections. These serious infections were reported as Adverse Event of Special Interest (AESI) in this study and no other AESI were reported. There were no cases of death during the study period. Clinical remission rates were 40.0%, 46.7%, 57.6%, and 55.1% at 8, 16, 24, and 52 weeks, and clinical response rates were 77.8%, 87.9%, 56.6%, and 81.4% at each visit, respectively. Endoscopic mucosal healing rates were 58.7% at 16 weeks and 46.2% at 52 weeks.

Tofacitinib was effective in Korean patients with moderate to severe active UC and the safety findings were consistent with the known safety profile of tofacitinib. This study confirmed the safety and effectiveness of tofacitinib in Korean patients with moderate to severe active UC in routine clinical settings.

This study is registered in the ClinicalTrials.gov under the identifier NCT04071405, registered on 28 August 2019.

Blood vessels show various COVID-19-related conditions including thrombosis and cytokine propagation. Existing in vitro blood vessel models cannot represent the consequent changes in the vascular structure or determine the initial infection site, making it difficult to evaluate how epithelial and endothelial tissues are damaged. Here, we developed a microphysiological system (MPS) that co-culture the bronchial organoids and the vascular bed to analyze infection site and interactions. In this system, virus-infected organoids caused damage in vascular structure. However, vasculature was not damaged or infected when the virus was directly introduced to vascular bed. The knockout of interferon-related genes and inhibition of the JAK/STAT pathway reduced the vascular damage, indicating the protective effect of interferon response suppression. The results demonstrate selective infection of bronchial epithelial cells and vascular damage by cytokines and also indicate the applicability of MPS to investigate how the infection influences vascular structure and functions.

Nucleic acid-sensing Toll-like receptors (TLR) 3, 7/8, and 9 are key innate immune sensors whose activities must be tightly regulated to prevent systemic autoimmune or autoinflammatory disease or virus-associated immunopathology. Here, we report a systematic scanning-alanine mutagenesis screen of all cytosolic and luminal residues of the TLR chaperone protein UNC93B1, which identified both negative and positive regulatory regions affecting TLR3, TLR7, and TLR9 responses. We subsequently identified two families harboring heterozygous coding mutations in UNC93B1, UNC93B1+/T93I and UNC93B1+/R336C, both in key negative regulatory regions identified in our screen. These patients presented with cutaneous tumid lupus and juvenile idiopathic arthritis plus neuroinflammatory disease, respectively. Disruption of UNC93B1-mediated regulation by these mutations led to enhanced TLR7/8 responses, and both variants resulted in systemic autoimmune or inflammatory disease when introduced into mice via genome editing. Altogether, our results implicate the UNC93B1-TLR7/8 axis in human monogenic autoimmune diseases and provide a functional resource to assess the impact of yet-to-be-reported UNC93B1 mutations.

Rheumatoid Arthritis (RA) is a systemic autoimmune disease involving pro-inflammatory cytokines that can be therapeutically targeted by antibodies or kinase inhibitors. Nevertheless, these drugs fail in a subset of patients independent of the abundance of the targeted cytokines. We aim to explore the cellular basis of this phenomenon by analyzing the relation of cytokine abundance and activation of downstream signaling pathways in RA.

The study included 62 RA patients and 9 healthy controls (HC). Phosphorylation of STAT 1-6 in various immune cell subsets was determined ex vivo using a novel robust flow cytometry-based protocol. Serum concentrations of IL-6, IL-10, IL-12p70, IL-17 A, interferon gamma, and TNFα in the same samples were measured using highly sensitive single molecule array (SIMOA).

We found an increase in circulating cytokines in RA patients, while STAT activity was lower in RA patients compared to HC. Based on STAT activity we determined three endotypes in active RA patients (cDAI>10, n = 28): 1) those with active STAT5a/b signaling in T cells (n = 7/28), 2) those with a low STAT activity in all assessed cell types (n = 14/28), and 3) those with active STAT1 and STAT3 signaling mainly in myeloid cells (n = 7/28). Integrating intracellular STAT activation and cytokine analysis revealed diminished JAK/STAT signaling in a subset of patients (n = 8/20) despite elevated serum cytokine concentrations.

Diminished JAK/STAT signaling in active RA may partly explain unresponsiveness to therapy targeting cytokine signaling. Analysis of JAK/STAT phosphorylation may identify patients at risk for non-response to these therapies.

This investigation seeks to elucidate the role of the Granulocyte Colony-Stimulating Factor (G-CSF) in the progression of hepatocellular carcinoma (HCC), as well as the impact of the substance on related signaling pathways within the disease matrix.

Nude mouse tumor-bearing assay was used to detect tumor progression. Levels of Mannose/CD68 and CD34/Mannose within these samples and the concentrations of Mannose and inducible Nitric Oxide Synthase (iNOS) in macrophages were quantified using immunofluorescence techniques. The angiogenic capability was assessed via tube formation assays, and protein expressions of G-CSF, Vascular Endothelial Growth Factor (VEGF), Transforming Growth Factor-beta (TGF-β), Matrix Metalloproteinases 2 and 9 (MMP2/9), SH2-containing protein tyrosine phosphatase-2 (SHP-2), phosphorylated PI3K/total PI3K (P-PI3K/t-PI3K), phosphorylated AKT/total AKT (P-AKT/t-AKT), and phosphorylated mTOR/total mTOR (P-mTOR/t-mTOR) were measured through Western Blot analysis in both tumor tissues and macrophages.

Administration of G-CSF resulted in a marked augmentation of tumor volume. Macrophage Mannose expression was significantly elevated upon G-CSF treatment, while iNOS levels were conspicuously diminished. G-CSF substantially enhanced the secretion of VEGF, TGF-β, and MMPs in tumor tissues. Macrophage parameters, following incubation in G-CSF pre-treated conditioned medium, indicated enhanced tube-forming capabilities relative to the control, an effect mitigated by the introduction of specific inhibitors. Furthermore, the G-CSF group exhibited a notable reduction in SHP-2 expression, alongside a substantial elevation in the phosphorylation levels of the PI3K/AKT/mTOR pathway proteins across all tumor-bearing paradigms.

G-CSF ostensibly facilitates the advancement of hepatocellular carcinoma by activating the PI3K/AKT/mTOR signaling cascade within Tumor-Associated Macrophages (TAM).

Tyrosine kinase 2 (TYK2) mediates cytokine signaling through type 1 interferon, interleukin (IL)-12/IL-23, and the IL-10 family. There appears to be an association between TYK2 genetic variants and inflammatory conditions, and clinical evidence suggests that selective inhibition of TYK2 could produce a unique therapeutic profile. Here, we describe the discovery of compound 9 (GLPG3667), a reversible and selective TYK2 adenosine triphosphate competitive inhibitor in development for the treatment of inflammatory and autoimmune diseases. The preclinical pharmacokinetic profile was favorable, and TYK2 selectivity was confirmed in peripheral blood mononuclear cells and whole blood assays. Dermal ear inflammation was reduced in an IL-23-induced in vivo mouse model of psoriasis. GLPG3667 also completed a phase 1b study (NCT04594928) in patients with moderate-to-severe psoriasis where clinical effect was shown within the 4 weeks of treatment and it is now in phase 2 trials for the treatment of dermatomyositis (NCT05695950) and systemic lupus erythematosus (NCT05856448).

Pyoderma gangrenosum (PG) is a rare inflammatory dermatologic condition with neutrophilic infiltration of the skin that causes pustules and ulcerations. Janus kinase (JAK) inhibitors are immunomodulating agents that have been recently described in the literature as an effective treatment for PG. We describe a patient with PG on the lower extremities successfully treated with baricitinib. We also conducted a narrative review of the literature of PG patients treated with JAK inhibitors who were refractory to other treatments.

Fibrosis drives end-organ damage in many diseases. However, clinical trials targeting individual upstream activators of fibroblasts, such as TGFβ, have largely failed. Here, we target the leukemia inhibitory factor receptor (LIFR) as a "master amplifier" of multiple upstream activators of lung fibroblasts. In idiopathic pulmonary fibrosis (IPF), the most common fibrotic lung disease, we found that lung myofibroblasts had high LIF expression. Further, TGFβ1, one of the key drivers of fibrosis, upregulated LIF expression in IPF fibroblasts. In vitro anti-LIFR antibody blocking on human IPF lung fibroblasts reduced induction of profibrotic genes downstream of TGFβ1, IL-4 and IL-13. Further, siRNA silencing of LIFR in IPF precision cut lung slices reduced expression of fibrotic proteins. Together, we find that LIFR drives an autocrine positive feedback loop that amplifies and sustains pathogenic activation of IPF fibroblasts downstream of multiple external stimuli, implicating LIFR as a therapeutic target in fibrosis.

Fibroblasts have a central role in the pathogenesis of fibrotic diseases. However, due to in part to multiple profibrotic stimuli, targeting a single activator of fibroblasts, like TGFβ, has not yielded successful clinical treatments. We hypothesized that a more effective therapeutic strategy is identifying a downstream "master amplifier" of a range of upstream profibrotic stimuli. This study identifies the leukemia inhibitory factor receptor (LIFR) on fibrotic lung fibroblasts amplifies multiple profibrotic stimuli, such as IL-13 and TGFβ. Blocking LIFR reduced fibrosis in ex vivo lung tissue from patients with idiopathic pulmonary fibrosis (IPF). LIFR, acting as a master amplifier downstream of fibroblast activation, offers an alternative therapeutic strategy for fibrotic diseases.

Approved options for advanced therapy in pediatric inflammatory bowel disease (IBD) are limited. Although Janus kinase (JAK) inhibitors are approved in adult IBD, their benefit in pediatric populations is not yet delineated. We present a 13-year-old female patient with ulcerative colitis (UC) refractory to numerous therapies and courses of prednisone that ultimately responded to a JAK inhibitor. Initial treatment consisted of 5-aminosalicylate and azathioprine. This was changed to adalimumab due to persistent symptoms. Repeat colonoscopy revealed pancolitis, thus she was transitioned to vedolizumab. She was hospitalized twice for uncontrolled symptoms on vedolizumab and subsequent scope showed continued pancolitis. As a result, she transitioned to ustekinumab without symptomatic relief after adjusting to monthly dosing. The family declined colectomy, opting to exhaust all medical therapies. Upadacitinib was started and her symptoms resolved within 1 week, and she remains in steroid-free remission. This case illustrates the possible role of JAK inhibitors in extensively refractory pediatric UC patients before colectomy.

Atopic dermatitis (AD) is a chronic skin disease characterized by type 2-skewed immune responses, and significantly influenced by cytokines dependent on Janus kinases (JAKs). Upadacitinib, a JAK1 inhibitor, is effective for moderate-to-severe AD. This study aims to identify biomarkers that reflect long-term therapeutic effects of upadacitinib 15 mg or 30 mg.

A retrospective study from August 2021 to July 2023 included 213 AD patients treated with upadacitinib 15 mg and 70 AD patients with 30 mg. We analyzed eczema area and severity index (EASI), peak pruritus-numerical rating scale (PP-NRS), serum immunoglobulin E (IgE), thymus and activation-regulated chemokine (TARC), lactate dehydrogenase (LDH), and total eosinophil count (TEC) at weeks 0, 4, 12, 24, 36, and 48 of treatment.

Both treatments with upadacitinib 15 mg and 30 mg significantly reduced EASI and PP-NRS scores over week 4 to 48 compared to baseline. Upadacitinib 15 mg or 30 mg treatment significantly decreased TEC compared to baseline through week 4 to 36 or week 4 to 48, respectively. The percent reduction of TEC correlated with those of EASI and PP-NRS through week 4 to 48 of treatment with upadacitinib 15 mg, or through week 12 to 48 with 30 mg, respectively. After adjusting for % reductions of other laboratory markers, the significance of correlations was preserved at weeks 36 and 48 of 15 mg treatment, while at weeks 4 and 36 of 30 mg treatment.

The % reduction of TEC correlated with those of EASI and PP-NRS during upadacitinib treatment, indicating its potential as a biomarker reflecting treatment responses to upadacitinib in AD patients. However, the variability of significant correlation during treatment indicates that further inspection is needed for its usefulness in monitoring responses to upadacitinib treatment for AD.

To assess the drug survival and change of disease activity using a second Janus kinase inhibitor (JAKi) after failure to a JAKi and subsequent biologic disease-modifying anti-rheumatic drugs (bDMARDs) in patients with difficult-to-treat rheumatoid arthritis (RA).

This retrospective cohort study included 32 patients with difficult-to-treat RA who failed to a JAKi and subsequently to one or more bDMARDs and then switched to a second JAKi. To assess drug survival, electronic medical records of each patient were reviewed. Data on whether the second JAKi was discontinued, and the reasons for discontinuation were collected. The change of disease activity was assessed by analyzing changes in tender joint count (TJC), swollen joint count (SJC), patient's global assessment of disease activity on a visual-analogue scale (VAS), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), Disease Activity Score for 28 joints with ESR (DAS28-ESR), and DAS28-CRP from baseline to that at six months from initiation of the second JAKi.

Overall, discontinuation of the second JAKi occurred in 20 (62.5%) patients. Primary failure, secondary failure, adverse events, and insurance coverage issues were the reasons for discontinuation in 9 (45.0%), 5 (25.0%), 2 (10.0%), and 4 (20.0%) patients, respectively. The estimated 2-year drug survival rate was 39.3%. In terms of change of disease activity, the second JAKi significantly improved TJC (p < 0.001), SJC (p < 0.001), VAS (p < 0.001), CRP (p = 0.026), DAS28-ESR (p < 0.001), and DAS28-CRP (p < 0.001) at 6-month compared with that at the baseline.

Second JAKi could be a therapeutic option in patients with difficult-to-treat RA who have failed to a JAKi and subsequent bDMARDs.