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Systemic amyloidosis is recognized as a serious complication of rheumatoid arthritis or inflammatory bowel disease, but also of inflammatory skin disease. However, the detailed molecular mechanism of amyloidosis associated with cutaneous inflammation remains unclear, and therapeutic approaches are limited. Here, we investigated the pathophysiology of amyloidosis secondary to cutaneous inflammation and the therapeutic effects of Janus kinase (JAK) inhibitors by examining a mouse model of spontaneous dermatitis (KCASP1Tg mice). Moreover, KCASP1Tg mice were crossed with interleukin-17A (IL-17A) knockout mice to generate IL-17A-/KCASP1Tg and examine the role of IL-17A in amyloidosis under cutaneous inflammation. KCASP1Tg mice showed severe amyloid deposition in the liver and spleen. Increased serum-neutral fat levels and decreased lymphocyte production were observed in the spleen. Overproduction of amyloidosis was partially ameliorated by the administration of JAK inhibitors and was further improved in IL-17A-/KCASP1Tg mice. IL-17A-producing cells included CD4, gamma delta, and CD8 T cells. In summary, our results from the analysis of a mouse model of dermatitis revealed that skin-derived inflammatory cytokines can induce amyloid deposition in the liver and spleen, and that the administration of JAK inhibitors and, even more, IL-17A ablation, reduced amyloidosis. This study demonstrates that active control of skin inflammation is essential to prevent internal organ amyloidosis.

Atopic dermatitis (AD) is the most common chronic inflammatory skin disease and significantly impacts patients’ lives, particularly in its severe forms. AD clinical presentation varies over the course of the disease, throughout different age groups, and across ethnicities. AD is characterized by a spectrum of clinical phenotypes as well as endotypes. Starting from the current description of AD pathogenesis, this review explores the rationale of approved AD therapies from emollients to biologicals and introduces novel promising drugs.

Intense itching significantly reduces the quality of life, and atopic dermatitis is associated with psychiatric conditions, such as anxiety and depression. Psoriasis, another inflammatory skin disease, is often complicated by psychiatric symptoms, including depression; however, the pathogenesis of these mediating factors is poorly understood. This study used a spontaneous dermatitis mouse model (KCASP1Tg) and evaluated the psychiatric symptoms. We also used Janus kinase (JAK) inhibitors to manage the behaviors. Gene expression analysis and RT-PCR of the cerebral cortex of KCASP1Tg and wild-type (WT) mice were performed to examine differences in mRNA expression. KCASP1Tg mice had lower activity, higher anxiety-like behavior, and abnormal behavior. The mRNA expression of S100a8 and Lipocalin 2 (Lcn2) in the brain regions was higher in KCASP1Tg mice. Furthermore, IL-1β stimulation increased Lcn2 mRNA expression in astrocyte cultures. KCASP1Tg mice had predominantly elevated plasma Lcn2 compared to WT mice, which improved with JAK inhibition, but behavioral abnormalities in KCASP1Tg mice did not improve, despite JAK inhibition. In summary, our data revealed that Lcn2 is closely associated with anxiety symptoms, but the anxiety and depression symptoms caused by chronic skin inflammation may be irreversible. This study demonstrated that active control of skin inflammation is essential for preventing anxiety.

Generalized Pustular Psoriasis (GPP) is a recurrent dermatological condition characterized by widespread erythematous plaques, scaling, and sterile pustules. Notably, in a subset of patients, these lesions manifest exclusively in localized areas. We report a case where abrocitinib was used to treat the localized type of GPP, achieving relatively good clinical efficacy and without obvious side effects. To date, there are no published reports on the use of abrocitinib for GPP treatment, either domestically or internationally, making this case a valuable reference for clinicians and researchers.

Juvenile idiopathic arthritis (JIA) is the most common extraocular disease associated with pediatric uveitis. Despite the growing knowledge about the pathogenetic and clinical characteristics of the disease, it still remains a challenge for both the pediatric rheumatologist and ophthalmologist. Since uveitis is asymptomatic in most cases, it is generally detected by parents in a late phase of the disease when complications have occurred with consequent severe vision loss. Improvement in attentive screening and early treatment initiation to suppress inflammation has considerably reduced the sight-threatening outcomes of JIA-associated chronic anterior uveitis (JIA-CAU). Initial treatment with topical steroids is effective in most cases. However, more severe cases require the use of periocular or systemic corticosteroids, possibly leading to long-term complications. These include growth retardation, cataract and glaucoma. Systemic immunosuppressive agents are then employed in patients resistant to first-line therapy or to reduce steroid-associated complications. In this review, we will discuss the immunosuppressant agents currently employed for the treatment of the disease, including anti-tumor necrosis factor (TNF)α biologics approved or not by the regulatory agencies. We will also highlight how new therapeutic options like biologic targeting cytotoxic T-lymphocyte antigen-4 (CTLA-4) co-stimulatory molecule, interleukin-6 receptor (IL-6R) or B lymphocytes might represent exciting new options for patients resistant to conventional therapy. Finally, the potential use of janus kinase (JAK) inhibitors recently approved for the treatment of several inflammatory rheumatic diseases in adults will be also discussed.

Background & Aims Up to 15% of ulcerative colitis (UC) patients with an ileo‐anal pouch will develop chronic or antibiotic refractory pouchitis. We aimed to evaluate the efficacy and safety of tofacitinib in these refractory patients. Methods In this prospective single center study, adult UC patients with chronic or antibiotic refractory pouchitis (pouchitis disease activity index [PDAI] ≥ 7) were treated with tofacitinib 10 mg twice daily for 8 weeks. Clinical, biochemical, endoscopic and histologic disease activity was assessed at baseline and at week 8. The primary endpoint was the proportion of patients achieving clinical remission (PDAI < 7 and a reduction of ≥3 points from baseline) or clinical response (decrease ≥2 points from baseline). Results Thirteen patients were included and treated with tofacitinib. After 8 weeks, 31% achieved PDAI‐defined remission (4/13) and 54% achieved response (7/13). Both the total PDAI score (11 [interquartile range 9–12.75] vs. 8 [4.5–9.75], p = 0.033) and the clinical PDAI subscore (4 [3–4] vs. 2 [0.25–3.75], p = 0.014) decreased significantly from baseline compared to week 8 or early withdrawal, respectively. We did not observe a change in endoscopic or histological PDAI subscores. Conclusion In this pilot study, clinical remission in patients with chronic pouchitis was achieved in 31% of patients after 8 weeks of treatment with tofacitinib. Total and clinical PDAI dropped significantly compared with baseline, but we did not observe a significant change in endoscopic or histologic disease activity. Presumably, a treatment duration of 8 weeks is insufficient to induce mucosal healing in these refractory patients. Tofacitinib achieved clinical remission in 31% of chronic pouchitis patients after 8 weeks, of treatment, with significant reductions in total and clinical PDAI scores but no significant changes in endoscopic or histologic disease activity.

Background Gain-of-function mutations in STING1 (also known as TMEM173) which result in constitutive activation of STING, have been reported to cause STING-associated vasculopathy with onset in infancy (SAVI). Although a wider spectrum of associated manifestations and perturbations in disease onset have been observed since its description, the genotype-phenotype correlations are not definite, and there is no established treatment protocol for SAVI. Case presentation Herein, we report a kindred, heterozygous STING mutation (p.V155M) in which the 2-year-old proband suffered from severe interstitial lung disease (ILD) while her father was initially misdiagnosed with connective tissue disease associated with ILD at an adult age. Baricitinib was initiated after the diagnosis of SAVI in the proband combined with steroids, and during the 14-month follow-up, the respiratory symptoms were improved. However, as the improvement of laboratory indicators was limited, especially in autoimmune indices, and the lung CT images remained unaltered, it seems that JAK1/2 inhibition was unsatisfactory in completely controlling the inflammation of the disease in our study. Conclusions Baricitinib was shown to elicit some effect on the ILD but failed to control the inflammation of the disease completely. Further exploration of JAK inhibitors or other therapeutic strategies are needed to more optimally treat this inflammatory disease.

STING-associated vasculopathy with onset in infancy (SAVI) is a rare type Ι interferonopathy caused by gain of function mutations in an encoding stimulator of interferon genes (STING) protein 1. SAVI is characterized by neonatal or infantile-onset systemic inflammation, mainly affecting peripheral cutaneous blood vessels, skin, and lungs. The main disease manifestations include recurrent febrile episodes, cough, dyspnea, and failure to thrive, in association with progressive interstitial lung disease, polyarthritis, and cold-induced red violet plaques or papules on fingers, knees, toes, heels, nasal tip, and ears that can lead to distal ulcerations, skin necrosis, tissue loss, and autoamputation. For the management of SAVI, JAK inhibitors can be a valuable therapeutic intervention that hampers disease progression, while conventional immunosuppressive treatments have shown minimal efficacy. This review aims to describe the underlying pathophysiologic mechanisms of SAVI, highlighting the main clinical manifestations and discussing the current treatment approaches.

Background. Since March 2023, AIFA has introduced new reimbursement criteria for JAK-inhibitors (JAKis), restricting their use to patients with rheumatoid arthritis (RA) without specific risk factors and with previous failure of bDMARD therapy. These restrictions have influenced prescribing behavior, leading in some cases to treatment changes in patients already receiving JAKis. The primary objective of this study is to evaluate the frequency of maintenance of remission/low disease activity (REM/LDA) at 6 months, and to identify potential associated factors, in patients undergoing treatment modification compared with those who continued the ongoing therapy.   Materials annd Methjods. In this prospective, multicenter, observational cohort study, we enrolled patients with RA in stable REM/LDA for at least 6 months on JAKi therapy (03/2023–07/2024), for whom a therapeutic modification was proposed (dose reduction, treatment discontinuation with switch to another bDMARD, or discontinuation without switching) due to non-fulfillment of AIFA reimbursement conditions. At 6-month follow-up (T6), the frequency of REM/LDA maintenance was assessed, while additional therapeutic modifications (cs/b/tsDMARDs) and adverse events (AEs) were evaluated during the 12-month total follow-up. Associations between clinical-demographic characteristics and T6 outcomes were analyzed using univariate logistic regression.   Results. A total of 127 patients were enrolled (Table 1). Among them, 36 underwent JAKi modification at baseline (17 switches, 14 dose reductions, 5 discontinuations), while 91 maintained JAKi therapy, of whom 16 remained eligible for reimbursement according to AIFA criteria (Figure 1A). At T6, 109 patients were reassessed. Maintenance of REM/LDA at T6 was significantly less frequent in the group that modified therapy at baseline compared to those who continued treatment (23 (76.7%) vs 73 (92.3%), p=0.024; OR 0.27, 95% CI 0.08–0.88) (Figure 1B). Univariate analysis showed that dyslipidemia and history of malignancy were associated with reduced REM/LDA maintenance, whereas first-line bDMARD use correlated with greater clinical stability (Table 2). Patients who modified therapy at baseline showed a higher frequency of further treatment changes (19 (54.3%) vs 26 (29.6%), p=0.010) and a higher mean (SD) number of AEs (0.43 (0.85) vs 0.23 (0.62), p=0.12) during the 12-month follow-up (Table 3).   Conclusions. The analysis of the JAK-SWAP RER study suggest that modifying an effective JAK inhibitor regimen in clinically stable RA patients is associated with poorer clinical outcomes at 6 months, an increased need for further treatment changes, and a trend toward a higher rate of AEs. A conservative management approach should be preferred in patients in REM/LDA, even following changes in reimbursement criteria, particularly in those treated in later therapeutic lines.

Alopecia areata (AA) is a common chronic tissue-specific autoimmune disease, resulting in hair loss, that affects up to 2% of the general population. The exact pathobiology of AA has still remained elusive, while the common theory is the collapse of the immune privilege of the hair follicle caused by immunological mechanism. Multiple genetic and environment factors contribute to the pathogenesis of AA. There are several clinical treatments for AA, varying from one or multiple well-defined patches to more diffuse or total hair loss of the scalp (alopecia totalis) or hair loss of the entire body (alopecia universalis). The available treatments for AA, such as corticosteroids and other immunomodulators, minoxidil, and contact immunotherapy, are of limited efficacy with a high risk of adverse effects and high recurrence rates, especially for patients with severe AA. Recent insights into the pathogenesis of AA have led to the development of new treatment strategies, such as Janus kinase (JAK) inhibitors, biologics, and several small molecular agents. In addition, modern therapies for AA, including antihistamines, platelet-rich plasma (PRP) injection, and other novel therapies have been well explored. In this review, we discussed the recent advances in the pathogenesis, diagnosis, and treatment of AA.