Influence of Safety Warnings on the Prescribing Attitude of JAK Inhibitors for Rheumatoid Arthritis in Italy.

Background/Objectives: The Janus kinase inhibitors (JAKi) tofacitinib (TOFA), baricitinib (BARI), upadacitinib (UPA), and filgotinib (FILGO) are effective drugs for the treatment of rheumatoid arthritis. However, the US Food and Drug Administration (FDA) raised concerns about the safety of TOFA after its approval. This prompted the European Medicines Agency (EMA) to issue two safety warnings for limiting TOFA use, then extended a third warning to all JAKi in patients at high risk of developing serious adverse effects (SAE). These include thrombosis, major adverse cardiac events (MACE), and cancer. The purpose of this work was to analyze how the first two safety warnings from the EMA affected the prescribing of JAKi by rheumatologists in Italy. Methods: All patients with rheumatoid arthritis who had been prescribed JAKi for the first time in a 36-month period from 1 July 2019, to 30 June 2022 were considered. Data were obtained from the medical records of 29 Italian tertiary referral rheumatology centers. Patients were divided into three groups of 4 months each, depending on whether the JAKi prescription had occurred before the EMA's first safety alert (1 July-31 October 2019, Group 1), between the first and second alerts (1 November 2019-29 February 2020, Group 2), or between the second and third alerts (1 March 2021-30 June 2021, Group 3). The percentages and absolute changes in the patients prescribed the individual JAKi were analyzed. Differences among the three groups of patients regarding demographic and clinical characteristics were also assessed. Results: A total of 864 patients were prescribed a JAKi during the entire period considered. Of these, 343 were identified in Group 1, 233 in Group 2, and 288 in Group 3. An absolute reduction of 32% was observed in the number of patients prescribed a JAKi between Group 1 and Group 2 and 16% between Group 1 and Group 3. In contrast, there was a 19% increase in the prescription of a JAKi in patients between Group 2 and Group 3. In the first group, BARI was the most prescribed drug (227 prescriptions, 66.2% of the total), followed by TOFA (115, 33.5%) and UPA (1, 0.3%). In the second group, the most prescribed JAKi was BARI (147, 63.1%), followed by TOFA (65, 27.9%) and UPA (33, 11.5%). In the third group, BARI was still the most prescribed JAKi (104 prescriptions, 36.1%), followed by UPA (89, 30.9%), FILGO (89, 21.5%), and TOFA (33, 11.5%). The number of patients prescribed TOFA decreased significantly between Group 1 and Group 2 and between Group 2 and Group 3 (p ˂ 0.01). The number of patients who were prescribed BARI decreased significantly between Group 1 and Group 2 and between Group 2 and Group 3 (p ˂ 0.01). In contrast, the number of patients prescribed UPA increased between Group 2 and Group 3 (p ˂ 0.01). Conclusions: These data suggest that the warnings issued for TOFA were followed by a reduction in total JAKi prescriptions. However, the more selective JAKi (UPA and FILGO) were perceived by prescribers as favorable in terms of the risk/benefit ratio, and their use gradually increased at the expense of the other molecules.

Pathogenesis of Hemophagocytic Lymphohistiocytosis/Macrophage Activation Syndrome: A Case Report and Review of the Literature.

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening condition characterized by the uncontrolled activation of cytotoxic T lymphocytes, NK cells, and macrophages, resulting in an overproduction of pro-inflammatory cytokines. A primary and a secondary form are distinguished depending on whether or not it is associated with hematologic, infectious, or immune-mediated disease. Clinical manifestations include fever, splenomegaly, neurological changes, coagulopathy, hepatic dysfunction, cytopenia, hypertriglyceridemia, hyperferritinemia, and hemophagocytosis. In adults, therapy, although aggressive, is often unsuccessful. We report the case of a 41-year-old man with no apparent history of previous disease and an acute onset characterized by fever, fatigue, and weight loss. The man was from Burkina Faso and had made trips to his home country in the previous five months. On admission, leukopenia, thrombocytopenia, increased creatinine and transaminases, LDH, and CRP with a normal ESR were found. The patient also presented with hypertriglyceridemia and hyperferritinemia. An infectious or autoimmune etiology was ruled out. A total body CT scan showed bilateral pleural effusion and hilar mesenterial, abdominal, and paratracheal lymphadenopathy. Lymphoproliferative disease with HLH complication was therefore suspected. High doses of glucocorticoids were then administered. A cytologic analysis of the pleural effusion showed anaplastic lymphoma cells and bone marrow aspirate showed hemophagocytosis. An Epstein-Barr Virus (EBV) DNA load of more than 90000 copies/mL was found. Bone marrow biopsy showed a marrow localization of peripheral T lymphoma. The course was rapidly progressive until the patient died. HLH is a rare but usually fatal complication in adults of hematologic, autoimmune, and malignant diseases. Very early diagnosis and treatment are critical but not always sufficient to save patients.

Inflammation, Autoimmunity, and Infection in Fibromyalgia: A Narrative Review.

Fibromyalgia (FM) is a chronic disease characterized by widespread musculoskeletal pain of unknown etiology. The condition is commonly associated with other symptoms, including fatigue, sleep disturbances, cognitive impairment, and depression. For this reason, FM is also referred to as FM syndrome. The nature of the pain is defined as nociplastic according to the latest international classification and is characterized by altered nervous sensitization both centrally and peripherally. Psychosocial conditions have traditionally been considered critical in the genesis of FM. However, recent studies in animal models and humans have provided new evidence in favor of an inflammatory and/or autoimmune pathogenesis. In support of this hypothesis are epidemiological data of an increased female prevalence, similar to that of autoimmune diseases, and the frequent association with immune-mediated inflammatory disorders. In addition, the observation of an increased incidence of this condition during long COVID revived the hypothesis of an infectious pathogenesis. This narrative review will, therefore, discuss the evidence supporting the immune-mediated pathogenesis of FM in light of the most current data available in the literature.

Giant Cell Arteritis: Advances in Understanding Pathogenesis and Implications for Clinical Practice.

Giant cell arteritis (GCA) is a noninfectious granulomatous vasculitis of unknown etiology affecting individuals older than 50 years. Two forms of GCA have been identified: a cranial form involving the medium-caliber temporal artery causing temporal arteritis (TA) and an extracranial form involving the large vessels, mainly the thoracic aorta and its branches. GCA generally affects individuals with a genetic predisposition, but several epigenetic (micro)environmental factors are often critical for the onset of this vasculitis. A key role in the pathogenesis of GCA is played by cells of both the innate and adaptive immune systems, which contribute to the formation of granulomas that may include giant cells, a hallmark of the disease, and arterial tertiary follicular organs. Cells of the vessel wall cells, including vascular smooth muscle cells (VSMCs) and endothelial cells, actively contribute to vascular remodeling responsible for vascular stenosis and ischemic complications. This review will discuss new insights into the molecular and cellular pathogenetic mechanisms of GCA, as well as the implications of these findings for the development of new diagnostic biomarkers and targeted drugs that could hopefully replace glucocorticoids (GCs), still the backbone of therapy for this vasculitis.

When Autoantibodies Are Missing: The Challenge of Seronegative Rheumatoid Arthritis.

Seronegative rheumatoid arthritis (SNRA) is characterized by the absence of both rheumatoid factor (RF) and antibodies against the cyclic citrullinated protein (ACPA) in serum. However, the differences between the two forms of RA are more complex and have not yet been definitively characterized. Several lines of evidences support the idea that there are specific elements of the two forms, including genetic background, epidemiology, pathogenesis, severity of progression over time, and response to therapy. Clinical features that may differentiate SNRA from SPRA are also suggested by data obtained from classical radiology and newer imaging techniques. Although new evidence seems to provide additional help in differentiating the two forms of RA, their distinguishing features remain largely elusive. It should also be emphasized that the distinctive features of RA forms, if not properly recognized, can lead to the underdiagnosis of SNRA, potentially missing the period called the "window of opportunity" that is critical for early diagnosis, timely treatment, and better prognosis. This review aims to summarize the data provided in the scientific literature with the goal of helping clinicians diagnose SNRA as accurately as possible, with emphasis on the most recent findings available.

ERAP1 and ERAP2 Haplotypes Influence Suboptimal HLA-B*27:05-Restricted Anti-Viral CD8+ T Cell Responses Cross-Reactive to Self-Epitopes.

The human leukocyte antigen (HLA)-B*27 family of alleles is strongly associated with ankylosing spondylitis (AS), a chronic inflammatory disorder affecting the axial and peripheral joints, yet some HLA-B*27 variants not associated with AS have been shown. Since no major differences in the ligandome of associated compared to not-associated alleles have emerged, a plausible hypothesis is that the quantity rather than the quality of the presented epitopes makes the difference. In addition, the Endoplasmic Reticulum AminoPeptidases (ERAPs) 1 and 2, playing a crucial role in shaping the HLA class I epitopes, act as strong AS susceptibility factors, suggesting that an altered peptidome might be responsible for the activation of pathogenic CD8+ T cells. In this context, we have previously singled out a B*27:05-restricted CD8+ T cell response against pEBNA3A (RPPIFIRRL), an EBV peptide lacking the B*27 classic binding motif. Here, we show that a specific ERAP1/2 haplotype negatively correlates with such response in B*27:05 subjects. Moreover, we prove that the B*27:05 allele successfully presents peptides with the same suboptimal N-terminal RP motif, including the self-peptide, pDYNEIN (RPPIFGDFL). Overall, this study underscores the cooperation between the HLA-B*27 and ERAP1/2 allelic variants in defining CD8+ T cell reactivity to suboptimal viral and self-B*27 peptides and prompts further investigation of the B*27:05 peptidome composition.

Long-Term Retention Rate of Tofacitinib in Rheumatoid Arthritis: An Italian Multicenter Retrospective Cohort Study.

Background: Tofacitinib (TOFA) was the first Janus kinase inhibitor (JAKi) to be approved for the treatment of rheumatoid arthritis (RA). However, data on the retention rate of TOFA therapy are still far from definitive. Objective: The goal of this study is to add new real-world data on the TOFA retention rate in a cohort of RA patients followed for a long period of time. Methods: A multicenter retrospective study of RA subjects treated with TOFA as monotherapy or in combination with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) was conducted in 23 Italian tertiary rheumatology centers. The study considered a treatment period of up to 48 months for all included patients. The TOFA retention rate was assessed with the Kaplan-Meier method. Hazard ratios (HRs) for TOFA discontinuation were obtained using Cox regression analysis. Results: We enrolled a total of 213 patients. Data analysis revealed that the TOFA retention rate was 86.5% (95% CI: 81.8-91.5%) at month 12, 78.8% (95% CI: 78.8-85.2%) at month 24, 63.8% (95% CI: 55.1-73.8%) at month 36, and 59.9% (95% CI: 55.1-73.8%) at month 48 after starting treatment. None of the factors analyzed, including the number of previous treatments received, disease activity or duration, presence of rheumatoid factor and/or anti-citrullinated protein antibody, and presence of comorbidities, were predictive of the TOFA retention rate. Safety data were comparable to those reported in the registration studies. Conclusions: TOFA demonstrated a long retention rate in RA in a real-world setting. This result, together with the safety data obtained, underscores that TOFA is a viable alternative for patients who have failed treatment with csDMARD and/or biologic DMARDs (bDMARDs). Further large, long-term observational studies are urgently needed to confirm these results.

Therapeutic Effects of Apremilast on Enthesitis and Dactylitis in Real Clinical Setting: An Italian Multicenter Study.

INTRODUCTION: Enthesitis and dactylitis are difficult-to-treat features of psoriatic arthritis (PsA), leading to disability and affecting quality of life. OBJECTIVE: The aim of this study is to evaluate enthesitis (using the Leed enthesitis index (LEI)) and dactylitis at 6 and 12 months in patients treated with apremilast. METHODS: Patients affected by PsA from fifteen Italian rheumatological referral centers were screened. The inclusion criteria were: (a) enthesitis or dactylitisphenotype; (b) treatment with apremilast 30 mg bid. Clinical and treatment history, including PsA disease activity, were recorded. Mann-Whitney and chi-squared tests were used to assess the differences between independent groups, and Wilcoxon matched pairs signed-rank test assessed the differences between dependent samples. A p-value of <0.05 was considered statistically significant. RESULTS: The Eph cohort consisted of 118 patients (median LEI 3); the Dph cohort included 96 patients with a median dactylitis of 1 (IQR 1-2). According to an intention to treat analysis, 25% and 34% of patients with enthesitis achieved remission (i.e., LEI = 0) in T1 and T2. The remission of dactylitis was 47% in T1 and 44% in T2. The per protocol analysis (patients observed for at least 12 months) showed that both dactylitis and LEI significantly improved in T1 (median LEI 1 (IQR 1-3)) and T2 (median LEI 0 (IQR 1-2)). CONCLUSION: Eph and Dph PsA patients treated with apremilast experienced a significant improvement in enthesitis and dactylitis activity. After 1 year, enthesitis and dactylitis remission was achieved in more than one-third of patients.

Advances in the Pathogenesis and Treatment of Systemic Lupus Erythematosus.

Systemic lupus erythematosus (SLE) is a genetically predisposed, female-predominant disease, characterized by multiple organ damage, that in its most severe forms can be life-threatening. The pathogenesis of SLE is complex and involves cells of both innate and adaptive immunity. The distinguishing feature of SLE is the production of autoantibodies, with the formation of immune complexes that precipitate at the vascular level, causing organ damage. Although progress in understanding the pathogenesis of SLE has been slower than in other rheumatic diseases, new knowledge has recently led to the development of effective targeted therapies, that hold out hope for personalized therapy. However, the new drugs available to date are still an adjunct to conventional therapy, which is known to be toxic in the short and long term. The purpose of this review is to summarize recent advances in understanding the pathogenesis of the disease and discuss the results obtained from the use of new targeted drugs, with a look at future therapies that may be used in the absence of the current standard of care or may even cure this serious systemic autoimmune disease.

New Insights into Pathogenesis and Treatment of ANCA-Associated Vasculitis: Autoantibodies and Beyond.

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis is a group of rare systemic diseases affecting small-caliber vessels. The damage caused by AAV mainly involves the lung and kidneys. AAV includes three different types: granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA). Although the different phenotypic forms of AAV share common features, recent studies have shown that there are significant differences in terms of pathogenetic mechanisms involving both the adaptive and innate immune systems. Advances in our understanding of pathogenesis have enabled the development of immuno-targeted therapies. This review illustrates the characteristics of the various forms of AAV and the new therapies available for this disease that can have lethal consequences if left untreated.

Predictors of DAPSA Response in Psoriatic Arthritis Patients Treated with Apremilast in a Retrospective Observational Multi-Centric Study.

BACKGROUND: To date, only a few real-world-setting studies evaluated apremilast effectiveness in psoriatic arthritis (PsA). The aims of this retrospective observational study are to report long-term Disease Activity Index for Psoriatic Arthritis (DAPSA) response of apremilast in PsA patients and to analyze the predictors of clinical response. METHODS: All PsA consecutive patients treated with apremilast in fifteen Italian rheumatological referral centers were enrolled. Anamnestic data, treatment history, and PsA disease activity (DAPSA) at baseline, 6 months, and 12 months were recorded. The Mann-Whitney test and chi-squared tests assessed the differences between independent groups, whereas the Wilcoxon matched pairs signed-rank test assessed the differences between dependent samples. Logistic regressions verified if there were factors associated with achievement of DAPSA low disease activity or remission at 6 and 12 months. RESULTS: DAPSA low disease activity or remission rates at 6 and 12 months were observed, respectively, in 42.7% (n = 125) and 54.9% (n = 161) patients. Baseline DAPSA was inversely associated with the odds of achieving low disease activity or remission at 6 months (odds ratio (OR) 0.841, 95% confidence interval (CI) 0.804-0.879; p < 0.01) and at 12 months (OR 0.911, 95% CI 0.883-0.939; p < 0.01). CONCLUSIONS: Almost half of the PsA patients receiving apremilast achieved DAPSA low disease activity or remission at 6 and 12 months. The only factor associated with achievement of low disease activity or remission at both 6 and 12 months was baseline DAPSA.

Janus Kinase Inhibitors: A New Tool for the Treatment of Axial Spondyloarthritis.

Axial spondyloarthritis (axSpA) is a chronic inflammatory disease involving the spine, peripheral joints, and entheses. This condition causes stiffness, pain, and significant limitation of movement. In recent years, several effective therapies have become available based on the use of biologics that selectively block cytokines involved in the pathogenesis of the disease, such as tumor necrosis factor-α (TNFα), interleukin (IL)-17, and IL-23. However, a significant number of patients show an inadequate response to treatment. Over 10 years ago, small synthetic molecules capable of blocking the activity of Janus kinases (JAK) were introduced in the therapy of rheumatoid arthritis. Subsequently, their indication extended to the treatment of other inflammatory rheumatic diseases. The purpose of this review is to discuss the efficacy and safety of these molecules in axSpA therapy.

Peripheral microcirculation alteration as cause of posterosuperior rotator cuff tear: the possible indirect contribution of nailfold capillaroscopy.

BACKGROUND: Most of the recent literature regarding rotator cuff tear etiology identifies in peripheral microcirculation disorders the probable main cause of tissue degeneration, and consequently of tendon rupture. Nailfold capillaroscopy is a practical and inexpensive diagnostic technique used to evaluate the health status of peripheral microcirculation, and recently, its use has found other indications in addition to that of diagnosing connective tissue diseases and Raynaud phenomenon. We verified the possible indirect contribution of nailfold capillaroscopy in the identification of peripheral microcirculation disturbances in a group of patients with rotator cuff tear and whether these possible alterations could be related to rotator cuff tear size. MATERIALS AND METHODS: A case-control study was performed. One hundred patients (56 male, 44 female; mean age ± standard deviation [SD]: 60.46 ± 5.46 years) with different-sized posterosuperior cuff tears and 100 healthy controls (38 male, 62 female; mean age ± SD: 60.40 ± 6.34 years) were submitted to capillaroscopic examination. The following parameters were examined: capillary morphology and density, avascular areas, visibility of the subpapillary venous plexus, enlarged and giant capillaries, ectasias and microaneurysms, neoangiogenesis, hemosiderin deposits, pericapillary edema, and capillary blood flow. Severe exclusion criteria were applied. Statistical analysis was performed. RESULTS: Visibility of subpapillary venous plexus (P < .001), pericapillary edema (P < .001), capillary blood flow (P < .001), ectasias and microaneurysms (P < .001), and neoangiogenesis (P = .04) were significantly associated with presence of a rotator cuff tear. CONCLUSIONS: Our results support the hypothesis that microcirculation disorder has a relevant role in the genesis of cuff degeneration and, consequently, of tendon rupture. However, these alterations do not seem to be related to rotator cuff tear size.

The Double Game Played by Th17 Cells in Infection: Host Defense and Immunopathology.

T-helper 17 (Th17) cells represent a subpopulation of CD4+ T lymphocytes that play an essential role in defense against pathogens. Th17 cells are distinguished from Th1 and Th2 cells by their ability to produce members of the interleukin-17 (IL-17) family, namely IL-17A and IL-17F. IL-17 in turn induces several target cells to synthesize and release cytokines, chemokines, and metalloproteinases, thereby amplifying the inflammatory cascade. Th17 cells reside predominantly in the lamina propria of the mucosa. Their main physiological function is to maintain the integrity of the mucosal barrier against the aggression of infectious agents. However, in an appropriate inflammatory microenvironment, Th17 cells can transform into immunopathogenic cells, giving rise to inflammatory and autoimmune diseases. This review aims to analyze the complex mechanisms through which the interaction between Th17 and pathogens can be on the one hand favorable to the host by protecting it from infectious agents, and on the other hand harmful, potentially generating autoimmune reactions and tissue damage.

Clinical Features of Infectious Uveitis in Children Referred to a Hospital-Based Eye Clinic in Italy.

Background and Objectives: To investigate the etiology, clinical features, ocular complications, and visual outcomes in children with infectious uveitis referred to a tertiary uveitis hospital-based service. Materials and Methods: Children with infectious uveitis were included in a retrospective cohort study. The data set was obtained after reviewing the medical records of pediatric patients with uveitis of different causes referred to our center during the period from 2009 to 2019. Clinical evaluations were performed at the time of diagnosis and the end of follow-up. Results: Uveitis of infectious origin was present in 57 (72 eyes) of 314 (18.1%) patients examined. The median age at presentation was 10.9 years (6.1-15.8), 52.6% of patients were female, and 47.4% were male. The main cause of infectious uveitis was viral (56.1% of cases), followed by Toxoplasma gondii infection (24.5%). The anatomical location of uveitis was posterior in 40.3%, anterior in 36.8%, panuveitis in 15.7%, and intermediate in 7% of cases. Ocular involvement was unilateral in 42 children (73.7%) and bilateral in 15 (26.3%) cases. The main causes of reduced visual acuity were cataract and maculopathy in 57.1% and 28.5% of cases, respectively. During the follow-up period, 75% of patients showed significant improvements in visual acuity. Conclusions: Specialist management in a tertiary referral eye care center facilitates early diagnosis and effective treatment of this serious cause of morbidity and vision loss in children.

The Role of Interleukin-17 in Juvenile Idiopathic Arthritis: From Pathogenesis to Treatment.

Background and Objectives: Interleukin-17 (IL-17) is a cytokine family consisting of six members and five specific receptors. IL-17A was the first member to be identified in 1993. Since then, several studies have elucidated that IL-17 has predominantly pro-inflammatory activity and that its production is involved in both the defense against pathogens and the genesis of autoimmune processes. Materials and Methods: In this review, we provide an overview of the role of interleukin-17 in the pathogenesis of juvenile idiopathic arthritis (JIA) and its relationship with IL-23, the so-called IL-23-IL-17 axis, by reporting updated findings from the scientific literature. Results: Strong evidence supports the role of interleukin-17A in the pathogenesis of JIA after the deregulated production of this interleukin by both T helper 17 (Th17) cells and cells of innate immunity. The blocking of IL-17A was found to improve the course of JIA, leading to the approval of the use of the human anti-IL17A monoclonal antibody secukinumab in the treatment of the JIA subtypes juvenile psoriatic arthritis (JPsA) and enthesitis-related arthritis (ERA). Conclusions: IL-17A plays a central role in the pathogenesis of JIA. Blocking its production with specific biologic drugs enables the effective treatment of this disabling childhood rheumatic disease.

Juxtapapillary Choroidal Neovascularization in a Young Woman with Tubulointerstitial Nephritis and Uveitis (TINU) Syndrome with Onset in Pediatric Age.

We describe the unusual case of a young woman with tubulointerstitial nephritis and uveitis (TINU) with bilateral diffuse uveitis and optic nerve inflammatory involvement since she was a child in the 1990s. Imaging diagnostic tools such as fluorescein angiography, indocyanine green angiography, optical coherence tomography (OCT), and OCT angiography revealed inactive juxtapapillary choroidal neovascularization (CNV) after 25 years of follow-up. After treatment, uveitis went into remission with BCVA 20/20 in both eyes and CNV lesions became inactive. Although anterior uveitis is more frequently reported in TINU, posterior uveitis with inflammatory involvement of the optic nerve should be accurately investigated to rule out juxtapapillary CNV, both at the time of active uveitis and during follow-up, since TINU may be complicated by CNV even at the later stages of the inflammatory process.

Tubulointerstitial Nephritis and Uveitis Syndrome (TINU): A Case Series in a Tertiary Care Uveitis Setting.

BACKGROUND: Tubulointerstitial nephritis and uveitis syndrome (TINU) is a rare disorder typically characterized by sudden-onset non-granulomatous anterior uveitis associated with tubulointerstitial nephritis (TIN). However, the prevalence and clinical features of TINU are still a matter of debate. To add information about TINU, we describe here the clinical features of a series of patients affected by TINU in a retrospective study. METHODS: A total of 9358 clinical records of both adult and pediatric patients up to 21 years of age, referred to the Uveitis Center of the Sapienza University of Rome, were examined. The medical records covered a period from 1990 to 2020. Various demographic and clinical features were analyzed in patients who met the criteria for TINU. RESULTS: Twenty-one patients with TINU were identified. TINU was classified as definite, possible, or probable by the currently recognized international criteria. The median age at diagnosis was 14 years (interquartile range 12-35). Females were predominant (15/21, 71.4%). In most cases (14/21, 66.6%), patients developed ocular disease concurrently with renal disease. The most frequent type of ocular involvement was bilateral anterior uveitis (9/21, 42.8%). In two cases, patients presented with bilateral intermediate uveitis; in three cases, they presented with bilateral or unilateral alternating posterior uveitis; and in four cases, they presented with bilateral panuveitis. In one case, the uveitis was anterior in the right eye (OD) and posterior in the left eye (OS), and two cases presented with bilateral asynchronous or unilateral alternating anterior uveitis. All patients received treatment with systemic corticosteroids and topical ocular therapy. At the end of the follow-up, a significant improvement in ocular signs and symptoms with a return to normal visual acuity was generally observed. In all patients, acute kidney injury (AKI) reverted completely and none progressed to chronic kidney disease (CKD). CONCLUSIONS: Patients with TINU may often present with atypical uveitis. We suggest that patients with sudden-onset uveitis, even if not bilateral anterior, should be referred to a nephologist for an assessment of the possible presence of renal disease.

Apremilast retention rate in clinical practice: observations from an Italian multi-center study.

OBJECTIVE: There are few real-world setting studies focused on apremilast effectiveness (i.e., retention rate) in psoriatic arthritis (PsA). The main aim of this retrospective observational study is the assessment of apremilast 3-year retention rate in real-world PsA patients. Moreover, the secondary objective is to report the reasons of apremilast discontinuation and the factors related to treatment persistence. METHODS: In fifteen Italian rheumatological referral centers, all PsA consecutive patients who received apremilast were enrolled. Anamnestic data, treatment history, and PsA disease activity (DAPSA) at baseline were recorded. The Kaplan-Meier curve and the Cox analysis computed the apremilast retention rate and treatment persistence-related risk factors. A p-value < 0.05 was considered statistically significant. RESULTS: The 356 enrolled patients (median age 60 [interquartile range IQR 52-67] yrs; male prevalence 42.7%) median observation period was 17 [IQR 7-34] months (7218 patients-months). The apremilast retention rate at 12, 24, and 36 months was, respectively, 85.6%, 73.6%, and 61.8%. The main discontinuation reasons were secondary inefficacy (34% of interruptions), gastro-intestinal intolerance (24%), and primary inefficacy (19%). Age and oligo-articular phenotype were related to treatment persistence (respectively hazard ratio 0.98 IQR 0.96-0.99; p = 0.048 and 0.54 IQR 0.31-0.95; p = 0.03). CONCLUSION: Almost three-fifths of PsA patients receiving apremilast were still in treatment after 3 years. This study confirmed its effectiveness and safety profile. Apremilast appears as a good treatment choice in all oligo-articular PsA patients and in those ones burdened by relevant comorbidities. Key Points • Apremilast retention rates in this real-life cohort and trials are comparable. • The oligo-articular phenotype is associated with long-lasting treatment (i.e., 3 years). • No different or more prevalent adverse events were observed.

Management Strategies of Juvenile Idiopathic Arthritis-Associated Chronic Anterior Uveitis: Current Perspectives.

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.