The steroid-sparing effect of JAK inhibitors across multiple patient populations.

Introduction: JAK-inhibitors (JAK-i) represent an effective treatment in Rheumatoid Arthritis (RA) and Psoriatic Arthritis (PsA). Oral glucocorticoids (OGC) are commonly used in combination with JAK-i to reach therapeutic target. We aimed to assess, in a real-life setting, the reduction of OGC dose during JAK-i treatment in active RA and PsA patients. Methods: We prospectively enrolled 103 patients (88 RA, 15 PsA) treated with JAK-i: 24% bio-naïve (b-naïve), 76% bDMARD-insufficient responders (bDMARD-IR) and 40% difficult to treat (D2T), defined as failure of ≥2 bDMARDs with different mechanism of action. Disease activity (DAS28 and DAPSA, VAS-pain, GH) and OGC dose was collected at baseline and after 3, 6 and 12 months (T3, T6, T12) of treatment. Results: In all the cohort and in b-naïve patients we reported a reduction of OGC dose at all time-points; bDMARD-IR patients were able to reduce OGC dose at T3 and T12; D2T ones only at T3. We reported an improvement of disease activity and withdrawal of OGC as early as three months of therapy, at all time-points, regardless of line of bDMARD treatment. Conclusion: Chronic OGC may cause detrimental bone, metabolic, cardiovascular side effects and infections; therefore JAK-i steroid-sparing effect may be beneficial for patients in long-term treatment.

A Rare but Fatal Behçet Variant: The Hughes-Stovin Syndrome-Successful Case Report and New Evidence from Literature Review.

Hughes-Stovin syndrome (HSS) is a rare potentially fatal vasculitis supposedly belonging to the spectrum of Behçet disease without ocular involvement. HSS tends to play by a temporal pattern, starting with thrombosis and followed by formation of pulmonary aneurysms. Since its mortality can reach 25% of cases, early recognition and appropriate therapy represent the major clinical challenges. We describe a rare case of HSS successfully treated via multidisciplinary management by an endovascular approach and immunosuppressive therapy.

Case Report: Crossing a rugged road in a primary immune regulatory disorder.

Over the last decades, Inborn Errors of Immunity (IEI) characterized by an immune dysregulatory picture, isolated or combined with infections, have been increasingly identified and referred as Primary Immune Regulatory Disorders (PIRD). PIRD diagnosis may be difficult due to heterogeneity of time onset, sequence of clinical manifestations and laboratory abnormalities. Moreover, the dissection of a PIRD vs. a secondary immunodeficiency (SID) might be a real challenge since the same indications for immunosuppressant treatments might represent per se a PIRD clinical expression. Here we report a female patient with a history of recurrent respiratory and urinary tract infections since early infancy and a diagnosis of Rheumatoid Arthritis in adulthood. After poor response to several biologicals she was treated with Rituximab and sent to immunology referral for a severe hypogammaglobulinemia. Clinical and immunological features matched a diagnosis of common variable immunodeficiency and when IgG replacement therapy and antibiotic prophylaxis were added a good infectious control was obtained. Next generation sequencing analysis has revealed a novel heterozygous VUS in the IKBKB gene (c.1465A > G; p.Ser489Gly). Functional analysis has shown a reduced capacity of B lymphocytes and CD4 positive T cells in inducing IκBα degradation, with negative impact on NF-kB pathway. Due to recurrent infections attributed to a common condition in childhood and to an exclusive autoimmunity-centered approach in adulthood, both diagnosis and suitable treatment strategies have suffered a significant delay. To reduce the diagnostic delay, pediatricians, general practitioners and specialists should be aware of IEI and the challenges to differentiate them from SID. Furthermore, genetic characterization and functional analysis may contribute to a personalized approach, in a perspective of targeted or semi-targeted therapy.

Evaluation of alexithymia in patients affected by rheumatoid arthritis and psoriatic arthritis: A cross-sectional study.

Rheumatoid arthritis (RA) and psoriatic arthritis (PsA) are chronic autoimmune diseases leading to joint damage, functional limitation, and disability and are typically associated with several comorbidities. Alexithymia is a personality trait characterized by a disregulation of emotion processing and regulation of emotions that involves a dissociation of emotional and physical responses to life events. A broad association between alexithymia and symptoms as depression, inflammation, and pain has been demonstrated. We aimed at evaluate an association among inflammatory arthritis, as RA and PsA, and alexithymia, and a possible link with clinical characteristics and disease activity.In this cross-sectional study, we enrolled, from January to December 2017, patients affected by RA or PsA referring to the outpatient's clinic of the Rheumatology Unit of the University of Rome Tor Vergata. The 20-item Toronto Alexithymia Scale (TAS-20) was used to assess alexithymia. Disease activity, function, quality of life, and clinimetric indexes were assessed.A total of 50 RA patients and 51 PsA patients were enrolled. The TAS-20 score showed 38.6% (39/101) patients had alexithymia, 26.7% (27/101) patients were in the borderline of alexithymia and 34.7% (35/101) patients did not have alexithymia. A statistical significant association was observed between alexithymia and inflammatory indices (ESR: P = .029, CRP: P = .043) and between alexithymia and clinimetric parameters (ptVAS, pVAS, GH, P < .0001 for all comparisons). A significant trend of association has been demonstrated between alexithymia and female gender and concomitant steroid therapy. No correlations among variables such as age, duration of disease, and comorbidities and alexithymia status were observed.This study suggests that alexithymia assessment should be a part of the comprehensive management of RA and PsA patients.

Factors Predicting 2 Years of Remission and Low Disease Activity in Rheumatoid Arthritis Patients Treated with TNF-inhibitors.

BACKGROUND: The goals of treatment for rheumatoid arthritis (RA) are remission and low disease activity (LDA). However, many patients do not reach or maintain these targets with regard to disease control. OBJECTIVES: To identify predictive factors of remission/LDA in a cohort of RA patients who started treatment with first line tumor necrosis factor-inhibitors (TNF-i). METHODS: We included 308 RA patients treated with first line TNF-i for 2 years to evaluate remission/LDA based on the 28-joint disease activity score (DAS28). Predictive factors considered for achievement of remission/LDA were: gender, age at the time of TNF-i treatment, early arthritis, baseline C-reactive protein (CRP) and erythrocyte sedimentation rate levels, RF/anti-citrullinated protein antibody positivity, good/moderate European League Against Rheumatism response at 6 months, co-morbidities, and concomitant disease modifying antirheumatic drugs (DMARDs). Intention to treat, receiver operating characteristic curve, and univariate and multivariate analyses by logistic regression were performed. RESULTS: Positive predictors of remission/LDA in both the univariate and the multivariate analyses were: male gender, age at the time of TNF-i treatment ≤ 54 years, negative baseline CRP, and concomitant DMARDs. The presence of any co-morbidity resulted to be a negative predictor of remission/LDA in both the univariate and the multivariate analyses. CONCLUSIONS: Demographic and clinical features were identified as reliable predictors of both the achievement and the maintenance of treatment targets in a cohort of RA patients treated for 2 years with first line TNF-i.

Systemic Sclerosis: Exploring the Potential Interplay Between Thyroid Disorders and Pregnancy Outcome in an Italian Cohort.

BACKGROUND: Evidence has shown that pregnancy failure (PF) in women with systemic sclerosis (SSc) consists mainly of preterm delivery (PD) and intrauterine growth restriction (IUGR). Thyroid dysfunction (TD) and Hashimoto's thyroiditis (HT) represent a common feature of SSc. Since TD has been associated with PF, its presence in SSc women may potentially affect pregnancy outcome. OBJECTIVES: To analyze the interplay between TD and PF in a cohort of SSc women. METHODS: SSc women (n=77) and age-matched controls from the general obstetric population (n=50) were included. Clinical/biochemical/instrumental data exploring TD and the visceral involvement were collected in the context of a clinical practice setting. Pregnancy outcome was assessed by registering the history of primary infertility, recurrent spontaneous abortion, PD (≤ 37 gestational week), IUGR, and intrauterine fetal death. RESULTS: A higher prevalence of PD/IUGR was recorded in the SSc cohort than the controls (P = 0.04). SSc women with PF showed a higher prevalence of diffuse SSc than women without PF (P = 0.03). Scl-70 positive SSc women had a higher prevalence of PF than women with anti-centromere positivity (P = 0.01). A higher prevalence of HT was recorded in SSc women with PF than in patients without (P = 0.04). CONCLUSIONS: Our findings support the evidence that women with SSc can have successful pregnancies despite a higher prevalence of PD/IUGR. Diffuse SSc and Scl-70 positivity may predispose SSc women to PF. Routine thyroid workup may be included in the multi-specialist monitoring of SSc women for the early detection of thyroid dysfunctions.

Effects of Abatacept on T-Lymphocyte Sub-populations and Immunoglobulins in Patients Affected by Rheumatoid Arthritis.

BACKGROUND: Abatacept acts as a co-stimulation modulator preventing activation of T cells. Although it is approved for the treatment of rheumatoid arthritis (RA), its effects on adaptive immune response have not been fully elucidated. OBJECTIVES: To observe, in a cohort study, based on a clinical practice setting, the variation of peripheral blood T cells, immunoglobulin levels, and autoantibodies in the serum of RA patients during abatacept therapy. METHODS: Our study comprised 48 RA patients treated with abatacept. All clinical data were collected at baseline and after 3 months of treatment. Clinical and laboratory tests included erythrocyte sedimentation rate, C-reactive protein, 28-joint disease activity score, RF, anti-citrullinated protein antibody, total immunoglobulins, immunoglobulin A (IgA), immunoglobulin G (IgG), immunoglobulin M (IgM), and lymphocyte sub-population. RESULTS: Total immunoglobulin serum levels significantly decreased after 3 months of treatment and correlated positively with disease activity both at baseline and after 3 months of abatacept treatment. A reduction of serum IgM, IgG, IgA and RF was also demonstrated. The absolute number and percentage of cytotoxic (CD8+) T cells significantly decreased after 3 months of abatacept treatment, in particular the percentage of cytotoxic (CD8+) T cells significantly decreased only in patients responding to the treatment. CONCLUSIONS: Our results highlight a different role of abatacept in the modulation of the adaptive immune response in RA by the reduction of polyclonal B-cell activation and cytotoxic T cells.

Polymorphisms in STAT4, PTPN2, PSORS1C1 and TRAF3IP2 Genes Are Associated with the Response to TNF Inhibitors in Patients with Rheumatoid Arthritis.

OBJECTIVE: Rheumatoid Arthritis (RA) is a progressive autoimmune disease characterized by chronic joint inflammation and structural damage. Remission or at least low disease activity (LDA) represent potentially desirable goals of RA treatment. Single nucleotide polymorphisms (SNPs) in several genes might be useful for prediction of response to therapy. We aimed at exploring 4 SNPs in candidate genes (STAT4, PTPN2, PSORS1C1 and TRAF3IP2) in order to investigate their potential role in the response to therapy with tumor necrosis factor inhibitors (TNF-i) in RA patients. METHODS: In 171 RA patients we investigated the following SNPs: rs7574865 (STAT4), rs2233945 (PSORS1C1), rs7234029 (PTPN2) and rs33980500 (TRAF3IP2). Remission, LDA, and EULAR response were registered at 6 months and 2 years after initiation of first line TNF-i [Adalimumab (ADA) and Etanercept (ETN)]. RESULTS: STAT4 variant allele was associated with the absence of a good/moderate EULAR response at 2 years of treatment in the whole RA group and in ETN treated patients. The PTPN2 SNP was associated with no good/moderate EULAR response at 6 months in ADA treated patients. Patients carrying PSORS1C1 variant allele did not reach LDA at 6 months in both the whole RA group and ETN treated patients. TRAF3IP2 variant allele was associated with the lack of LDA and remission achievement at 6 months in all RA cohort while an association with no EULAR response at 2 years of treatment occurred only in ETN treated patients. CONCLUSIONS: For the first time, we reported that SNPs in STAT4, PTPN2, PSORS1C1, and TRAF3IP2 are associated with response to TNF-i treatment in RA patients; however, these findings should be validated in a larger population.

Serological markers associated with disease activity in patients with rheumatoid arthritis treated with rituximab.

OBJECTIVE: To evaluate prospectively serological markers at baseline and during treatment in patients with rheumatoid arthritis (RA) initiating rituximab treatment, following failure of antitumour necrosis factor (TNF)-α therapy. METHODS: Patients with RA and healthy control subjects were recruited. Plasma complement (C)3, C4, rheumatoid factor (RF), anticitrullinated protein antibody (ACPA), immunoglobulin (Ig)M, A and G, disease activity scores (DAS) and therapeutic response were recorded at baseline and at 6, 12 and 18 months. RESULTS: Patients (n = 35) had significantly higher C3 and C4 levels than controls (n = 30). At 12 months after initiation of rituximab, C3 and C4 levels were significantly lower in patients who responded to treatment, compared with nonresponders. There were direct correlations between C3 levels and DAS at 12 months in the study population as a whole, and between IgM levels and DAS in responding patients after 6, 12 and 18 months' treatment. CONCLUSIONS: C3 and IgM levels may represent potentially useful serological markers of disease activity during rituximab treatment in patients with RA.

Use of anti-tumor necrosis factor alpha therapy in patients with concurrent rheumatoid arthritis and hepatitis B or hepatitis C: a retrospective analysis of 32 patients.

The safety of tumor necrosis factor-alpha (TNF-α) inhibitors in the setting of hepatitis B virus (HBV) and hepatitis C virus (HCV) infections is controversial. The use of anti-TNF-α in rheumatoid arthritis (RA) is associated with an increased risk of hepatitis re-activation. This paper reports experience of using etanercept and adalimumab in 32 patients with RA and previous HBV or HCV infection. No cases of HBV or HCV reactivation were seen. In just over a fifth of patients, increased transaminases levels were seen, which were associated with concomitant use of disease-modifying antirheumatic drugs, isoniazid prophylaxis, or alcohol abuse. In our experience, anti-TNF-α therapy appears to be safe in RA patients with previous HBV or HCV infection, but monitoring remains necessary in these patients.

Role of the complement system in rheumatoid arthritis and psoriatic arthritis: relationship with anti-TNF inhibitors.

The complement system is an essential component of innate immunity and also plays an important role in modulating adaptive immunity. It comprises more than 30 plasma and membrane-bound proteins and can be activated through three pathways: the classical, the alternative and the lectin pathways. Its activation contributes to the pathogenesis of several autoimmune and inflammatory conditions. The evidence of complement activation in synovial fluid of Rheumatoid Arthritis (RA) patients is abundant, while few data exist in Psoriatic Arthritis (PsA) patients. Levels of complement proteins are generally depressed in the synovial fluid of patients with RA, reflecting consumption of complement. On the other hand, elevated levels of several complement cleavage products have been observed in synovial fluid. Involvement of complement in the pathogenesis of RA was also confirmed in animal models of arthritis: mice deficient for complement proteins are protected against the development of collagen-induced arthritis and administration of the anti-C5 monoclonal antibody prevents the onset of this arthritis. In the last decade anti-tumor necrosis factor agents have shown to be effective for the treatment of both RA and PsA and some studies suggest that the interaction between TNFα and complement system may contribute to the pathogenesis of these diseases. Reduction of the complement activation could be one of the mechanism by which TNFα-inhibitors exert their effectiveness in inflammatory arthritides. Because of these findings, complement could be an attractive therapeutic target both in RA and in PsA.

Retinal functional changes measured by frequency-doubling technology in patients treated with hydroxychloroquine.

BACKGROUND: Antimalarial drugs such as chloroquine (CQ) and hydroxychloroquine (HCQ) are mainly used in the treatment of rheumatologic diseases, and their use may be associated with irreversible retinal toxicity. Previous studies indicate early paracentral visual field loss (Humphrey 10-2) in patients taking HCQ". These paracentral defects appear before changes in other clinical parameters as visual acuity and fundoscopy. The mechanism of CQ toxicity remains unclear. It was reported that toxic doses of CQ administered for as long as 4.5 years to Rhesus monkeys caused an initial dramatic effect on ganglion cells, followed later by photoreceptors and RPE degeneration. The purpose of this study is to explore early retinal functional changes measured by frequency-doubling technology (FDT) in patients treated with hydroxychloroquine (HCQ). METHODS: Forty-eight eyes of 48 subjects treated with hydroxychloroquine (HCQ), with no signs of retinal toxicity, and 36 eyes of 36 age and sex-matched healthy subjects were enrolled in this cross-sectional, prospective, observational, case control study. Functional testing included frequency-doubling Humphrey-matrix perimetry (FDP), white-on-white Humphrey visual field perimetry (HFA), using the 24-2 and 10-2 threshold programs, multifocal electroretinogram (mfERG, Veris 4.9) and low contrast sensitivity (CS) measurement. RESULTS: FDP mean deviation (MD) was found to be significantly reduced in HCQ-treated patients compared to controls both in the 24-2 (-1.38 ± 2.41 dB vs 0.21 ± 1.83 dB, p < 0.01) and in the 10-2 program (-0.97 ± 2.88 dB vs 0.15 ± 1.72 dB, p < 0.01). FDP pattern standard deviation (PSD) was found to be significantly worse in HCQ-treated patients compared to controls both in the 24-2 (2.70 ± 0.65 dB vs 2.41 ± 0.31 dB, p < 0.01 and in the 10-2 program (2.86 ± 0.48 dB vs 2.48 ± 0.39 dB, p < 0.01). HFA PSD and CS was also significantly reduced in HCQ patients, while response amplitude densities (RAD) were similar between patients and controls. A statistically significant difference in the ratio of the 5°-10° RAD and the 0°-2.5° RAD (0.31 ± 0.08 vs 0.36 ± 0.07 respectively, p < 0.05) was found between groups. CONCLUSION: Frequency doubling perimetry could be useful to detect early retinal impairment in patients treated with hydroxychloroquine.