The Evaluation of Effectiveness and Safety of Guselkumab in Patients with Psoriatic Arthritis in a Prospective Multicentre "Real-Life" Cohort Study.

INTRODUCTION: Guselkumab is an interleukin-23 (IL-23) inhibitor licensed for the treatment of psoriatic arthritis (PsA). This study aimed to evaluate the 6-month effectiveness of guselkumab in patients with PsA in a "real-life" multicentre patient cohort. We also estimated the drug retention rate (DRR) of gusulkumab, also assessing the impact of comorbidities and patient clinical characteristics, in a collective 18-month prospective follow-up. METHODS: Between December 2021 and September 2023, consecutive patients with PsA were evaluated if treated at least for 6 months with guselkumab in a prospective multicentre study to evaluate the effectiveness of the drug by means of disease activity index for psoriatic arthritis (DAPSA) and cumulative DRR. RESULTS: A total of 111 patients with PsA were evaluated and treated with guselkumab (age 56.8 ± 9.9, male sex 20.7%). These patients were mainly characterised by active and long-standing PsA with median disease duration of 6.0 (7.0) years (55.9% disease duration ≥ 5 years), 55.0% showed comorbidities, 78.4% of patients were previously treated with biologic disease-modifying anti-rheumatic drugs (bDMARDs), and 60.4% concomitantly with conventional synthetic DMARDs (csDMARDs). After 6 months, a significant reduction of DAPSA was observed (ß - 15.47, p = 0.001, 95% CI - 23.15 to - 9.79) with 39.6% of patients achieving a DAPSA ≤ 14. At the end of cumulative follow-up, 71.2% of patients were still treated with guselkumab whereas 24.3% discontinued the drug because of inefficacy. An 18-month DRR of guselkumab of 66.7% was estimated with a mean time of administration of 9.8 ± 4.1 months. The results of the DRR were stratified according to patient clinical characteristics. The DRR of guselkumab appeared to be not influenced by long disease duration, comorbidities, obesity, concomitant csDMARDs, and previous bDMARDs. CONCLUSION: The "real-life" 6-month effectiveness of guselkumab was shown in patients with PsA, mainly characterised by active long-standing disease, previously treated with bDMARDs, and with comorbidities. Furthermore, a good DRR of guselkumab was estimated in the cumulative 18 months of follow-up and appeared to be not influenced by long disease duration, comorbidities, obesity, and previous bDMARDs.

Intestinal microbiota changes induced by TNF-inhibitors in IBD-related spondyloarthritis.

BACKGROUND: The close relationship between joints and gut inflammation has long been known and several data suggest that dysbiosis could link spondyloarthritis (SpA) to inflammatory bowel diseases (IBD). The introduction of biological drugs, in particular tumour necrosis factor inhibitors (TNFi), revolutionised the management of both these diseases. While the impact of conventional drugs on gut microbiota is well known, poor data are available about TNFi. AIM: To investigate the impact of TNFi on gut microbiota. METHODS: We evaluated 20 patients affected by enteropathic arthritis, naïve for biological drugs, treated with TNFi at baseline and after 6 months of therapy. All patients followed a Mediterranean diet. Patients performed self-sampling of a faecal sample at baseline and after 6 months of therapy. NGS-based ITS and 16S rRNA gene sequencing was performed, followed by the taxonomic bioinformatics analysis. RESULTS: After 6 months of therapy, we detected a remarkable increase in Lachnospiraceae family (Δ +10.3, p=0.04) and Coprococcus genus (Δ +2.8, p=0.003). We also noted a decreasing trend in Proteobacteria (Δ -8.0, p=0.095) and Gammaproteobacteria (Δ -9, p=0.093) and an increasing trend in Clostridia (Δ +8.2, p=0.083). We did not find differences between TNFi responders (SpA improvement or IBD remission achieved) and non-responders in terms of alpha and beta diversity. CONCLUSIONS: Our findings are consistent with the hypothesis that TNFi therapy tends to restore the intestinal eubiosis.

Rheumatic manifestations in inflammatory bowel disease.

Rheumatic manifestations are the most frequent extra-intestinal manifestations (EIMs) in inflammatory bowel disease (IBD) patients, and they are responsible for a relevant reduction of quality of life. IBD is associated with a variety of musculoskeletal manifestations such as arthritis and non-inflammatory pain as well as with metabolic diseases, such as osteoporosis. Different imaging techniques (primarily ultrasound, magnetic resonance imaging and X-rays) can help the clinician to correctly identify the nature of manifestations and to treat the patient accordingly. Nowadays, in the setting of IBD-related arthritides, different drugs are available and can be effective on both articular and intestinal involvement. Therefore, a multi-disciplinary approach provides an early diagnosis and a better clinical outcome that can only be given from the recognition and consideration of the different EIMs. As for rheumatic manifestations, namely IBD-related arthritis, an early intervention allows to control disease activity and to prevent structural damage.

Increased eryptosis in patients with primary antiphospholipid syndrome (APS): a new actor in the pathogenesis of APS.

OBJECTIVES: Antiphospholipid syndrome (APS) is an autoimmune disease characterised by a hypercoagulable state and the presence of antiphospholipid antibodies (aPL). During the mechanism of red blood cells (RBCs) death, called eryptosis, RBCs can adhere to vascular wall participating in the development of a pro-thrombotic state. It is known that enhanced eryptosis contributes to several pathological conditions but the role of this process in APS has not been investigated yet. We analysed spontaneous eryptosis in a cohort of APS patients and aPL carriers (asymptomatic subjects with positive aPL tests). The effect on eryptosis of antibodies (Abs) purified from serum of APS patients and aPL carriers was also investigated. METHODS: In this study, 30 patients with primary APS (PAPS) and 17 aPL carriers were recruited. Twenty healthy donors (HD) and 13 patients affected by autoimmune haemolytic anaemia (AHIA) were also recruited. RBCs were incubated with PAPS and aPL carriers Abs, purified by ammonium sulfate precipitation. Levels of eryptosis were analysed by flow cytometry. RESULTS: In vitro Abs from APS patients induced eryptosis in RBCs isolated from HD after 4 h of culture. On the contrary, Abs from aPL carriers had no effect on the percentage of phosphatidylserine-exposing RBCs. Ex vivo, APS patients showed higher levels of spontaneous eryptosis compared to HD and aPL carriers. CONCLUSIONS: In this study, we demonstrated a potential new aspect of APS pathogenesis based on the ability of Abs isolated from APS patients, not identified in aPL carriers, to stimulate eryptosis suggesting a possible contribution of this process in the clinical manifestations of APS.

Homocysteinylated alpha 1 antitrypsin as an antigenic target of autoantibodies in seronegative rheumatoid arthritis patients.

Rheumatoid arthritis (RA) is a chronic autoimmune disease and rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPA) are the most frequently detected autoantibodies (autoAbs). To date, more than 20% of RA cases are still defined as seronegative forms (seronegative RA, SN-RA). The aim of this study was to identify new antigenic targets of autoAbs in RA patients, which can also be recognized in SN-RA. Using a proteomic approach, we tested sera from SN-RA patients by analyzing synovial fluid (SF) proteins from these patients. Sera from SN-RA patients revealed a strong reactive spot, corresponding to alpha 1 antitrypsin (A1AT). Reverse-phase nanoliquid chromatography and tandem mass spectrometry (Matrix Assisted Laser Desorption/Ionization-Time Of Flight, MALDI-TOF/TOF) confirmed the presence of A1AT in SF and showed that homocysteinylation was one of the post-translational modifications of A1AT. Homocysteinylated (Hcy)-A1AT immunoprecipitated from SN-RA patients' SFs and in vitro modified Hcy-A1AT were used as antigens by Enzyme-Linked ImmunoSorbent Assay (ELISA) to test the presence of specific autoAbs in sera from 111 SN-RA patients, 132 seropositive (SP)-RA patients, and from 95 patients with psoriatic arthritis, 40 patients with osteoarthritis, and 41 healthy subjects as control populations. We observed that a large portion of SN-RA patients (75.7%), and also most of SP-RA patients' sera (87.1%) displayed anti-Hcy-A1AT autoAbs (anti-HATA). Native A1AT was targeted at a lower rate by SP-RA patients autoAbs, while virtually no SN-RA patients' sera showed the presence of anti-native A1AT autoAbs. In conclusion, anti-HATA can be considered potential biomarkers for RA, also in the SN forms. The discovery of novel autoAbs targeting specific autoantigens can represent higher clinic significance for all RA patients' population.

TNFα expressed on the surface of microparticles modulates endothelial cell fate in rheumatoid arthritis.

BACKGROUND: Rheumatoid arthritis (RA) is associated with a high prevalence of atherosclerosis. Recently increased levels of microparticles (MPs) have been reported in patients with RA. MPs could represent a link between autoimmunity and endothelial dysfunction by expressing tumor necrosis factor alpha (TNFα), a key cytokine involved in the pathogenesis of RA, altering endothelial apoptosis and autophagy. The aim of this study was to investigate TNFα expression on MPs and its relationship with endothelial cell fate. METHODS: MPs were purified from peripheral blood from 20 healthy controls (HC) and from 20 patients with RA, before (time (T)0) and after (T4) 4-month treatment with etanercept (ETA). Surface expression of TNFα was performed by flow cytometry analysis. EA.hy926 cells, an immortalized endothelial cell line, were treated with RA-MPs purified at T0 and at T4 and also, with RA-MPs in vitro treated with ETA. Apoptosis and autophagy were then evaluated. RESULTS: RA-MPs purified at T0 expressed TNFα on their surface and this expression significantly decreased at T4. Moreover, at T0 RA-MPs, significantly increased both apoptosis and autophagy levels on endothelial cells, in a dose-dependent manner. RA-MPs did not significantly change these parameters after 4 months of in vivo treatment with ETA. CONCLUSIONS: Our data demonstrate that MPs isolated from patients with RA exert a pathological effect on endothelial cells by TNFα expressed on their surface. In vivo and in vitro treatment with ETA modulates this effect, suggesting anti-TNF therapy protects against endothelial damage in patients with RA.

CD4 T lymphocyte autophagy is upregulated in the salivary glands of primary Sjögren's syndrome patients and correlates with focus score and disease activity.

BACKGROUND: Primary Sjögren's syndrome (pSS) is a common chronic autoimmune disease characterized by lymphocytic infiltration of exocrine glands and peripheral lymphocyte perturbation. In the current study, we aimed to investigate the possible pathogenic implication of autophagy in T lymphocytes in patients with pSS. METHODS: Thirty consecutive pSS patients were recruited together with 20 patients affected by sicca syndrome and/or chronic sialoadenitis and 30 healthy controls. Disease activity and damage were evaluated according to SS disease activity index, EULAR SS disease activity index, and SS disease damage index. T lymphocytes were analyzed for the expression of autophagy-specific markers by biochemical, molecular, and histological assays in peripheral blood and labial gland biopsies. Serum interleukin (IL)-23 and IL-21 levels were quantified by enzyme-linked immunosorbent assay. RESULTS: Our study provides evidence for the first time that autophagy is upregulated in CD4+ T lymphocyte salivary glands from pSS patients. Furthermore, a statistically significant correlation was detected between lymphocyte autophagy levels, disease activity, and damage indexes. We also found a positive correlation between autophagy enhancement and the increased salivary gland expression of IL-21 and IL-23, providing a further link between innate and adaptive immune responses in pSS. CONCLUSIONS: These findings suggest that CD4+ T lymphocyte autophagy could play a key role in pSS pathogenesis. Additionally, our data highlight the potential exploitation of T cell autophagy as a biomarker of disease activity and provide new ground to verify the therapeutic implications of autophagy as an innovative drug target in pSS.

Musculoskeletal ultrasonography in gout.

Gout is a frequent inflammatory disease induced by the deposition of monosodium urate crystals in joints and extra-articular tissues. The natural history of the disease includes four different phases: asymptomatic hyperuricemia, acute attacks, intercritical phase, and chronic tophaceous gout. Imaging techniques have several applications in the diagnosis, clinical monitoring and management of the disease but particularly, musculoskeletal ultrasound is able to detect a wide set of abnormalities in gout. This review reports the most relevant findings detectable by ultrasound and the current available data in the literature regarding the role of musculoskeletal ultrasound in gout..

Musculoskeletal ultrasound in the evaluation of Polymyalgia Rheumatica.

Polymyalgia rheumatica (PMR) is a relatively frequent disease affecting individuals older than 50 years and is characterized by inflammatory involvement of the shoulder and hip girdles and the neck. Clinical manifestations are represented by pain and morning stiffness in this regions. An extensive and comprehensive assessment of the inflammatory status is crucial in PMR patients, including imaging evaluation. This narrative review reports the current available data in the literature about the role of musculoskeletal ultrasound in PMR.

Power Doppler ultrasound monitoring of response to anti-tumour necrosis factor alpha treatment in patients with rheumatoid arthritis.

OBJECTIVES: To monitor by power Doppler US (PDUS) the short-term response to anti-TNFα therapy in six target joints of RA patients; to correlate PDUS findings with clinical assessments and laboratory indices of disease activity. METHODS: Consecutive RA patients starting anti-TNFα therapy were included and studied at baseline and 3 months later. Clinical (number of tender joints; number of swollen joints; Visual Analogue Scale; DAS28) and laboratory (ESR and CRP) assessments were performed. All patients were evaluated by PDUS at six target joints (II MCP, wrist, knee bilaterally). The components of synovitis (synovial hypertrophy, joint effusion, and power Doppler) were analysed and graded (0-3 semi-quantitative score). Moreover, by summing the PDUS findings, three different scores were calculated: a single inflammatory lesion score (0-18, for synovial hypertrophy, effusion, power Doppler), a joint score (0-18; at II MCP, wrist and knee joints) and a global score (0-54; sum of all abnormalities). RESULTS: Sixty-eight RA patients were studied. A significant decrease in the joint score in all articular sites (MCP, P = 0.003; knee, P = 0.002; wrist, P = 0.0001) as well as in the scores of the single components of synovitis (P = 0.0001-0.002) and in the global 6-joint score (P = 0.0001) was found. All clinical and laboratory parameters were significantly decreased at follow-up (P = 0.0001-0.001). A moderate significant positive correlation was observed between the global PDUS score and DAS28 (r = 0.38; P = 0.001). CONCLUSION: PDUS is a sensitive-to-change imaging modality for monitoring the short-term response to anti-TNFα treatment in RA patients. The assessment of a limited number of joints makes the evaluation feasible in rheumatology practice as a complementary tool to clinical assessment.

The use of musculoskeletal ultrasound in a rheumatology outpatient clinic.

INTRODUCTION: Musculoskeletal ultrasound (US) represents a valid, reliable and sensitive-to-change tool for the evaluation of patients suffering from rheumatic conditions. This method demonstrates a wide applicability and availability, finding place in the clinical practice in rheumatology outpatient clinic. AIM: To perform an epidemiological evaluation related to the use of US in a university rheumatology outpatient clinic. MATERIAL AND METHODS: During a 3-month period, data concerning consecutive patients attending to the US Unit of Department of Rheumatology, Sapienza University of Rome were registered. We collected the demographic data, the diagnosis, the reason for the US examination, the examined joints, as well as the requesting physicians' specialty. RESULTS: In the period October-December 2013, 572 patients (M/F 137/435; mean age+/-SD 55.2+/-15.8 years) were registered. The US examination was more frequently requested for the following diseases: rheumatoid arthritis (29.5%), osteoarthritis (10.6%), spondyloarthritis (9.1%), and connective tissue diseases (8.9%). In 239 of cases (41.8%), the US evaluation was requested for other indications. The US evaluation was requested slightly more frequently for monitoring (55.7%) compared to diagnosis (44.3%). The requesting physician was a rheumatologist in the majority of the cases (80.6%). The most frequent requested were the hand joints (28.9%) and wrists (23.3%). CONCLUSIONS: US examinations are most frequently used in the evaluation of patients with rheumatoid arthritis and mainly to monitor the disease. The exam is requested mostly by rheumatologists. The hand joints and wrists were the most frequently evaluated.