The Conundrum of Psoriatic Arthritis: a Pathogenetic and Clinical Pattern at the Midpoint of Autoinflammation and Autoimmunity.

Psoriatic arthritis (PsA) is a chronic inflammatory condition characterized by psoriasis, synovitis, enthesitis, spondylitis, and the possible association with other extra-articular manifestations and comorbidities. It is a multifaceted and systemic disorder sustained by complex pathogenesis, combining aspects of autoinflammation and autoimmunity. Features of PsA autoinflammation include the role of biomechanical stress in the onset and/or exacerbation of the disease; the evidence of involvement of the innate immune response mediators in the skin, peripheral blood and synovial tissue; an equal gender distribution; the clinical course which may encounter periods of prolonged remission and overlapping features with autoinflammatory syndromes. Conversely, the role of autoimmunity is evoked by the association with class I major histocompatibility complex alleles, the polyarticular pattern of the disease which sometimes resembles rheumatoid arthritis and the presence of serum autoantibodies. Genetics also provide important insights into the pathogenesis of PsA, particularly related to class I HLA being associated with psoriasis and PsA. In this review, we provide a comprehensive review of the pathogenesis, genetics and clinical features of PsA that endorse the mixed nature of a disorder at the crossroads of autoinflammation and autoimmunity.

Effectiveness and safety of secukinumab in axial spondyloarthritis: a 24-month prospective, multicenter real-life study.

Objectives: To evaluate, in a multicentric Italian cohort of axial spondyloarthritis (axSpA) patients on Secukinumab (SEC) followed for 24 months: (1) the long-term effectiveness and safety of SEC; (2) the drug retention rate and low disease activity (LDA) measured as Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) < 4/Ankylosing Spondylitis Disease Activity Score (ASDAS) < 2.1 and very low disease activity (VLDA) measured as BASDAI < 2/ASDAS < 1.3; (3) any differences in outcomes according to line of biological treatment (naïve/non-naïve), gender (male/female), subtype of axSpA [radiographic axSpA (r-axSpA)/non-radiographic axSpA (nr-axSpA)]. Methods: Consecutive axSpA patients treated with SEC were evaluated prospectively. Disease characteristics, previous/ongoing treatments, comorbidities, and follow-up duration were collected. Disease activity/functional/clinimetric scores and biochemical-values were recorded at baseline (T0), 6 (T6), 12 (T12), and 24 (T24) months. Effectiveness was evaluated over-time with descriptive statistics; multivariate Cox and logistic regression models were used to evaluate predictors of drug discontinuation and LDA at T6. Infections and adverse events were recorded. Results: A total 249 patients (47.8% male; median age 51) were enrolled; 40.9% had HLA-B27; 53.8% had r-axSpA, and 46.2% nr-axSpA. SEC was prescribed in 28.9% naïve and in 71.1% non-naïve patients. SEC effectiveness was shown as an improvement in several outcomes, such as ASDAS [T0 = 3.5 (2.9-4.4) versus T24 = 1.9 (1.2-2.4); p = 0.02] and BASDAI [T0 = 6.5 (5.0-7.5) versus T24 = 2.8 (1.8-4.0); p = 0.03]. At T24, naïve patients showed better physical functioning and lower disease activity than non-naïve. After 24 months of treatment, 90.7% of naïve and 75.3% of non-naïve patients achieved LDA (BASDAI < 4). Treatment was discontinued in 24.5% patients, mainly due to primary/secondary loss of effectiveness, and in 6.8% due to adverse events. Retention rate at T24 was 75% in the whole population, with some difference depending on gender (p = 0.002). Conclusion: In a real-life clinical setting, SEC proved to be safe and effective in axSpA, mainly in naïve-patients, with a notable drug retention rate. No differences were observed between r-axSpA and nr-axSpA.

Paradoxical psoriatic arthritis in a patient with psoriasis treated with guselkumab.

Paradoxical psoriatic arthritis (PPsA) may be associated with guselkumab treatment. We describe a patient in whom PPsA required a change from guselkumab to ixekizumab. The pathophysiology of this paradoxical reaction is most likely a cytokine imbalance.

Corticosteroid injection treatment for dactylitis in psoriatic arthritis.

Dactylitis - a hallmark clinical feature of psoriatic arthritis (PsA) - that occurs in 30-50% of PsA patients, is a marker of disease severity for PsA progression, an independent predictor of cardiovascular morbidity and impairs the motor functions of PsA patients. There is a paucity of evidence for the treatment due to the absence of randomized controlled trials assessing dactylitis as a primary endpoint and current practice arises from the analysis of dactylitis as a secondary outcome. Corticosteroid (CS) injections for dactylitis in PsA patients are a therapeutic treatment option for patients with isolated dactylitis or for patients with flares in tendon sheaths, despite stable and effective systemic treatment. The aim of this narrative review is to briefly illustrate the clinical aspects of dactylitis in PsA, the imaging and clinimetric tools used to diagnose and monitor dactylitis, the current treatment strategies and principally to provide a comprehensive picture of the clinical efficacy and safety with ultrasound-guide and blind techniques of CS injections for dactylitis in PsA patients.

Anti-IL-17 Agents in the Treatment of Axial Spondyloarthritis.

Axial spondyloarthritis (axSpA) describes a group of chronic inflammatory rheumatic diseases primarily involving the axial skeleton. IL-17 is involved in the pathogenesis of numerous inflammatory diseases, including inflammatory arthritis. Until a few years ago, the only biological agents licensed for the treatment of axSpA and nr-axSpA were TNF inhibitors. However, as some patients did not respond to TNF inhibition or experienced secondary failure, the introduction of the first two IL-17 inhibitors (secukinumab [SEC] and ixekizumab [IXE]) has extended the treatment options, and there are now three others (bimekizumab, brodalumab and netakimab) in various stages of clinical development. The last ten years have seen the development of a number of therapeutic recommendations that aimed at improving the management of axSpA patients. The aim of this narrative review of the published literature concerning the role of IL-17 in the pathogenesis of SpA, and the role of IL-17 inhibitors in the treatment of axSpA, is to provide a comprehensive picture of the clinical efficacy and safety of the drugs themselves, and the treatment strategies recommended in the international guidelines.

Targeting human plasmacytoid dendritic cells through BDCA2 prevents skin inflammation and fibrosis in a novel xenotransplant mouse model of scleroderma.

OBJECTIVES: Plasmacytoid dendritic cells (pDC) have been implicated in the pathogenesis of autoimmune diseases, such as scleroderma (SSc). However, this has been derived from indirect evidence using ex vivo human samples or mouse pDC in vivo. We have developed human-specific pDC models to directly identify their role in inflammation and fibrosis, as well as attenuation of pDC function with BDCA2-targeting to determine its therapeutic application. METHODS: RNAseq of human pDC with TLR9 agonist ODN2216 and humanised monoclonal BDCA2 antibody, CBS004. Organotypic skin rafts consisting of fibroblasts and keratinocytes were stimulated with supernatant from TLR9-stimulated pDC and with CBS004. Human pDC were xenotransplanted into Nonobese diabetic/severe combined immunodeficiency (NOD SCID) mice treated with Aldara (inflammatory model), or bleomycin (fibrotic model) with CBS004 or human IgG control. Skin punch biopsies were used to assess gene and protein expression. RESULTS: RNAseq shows TLR9-induced activation of human pDC goes beyond type I interferon (IFN) secretion, which is functionally inactivated by BDCA2-targeting. Consistent with these findings, we show that BDCA2-targeting of pDC can completely suppress in vitro skin IFN-induced response. Most importantly, xenotransplantation of human pDC significantly increased in vivo skin IFN-induced response to TLR agonist and strongly enhanced fibrotic and immune response to bleomycin compared with controls. In these contexts, BDCA2-targeting suppressed human pDC-specific pathological responses. CONCLUSIONS: Our data indicate that human pDC play a key role in inflammation and immune-driven skin fibrosis, which can be effectively blocked by BDCA2-targeting, providing direct evidence supporting the development of attenuation of pDC function as a therapeutic application for SSc.

Effectiveness and safety of secukinumab in 608 patients with psoriatic arthritis in real life: a 24-month prospective, multicentre study.

OBJECTIVES: To evaluate in a multicentric Italian cohort of patients with psoriatic arthritis (PsA) on secukinumab followed for 24 months: (1) the long-term effectiveness and safety of secukinumab, (2) the drug retention rate and minimal disease activity (MDA), (3) differences in the outcomes according to the biological treatment line: biologic-naïve patients (group A) versus multifailure (group B) patients. METHODS: Consecutive patients with PsA receiving secukinumab were evaluated prospectively. Disease characteristics, previous/ongoing treatments, comorbidities and follow-up duration were collected. Disease activity/functional/clinimetric scores and biochemical values were recorded at baseline (T0), 6(T6), 12(T12) and 24(T24) months. Effectiveness was evaluated overtime with descriptive statistics; multivariate Cox and logistic regression models were used to evaluate predictors of drug-discontinuation and MDA at T6. Infections and adverse events were recorded. RESULTS: 608 patients (41.28% men; mean (SD) age 52.78 (11.33)) were enrolled; secukinumab was prescribed as first-line biological treatment in 227 (37.34%) patients, as second (or more)-line biological treatment in 381 (62.66%). Effectiveness of secukinumab was shown with an improvement in several outcomes, such as Ankylosing Spondylitis Disease Activity Score (T0=3.26 (0.88) vs T24=1.60 (0.69) ;p=0.02) and Disease Activity Index for Psoriatic Arthritis (T0=25.29 (11.14) vs T24=7.69 (4.51); p<0.01). At T24, group A showed lower Psoriasis Area Severity Index (p=0.04), erythrocyte sedimentation rate and C reactive protein (p=0.03 ;p=0.05) and joint count (p=0.03) compared with group B. At T24, MDA was achieved in 75.71% of group A and 70.37% of group B. Treatment was discontinued in 123 (20.23%) patients, mainly due to primary/secondary loss of effectiveness, and in 22 due to adverse events. Retention rate at T24 was 71% in the whole population, with some difference depending on secukinumab dosage (p=0.004) and gender (p=0.05). CONCLUSIONS: In a real-life clinical setting, secukimumab proved safe and effective in all PsA domains, with notable drug retention rate.

UCLA Scleroderma Clinical Trials Consortium Gastrointestinal Tract (GIT) 2.0 Reflux Scale Correlates With Impaired Esophageal Scintigraphy Findings in Systemic Sclerosis.

OBJECTIVE: The University of California Los Angeles Scleroderma Clinical Trials Consortium Gastrointestinal Tract 2.0 (GIT 2.0) instrument is a self-report tool measuring gastrointestinal (GI) quality of life in patients with systemic sclerosis (SSc). Scarce data are available on the correlation between patient-reported GI symptoms and motility dysfunction as assessed by esophageal transit scintigraphy (ETS). METHODS: We evaluated the GIT 2.0 reflux scale in patients with SSc admitted to our clinic and undergoing ETS, and correlated their findings. RESULTS: Thirty-one patients with SSc undergoing ETS were included. Twenty-seven were female, and 9 had diffuse cutaneous SSc. Twenty-six of 31 (84%) patients had a delayed transit and an abnormal esophageal emptying activity (EA); they also had a higher GIT 2.0 reflux score (P = 0.04). Mean EA percentage was higher in patients with none to mild GIT 2.0 reflux score (81.1 [SD 11.5]) than in those with moderate (55.7 [SD 17.8], P = 0.003) and severe to very severe scores (55.8 [SD 19.7], P = 0.002). The percentage of esophageal EA negatively correlated with the GIT 2.0 reflux score (r = -0.68, P < 0.0001), but it did not correlate with the other GIT 2.0 scales and the total GIT 2.0 score. CONCLUSION: SSc patients with impaired ETS findings have a higher GIT 2.0 reflux score. The GIT 2.0 is a complementary tool for objective measurement of esophageal involvement that can be easily administered in day-to-day clinical assessment.

Golimumab effectiveness in biologic inadequate responding patients with rheumatoid arthritis, psoriatic arthritis and spondyloarthritis in real-life from the Italian registry GISEA.

OBJECTIVE: To evaluate the clinical effectiveness of golimumab in biologic inadequate responder (IR) patients with Rheumatoid arthritis (RA), Spondyloarthritis (SpA), and Psoriatic arthritis (PsA). METHODS: We analyzed 1424 patients on golimumab from the GISEA registry. Drug survival was estimated by Kaplan-Meier analysis in biologic-naïve, 1-biologic IR, ≥2-biologics IR patients. Hazard ratios (HRs) of discontinuing golimumab at 2 years were assessed by multivariate Cox regression. Patients achieving CDAI based low disease activity (LDA) or BASDAI<4 were calculated at 6 and 12 months. RESULTS: In RA (n.370), the 2-years survival on golimumab was 61.4% in 1-biologic IR, 51.9% in≥2-biologics IR, and 73.1% in biologic-naive patients (P=0.002 vs≥2-biologics IR). In SpA (n.502), the survival was similar among 1-biologic IR (80%), ≥2-biologics IR (76.5%), and biologic-naive (74.6%) patients (P>0.05). In PsA (n.552) the survival was 72% in 1-biologic IR, 72.5% in≥2-biologics IR, and 71.8% in naïve-biologic (P>0.05). Predictors of golimumab discontinuation were monotherapy (HR 1.65) for RA, female gender for SpA (HR 2.48) and PsA (HR 1.57). In RA, patients on CDAI-LDA were lower in 1-biologic IR (40%) or≥2 biologics IR (40%) than in biologic-naïve (60%) group at 6 months (P=0.02), but no difference was observed at 12 months. In PsA and SpA, the percentage of patients on CDAI-LDA or BASDAI<4 at 6 months was almost identical across the subgroups. CONCLUSIONS: Golimumab had similar effectiveness in biologic-failure and biologic-naïve SpA and PsA, but seems to be less effective in multi-failure RA patients, especially as monotherapy. The best outcomes were seen in male patients.

Safety of treatment options for spondyloarthritis: a narrative review.

INTRODUCTION: Spondyloarthritis (SpA) are chronic inflammatory diseases with overlapping pathogenic mechanisms and clinical features. Treatment armamentarium against SpA includes non-steroidal anti-inflammatory drugs, glucocorticoids, conventional disease-modifying antirheumatic drugs (DMARDs, including sulfasalazine, methotrexate, leflunomide, cyclosporine), targeted synthetic DMARDs (apremilast) and biological DMARDs (TNF inhibitors, anti-IL 12/23 and anti-IL-17 agents). AREAS COVERED: A narrative review of published literature on safety profile of available SpA treatment options was performed. Readers will be provided with a comprehensive overview on frequent and rare adverse events associated with each drug listed in current SpA treatment recommendations. EXPERT OPINION: The overall safety profile of such molecules is good and serious adverse events are rare but need to be promptly recognized and treated. However, the monitoring of adverse events is a major challenge for clinicians because it is not adequately addressed by current treatment recommendations. A tailored treatment is crucial and rheumatologists must accurately select patients in order to identify those more susceptible to develop adverse events.