Relapses and serious adverse events during rituximab maintenance therapy in ANCA-associated vasculitis: a multicentre retrospective study.

OBJECTIVES: There are limited real-life data regarding the efficacy and safety of rituximab (RTX) as a remission-maintenance agent in microscopic-polyangiitis (ΜPA) and granulomatosis-with-polyangiitis (GPA). We aimed to estimate the incidence and risk factors for relapses, as well serious-adverse-events (SAEs) in MPA/GPA patients during RTX-maintenance. METHODS: Retrospective cohort of newly-diagnosed/relapsing GPA/MPA patients who received RTX-maintenance (≥1 RTX-cycle, ≥6 months follow-up) following complete-remission (Birmingham-Vasculitis-Activity-Score-version-3 = 0 plus prednisolone ≤7.5 mg/day) with induction regimens. SAEs included serious-infections, COVID-19-associated hospitalizations, deaths, cardiovascular-events, malignancies and hypogammaglobulinemia. Incidence-rates (IR) and relapse-free survival through Kaplan-Meier plots were estimated. Cox-regression was conducted to investigate factors associated with the time-to-relapse. RESULTS: 101 patients were included; 48% females, 69% GPA, 53% newly diagnosed, median age: 63 years. During follow-up (294.5 patient-years, median: 3 RTX-cycles), 30 relapses (57% major) occurred among 24 patients (24%, IR 10.2/100 patient-years). Kidney involvement (adjusted-Hazard-Ratio/aHR: 0.20; 95% CI: 0.06-0.74, p= 0.016), prior induction with RTX plus cyclophosphamide (vs RTX monotherapy: aHR = 0.02; 95% CI: 0.001-0.43, p= 0.012) and shorter time-interval until complete-remission (aHR = 1.07; 95% CI: 1.01-1.14, p= 0.023) were associated with decreased relapse-risk. We recorded 17 serious-infections (IR 5.8/100 patient-years), 11 COVID-19-associated hospitalizations (IR 3.7/100 patient-years), 4 malignancies (IR 1.4/100 patient-years), 6 cardiovascular-events (IR 2/100 patient-years) and 10 deaths (IR 3.4/100 patient-years). CONCLUSION: In this real-world study, relapses during RTX-maintenance occurred in approximately in 1 out of 4 patients. Kidney involvement, induction with RTX plus cyclophosphamide and earlier achievement of complete-remission were associated with lower relapse-risk. Serious-infections rate was consistent with previous reports, whereas an increased rate of COVID19-associated hospitalizations was observed.

Identification and characteristics of patients with potential difficult-to-treat Psoriatic Arthritis: exploratory analyses of the Greek PsA registry.

OBJECTIVE: To present the characteristics of patients with potential difficult-to-treat (D2T) psoriatic arthritis (PsA). METHODS: We used data from the Greek multicentre registry of PsA patients. D2T-PsA was defined as follows: patients with at least 6-months disease duration, who have failed to at least 1 csDMARD and at least 2 bDMARDs/tsDMARDs with a different mechanism of action and have either at least moderate disease activity (MODA) defined as DAPSA > 14, and/or are not at minimal disease activity (MDA). Demographic and clinical characteristics were compared between D2T and non-D2T PsA patients. In two sensitivity analyses, patients classified as D2T solely according to the MODA or MDA criterion were examined separately. RESULTS: Among 467 patients included, 77 (16.5%) were considered D2T and 390 non-D2T PsA. Compared with non-D2T, patients with D2T PsA presented more commonly with extensive psoriasis (p< 0.0001) and were more likely to have higher BMI (p= 0.023) and a history of inflammatory bowel disease (p= 0.026). In the MODA and MDA sensitivity analyses, 7.5% and 12.5% of patients were considered D2T, respectively. In both sensitivity analyses, extensive psoriasis was again identified as an independent variable for D2T PsA (p= 0.001 and p= 0.008, respectively). Moreover, female gender (p= 0.034) in the MODA analysis and axial disease (p= 0.040) in the MDA analysis were independent variables for D2T PsA. CONCLUSION: Despite the availability of therapies, D2T PsA is common in real-life cohorts of patients with PsA and extensive psoriasis. High BMI, female gender, axial-disease, and history of IBD were also associated with D2T PsA.

Health-related quality of life in patients with ANCA vasculitides compared to rheumatoid arthritis: a cross-sectional comparative study.

OBJECTIVES: There are limited data regarding health-related quality of life (HRQoL) in patients with ANCA-associated vasculitides (AAVs). We aimed to evaluate the HRQoL in patients with AAVs and compare it to another chronic inflammatory disease like RA and to healthy controls (HC). METHODS: This was a multicentre, cross-sectional study of patients with AAVs and RA recruited from three tertiary rheumatology clinics. HRQoL was assessed with the Short Form 36 Health Survey, which included the physical and mental component summary scores (PCS and MCS). Data from 1007 HC served as historical controls. RESULTS: Sixty-six patients with AAVs and 71 with RA were included. Both AAV and RA patients had significantly lower PCS and MCS scores compared with HC (P < 0.05). HRQoL in AAV patients was worse in patients with microscopic polyangiitis compared with granulomatosis with polyangiitis (physical components) and those with high (VDI ≥ 3) vs low (VDI < 3) damage scores while it did not differ between those with active (BVASv3 ≥ 1) vs. inactive (BVASv3 < 1) disease. In contrast, in RA patients, HRQoL correlated both with disease activity (assessed by the DAS28-ESR) and functional impairment/damage (assessed by the HAQ). Although overall patients with RA had similar HRQoL compared with those with AAVs, those with active RA had worse HRQoL compared with those with active AAV. CONCLUSIONS: In patients with AAVs, HRQoL correlated more with organ damage and less with disease activity whereas in RA patients, it correlated with both. These data emphasize the need for AAV therapies aiming at preventing organ damage and thus improving HRQoL.

Pulmonary-Renal Syndrome During COVID-19 Pandemic Revealed a Rare Case of Anti-GBM Disease.

Anti-GBM disease is a rare, life-threatening small vessel vasculitis caused by circulating anti-GBM antibodies resulting to rapidly progressive glomerulonephritis and/or pulmonary haemorrhage. The gold standard for the diagnosis is the renal biopsy with the pathognomonic finding of linear deposition of IgG along the glomerular capillaries. Early diagnosis and intervention are key determinants of the response to therapy and long-term prognosis of these patients. However, during COVID-19 pandemic recognizing a pulmonary-renal syndrome caused by autoimmune diseases has become challenging. Herein, we aimed to describe a rare case of anti-GBM disease with pulmonary haemorrhage and rapidly progressive glomerulonephritis in a young man in a tertiary referral hospital in Greece, while COVID-19 pandemic was at its peak. Although the patient presented high level of creatinine and crescents, the early diagnosis and start of treatment resulted to favourable renal prognosis.

Ixekizumab therapy following secukinumab inadequate response in psoriatic arthritis: a case series focusing on axial disease.

There are limited data regarding cycling between interleukin-17 (IL-17) inhibitors in psoriatic arthritis (PsA). We aimed to report the efficacy of an IL-17 inhibitor (ixekizumab-IXE) after inadequate response (IR) of another one (secukinumab-SEC) in patients with PsA. Case series of PsA patients who received IXE after SEC-IR in four rheumatology centers between 1/9/2021 and 1/9/2022 were included. Peripheral arthritis was assessed with disease activity in psoriatic arthritis score (DAPSA) and skin involvement with body surface area (BSA). Axial disease was defined as having both imaging and clinical features and its activity was measured with the ankylosing spondylitis disease activity score (ASDAS). Twenty-four patients (54.2% female, mean [SD] age: 51.6 [14.1]) who were SEC-IR and received IXE either immediately (n = 11) or after ≥ 1 interposed biologic disease modifying anti-rheumatic drug (bDMARD) (n = 13) were included. Patients were followed on IXE for a mean [SD] period of 9.6 [4.9] months. Among patients with peripheral arthritis (n = 24), the mean [SD] DAPSA decreased from 22.8 [8.6] to 13.6 [7.8] during follow-up (p = 0.0001) with 62.5% of patients showing improvement in the DAPSA disease activity categories. For patients with axial involvement (n = 16), a clinically meaningful improvement (Δ ≥ 1.1 in ASDAS) was noted in 50% (8/16), while dactylitis and enthesitis resolution was observed in 60% (3/5) and 83% (5/6) of patients, respectively. Regarding psoriasis, the mean [SD] BSA of involved skin decreased from 8.7 [8.7] to 2.4 [3.3] (p = 0.001). In this case series, treatment with IXE after inadequate response to another IL-17 inhibitor (SEC) was efficacious in a real-world setting in patients with PsA, including axial disease.

Disease Profile and Achievement of Therapeutic Goals in a Modern, Nationwide Cohort of 923 Patients with Psoriatic Arthritis.

Background: Psoriatic arthritis (PsA) is a heterogenous chronic inflammatory disease affecting skin, joints, entheses, and spine with various extra-musculoskeletal manifestations and comorbidities. The reported patient, disease and treatment characteristics in the modern therapeutic era are limited. Methods: In this cross-sectional, multi-centre, nationwide study, we recorded the demographic, clinical, and therapeutic characteristics as well as the comorbidities of patients with PsA seen for 1 year (1/1/2022-31/12/2022). Results: 923 patients (55% females) with a median (IQR) age of 57 (48-65) years and a mean disease duration of 9.5 years were enrolled. Family history of psoriasis and PsA was noted in 28.3% and 6.3%, respectively. Most patients had limited psoriasis (BSA<3: 83%) while enthesitis, dactylitis, nail and axial involvement reported in 48.3%, 33.2%, 43% and 25.9% of patients, respectively. Regarding comorbidities, approximately half of patients had dyslipidaemia (42%) or hypertension (45.4%), 36.8% were obese and 17% had diabetes while 22.7% had a depressive disorder. Overall, 60.1% received biologics and among them more patients treated with anti-IL-17 or -12/23 agents were on monotherapy (64.2%) compared to those on TNFi monotherapy (49.4%, p=0.0001). The median PsA activity as assessed by the DAPSA score was 6 (IQR: 2.3 - 13.1) with 46% of patients reaching minimal disease activity status (MDA). Conclusion: In this large, real life, modern cohort of patients with PsA with frequent comorbidities who were treated mainly with biologics, almost half achieved minimal disease activity. These results show the value of existing therapeutic approaches while at the same time highlight the existing unmet needs.

Patient characteristics, treatment patterns and disease outcomes in patients with psoriatic arthritis followed in a combined Dermatology-Rheumatology clinic: a retrospective real-world study.

The aim of this study was to assess the patient characteristics, treatment patterns and disease outcomes in patients with psoriatic arthritis (PsA) referred to a combined Dermatology-Rheumatology (Derm-Rheum) Clinic. This was a retrospective study of patients seen in a combined Derm-Rheum Clinic (February 2018 to June 2020) in a Tertiary University Hospital. Consecutive patients with suspicious musculoskeletal symptoms or a known diagnosis of PsA referred to the Derm-Rheum Clinic were examined and followed simultaneously by experienced dermatologists and rheumatologists. Among 151 patients with psoriasis (PSO) with suspicious musculoskeletal complaints, 129 (85%) with a final diagnosis of PsA were included (56% females, mean age: 55 years, median disease duration: 14.2 years). In 62% of these patients (n = 94), PsA was diagnosed for the 1st time. At initial evaluation, 95% had peripheral arthritis, 45% nail involvement, 23% axial involvement, 12% enthesitis and 6% dactylitis with a median DAPSA and PASI scores of 20.5 and 1.6, respectively. 31% of the patients were not receiving any systemic treatment, 45% were on biologics, 29% on non-biologics and 10% on targeted synthetic agents (apremilast). At last visit (median interval time: 15 months), only 8% did not receive any systemic therapy (p < 0.001 compared to 1st visit), 62% were on biologics (p = 0.009 compared to 1st visit), 46% on non-biologics (p = 0.01 compared to 1st visit) and 10% remained on apremilast. The median DAPSA and PASI scores decreased significantly to 5.3 and 0, respectively. In conclusion, about 2/3 of patients with PSO and musculoskeletal complaints referred to a combined Derm-Rheum Clinic were diagnosed for the 1st time with PsA. During follow-up, the percentage of PsA patients on systemic therapies significantly increased with major improvement of disease activity indices. These data emphasize the value of combined Derm-Rheum Clinics for earlier referral, diagnosis, and more effective treatment of PsA patients.

Correlation of patient preferences to treatment outcomes in patients with rheumatoid arthritis treated with tumour necrosis factor inhibitors in Greece.

OBJECTIVES: To investigate possible associations between rheumatoid arthritis (RA) patient-expressed preferences over anti-tumour necrosis factor (anti-TNF) treatment and clinical and patient-reported outcomes. METHODS: PANORAMA was a non-interventional, prospective, multicentre, cohort study of 12 months duration, in patients with moderate-to-severe RA who initiated or switched to anti-TNF treatment. After initiation of anti-TNF, patients completed a preferences questionnaire on attributes related to anti-TNF treatment. Satisfaction with treatment was assessed with the Treatment Satisfaction Questionnaire for Medication (TSQM); compliance and persistence to treatment were recorded via a patient diary. Univariate and multivariate analyses were applied to assess correlations between patients' preferences over treatment with clinical and patient-reported outcomes. RESULTS: A total of 254 patients were enrolled; 66.1% (168/254) had highly active disease (DAS28-ESR > 5.1), while 65.4% (166/254) were biological-naïve. The 12-month drug-survival rate was 72.3%, while the respective rates of good EULAR response and remission (DAS28-ESR < 2.6) were 56.5% and 40.8%, respectively. By univariate analysis, fulfilment of patient preferences over treatment was associated with increased probability of remaining on therapy (p = 0.019), good EULAR response (p < 0.001) and satisfaction with treatment (p < 0.001). By multivariate analysis, fulfilment of patient preferences was the most important predictor for good EULAR response (OR 5.56, p < 0.001; finding confirmed and after propensity scoring matching), while seropositivity (HR 1.18, p = 0.047) and a high ESR (> 35 mm/h, HR 1.16, p = 0.071) predicted drug survival. CONCLUSIONS: In anti-TNF-treated RA patients, fulfilment of treatment preferences was independently associated with a good EULAR response and correlated with drug persistence at 12 months, emphasising the importance of patient preferences in treatment outcomes. Key Points • In anti-TNF treated RA patients, fulfilment of patients' treatment preferences is associated with a good clinical response at 12 months. • A shared decision-making process can maximise treatment's outcome in anti-TNF treated patients.

Conversion and Reversion Rates of Tuberculosis Screening Assays in Patients With Rheumatic Diseases and Negative Baseline Screening Under Long-Term Biologic Treatment.

BACKGROUND: To determine the conversion and reversion rates of tuberculosis (TB) screening tests (Tuberculin Skin Test-TST, Interferon Gamma Release Assay-IGRA: T-SPOT.TB) during biologic treatment in patients with rheumatic diseases and negative baseline screening. METHODS: This was a long-term, longitudinal cohort study of 50 patients with rheumatic diseases and negative baseline TB screening (TST: < 5 mm, negative T-SPOT.TB) treated with tumor necrosis factor inhibitors (TNFi) or other non-TNFi biologics. Patients were rescreened at a mean time of 1.4 (first rescreening) and 6.9 (second rescreening) years from baseline, with both assays. The conversion (negative to positive) and reversion (positive to negative) rate was calculated for each TB screening test. RESULTS: Fifty patients (mean age = 60 years) with various rheumatic diseases (rheumatoid arthritis: n = 24, spondyloarthropathies: n = 23, other: n = 3) were enrolled. During the first phase (baseline to first rescreening), all patients were treated with TNFi while during the second phase (first to second rescreening), TNFi (54%) and non-TNFi (46%) were used. Fifteen patients (30%) displayed conversion of at least 1 screening assay during follow-up (10 at the first and 5 at the second rescreening). This conversion rate was higher with TST (n = 11, 22% or 3.47/100 patient-years) compared to T-SPOT.TB (n = 4, 8% or 1.74/100 patient-years). Among the 10 converters at the first rescreening, 5 received isoniazid (INH) preventive therapy and 5 did not; an equal number of patients (3/5, 60%) reverted to negative with or without INH therapy. None of the patients developed active TB during follow-up (6.9 ± 1.0 years). CONCLUSIONS: Approximately one-third of patients with rheumatic diseases and negative baseline TB screening developed conversion of at least 1 screening test during long-term biologic treatment. This occurred most often with TST and was usually a transient event. These findings do not support routine serial TB retesting in biologic-treated patients with rheumatic diseases in the absence of TB risk factors.

High 3-year golimumab survival in patients with rheumatoid arthritis, ankylosing spondylitis and psoriatic arthritis: real world data from 328 patients.

OBJECTIVES: Our primary objective was to study the long-term survival on drug (SOD) of patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA) and ankylosing spondylitis (AS) treated with golimumab (GLM) in real life settings. METHODS: This was a retrospective, observational study of all patients treated with GLM in 4 Academic Centres in Greece during a 4-year period (09/2010-06/2014). SOD was analysed using Kaplan-Meier survival analysis, while Cox regression analysis estimating hazard ratios (HRs) for different baseline variables associated with drug discontinuation was performed for each disease. RESULTS: 328 patients (RA: 166, PsA: 82, AS: 80) were included. The estimated SOD at 2 and 3 years was 68% and 62% overall and was better for AS (79% and 76%) compared to RA (69% and 60%, p=0.067) and PsA (58% and 53%, p=0.001) patients; no difference was noted between RA and PsA patients (p=0.204). There was no difference in SOD between biologic-naïve and experienced nor between non-biologic co-treated or GLM monotherapy treated patients. Seropositivity (rheumatoid factor and/or anti-cyclic citrullinated peptide antibodies) was associated with a lower risk for GLM discontinuation by multivariate analysis (HR=0.5, 95% CI=0.0.25-1.1, p=0.05) in RA patients. During 606 patient-years of follow-up, 11 (3.3%) patients discontinued GLM due to adverse events (AE), accounting for 11% of treatment discontinuations. The rates of serious AEs and serious infections were 2.3 and 1.0/100-patient-years, respectively. CONCLUSIONS: In this real-life study, GLM showed a high 3-year SOD in patients with inflammatory arthritides with a low rate of discontinuation due to AEs.

Hepatitis B Reactivation in Rheumatic Diseases: Screening and Prevention.

Hepatitis B virus (HBV) reactivation (HBVr) has been an increasingly recognized and appreciated risk of immunosuppressive therapies in rheumatic patients. Despite its potential for significant morbidity and mortality, HBVr is a fully preventable complication with appropriate pretreatment screening and close monitoring of susceptible patients. Better knowledge of the risk for HBVr with the different antirheumatic agents and the establishment of the new-generation oral antivirals in clinical practice has greatly improved the design of screening and therapeutic algorithms. In this review, all available data regarding HBVr in rheumatic patients are critically presented and a screening and therapeutic algorithm is proposed.

Increased Frequency of Peripheral B and T Cells Expressing Granulocyte Monocyte Colony-Stimulating Factor in Rheumatoid Arthritis Patients.

OBJECTIVES: Granulocyte monocyte colony-stimulating factor (GM-CSF) is currently considered a crucial inflammatory mediator and a novel therapeutic target in rheumatoid arthritis (RA), despite the fact that its precise cellular sources remain uncertain. We studied the expression of GM-CSF in peripheral lymphocytes from RA patients and its change with antirheumatic therapies. METHODS: Intracellular GM-CSF expression was assessed by flow cytometry in stimulated peripheral B (CD19+) and T (CD3+) cells from RA patients (n = 40), disease (n = 31 including osteoarthritis n = 15, psoriatic arthritis n = 10, and systemic rheumatic diseases n = 6) and healthy (n = 16) controls. The phenotype of GM-CSF+ B cells was assessed as well as longitudinal changes in GM-CSF+ lymphocytes during methotrexate (MTX, n = 10) or anti-tumor necrosis factor (anti-TNF, n = 10) therapy. RESULTS: Among untreated RA patients with active disease (Disease Activity Score 28-C-reactive protein = 5.6 ± 0.89) an expanded population of peripheral GM-CSF+ B (4.1 ± 2.2%) and T (3.4 ± 1.6%) cells was detected compared with both disease (1.7 ± 0.9%, p < 0.0001 and 1.7 ± 1.3%, p < 0.0001, respectively) and healthy (0.3 ± 0.2%, p < 0.0001 and 0.6 ± 0.6%, p < 0.0001) controls. RA GM-CSF+ B cells displayed more commonly a plasmablast or transitional phenotype (37.12 ± 18.34% vs. 14.26 ± 9.46%, p = 0.001 and 30.49 ± 15.04% vs. 2.45 ± 1.84%, p < 0.0001, respectively) and less a memory phenotype (21.46 ± 20.71% vs. 66.99 ± 16.63%, p < 0.0001) compared to GM-CSF- cells. GM-CSF expression in RA patients did not correlate to disease duration, activity or serological status. Anti-TNF treatment led to a statistically significant decrease in GM-CSF+ B and T cells while MTX had no significant effect. DISCUSSION: This is the first study showing an expanded population of GM-CSF+ B and T lymphocytes in patients with active RA which declined after anti-TNF therapy.

Prevention of HBV reactivation in patients treated with biologic agents.

Owing to the sensitive equilibrium between the hepatitis B virus (HBV) and the host's immune system in infected and exposed individuals, the immunosuppression caused by biologic treatment has been strongly linked to HBV reactivation (HBVr). HBVr in the setting of biologic therapy is a cause of considerable morbidity, hospitalization, interruption of treatment and mortality. However, recent literature has established that this is a largely preventable problem. Thus, it is essential for clinicians using biologic agents to be aware of HBVr potential and screen all susceptible patients. The risk for HBVr may vary depending on the host's HBV infection status and the potency of immunosuppression. The appropriate pre-emptive antiviral prophylaxis or monitoring for individuals at risk is emphasized in the latest evidence-based guidelines, but a number of unanswered questions remain.

Frequent conversion of tuberculosis screening tests during anti-tumour necrosis factor therapy in patients with rheumatic diseases.

OBJECTIVES: To determine the rate of tuberculosis (TB) screening test conversion during anti-tumour necrosis factor (TNF) therapy in rheumatic patients with negative baseline screening. METHODS: This was a prospective study of rheumatic patients with negative baseline TB screening (tuberculin skin test (TST): <5 mm, and negative T-SPOT.TB, QuantiFERON-TB Gold In Tube (QFT-GIT) and chest X-ray) treated with anti-TNF agents. All patients underwent re-screening for TB with all assays 1 year later. Factors associated with TB test conversion were analysed and compared between 'converters' and 'non-converters'. RESULTS: Seventy patients (mean age 50.6±15.5 years) with rheumatic disease (33 with rheumatoid arthritis, 33 with spondyloarthropathies and 4 with other conditions) were enrolled. Patients were treated with different anti-TNFs (27 with adalimumab, 14 etanercept, 16 infliximab, 8 golimumab, 5 certolizumab pegol) for 1 year. Twenty patients (29%) displayed conversion of at least one screening assay 12 months after anti-TNF therapy: conversion of TST occurred in 9 (13%), T-SPOT.TB in 7 (10%) and QFT-GIT in 5 (7%). Only one patient had concomitant conversion of more than one screening test. Univariate and multivariate analysis revealed that only infliximab was associated with a decreased rate of TB screening assay conversion (OR 0.048, 95% CI 0.004 to 0.606, p=0.017). No patient (40% received isoniazid therapy) developed active TB during follow-up (27±12 months). CONCLUSIONS: Approximately one third of patients with negative baseline TB screening develop conversion of at least one screening test during anti-TNF treatment. These findings should be considered when designing re-screening strategies and contemplating latent TB therapy.