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.

CD32 (FcγRIIB) expression is low on CD21low B cells from systemic sclerosis patients with digital ulcers, interstitial lung disease, and anti-topoisomerase I autoantibodies.

CD21low B cells have recently been found increased in SSc-associated digital ulcers (DUs) or interstitial lung disease (ILD). To further characterize CD21low B cells which encompass autoreactive cells, we analyzed their expression of the inhibitory CD32 receptor in SSc. Peripheral blood mononuclear cells from 27 patients with SSc and 15 age-and sex-matched healthy controls (HCs) were analyzed with multicolor flow cytometry. CD21low B cells were significantly increased in patients with DUs (51.3%) compared to HCs (28.1%) and in patients with ILD (53.1%) compared to HCs. CD21lowCD32low B cells were significantly increased in patients with DUs (23.8%) compared to HCs (4.4%), in patients with ILD (28.4%) compared to HCs, and in anti-topoisomerase I (+) patients (21.5%) compared to HCs and to anti-topoisomerase I (-) patients (2.4%). Autoreactive B cells recognizing Topoisomerase I were predominantly within CD32low cell fraction. Our study further supports the autoreactive status of CD21lowCD32low B cells in SSc patients.

Omicron variant dominance and anti-SARS-CoV-2 vaccination are key determinants for a milder course of COVID-19 in patients with systemic autoimmune rheumatic diseases.

INTRODUCTION: This study aimed to determine whether the introduction of anti-SARS-CoV-2 vaccines and the dominance of the omicron variant had a significant impact on the outcome of COVID-19 in patients with systemic autoimmune rheumatic diseases (SAIRDs). METHODS: Using data entered to the Greek Rheumatology Society COVID-19 registry, we investigated the incidence of hospitalization and death due to COVID-19, during the successive periods of the pandemic according to the prevalent strain (wild-type, Alpha, Delta, Omicron) in vaccinated and unvaccinated patients. Variables independently associated with hospitalization and death were explored using multivariate regression analyses, while Kaplan-Meier curves were used to depict survival data. RESULTS: From August 2020 until June 30, 2022, 456 cases (70.2% females) of COVID-19 with a mean age (± SD) of 51.4 ± 14.0 years were reported. In unvaccinated patients, the proportions of hospitalization and death were 24.5% and 4%, compared to 12.5% and 0.8% in the vaccinated group (p < 0.001 for both comparisons). The rates of hospitalization for the wild-type, Alpha, Delta, and Omicron periods were 24.7%, 31.3%, 25.9%, and 8.1% respectively (p < 0.0001), while the case fatality rates were 2.7%, 4%, 7%, and 0%, respectively (p = 0.001). Using multivariable regression analysis, factors independently associated with hospitalization were infection by a non-Omicron variant, being non-vaccinated, exposure to rituximab, older age, and respiratory and cardiovascular disease. Independent predictors for death were contracting COVID-19 during the Alpha or Delta period, pulmonary disease, and older age, while being vaccinated was protective. CONCLUSIONS: In this 2-year analysis, the rates of hospitalization and death among patients with SAIRDs have declined significantly. Vaccination and the dominance of the Omicron variant appear to be the major determinants for this shift. Key points • During the late phase of the pandemic, the proportion of severe COVID-19 cases, defined as requiring hospitalization or resulting in death, in patients with systemic autoimmune rheumatic diseases has declined. • Anti-SARS-CoV-2 vaccination and the dominance of the Omicron strain are the key factors that have independently contributed to this shift.

Anorexia Nervosa in Juvenile Systemic Lupus Erythematosus (SLE): A Causality Dilemma.

Juvenile-onset systemic lupus erythematosus (jSLE) is an autoimmune disorder with multifaceted clinical findings in different organ systems. Neuropsychiatric manifestations affect more than half of SLE patients, and there is increasing evidence that anorexia nervosa (AN), a feeding and eating disorder (FED) characterized by significantly reduced energy intake, is among them. Herein, a review of the literature on the potential association between jSLE and AN was performed. Reported clinical cases were identified, and putative pathophysiological mechanisms were sought that could potentially explain the observed relationship between these two pathological entities. Four reports of isolated cases and a case series including seven patients were identified. In this limited patient pool, the diagnosis of AN preceded that of SLE in the majority of cases, whereas in all cases both entities were diagnosed within a time span of two years. Many explanations for the observed relationships have been proposed. AN has been associated with the stress of chronic disease diagnosis; on the other hand, the chronic inflammation associated with AN may contribute to the development/appearance of SLE. Adverse childhood experiences, concentrations of leptin, shared autoantibodies, and genetic traits appear to be important factors in this well-established interplay. In essence, it seems important to increase clinician awareness of the concomitant development of AN and SLE and invite further research on the subject.

COVID-19 vaccine-associated myositis: a comprehensive review of the literature driven by a case report.

Several cases of vaccine-associated manifestations have been published including cases of inflammatory myositis. Herein, we comprehensively review the literature on the occasion of case of a woman with inflammatory myositis following COVID-19 vaccination. A 67-year-old woman presented with left arm edema, rash, and weakness after the 2nd dose of the BTN162b2 vaccine. Raised muscle enzymes and inflammatory markers with muscle edema on MRI and myositis findings on the electromyogram established the diagnosis. She was successfully treated with methylprednisolone pulses, intravenous immunoglobulin, methotrexate, and hydroxychloroquine. Cases of inflammatory myositis, dermatomyositis, or interstitial lung disease with myositis-specific autoantibodies or myositis-associated autoantibodies within 12 weeks from SARS-CoV-2 vaccination were included. Cases with malignancy, prior or subsequent COVID-19 infection, preexisting myositis/interstitial lung disease (ILD)/dermatomyositis (DM), or other connective tissue diseases were excluded. From our search, 49 cases were identified (mean age: 56.55 + 17.17 years), 59% were women, while 12 patients received the ChAdOx1 vaccine, 27 the BNT162b2, 8 the mRNA-1273, 1 the DB15806, and 1 the Ad26.COV2.S (overall, 70% received mRNA vaccines). Muscle involvement was the most common manifestation (79.5%), followed by skin involvement (53%) and ILD (34.6%), which were more common in the m-RNA vaccinees. Muscle biopsy, MRI findings, and autoantibody profile varied significantly, while successful immunosuppressive treatment was applied in most cases. Inflammatory myositis after COVID-19 vaccination has been well documented worldwide. Current evidence in support of a pathogenic link is challenging due to significant variation in clinical manifestations, radiological, histopathological, and immunological features.

Nutritional Aspects of Juvenile Idiopathic Arthritis: An A to Z for Dietitians.

Juvenile idiopathic arthritis (JIA) represents a chronic, autoimmune, rheumatic musculoskeletal disease with a diagnosis before 16 years of age. Chronic arthritis is a common manifestation in all JIA subtypes. The nature of JIA, in combination to its therapy often results in the development of nutrition-, gastrointestinal (GI)- or metabolic-related issues. The most-common therapy-related nutritional issues involve methotrexate (MTX) and glucocorticosteroids (GCC) adverse events. MTX is a folic acid antagonist, thus supplementation with folic acid in required for improving GI side effects and correcting low serum levels. On the other hand, long-term GCC administration is often associated with hyperglycemia, insulin resistance and growth delay. This relationship is further aggravated when more joints are affected and greater doses of GCC are being administered. Apart from stature, body mass index z-scores are also suboptimal in JIA. Other signs of malnutrition include decreased phase angle and muscle mass, especially among patients with polyarthritis JIA. Evidence also points to the existence of an inverse relationship between disease activity and overweight/obesity. Specific dietary patterns, including the anti-inflammatory diet, might confer improvements in selected JIA outcomes, but the level of available research is yet insufficient to draw safe conclusions. The majority of patients exhibit suboptimal vitamin D status; hence, supplementation is recommended. Collectively, the evidence indicates that, due to the age of onset and the complexity of the disease, along with its pharmacotherapy, children with JIA are prone to the development of several nutritional problems, warranting expert monitoring. Vitamin deficiencies, oral and GI-problems limiting dietary intake, faltering growth, overweight and obesity, physical inactivity, or impaired bone health are among the many nutritional issues in JIA requiring dietitian support.

Secukinumab, ixekizumab, bimekizumab and brodalumab for psoriasis and psoriatic arthritis.

In recent years, the role of interleukin-17 (IL-17) in orchestrating and manipulating proinflammatory immune responses has received special attention. It has become apparent from murine studies and clinical trials that due to its inhibitory effect on immunoregulation and its stimulatory action on promoting proinflammatory responses, IL-17 is an ideal cytokine to target for drug development, in order to cease its induction or eliminate IL-17-producing cells of any kind. Several monoclonal antibodies have been developed and tested as potent inhibitors of IL-17 in various inflammatory diseases. This review summarizes data from relevant clinical trials on recent developments of the application of inhibitors of IL-17 in psoriasis and psoriatic arthritis, namely secukinumab, ixekizumab, bimekizumab and brodalumab.

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.

Giant Hip Synovial Cyst Causing Deep Vein Thrombosis and Femoral Head Osteonecrosis in a Rheumatoid Arthritis Patient.

Hip synovial cysts are rare. However, in patients with Rheumatoid Arthritis (RA) they present in higher frequency than in general population. Herein, we present an unusual case of a 67-year-old man with RA that presented with unilateral leg oedema and Deep Vein Thrombosis (DVT). Computed tomography (CT) scan revealed a giant cystic lesion adjacent to the right hip joint with longitudinal diameter of 14 cm. Magnetic Resonance Imaging (MRI) confirmed the characteristics of the cyst. Interestingly enough, there was evidence of osteonecrosis of the femoral head. CT guided Fine Needle aspiration (FNA) of the fluid revealed fluid consistency similar to synovial fluid, while it excluded infectious process and malignancy. Patient was finally treated with total hip arthroplasty 3 months after the initiation of low molecular weight heparin (LMWH) in treatment dose.

Better outcomes of COVID-19 in vaccinated compared to unvaccinated patients with systemic rheumatic diseases.

OBJECTIVE: Τo report outcomes of breakthrough COVID-19 in comparison with COVID-19 in unvaccinated patients with systemic rheumatic diseases (SRDs). METHODS: Patients with SRD with COVID-19 (vaccinated and unvaccinated) were included by their rheumatologists in a registry operated by the Greek Rheumatology Society in a voluntarily basis. Type, date and doses of SARS-CoV-2 vaccines were recorded, and demographics, type of SRD, concurrent treatment, comorbidities and COVID-19 outcomes (hospitalisation, need for oxygen supplementation and death) were compared between vaccinated and unvaccinated patients. RESULTS: Between 1 March 2020 and 31 August 2021, 195 patients with SRD with COVID-19 were included; 147 unvaccinated and 48 vaccinated with at least one dose of a SARS-CoV-2 vaccine (Pfizer n=38 or AstraZeneca n=10). Among vaccinated patients, 29 developed breakthrough COVID-19 >14 days after the second vaccine dose (fully vaccinated), while 19 between the first and <14 days after the second vaccine dose (partially vaccinated). Despite no differences in demographics, SRD type, treatment or comorbidities between unvaccinated and vaccinated patients, hospitalisation and mortality rates were higher in unvaccinated (29.3% and 4.1%, respectively) compared with partially vaccinated (21% and 0%) or fully vaccinated (10.3% and 0%) patients. CONCLUSIONS: Vaccinated patients with SRD with breakthrough COVID-19 have better outcomes compared with unvaccinated counterparts with similar disease/treatment characteristics.

Arthritis and Myositis in a Patient Treated with Programmed Cell Death-1 (PD-1) Inhibitor Pembrolizumab for Lung Cancer.

Immune checkpoint inhibitors (ICIs) are a new class of drug that have demonstrated efficacy across many cancer types. Because of their nature and mode of action, ICIs unleash immune activation raising concerns as to whether they can be used in patients with concomitant autoimmune or auto-inflammatory diseases. Their usage can lead to the development of autoimmune phenomena known as immune related adverse events (irAEs), virtually affecting every organ. As the use of ICIs is drastically increasing, evidence of irAEs has been accumulating. Herein, we report a case of inflammatory myositis and arthritis 6 months after pembrolizumab therapy, an anti-programmed death-1 (PD1) ICI in a patient with lung cancer, aiming at raising awareness of the diagnostic and clinical challenges clinicians may face when checkpoint inhibitors-related rheumatologic irAEs are developed.

A study of antigen-specific anti-cytomegalovirus antibody reactivity in patients with systemic sclerosis and concomitant anti-Ro52 antibodies.

Anti-Ro52 autoantibody (autoAb), highly prevalent in Sjogren's syndrome (SjS) and systemic lupus erythematosus (SLE), is also frequent in systemic sclerosis (SSc). Viral agents, such as human cytomegalovirus (HCMV), have been considered as a trigger for SSc and SSc-associated autoAbs. To seek for antigen-specific anti-HCMV associations with anti-Ro52, we assessed the dominant anti-HCMV ab responses in anti-Ro52 antibody (ab)-positive and -negative patients with SSc and compared them with those in SLE and SjS. 116 Anti-HCMV ab(+) sera were analyzed, including 70 from anti-Ro52(+) patients (29 SSc, 23 SLE and 18 SjS) and 46 from anti-Ro52(-) patients (29 with SSc, 9 with SLE and 8 with SjS) as negative controls. Abs against specific HCMV pp130/UL57, pp65/UL83, pp55/UL55, pp52/UL44, p38 and pp28/UL99 antigens were tested by immunoblotting. Anti-Ro52(+) SSc patients reacted more frequently against pp52/UL44 and p38 compared to anti-Ro52(-) [(13/29, 44.8%; 95% CI 26.7-62.9% vs. 1/29, 3.4%; 95% CI 0-10%, p < 0.001, and 9/29, 31.0%; 95% CI 14.2-47.8% vs. 2/29, 6.9%; 95% CI 0-16.1%, p = 0.041, respectively]. No such differences were noted between anti-Ro52(+) and anti-Ro52(-) SLE or SjS patients. Also, antibody titres against HCMV pp65/UL83, pp52/UL44 and p38 antigens were higher in anti-Ro52(+) than anti-Ro52(-) SSc patients (p < 0.01). Ab responses against specific HCMV antigens differ among anti-Ro52 ab-positive and -negative patients with SSc (as well as between SSc and SLE or SjS), but whether these differences are epiphenomenal remains to be seen.

Autoantibodies against specific nuclear antigens are present in psoriatic disease and are diminished by secukinumab.

Anti-nuclear antibodies (ANA) are frequently detected in patients with psoriasis (Ps) and psoriatic arthritis (PsA), but their target autoantigens remain unknown. We assessed antibody (ab) reactivity against 23 known nuclear antigens in patients with Ps and PsA and assess the effects of secukinumab (anti-IL17A) treatment on ANA levels. A total of 201 patients, 101 with Ps and 100 with PsA, and 50 ANA-negative healthy controls (HCs) were tested for ANAs by a line immunoassay testing reactivity to 23 nuclear antigens. Ab reactivity to at least 1 antigen was found in 20.4% psoriatic disease patients (25.7% Ps and 15% PsA) compared to 8% HCs (p = ns), the most frequent being against dense fine speckled 70 (DFS70) (6.5%). In Ps and PsA patients with secukinumab-induced remission, anti-DFS70 and other antigen-specific autoantibodies were diminished over time. No decline was noted for IgG abs against antigens from pathogens such as cytomegalovirus, Epstein-Barr virus and Helicobacter pylori. Autoantibody decrease was associated with significant reduction of plasmablasts, follicular B and follicular T cells. In conclusion, one third of antigen-specific ANA patients with psoriatic disease recognize DFS70. Secukinumab decreases nuclear antigen autoreactivity, plasmablasts, follicular B and follicular T cells, highlighting a new mechanism of its action.

Antigen-specific humoral responses against Helicobacter pylori in patients with systemic sclerosis.

Helicobacter pylori (Hp) is a likely trigger of systemic sclerosis (SSc), but systemic antigen-specific antibody (Ab) responses in a well-defined cohort of SSc patients have not been thoroughly assessed. Line immunoassay and immunoblotting testing Abs against 15 Hp antigens were performed in 91 SSc patients and 59 demographically matched healthy controls (HCs). Results were validated in an independent cohort of 35 SSc patients. Anti-Hp positivity was detected in 67% SSc patients vs 76.3% HCs. Among anti-Hp (+) individuals, anti-p67-FSH was less frequent in SSc than HCs (p = 0.016), whereas reactivity to the remaining 14 Hp antigens did not differ between patients and HCs. Anti-p67 Abs were less frequent in diffuse cutaneous SSc (dcSSc) compared with HCs (p = 0.018). Anti-p57 and anti-p33 Ab levels were lower in SSc vs HCs (p = 0.007 and p = 0.035, respectively). Anti-p57 and anti-p33 Ab levels were lower in limited cutaneous SSc (lcSSc) (p = 0.010) and dcSSc (p = 0.024), respectively, compared with HCs. Anti-p50 and anti-p17 Ab titers tended to be higher in dcSSc than in lcSSc. Sera from the independent SSc cohort showed comparable results. Anti-VacA Abs were more frequent in pulmonary arterial hypertension (p = 0.042), and anti-p30 Abs were more frequent in calcinosis (p = 0.007), whereas anti-VacA Ab levels were higher in lung fibrosis (p = 0.02). In conclusion, anti-Hp Abs are neither more frequent nor elevated in SSc compared with healthy population, the only exception being the higher frequency and levels of anti-VacA Abs in pulmonary hypertension and lung fibrosis, respectively. These results suggest that Hp is unlikely to be involved in the development of SSc.

Progressive multifocal leukoencephalopathy in a patient with systemic sclerosis treated with methotrexate: A case report and literature review.

Reactivation of viruses occurs in autoimmune disorders in the setting of certain immunosuppressive drugs. We describe a 54-year-old female with systemic sclerosis and extensive cutaneous calcinosis who had been treated with methotrexate for 18 months and presented with headache and neurological deficits. She was diagnosed with progressive multifocal leukoencephalopathy, a rare disease caused by JC virus. Methotrexate was discontinued and mirtazapine plus mefloquine were added. The patient showed a slow recovery and five years later she had complete resolution of progressive multifocal leukoencephalopathy clinical manifestations. Calcinosis had a limited response to various agents and severely affected daily activities of the patient. This case report, highlights the importance of clinical suspicion for progressive multifocal leukoencephalopathy in every patient with immune-mediated disease, even on weak immunosuppressant, who presents with central nervous system manifestations and also the unmet therapeutic need for systemic sclerosis-associated calcinosis.

Apremilast increases IL-10-producing regulatory B cells and decreases proinflammatory T cells and innate cells in psoriatic arthritis and psoriasis.

OBJECTIVES: Psoriatic arthritis (PsA) and psoriasis are immune-mediated inflammatory diseases sharing common immunological mechanisms. Regulatory B cells (Breg cells) producing IL-10 (B10 cells), a critical anti-inflammatory B-cell subset, were found to be decreased in both PsA and psoriasis. Apremilast, a phosphodiesterase-4(PDE4) inhibitor, increases IL-10 and therefore, we examined the effect of apremilast on Breg cells. METHODS: Fifty patients, including 20 with PsA and 30 with psoriasis, were included in the study. The effect of apremilast on Breg cells at 3, 6 and 12 months post-treatment, was examined by flow cytometry in ODN2006 (TLR9)-stimulated peripheral blood mononuclear cells and magnetically-isolated cells. Th1 cells, Th17 cells and NKT were also measured. RESULTS: Ex vivo stimulated cell analysis identified that post-apremilast (IL-10+CD19+) B10 cells were increased in all PsA and psoriasis patients and correlated with psoriatic skin and joint clinical improvement. Apremilast decreased IFNγ(+) T and NKT cells and IL-17(+)NKT cells. B10 cells also inversely correlated with Th1 cells, and IFNγ(+)NKT cells. CONCLUSION: These results suggest that Breg cells are a major target of apremilast in PsA and psoriasis and that apremilast-induced increase of Breg cells is associated with a decrease of Th1 cells, IFNγ-producing NKT cells and IL-17-producing NKT cells.