Anasarca and spontaneous intramuscular haemmorhage in a dermatomyositis patient: case report and review of the literature.

Dermatomyositis is a rare, autoimmune systemic disorder of unknown aetiology that presents as a constellation of clinical symptoms and signs primarily affecting skin and muscles. Patients with dermatomyositis can present with rare "non-canonical" manifestations. Focal or generalised oedema is an infrequent and often overlooked symptom of the disease, while spontaneous intramuscular haemorrhage is an even rarer and under-recognised, life-threatening complication that constitutes a medical emergency for clinical physicians. There are no known predisposing factors able to predict which patients will develop this complication and specific instructions considering treatment approach are currently lacking. Herein, we present a case of a patient with dermatomyositis complicated by both anasarca and spontaneous intramuscular haemorrhage. In order to raise awareness and timely diagnosis of such patients, we provide a review of the relevant literature and of the cases reported this far.

Risk for cancer development in familial Mediterranean fever and associated predisposing factors: an ambidirectional cohort study from the international AIDA Network registries.

Objective: Inflammation has been associated with an increased risk for cancer development, while innate immune system activation could counteract the risk for malignancies. Familial Mediterranean fever (FMF) is a severe systemic inflammatory condition and also represents the archetype of innate immunity deregulation. Therefore, the aim of this study is to investigate the risk for cancer development in FMF. Methods: The risk ratio (RR) for malignancies was separately compared between FMF patients and fibromyalgia subjects, Still's disease patients and Behçet's disease patients. Clinical variables associated with cancer development in FMF patients were searched through binary logistic regression. Results: 580 FMF patients and 102 fibromyalgia subjects, 1012 Behçet's disease patients and 497 Still's disease patients were enrolled. The RR for the occurrence of malignant neoplasms was 0.26 (95% Confidence Interval [CI.] 0.10-0.73, p=0.006) in patients with FMF compared to fibromyalgia subjects; the RR for the occurrence of malignant cancer was 0.51 (95% CI. 0.23-1.16, p=0.10) in FMF compared to Still's disease and 0.60 (95% CI. 0.29-1.28, p=0.18) in FMF compared to Behçet's disease. At logistic regression, the risk of occurrence of malignant neoplasms in FMF patients was associated with the age at disease onset (ß1 = 0.039, 95% CI. 0.001-0.071, p=0.02), the age at the diagnosis (ß1 = 0.048, 95% CI. 0.039-0.085, p=0.006), the age at the enrolment (ß1 = 0.05, 95% CI. 0.007-0.068, p=0.01), the number of attacks per year (ß1 = 0.011, 95% CI. 0.001- 0.019, p=0.008), the use of biotechnological agents (ß1 = 1.77, 95% CI. 0.43-3.19, p=0.009), the use of anti-IL-1 agents (ß1 = 2.089, 95% CI. 0.7-3.5, p=0.002). Conclusions: The risk for cancer is reduced in Caucasic FMF patients; however, when malignant neoplasms occur, this is more frequent in FMF cases suffering from a severe disease phenotype and presenting a colchicine-resistant disease.

The expanding clinical spectrum of autoinflammatory diseases with NOD2 variants: a case series and literature review.

Objective: To assess the impact conferred by NOD2 variants on the clinical spectrum of patients with systemic autoinflammatory diseases (SAIDs) in Greece. Methods: Consecutive patients (n=167) with confirmed SAIDs who underwent screening by next generation sequencing (NGS) targeting 26 SAID-associated genes, and carried at least one NOD2 gene variant, were retrospectively studied. The demographic, clinical and laboratory parameters were recorded. Results: In total, 24 rare NOD2 variants in 23/167 patients (14%) were detected. Notably, 18 patients had at least one co-existing variant in 13 genes other than NOD2. Nine patients had juvenile- and 14 adult-onset disease. All patients presented with symptoms potentially induced by the NOD2 variants. In particular, the candidate clinical diagnosis was Yao syndrome (YAOS) in 12 patients (7% of the whole SAID cohort). The clinical spectrum of patients with YAOS (mean episode duration 8 days) was fever (n=12/12), articular symptoms (n=8), gastrointestinal symptoms (n=7; abdominal pain/bloating in 7; diarrhea in 4; oral ulcers in 3), serositis (n=7), and rash (n=5), while the inflammatory markers were elevated in all but one patient. Most of these patients showed a poor response to nonsteroidal anti-inflammatory drugs (n=7/9), colchicine (n=6/8) and/or anti-TNF treatment (n=3/4), while a complete response was observed in 6/10 patients receiving steroids and 3/5 on anti-IL1 treatment. Another 8 patients were diagnosed with either FMF (n=6) or PFAPA syndrome (n=2) presenting with prominent diarrhea (n=7), oral ulcers (n=2), periorbital swelling and sicca-like symptoms (n=1), or maculopapular rash (n=1). One patient had a clinically undefined SAID, albeit characterized by oral ulcers and diarrhea. Finally, one patient presented with chronic relapsing urticaria with periorbital edema and inflammatory markers, and another one had a Crohn-like syndrome with good response to anti-IL-1 but refractory to anti-TNF treatment. Conclusion: NOD2 variants were detected in 1 out of 7 SAID patients and seem to have an impact on disease phenotype and treatment response. Further studies should validate combined molecular and clinical data to better understand these distinct nosological entities.

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.

COVID-19 and protection of vaccination in patients with systemic sclerosis-associated interstitial lung disease.

Objectives: Data on COVID-19 in patients with interstitial lung disease are scarce and whether SARS-CoV-2 may trigger interstitial lung disease progression remains unknown. We aimed to analyze outcomes of COVID-19 in patients with systemic sclerosis-associated interstitial lung disease, including possible thoracic radiographic progression. Patients and Methods: All 43 patients with systemic sclerosis-associated interstitial lung disease followed in our center (mean ± SD, 55.2 ± 11.6 years, 36 female) with confirmed SARS-CoV2 infection up to 1 September 2022 were analyzed. Individual interstitial lung disease extent on high resolution CT (HRCT) performed before (up to 3 months) and after COVID-19 (2-5 months) was compared. Results: At SARS-CoV-2 infection, 9/43 patients were unvaccinated, whereas 5, 26, and 3 had received 2, 3, or 4 doses of an mRNA vaccine, respectively. Thirty-one patients were either on monotherapy with immunosuppressives (mycophenolate, n = 7; cyclophosphamide, n = 2; methotrexate, n = 10; tocilizumab, n = 7; rituximab, n = 1; etanercept, n = 1), or their combinations (n = 3). Eight patients (20%), of whom four unvaccinated, required hospitalization for pneumonia and three (7%) died of acute respiratory failure (n = 2, both unvaccinated) or cardiac arrest. Lack of vaccination was the only independent predictor for hospitalization (OR = 7.98, 95% CI: 1.25-51.09) and marginally for death (OR = 32.7, 95% CI: 0.97-1110.98), regardless of the presence of diffuse systemic sclerosis, interstitial lung disease extent greater than 20% or immunosuppressive treatment. In 22 patients with available HRCT pairs (vaccinated = 20), the interstitial lung disease extent before COVID-19 (20.4%± 17.8%) remained unchanged (22.4% ± 18.5%) in all but one patient. Conclusion: SARS-CoV-2 vaccination is of outmost importance for every systemic sclerosis patient with interstitial lung disease. COVID-19 does not seem to promote progression of systemic sclerosis-associated interstitial lung disease in vaccinated patients, but further studies are warranted.

Depression and anxiety in a real-world psoriatic arthritis longitudinal study: should we focus more on patients' perception?

OBJECTIVES: Longitudinal studies using validated tools to evaluate depression and anxiety in psoriatic arthritis (PsA) are lacking. We aimed to estimate their course in PsA and to examine possible associations with disease-related parameters and patient-reported outcomes (PROs). METHODS: PsA patients attending two outpatient rheumatology clinics were consecutively enrolled (January 2019-June 2021, n=128). The hospital anxiety and depression scale (HADS) was used at two sequential visits (mean±SD: 10±6 months) to prospectively assess depression (HADS-Depression) and anxiety (HADS-Anxiety) (cut-off scores ≥11). Associations with demographic, clinical, laboratory features and PROs for quality of life (QoL) (EQ-5D), functional status (HAQ-DI) and nocebo-behaviour (Q-No) were examined. 'Change' was the difference between values at the first and second visit. RESULTS: Prevalence of depression and anxiety at the first visit was 19.5% and 21.1%, respectively. Depression was associated with EQ-5D [OR (95% CI): 1.70 (1.02-2.59), p=0.019] and anxiety with EQ-5D [1.81 (1.20 to 2.72), p=0.005], nocebo-behaviour [1.19 (1.01-1.40), p=0.04] and current corticosteroid use [6.95 (1.75-27.59), p=0.006]. At the second visit, HADS-Depression and HADS-Anxiety scores were improved in 40.9% and 41.9% of patients, respectively. While no associations were found for HADS-Anxiety score change, changes in HADS-Depression score correlated with changes in subjective (tender joint count, r= 0.204, p=0.049; PtG, r= 0.236, p=0.023; patient pain assessment, r= 0.266, p=0.01) but not objective (swollen joint count, ESR, CRP) parameters of disease activity. CONCLUSIONS: In PsA, depression and anxiety are associated with worse PROs, including QoL. Subjective parameters of disease activity parallel course of depression.

Normal C-reactive protein in active psoriatic arthritis: results from real-world clinical practice.

Background: The value of normal C-reactive protein (CRP) in psoriatic arthritis (PsA) is debatable. Objectives: To test the hypothesis that CRP is frequently normal in contemporary real-world PsA patients, despite active disease. Design: In this cross-sectional study, patients were divided into two groups: CRP ⩽ 0.5 mg/dl (normal) and CRP > 0.5 mg/dl (increased). Having as dependent variable the CRP status, these groups were compared for disease-related features, including composite disease activity indices [clinical Disease Activity in PSoriatic Arthritis (cDAPSA) and minimal disease activity (MDA)] and patient-reported outcomes (PROs). Agreement between CRP status and cDAPSA/MDA scores was calculated (Cohen's kappa). Methods: Data from consecutive PsA patients attending two outpatient rheumatology clinics (January 2019-June 2021) were analysed. Results: From 128 patients enrolled (51.6% females; mean ± standard deviation age: 53.4 ± 11.7 years; 23.4%, 48.4% and 64.1% treated with glucocorticoids, conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) and biologic DMARDs, respectively), two-thirds (66.4%, n = 85) had normal CRP values. CRP status was not associated with any of the disease-related parameters and PROs, but only with ESR [odds ratio: 1.04 (95% confidence interval: 1.01-1.06), p = 0.005]. Among patients with normal CRP, 45.9% (39/85) were on non-MDA state, while 21.2% (18/85) had cDAPSA-moderate and 5.9% (5/85) had cDAPSA-high disease activities. Conversely, 54.2% (39/72) of patients on non-MDA state and 52.3% (23/44) of those with cDAPSA-moderate or cDAPSA-high disease activity had normal CRP values. Cohen's kappa between normal CRP and MDA, cDAPSA-remission, and cDAPSA-remission/low disease activity was -0.26, -0.21 and -0.22, respectively, displaying total disagreement. Conclusion: Normal CRP in PsA should not be used as surrogate marker of remission or low/MDA, therefore needs to be interpreted with caution in clinical decision-making.

Autoinflammatory syndromes with coexisting variants in Mediterranean FeVer and other genes: Utility of multiple gene screening and the possible impact of gene dosage.

OBJECTIVE: To assess the possible impact conferred by co-existing variants in MEditerranean FeVer (MEFV) and other genes on systemic autoinflammatory disease (SAID) phenotype. METHODS: Consecutive patients (n = 42) who underwent screening for SAIDs by next generation sequencing (NGS) targeting 26 genes, and carried at least one MEFV gene variant, were retrospectively studied. A total of 63 MEFV gene variants mainly located in exon 10 (n = 29) and exon 2 (n = 19) were identified in 21 patients with juvenile- and 21 with adult-onset disease. RESULTS: The candidate clinical diagnosis was Familial Mediterranean Fever (FMF) in 11, polygenic SAIDs (PFAPA, Still's disease, atypical SAPHO and inflammatory bowel disease) in 9, whereas the disease could not be clinically defined in 22 patients. Notably, 33 out of the 42 patients (79%) had at least one co-existing variants in 19 genes other than MEFV. NGS confirmed all clinical diagnoses and helped defining diagnosis in 59% of the remaining cases. Patients with undefined SAIDs (n = 9) or atypical FMF phenotype (n = 12) carried significantly more disease-causing variants in genes other than MEFV compared to patients with typical FMF (n = 9). More than one variants in these genes were significantly associated with adult-onset disease, while disease-causing variants in the same genes were also associated with an overall more severe SAID phenotype. CONCLUSION: Co-existing variants in SAID-related genes may explain the phenotypic variability of these diseases. Further studies should validate combined molecular and clinical data in order to better understand the cumulative gene dosage effect and improve the classification of these patients.

COVID-19 vaccine safety and nocebo-prone associated hesitancy in patients with systemic rheumatic diseases: a cross-sectional study.

OBJECTIVE: To describe the rate and type of adverse effects (AEs) and the frequency of disease flares after COVID-19 vaccination and to assess the reasons for vaccination hesitancy (non-vaccination) in SRD patients. METHODS: Telephone interviews were conducted of SRD patients consecutively enrolled (15/06/2021-1/7/2021). Participants were asked about the type of AEs and disease flare after vaccination. Reasons for vaccination hesitancy were recorded. Univariate and mutivariable analyses examined associations of demographic, clinical and other features, with occurrence of AEs, disease flare and non-vaccination. For the latter, association with negative vaccination behaviour (not influenza vaccinated for the last 2 years) and nocebo-prone behaviour (denoting AEs attributed to negative expectations [Q-No questionnaire]) was also tested. RESULTS: 561 out of 580 contacted patients were included in the study. 441/561 (78.6%) patients were vaccinated [90% (Pfizer, Moderna), 10% (Astra-Zeneca)]. AEs were reported by 148/441 (33.6%), with rates being comparable between the three vaccines. AEs were more common in females and those with chronic obstructive pulmonary disease [OR, 95% CI; females: 2.23 (1.30-3.83); COPD: 3.31 (1.24-8.83)]. Disease flare was reported in 9/441 (2%) patients. For those unvaccinated, fear that the vaccine would be harmful (53.3%), could cause disease flare (24.2%) and/or could cause thrombosis (21.7%) were the main reasons to do so. Multivariable analysis identified as independent variables for non-vaccination: nocebo-prone behaviour (OR; 95% CI, 3.88; 1.76-8.55), negative vaccination behaviour (6.56; 3.21-13.42) and previous COVID-19 infection (2.83; 1.13-7.05). Higher educational status was protective (0.49; 0.26-0.92). CONCLUSION: No new safety signals for COVID-19 vaccination were observed. Vaccination campaign should target SRD patients with nocebo-prone and negative influenza vaccination behaviour.

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.

Psoriasis as an adverse reaction to biologic agents beyond anti-TNF-α therapy.

New onset or exacerbation of pre-existing psoriasis after therapeutic TNF-α inhibition is a well-described phenomenon. Over the last two decades, similar cases of paradoxical psoriasis have been reported following the administration of other biologic agents. We aimed to review all published cases of induced or exacerbated psoriasis after biologic therapy other than anti-TNF-α agents in order to further elucidate the pathophysiology of this phenomenon. A systematic literature review in the Medline database regarding any relevant case series or case reports on new onset or exacerbation of psoriasis after the administration of biologic agents targeting B cells, T cell co-stimulation, interleukin-1, interleukin-6, interleukin-17 and interleukin-12/23 was performed using appropriate key words. The literature search revealed nine articles (nine cases) of paradoxical psoriasis after ustekinumab and eight articles (nine cases) after secukinumab administration, both of which are approved therapies for psoriasis Moreover, 15 articles (23 cases) for rituximab, nine articles (12 cases) for abatacept, eight articles (nine cases) for tocilizumab, and one case report for anakinra have been published. In the majority of cases, patients had no prior history of psoriasis while 18 patients presented with exacerbation of pre-existing psoriatic lesions. Paradoxical psoriasis is not a specific adverse event of TNF-α inhibitors but is a possible side effect of any biologic agent interfering with the immune system. Awareness among physicians regarding early recognition is mandatory. Further clinical and experimental data are needed in order to unravel the pathophysiology of this unexpected phenomenon.

Increased influenza vaccination rates in patients with autoimmune rheumatic diseases during the Covid-19 pandemic: a cross-sectional study.

To assess non-compliance and potential changes in seasonal flu vaccination coverage before and during the Covid-19 pandemic in patients with autoimmune rheumatic diseases (ARDs). Consecutive patients with ARDs followed-up in 2 tertiary hospitals were telephone-interviewed (December 12-30, 2020) regarding seasonal flu vaccination during the 2019/20 and 2020/21 time periods. Self-reported disease flares that occurred after flu vaccination, as well as reasons for non-vaccination were recorded. One thousand fifteen patients were included. The rate of flu vaccination increased from 76% before to 83% during the COVID-19 pandemic (p = 0.0001). The rate of self-reported disease flares was < 1% among vaccinated patients. Reasons for not vaccination in both periods, respectively, included: 'was not recommended by their rheumatologists' (35.0vs.12.2%, p < 0.0001), 'did not feel that they would have any benefit' (36.9 vs. 32.6%), felt unsafe to do so (27.5 vs. 30.2%), or other reasons (18.9 vs. 23.8%). By multivariate analysis, age [OR = 1.03 (95% CI 1.02-1.04)] vs. [1.04 (95% CI 1.02-1.05)] and treatment with biologics [OR = 1.66 (95% CI 1.22-2.24) vs. [1.68 (95% CI 1.19-2.38)] were independent factors associated with vaccination in both periods. These findings, although are temporally encouraging, emphasize the need for continuous campaigns aiming at increasing patients' and physicians' awareness about the benefits of vaccination.

Nocebo-Prone Behaviour in Patients with Autoimmune Rheumatic Diseases during the COVID-19 Pandemic.

BACKGROUND: The COVID-19 pandemic is associated with emotional distress and significant disruptions in health-care services. These are key players in the development of nocebo phenomena. We aimed to investigate nocebo-prone behaviour in patients with autoimmune rheumatic diseases (ARD) amid the COVID-19 pandemic-associated lockdown. METHODS: Consecutive patients were telephone-interviewed during the COVID-19 pandemic in Greece. Clinical and socioeconomic characteristics (eg, level of education) were recorded. For nocebo behaviour, a four-item validated questionnaire (Q-No, cut-off score>15), was used. Results were compared with pre-COVID-19 Q-No scores collected from patients followed-up in our department. RESULTS: Nocebo behaviour was detected in 51/500 (10.2%) individuals. In patients with nocebo behaviour, use of anti-hypertensives was less common (17.6% vs 31.8%, p=0.04), but a higher level of education was more common (58.8% vs 35.9%, p=0.002), compared with patients with Q-No score ≤15; the latter retained statistical significance in multivariate regression analysis (p=0.009, OR [95%CI]: 2.29, [1.23-4.25]). Total Q-No scores were higher in the COVID-19-period compared to the pre-COVID-19 era [median (range); 12 (4-20) vs 11 (4-20), p=0.02]. Among 78 patients with available Q-No questionnaires in the pre-COVID-19 era, 11 (14.1%) displayed nocebo behaviour, which increased to 16 (20.5%) amid the COVID-19 pandemic. Interim development of nocebo behaviour was also associated with higher educational level (p=0.049, OR: 3.65, 95%CI: 1.005-13.268). CONCLUSION: A considerable proportion of ARD patients manifested nocebo-prone behaviour during the COVID-19 pandemic, which was more common among those with high educational level.