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.

Histological diversity of anti-PD1-induced colitis.

AIM: Histological data on anti-PD1-associated colitis are limited, while the colitis subtypes are still not clearly defined and different terms are being used. The aim of the study was to explore the histopathology of anti-PD1-induced colitis. METHODS AND RESULTS: Colonic biopsies from 9 patients under anti-PD1 agents presenting diarrhea were examined. Histological evaluation revealed colitis of mild to moderate severity in almost all cases. Four distinct dominant histological patterns were identified with nearly the same incidence: Ulcerative colitis (UC)-like (n=2), GVHD-like (n=2), collagenous-like (n=3) and a mixed colitis pattern combining features of microscopic and UC-like colitis (n=2). The latter was additionally characterized by high crypt epithelium apoptosis and cryptitis with mixed inflammatory infiltrate. Thickening of the subepithelial band of collagen, detachment of the surface epithelium and increased apoptosis of the crypt epithelium were commonly encountered features, irrespective of colitis subtype. CD4/CD8 ratio was lower in the "combined" and higher in the GVHD-like subtype. CONCLUSIONS: Anti-PD1-induced colitis is expressed by different patterns of injury which share distinct histological hallmarks harboring diagnostic value, while a "combined" colitis subtype is being established. The histological alterations are indicative of mucosa barrier damage after antΙ-PD1 treatment and its participation in the pathogenetic process.

Genetic Variants of the BAFF Gene and Risk of Fatigue Among Patients With Primary Sjögren's Syndrome.

Background/Purpose: Primary Sjögren's Syndrome (SS) is characterized by B lymphocyte hyperactivity with B cell activating factor (BAFF) acting as an important regulator. Single Nucleotide Polymorphisms (SNPs) of the BAFF gene have been implicated in the pathogenesis of several autoimmune diseases characterized by heightened fatigue levels, including primary SS. We aimed to explore potential associations between BAFF SNPs and fatigue status of primary SS patients. Methods: Fatigue status was assessed in 199 consecutive primary SS patients (Greek cohort) using the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) scale. Clinical, histological, laboratory, psychometric and personality data were also collected. DNA extracted from peripheral blood of all patients underwent evaluation for the presence of five BAFF SNPs (rs9514827, rs1041569, rs9514828, rs1224141, rs12583006) by PCR. To confirm our findings, an independent replicative cohort of 62 primary SS patients (Dutch cohort) was implemented. Finally, 52 multiple sclerosis (MS) patients were served as disease controls (MS cohort). Analysis of BAFF SNPs in association with fatigue levels was performed by the online platforms SNPStats and SHEsis and the SPSS 26 and Graph Pad Prism 8.00 software. Results: TT genotype of the rs9514828 BAFF polymorphism was significantly less frequent in the fatigued primary SS patients of the Greek cohort compared to the non-fatigued (14.1% vs 33.3%). The corresponding ORs [95%CI] in the dominant and overdominant models were 0.33 [0.15-0.72], p=0.003 and 0.42 [0.23-0.78], p=0.005 respectively. The association remained significant after adjustment for the variables contributing to fatigue in the univariate analysis (OR [95% CI]: 0.3 [0.1-0.9], p=0.026). Accordingly, in the Dutch cohort, there was a trend of lower mental fatigue among patients carrying the TT rs9514828 BAFF genotype compared to their CC counterparts (4.1 ± 2.4 vs 6.0 ± 2.2 respectively, p=0.06). The rs9514828 BAFF SNP was not significantly associated with fatigue in the MS cohort. Conclusions: We report a novel association between genetic makeup and primary SS-associated fatigue with the rs9514828 TT genotype decreasing the likelihood of fatigue development among these patients. These findings need validation in multi-center studies.

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.

Idiopathic retroperitoneal fibrosis: clinical features, treatment modalities, relapse rate in Greek patients and a review of the literature.

OBJECTIVES: Retroperitoneal fibrosis (RPF) is mostly idiopathic (iRPF); however, it can be secondary to drugs, malignancies, infections, or, as recently recognised, can be part of the IgG4-related diseases. The aim of our study was i) to describe the presenting clinical/laboratory/imaging features and treatment modalities used in patients with iRPF and ii) to evaluate factors potentially associated with disease relapse. METHODS: The medical records of patients diagnosed with iRPF and followed in four tertiary medical units in Athens, Greece from 2000 to 2018 were retrospectively evaluated. RESULTS: Sixty-seven patients with iRPF were included in the study. Seventy-three per cent were males, with a mean age at diagnosis 56.0±9.2 years. Low-back pain (63%) and constitutional symptoms (57%) were the commonest presenting symptoms. Elevated acute-phase reactants (78%), anaemia (43%) and impaired renal function (41%) were the most common laboratory findings. Serum IgG4 at diagnosis was evaluated in 36/67 patients and 36% of them had elevated levels (mean 297.7±166.3mg/dL). Diagnosis was mainly based on abdominal CT and/or MRI. Clinical/laboratory/radiological presentation did not differ between patients with elevated and normal serum IgG4 levels. Steroids were used as first-line treatment in 98%. Relapse occurred in 28.6% after a mean of 43.1±31.8 months. Relapse did not associate to initial clinical/imaging findings or to any treatment used, however patients with increased serum IgG4 had a significantly higher relapse rate (75% vs. 25%, p=0.005). CONCLUSIONS: Relapse occurred in one-fifth of patients independently of the initial clinical/radiographic presentation or treatment used. iRPF patients with baseline elevated serum IgG4 levels have a higher relapse rate.

Eosinophilic Fasciitis following Checkpoint Inhibitor Therapy with Pembrolizumab.

With the increasing number of indications for checkpoint inhibitor therapy in cancer patients, rheumatology specialists are often involved in the diagnosis and management of immune-related adverse events (irAEs). The most common rheumatic irAEs are arthritis, sicca syndrome, polymyalgia rheumatica, and myositis. Eosinophilic fasciitis, an already rare rheumatic disease, is a very unusual rheumatic irAE. Eosinophilic fasciitis, whether idiopathic or checkpoint inhibitor-associated, has very particular clinical symptoms and findings, such as the orange peel skin appearance and the Groove sign, which the physicians need to be aware of and recognise timely in order to diminish morbidity.

Medical education in Greece: Necessary reforms need to be re-considered.

For the past years, and even more now with the major challenge of the COVID-19 pandemic, we are faced with the inadequacies that undermine the healthcare system in Greece. As healthcare system performance and medical education are directly and reciprocally linked, a substantial part of healthcare services' dysfunctions could be partially attributed to the training of the young doctors. Thus, in order to improve the performance of the healthcare system in the best interest of patients and communities, the education of healthcare personnel should be a priority. By reviewing the existing literature in combination with our experience we attempt to delineate the weak points of the undergraduate and postgraduate medical education in Greece. Additionally, based on medical curricula from other countries, we suggest reforms in order to achieve a uniform, clinically oriented, emphasis on training in public health issues in undergraduate medical education. Reforms are also suggested for postgraduate training with regard not only to specialization curricula, but also to the accredited institutions which provide specialty training. Finally, the necessity for Continuing Medical Education (CME) is underlined; medical education must have a continuum that begins with undergraduate training but does not end there; it is life-long learning.

Primary Sjögren's Syndrome of Early and Late Onset: Distinct Clinical Phenotypes and Lymphoma Development.

Objectives: To study the clinical, serological and histologic features of primary Sjögren's syndrome (pSS) patients with early (young ≤35 years) or late (old ≥65 years) onset and to explore the differential effect on lymphoma development. Methods: From a multicentre study population of 1997 consecutive pSS patients, those with early or late disease onset, were matched and compared with pSS control patients of middle age onset. Data driven analysis was applied to identify the independent variables associated with lymphoma in both age groups. Results: Young pSS patients (19%, n = 379) had higher frequency of salivary gland enlargement (SGE, lymphadenopathy, Raynaud's phenomenon, autoantibodies, C4 hypocomplementemia, hypergammaglobulinemia, leukopenia, and lymphoma (10.3% vs. 5.7%, p = 0.030, OR = 1.91, 95% CI: 1.11-3.27), while old pSS patients (15%, n = 293) had more frequently dry mouth, interstitial lung disease, and lymphoma (6.8% vs. 2.1%, p = 0.011, OR = 3.40, 95% CI: 1.34-8.17) compared to their middle-aged pSS controls, respectively. In young pSS patients, cryoglobulinemia, C4 hypocomplementemia, lymphadenopathy, and SGE were identified as independent lymphoma associated factors, as opposed to old pSS patients in whom SGE, C4 hypocomplementemia and male gender were the independent lymphoma associated factors. Early onset pSS patients displayed two incidence peaks of lymphoma within 3 years of onset and after 10 years, while in late onset pSS patients, lymphoma occurred within the first 6 years. Conclusion: Patients with early and late disease onset constitute a significant proportion of pSS population with distinct clinical phenotypes. They possess a higher prevalence of lymphoma, with different predisposing factors and lymphoma distribution across time.

Sjögren's Syndrome: The Clinical Spectrum of Male Patients.

BACKGROUND: To compare the clinical, serological and histologic features between male and female patients with Sjögren's syndrome (SS) and explore the potential effect of gender on lymphoma development. METHODS: From a multicenter population (Universities of Udine, Pisa and Athens, Harokopion and Ioannina (UPAHI)) consisting of consecutive SS patients fulfilling the 2016 ACR/EULAR criteria, male patients were identified, matched and compared with female controls. Data-driven multivariable logistic regression analysis was applied to identify independent lymphoma-associated factors. RESULTS: From 1987 consecutive SS patients, 96 males and 192 matched female controls were identified and compared. Males had a higher frequency of lymphoma compared to females (18% vs. 5.2%, OR = 3.89, 95% CI: 1.66 to 8.67; p = 0.0014) and an increased prevalence of serum anti-La/SSB antibodies (50% vs. 34%, OR = 1.953, 95% CI: 1.19 to 3.25; p = 0.0128). No differences were observed in the frequencies of lymphoma predictors between the two genders. Data-driven multivariable logistic regression analysis revealed negative association of the female gender with lymphoma and positive association with lymphadenopathy. CONCLUSION: Male SS patients carry an increased risk of lymphoma development. Although statistics showed no difference in classical lymphoma predictors compared to females, data-driven analysis revealed gender and lymphadenopathy as independent lymphoma-associated features.

Anti-Ro52 and/or anti-Ro60 immune reactivity: autoantibody and disease associations.

OBJECTIVES: This study aims to characterise the clinical phenotype and autoantibody associations in an autoimmune population positive for anti-Ro52 and/or anti-Ro60 autoantibodies. METHODS: The sera of 508 individuals tested for autoantibody presence were found positive for anti-Ro52 and/or anti-Ro60. Medical records were available for 272 of them. Correlations of clinical, laboratory and other autoantibodies as well as disease phenotypes with the presence of anti-Ro52 and/or anti-Ro60 reactivity were examined. RESULTS: Combined serum anti-Ro52/anti-Ro60 reactivity was the most frequent one, mostly seen in Sjögren's syndrome (SS) and systemic lupus erythematosus (SLE) patients. In these patients this reactivity strongly associated with anti-La and/or anti-dsDNA autoantibodies. SS patients with combined anti-Ro52/anti-Ro60 and anti-La reactivity had clinical and/or laboratory risk factors for lymphoma development. Solo anti-Ro52 reactivity was primarily found in idiopathic inflammatory myopathies (IIM), primary biliary cholangitis (PBC), rheumatoid arthritis (RA) and SS patients. Solo anti-Ro52 also associated with anti-Jo1 and anti-M2 autoantibodies and with interstitial lung disease (ILD) in a context of IIM-related lung injury. ILD patients with combined anti-Ro52/anti-Ro-60 reactivity were diagnosed mostly as RA and/or SS. Solo anti-Ro60 reactivity strongly correlated with oral ulcers and co-existed with autoantibodies to Sm and nRNP/Sm. CONCLUSIONS: Testing for autoantibodies against both Ro peptides may guide diagnosis, classify clinical manifestations in disease entities and define prognosis in certain autoimmune disorders. A distinct weight could be given to the isolated anti-Ro specificities in the SS classification criteria.

Lesson of the month 2: Fever, arthralgias and hyperkeratotic, scaling and fissuring eruptions of the hands.

A 56-year-old male hairdresser, presented with fever and arthralgias. He had a worsening 'eczematous' palmar rash which had been attributed to irritation from colouring products used in his work. On examination, hyperkeratotic, fissuring eruptions were noted on the palmar side of his fingers and lung auscultation revealed crackles on both lower lobes. Laboratory testing showed elevated muscle enzymes. The clue to the diagnosis in our patient was the presence of hyperkeratotic, fissuring eruptions on the palmar side of his fingers, compatible with 'mechanic's hands'. This is a characteristic semiology reminiscent of hands of manual workers, resembling hand eczema. 'Mechanic's hands', fever, arthralgias, lung findings and elevated serum muscle enzymes raised the possibility of antisynthetase syndrome. Testing for myositis autoantibodies revealed anti-Jo-1 and anti-Ro52 reactivity supporting the diagnosis.Greater awareness of the typical clinical feature of 'mechanic's hands' will allow for earlier diagnosis and appropriate treatment in patients with antisynthetase syndrome.

Myositis autoantibody profiles and their clinical associations in Greek patients with inflammatory myopathies.

Myositis-specific (MSAs) or-associated autoantibodies (MAAs) have been linked to particular clinical phenotypes of idiopathic inflammatory myopathies (IIM) and appear to aid diagnosis. The objective of this study was to analyze the prevalence of MSAs and MAAs and their possible clinical associations in Greek IIM patients. This study comprised 95 IIM patients classified based on the 2017 EULAR/ACR classification criteria. All patients had MSAs and MAAs measured in their sera by line immunoblot assay. Dermatomyositis was the most prevalent IIM clinical subtype. MSAs were found in 44% of the patients, whereas MAAs in 23%. The most frequently detected MSA was anti-Jo-1 (22%), while the most frequently detected MAA was anti-Ro-52 (30%). The distributions of MSAs/MAAs did not differ between the five IIM subgroups, except for anti-Mi-2 which was only detected in dermatomyositis patients. Patients with at least one MSA and/or MAA positivity showed more frequently IIM characteristic skin rashes, while those presenting solely MAA positivity had more often puffy hands and Raynaud's phenomenon. Anti-Jo1-positive patients presented more frequently lung disease, while anti-Ro52 positivity related to mechanic's hands. Anti-Ro-52 and anti-Jo-1 strongly associated with one another. Prevalence of IIM subtypes and of MSAs/MAAs in our patients is in line with published reports in populations of similar geographic distribution. While MSA and/or MAA positivity did associate with particular clinical manifestations, it did not predict in our cohort specific IIM subgroup as defined by the latest EULAR/ACR classification criteria. Future studies are warranted to conclusively decide if these autoantibodies, measured with a standardized method, should or not be incorporated in every day clinical practice to aid IIM diagnosis.