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.

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.

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.

Tongue Atrophy in Sjögren Syndrome Patients with Mucosa-associated Lymphoid Tissue Lymphoma: Autoimmune Epithelitis beyond the Epithelial Cells of Salivary Glands?

OBJECTIVE: Primary Sjögren syndrome (pSS), an autoimmune epithelitis, bears the risk of evolving to non-Hodgkin lymphoma and most frequently to the mucosa-associated lymphoid tissue (MALT) subtype. Based on the observation that pSS patients with MALT present a more atrophic and more intensely fissured tongue, we aimed to semiquantify severity of tongue atrophy and clinically assess lingual appearance in pSS patients with and without MALT, and investigate whether tongue atrophy and fissured appearance could serve as clinical indicators/signs of MALT. METHODS: A blinded complete oral examination was performed in pSS patients with and without MALT. Tongue atrophy was scored using a semiquantified atrophy score. Clinical and laboratory variables were recorded for all patients. RESULTS: After excluding pSS patients with oral candidiasis, iron deficiency, and megaloblastic anemia, 19 pSS patients with salivary MALT were matched 1:3 for age, sex, and disease duration with 57 pSS patients without MALT. The pSS-MALT patients had increased prevalence of salivary gland enlargement, lymphadenopathy, monoclonal gammopathy, rheumatoid factor positivity, higher focus and Tarpley scores in the minor salivary gland biopsy, and hyposalivation, compared to the pSS non-MALT patients. A significantly higher prevalence of tongue atrophy (68% vs 30%, p = 0.006) and fissured tongue (89% vs 33%, p < 0.001) was observed in the former group. Multivariate analysis showed that fissured tongue appearance, hyposalivation, and lymphadenopathy associate independently with salivary MALT in pSS. CONCLUSION: These results suggest that pSS patients with lymphoid malignancy exhibit a more atrophic and more fissured tongue. This particular clinical tongue appearance can serve as an additional clinical sign for salivary MALT lymphoma in pSS patients.

Impact of risk factors associated with cardiovascular outcomes in patients with rheumatoid arthritis.

OBJECTIVES: Patients with rheumatoid arthritis (RA) have an excess risk of cardiovascular disease (CVD). We aimed to assess the impact of CVD risk factors, including potential sex differences, and RA-specific variables on CVD outcome in a large, international cohort of patients with RA. METHODS: In 13 rheumatology centres, data on CVD risk factors and RA characteristics were collected at baseline. CVD outcomes (myocardial infarction, angina, revascularisation, stroke, peripheral vascular disease and CVD death) were collected using standardised definitions. RESULTS: 5638 patients with RA and no prior CVD were included (mean age: 55.3 (SD: 14.0) years, 76% women). During mean follow-up of 5.8 (SD: 4.4) years, 148 men and 241 women developed a CVD event (10-year cumulative incidence 20.9% and 11.1%, respectively). Men had a higher burden of CVD risk factors, including increased blood pressure, higher total cholesterol and smoking prevalence than women (all p<0.001). Among the traditional CVD risk factors, smoking and hypertension had the highest population attributable risk (PAR) overall and among both sexes, followed by total cholesterol. The PAR for Disease Activity Score and for seropositivity were comparable in magnitude to the PAR for lipids. A total of 70% of CVD events were attributable to all CVD risk factors and RA characteristics combined (separately 49% CVD risk factors and 30% RA characteristics). CONCLUSIONS: In a large, international cohort of patients with RA, 30% of CVD events were attributable to RA characteristics. This finding indicates that RA characteristics play an important role in efforts to reduce CVD risk among patients with RA.

A comprehensive evaluation for the treatment of lupus nephritis.

Systemic lupus is the prototypic human autoimmune disease. It is a kaleidoscope of autoreactivities, with clear indications of both a genetic and environmental basis. Indeed, it is a disease that can manifest in virtually every tissue and organ and can also be found spontaneously in a number of animal species, including dogs, cats and horses. Moreover, there are multiple murine models of lupus, the first of which, New Zealand Black (NZB) mice, were discovered in 1959. Despite an enormous effort from scientists in multiple disciplines, the etiology of lupus remains elusive and the introduction of new therapies has been disappointing. Fortunately, significant advances have occurred to help patients through the general principles of internal medicine, including antibiotics, dialysis, and of course use of steroids and immunosuppressive agents. However, the magic bullet has yet to be discovered. One of the major causes of morbidity in lupus remains lupus nephritis and there has been significant effort and encouragement in understanding the pathogenesis, renal histologic classification, and use of therapeutic protocols to induce and sustain remission of lupus nephritis. Indeed, the first use of evidence-based clinical trials in lupus was initiated by Dr. Alfred D. Steinberg at NIH in pioneering studies involving either oral or intravenous pulses of cyclophosphamide, azathioprine or corticosteroids alone and/or some combination. Cyclophosphamide intravenously proved to be superior and the use of cyclophosphamide in combination with methylprednisolone remained the standard protocol for the treatment of lupus nephritis for decades. Although alternative therapies have been introduced, including mycophenolate mofetil, the use of therapies first pioneered at NIH may still be considered standard of care in the appropriate indications. More targeted therapies are much desired. In this review we provide a comprehensive overview of lupus nephritis and the evolution of clinical treatments.

Predictors of new atherosclerotic carotid plaque development in patients with rheumatoid arthritis: a longitudinal study.

INTRODUCTION: Rheumatoid arthritis (RA) is associated with increased cardiovascular morbidity and mortality attributed to both classical risk factors and chronic inflammation. We assessed longitudinally the factors associated with new carotid plaques in nondiabetic RA patients and apparently healthy individuals. METHODS: In our present prospective observational study, carotid plaques were identified by ultrasonography at baseline and follow-up end, separated by an average of 3.6 ± 0.2 years, in 64 patients (mean age 59.2 ± 12.0 and disease duration at baseline 7.8 ± 6.2 years, 83% women, clinical and laboratory evaluation every 3 to 6 months). In a substudy, 35 of the patients were matched 1:1 for traditional cardiovascular risk factors with 'healthy' controls and were studied in parallel. RESULTS: New atherosclerotic plaques formed in 30% of patients (first plaque in 9%) who were significantly older than the remaining patients. Tobacco use, blood pressure, body mass index, average cumulative low-density lipoprotein, high-sensitivity C-reactive protein, erythrocyte sedimentation rate level, RA stage, functional class, disease duration and treatment modalities during follow-up did not differ significantly between subgroups after application of the Bonferroni correction. RA was in clinical remission, on average, for approximately 70% of the follow-up time and was not different between subgroups. Multivariate analysis including all the above parameters revealed that age (P = 0.006), smoking (P = 0.009) and duration of low-dose corticosteroid use (P = 0.016) associated independently with new plaque formation. RA patients displayed similar numbers of newly formed carotid plaques to the tightly matched for traditional cardiovascular risk factors 'healthy' controls, although more patients than controls had carotid plaques at baseline. CONCLUSIONS: Formation of new atherosclerotic plaques in this small cohort of patients with well-controlled RA depended mainly on traditional cardiovascular risk factors and corticosteroid use, whereas an adverse effect of residual systemic inflammation was not readily detectable.

Histamine H3 and H4 receptors as novel drug targets.

The identification of histamine H3 (H3R) and H4 (H4R) receptors some years ago revived interest in histamine research and exposed attractive perspectives for the potential therapeutic exploitation of these new drug targets. While the H3R is mainly localised in the CNS, the H4R is primarily expressed in hematopoietic cells, indicating their function in neurotransmission and immunomodulation, respectively. Although structural similarities between H3R and H4R and species differences in their pharmacological profiles are causes of limitations in the evaluation of their biological profile, the development of selective ligands for these receptors facilitates the elucidation of their physiological and pathophysiological functions. The H3R is a recognised drug target for neuronal diseases, such as cognitive impairment, schizophrenia, sleep/wake disorders, epilepsy and neuropathic pain; a small number of selective H3R antagonists have already passed some clinical Phase II trials. The H4R is the newest identified member of the histamine receptor family. Preclinical data strongly suggest its potential therapeutic exploitation in allergy, inflammation, autoimmune disorders and possibly cancer. Considering the topicality of this area of research, this review focuses on the pharmacology of selected promising indications and the rationales for the application of H3R and H4R ligands.