IgA vasculitis nephritis-outcomes in adult-onset disease.

OBJECTIVES: IgA vasculitis (IgAV) in adults has been relatively under-investigated. Since outcomes are worse in other forms of vasculitis with increasing age, we investigated the outcomes of IgAV comparing younger adults (18-34), middle aged adults (35-64) and elderly patients (≥64 years) focusing on kidney outcomes. METHODS: We identified patients with renal biopsy confirmed IgAV nephritis and collected data regarding clinical features and progression to end stage kidney disease (ESKD). The relationship between patient factors and ESKD was analysed by regression. RESULTS: We identified 202 cases, 34% aged 18-34, 43% aged 35-64 and 23% were elderly (>64 years). Median follow up was 44 months. Elderly patients were more likely to present with ESKD (23.9%) compared with middle aged (13.7%) and younger adults (2.9%)(χ2 11.6, p= 0.002). In patients with independent kidney function at biopsy, there was no difference in outcomes between age groups. Male gender, Black ethnicity, diabetes, histological evidence of chronic renal damage and eGFR < 30mls/min were risk factors for development of ESKD. In this observational study 68.3% of patients received glucocorticoids and 56.9% additional immunosuppression. CONCLUSIONS: Elderly patients with IgAV are more likely to have ESKD at presentation, but there is no difference in renal survival between age groups, among those presenting with independent renal function. Renal impairment at biopsy is an independent risk factor for subsequent development of ESKD. There is significant variability in the timing of kidney biopsy and management of these patients among specialist centres. Young adults have outcomes more in keeping with childhood IgAV.

Prevalence and Clinical Implications of Scleroderma-Specific Autoantibodies in Seronegative Patients with Sicca Complaints.

Introduction: Previous studies have revealed the presence of anticentromere antibodies in patients with Sjögren's syndrome (SS), predominantly in those serologically negative for antibodies against Ro/SSA and La/SSB antigens (seronegative). The prevalence and clinical significance of specific autoantibodies for Systemic Sclerosis (SSc) in seronegative patients with sicca complaints (dry eyes, dry mouth) have not yet been studied. Aim of the study: Investigate the prevalence and clinical significance of SSc-specific autoantibodies in seronegative patients with sicca complaints. Methods: Among 212 patients with sicca symptoms that were investigated at the Laboratory of Physiology, Medical School of Athens, National and Kapodistrian University of Athens between the years 2017-2020 for the presence of antibodies against Ro/SSA and La/SSB antigens, we found 106 patients that did not meet the criteria for SS following a thorough investigation. We have already performed serological tests of 13 specific autoantibodies for Scleroderma by using the test EUROLINE Systemic Sclerosis (Nucleoli) profile (IgG) (EUROIMMUNE Medizinische Labordiagnostika AG) in 51 of these patients. Additionally, their demographic, clinical, and laboratory data have been recorded. Results: The presence of the specific SSc-specific autoantibodies was noticed in 29/51 patients (57%). More precisely, in 7/29 patients (24%) we recorded NOR90 as well as Th/To, in 5/29 (17%) Ku & Ro52, in 4/29 (14%) CENP-B, in 3/29 (10%) CENP-A & RP155, in 2/29 (7%) RP11 & PM/Scl 75 and finally in 1/29 (3.5%) Scl70, PM/Scl 100 & Fibrillarin respectively. The subsequent follow-up of these patients revealed signs of pulmonary hypertension and interstitial lung disease in some cases. Conclusions: The high prevalence of Scleroderma-specific autoantibodies in seronegative sicca patients discloses those needing tighter follow-up and systematic treatment.

The Role of Myositis-Specific and Myositis-Associated Autoantibodies and the Activation of Type I Interferon Pathway in the Generation of Clinical Phenotypes of Inflammatory Myopathies.

Idiopathic inflammatory myopathies (IIMs) are a group of heterogeneous autoimmune diseases with a prevalence of 20 cases per 100000 of population. Despite their diversity, IMMs are characterised by several common clinical features such as muscle inflammation, proximal muscle weakness, abnormal electromyography and/or muscle biopsy. Over the last years, it has been increasingly recognised that an array of autoantibodies known as myositis-specific antibodies (MSAs) and myositis-associated antibodies (MAAs) are associated with distinct clinical phenotypes and diverse prognosis. Although the exact underlying mechanism of IIMs is not fully understood, accumulating data suggest that the activation of type I interferon pathway plays a central role in disease development. Previous studies have reported the upregulation of type I interferon (IFN) induced genes in peripheral blood and muscle biopsies derived from myositis patients. Given the heterogeneity of inflammatory myopathies along with the central role of type I IFN pathway in disease pathogenesis, the aim of the current study is to elucidate the link between distinct clinical phenotypes of inflammatory myopathies with the presence of serum MSAs or MAAs, as well as with type I IFN activation.

Cardiovascular Magnetic Resonance Demonstrates Myocardial Inflammation of Differing Etiologies and Acuities in Patients with Genetic and Inflammatory Myopathies.

INTRODUCTION: Myopathies are heterogeneous neuromuscular diseases of genetic and/or inflammatory etiology that affect both cardiac and skeletal muscle. We investigated the prevalence of cardiac inflammation in patients with myopathies, cardiovascular symptoms, and normal echocardiography using cardiovascular magnetic resonance (CMR). METHODS: We prospectively evaluated 51 patients with various genetic (n = 23) and inflammatory (n = 28) myopathies (median age, IQR: 12 (11-15) years, 22% girls; 61 (55-65) years, 46% women, respectively) and compared their CMR findings to corresponding age- and sex-matched controls (n = 21 and 20, respectively) and to each other. RESULTS: Patients with genetic myopathy had similar biventricular morphology and function to healthy controls but showed higher late gadolinium enhancement (LGE), native T1 mapping, extracellular volume fraction (ECV), and T2 mapping values. Collectively, 22 (95.7%) patients with genetic myopathy had a positive T1-criterion and 3 (13.0%) had a positive T2-criterion according to the updated Lake Louise criteria. Compared with healthy controls, patients with inflammatory myopathy showed preserved left ventricular (LV) function and reduced LV mass, while all CMR-derived tissue characterization indices were significantly higher (p < 0.001 for all). All patients had a positive T1-criterion, and 27 (96.4%) had a positive T2-criterion. A positive T2-criterion or T2-mapping > 50 ms could discriminate between patients with genetic and inflammatory myopathies with a sensitivity of 96.4% and a specificity of 91.3% (AUC = 0.9557). CONCLUSIONS: The vast majority of symptomatic patients with inflammatory myopathies and normal echocardiography show evidence of acute myocardial inflammation. In contrast, acute inflammation is rare in patients with genetic myopathies, who show evidence of chronic low-grade inflammation.

Scleroderma specific autoantibodies in rheumatoid arthritis and Sjögren's syndrome patients with interstitial lung disease: Prevalence and associations.

Systemic sclerosis (SSc) has been classically linked to interstitial lung disease (ILD) development, often in association with specific SSc autoantibodies. In the present report, we aimed to estimate the prevalence of SSc autoantibodies in 60 seropositive RA and 41 primary SS patients complicated or not by ILD. SSc autoantibodies were determined in patients' sera by a commercial immunoblot assay. RA ILD patients displayed higher frequency of SSc-specific antibodies at strong titers compared to RA-with no lung involvement (25% vs 3.1%, p = 0.01)[OR 95% CI:10.9 (1.2-94.5)], with no differences detected between primary SS groups. These data indicate that many seropositive RA ILD patients probably represent an overlap RA/SSc entity, requiring tailored diagnostic and therapeutic approach.

Treatment Satisfaction, Patient Preferences, and the Impact of Suboptimal Disease Control in Rheumatoid Arthritis Patients in Greece: Analysis of the Greek Cohort of SENSE study.

Objectives: SENSE was an international, non-interventional cross-sectional study that assessed treatment satisfaction in patients with suboptimally controlled active rheumatoid arthritis (RA) who were under treatment with any approved agent exposed to ≤ 2 biological disease-modifying anti-rheumatic drugs (DMARDs) at the time of enrolment. The current publication concerns the subanalysis of the results from the Greek cohort. Methods: Treatment satisfaction was assessed with Treatment Satisfaction Questionnaire for Medication (TSQM), with good treatment satisfaction defined as TSQM global ≥80. Adherence to therapy was recorded on a visual analogue scale (VAS) and treatment expectations were assessed on a 7-point numerical rating scale. Results: Of 121 patients, 82.6% were women, of mean age 64.8 years and mean time from diagnosis 8.4 years. Patients had active disease (mean DAS28-ESR 4.5) and compromised functional status (mean [SD] HAQ-DI 1.1 [0.7]) while on treatment (43.8% on biologics and 5% on steroids). The mean TSQM global was 66.9. Treatment expectations were "general improvement of arthritis" and "less joint pain" (mean score [SD], 4.9 [1.8] each), "more joint flexibility" (4.8 [1.9]), and "lasting relief of RA symptoms" (4.8 [2.1]). Oral administration was preferred by 65.3% of patients. Good self-reported adherence (≥80%) was recorded in 93.4% of the patients. Treatment switch to another DMARD was planned by treating rheumatologist for only 49.6% of the participants, despite suboptimal RA control. Conclusion: Patients with suboptimally controlled RA in Greece have low treatment satisfaction and poor self-reported outcomes, albeit high self-reported treatment adherence. Similarly to the global SENSE study results, the need for patient-centric treatment approaches in order to improve disease outcomes is emphasised.

Scleroderma-specific autoantibodies: Should they be included in the diagnostic work-up for Sjögren's syndrome?

OBJECTIVES: Sicca complaints are a frequent reason for rheumatologic consultation. Testing for specific antibodies against Ro/SSA and La/SSB antigens and minor salivary gland (MSG) biopsy are among the main tools implemented in the diagnostic work-up. Anticentromere antibodies and sicca manifestations are frequently detected in Sjögren's syndrome (SS) and systemic sclerosis (SSc), respectively. Herein, we aimed to determine the frequency and clinical associations of a wide spectrum of scleroderma (SSc)-specific autoantibodies in consecutive patients referred for evaluation of possible SS. METHODS: Demographic, clinico-pathological, and laboratory data were recorded in 216 consecutive patients with sicca complaints. All study participants were tested for SSc-specific autoantibodies (against CENP, PM/Scl, Scl-70, Ku, NOR90, RP11, RP155, fibrillarin, PDGFR, and Th/To) using a commercially available immunoblot kit. According to band intensity, the identified autoantibodies were further classified in those with strong and medium titers. RESULTS: SSc-specific autoantibodies were detected in 41.7% (90/216) patients evaluated (19% at strong, 22.7% at medium titers) without significant differences between anti-Ro/SSA positive and negative groups. At strong titers was significantly higher in patients with MSG biopsies fulfilling SS histopathological criteria (30% vs 12.5%, p = 0.009). This association remained significant after adjustment for antibodies against Ro/SSA and La/SSB autoantigens [OR 95% (CI): 4.1 (1.5-10.6)]. CONCLUSION: SSc-specific autoantibodies are frequently detected among patients presenting with sicca complaints and at strong but not medium titers are independently associated with MSG biopsy positivity. Taken together, these data imply a useful role of SSc antibody testing in the diagnostic work-up and possibly in the classification criteria for SS.

+3179G/A Insulin-Like Growth Factor-1 Receptor Polymorphism: A Novel Susceptibility Contributor in Anti-Ro/SSA Positive Patients with Sjögren's Syndrome: Potential Clinical and Pathogenetic Implications.

BACKGROUND: Alterations of the insulin-like growth factor (IGF) pathway along with genetic variations of the IGF1 receptor (IGF1R) gene have been linked to the development of systemic autoimmunity, possibly through apoptosis induction. This study aims to investigate whether genetic variations of the IGF1R contribute to Sjögren's syndrome (SS) pathogenesis and explores potential functional implications. METHODS: DNA extracted from whole peripheral blood derived from 277 primary SS patients, complicated or not by lymphoma, and 337 Healthy controls (HC) was genotyped for the rs2229765 IGF1R polymorphism using the RFLP-PCR assay. Gene expression of IGF1R and IGF1 isoforms, caspases 1, 4, and 5, and inflammasome components NLRP3, ASC, IL1ß, IL18, IL33, IGFBP3, and IGFBP6 were quantitated by RT-PCR in total RNA extracted from minor salivary gland biopsies (MSGs) of 50 SS patients and 13 sicca controls (SCs). In addition, IGF1R immunohistochemical (IHC) expression was assessed in formalin-fixed, paraffin-embedded MSG tissue sections derived from 10 SS patients and 5 SCs. RESULTS: The prevalence of the A/A genotype of the rs2229765 IGF1R polymorphism was significantly higher in the anti-Ro/SSA positive SS population compared to healthy controls (24.8% vs. 10.7%, p = 0.001). Moreover, IGF1Rs at both mRNA and protein levels were reduced in SS-derived MSGs compared to SCs and were negatively associated with caspase 1 transcripts. The latter were positively correlated with NLRP3, ASC, and IL1ß at the salivary gland tissue level. IGF1R expression in peripheral blood was negatively correlated with ESR and IgG serum levels and positively correlated with urine-specific gravity values. CONCLUSIONS: The rs2229765 IGF1R variant confers increased susceptibility for seropositive primary SS. Dampened IGF1R mRNA and protein expression in salivary gland tissues could be related to increased apoptosis and subsequently to the activation of inflammasome pathways.

The Role of Novel Autoantibodies in the Diagnostic Approach and Prognosis of Patients with Raynaud's Phenomenon.

Raynaud's phenomenon (RP) is a condition characterised by distinct colour changes of the digits upon exposure to sympathomimetic conditions, such as cold temperature. It can be either primary or secondary, depending on whether it presents alone or as part of an underlying disorder. One of the most common causes of secondary RP are systemic autoimmune rheumatic diseases (SARDs), in which RP may precede the onset of other autoimmune features by many years. Thus, timely and accurate recognition of secondary RP is of great importance as it alters patient management and prognosis. An important step in the diagnostic approach of RP is the detection of antinuclear antibodies (ANAs) by indirect immunofluorescence. However, identification of specific autoantibodies is not yet common practice, though many of them have shown important clinical associations. Moreover, the role of some autoantibodies has not yet been elucidated, given their relatively recent discovery and low reported prevalence rates in autoimmune population. The goal of this study is to reveal clinical associations of these novel autoantibodies in SARDs through the application of an extended serology workup in patients presenting with RP.

Molecular and clinical spectrum of four pedigrees of TRAPS in Greece: results from a national referral center.

OBJECTIVE: Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) is a rare autosomal dominantly inherited autoinflammatory disease caused by mutations of the TNFRSF1A gene. To address the association between TNFRSF1A mutations and clinical phenotype, we analyzed four pedigrees of TRAPS patients. METHODS: Four Greek patients with TRAPS-like clinical features were screened for TNFRSF1A mutations by sequencing exons 2, 3 and 4. Following positive testing, twenty-two members of their families were also genetically and clinically screened. RESULTS: Twenty-six members of four unrelated Greek families were investigated. The C73Y (c.305G>A) mutation of the TNFRSF1A gene was identified in five patients, with two of the five carrying a concomitant R92Q variation. We also identified seven C73W (c.306C>G), two T50M (c.236C>T) and seven R92Q (c.362G>A) carriers. Symptoms varied and the C73Y, C73W and T50M mutations were associated with the most severe clinical manifestations. The R92Q phenotype ranged from asymptomatic to mild disease. Molecular modelling linked pathogenicity with aberrant TNFRSF1A disulphide bond formation. CONCLUSION: In this first pedigree analysis of TRAPS in Greece, we identified the rare C73Y TNFRSF1A mutation. A wide clinical spectrum was observed with the C73Y, C73W and T50M mutations that affect TNFRSF1A disulphide bonds and are associated with worse symptoms.

Type I interferon signature in Sjögren's syndrome: pathophysiological and clinical implications.

Type I interferons (IFN) have long been recognised as mediators of innate immune defense mechanisms against viral threats. Robust evidence over the last 15 years revealed their significant role in the pathogenesis of systemic autoimmune diseases, including systemic lupus erythematosus (SLE) and Sjögren's syndrome (SS). Despite the progress, methods of detection, initial triggers, biological functions and clinical associations in the setting of autoimmunity remain to be fully clarified. As therapeutic options for SS are currently limited, neutralising specific targets of the type I IFN pathway seems a promising option. In this review we summarise the current evidence regarding the role of type I IFN in SS.

Biologics in Sjögren's syndrome.

The use of biologic disease modifying antirheumatic drugs (bDMARDs) in systemic autoimmune diseases such as rheumatoid arthritis and at a lesser extent in lupus, has been well established. In Sjögren's syndrome (SS), despite the shared pathogenetic mechanisms with other autoimmune disorders, traditional immunomodulatory drugs have failed to address the main clinical features of the disease and use of biologics has been limited so far. Over the last years, our better understanding in disease pathogenesis has led to an expansion in the number of clinical trials exploring the effect and safety of biological agents with variable results. In the current review, the effect of targeting key molecular mechanisms involved in SS pathogenesis such as antigen presentation, B and T cell activation and germinal center formation is discussed.

Canakinumab for refractory RA: a case report.

Rheumatoid arthritis is a common autoimmune disease leading often to joint destruction and reduced quality of life. We report a case of a young woman with rheumatoid arthritis with fever and rapid, destructive joint involvement verified with magnetic resonance imaging. She had failed therapy with methotrexate and leflunomide, anti-TNF, IL-6 inhibitor, B cell depletion and IL-1RA. Her laboratory results remained insignificant despite the aggressiveness of her disease. In this case, the patient only partly responded to anakinra but developed side effects, and therefore was switched to Canakinumab that led to sustained remission. There are no clear biomarkers or other clues in order to separate early in the beginning of the disease course if a polyarticular inflammatory spectrum can be IL-1ß driven. The young age of the patient at onset of disease, its aggressive course, inflammatory fever without significant laboratory inflammatory markers but with polyarthritis affecting small joints, may raise the suspicion of an IL-1ß-driven disease and alert the treating rheumatologist to the use of IL-1ß inhibitors early in the disease course.

Diabetic nephropathy in type 1 diabetes.

Diabetic nephropathy (DN) also named diabetic kidney disease (DN) is one of the leading causes of mortality in people with diabetes. The aim of this review is to update the medical literature, the theories behind its early natural history, the pathways of its pathogenesis, its diagnosis and treatment. Poor glycemic control, hyperlipidemia, smoking, oxidative stress, accumulation of advanced glycated end products, environmental, genetic and epigenetic factors play an important role in the pathophysiological development of DN. Microalbuminuria has been traditionally used as the primary early diagnostic marker of microvascular complication unraveling the risk for progress to severe cardiorenal outcomes, but its prognostic role has been recently debated. The disease often leads to end-stage renal disease and it is often associated with major cardiovascular outcomes. Its early diagnosis is crucial for the patients in order to have a chance for proper treatment.

Biomarkers of diabetic nephropathy: A 2017 update.

Diabetic nephropathy (DN), also named diabetic kidney disease (DKD), is a devastating complication in patients with both type 1 and 2 diabetes mellitus (T1D and T2D) and its diagnosis has been traditionally based on the presence of micro-albuminuria (MA). The aim of this article is to update, through review of the relevant medical literature, the most promising biomarkers for early DKD detection. MA has historically been employed as an early marker of microvascular complications, indicating risk for advanced CKD. However, due to the inability of MA to adequately predict DKD, especially in young patients or in non-albuminuric DKD, additional biomarkers of glomerular and/or tubular injury have been proposed to uncover early renal dysfunction and structural lesions, even before MA occurs. Defining new predictive biomarkers to use alongside urinary albumin excretion (UAE) during the initial stages of DKD would provide a window of opportunity for preventive and/or therapeutic interventions to prevent or delay the onset of irreversible long-term complications and to improve outcomes by minimizing the rates of severe cardio-renal morbidity and mortality in DKD patients.