Background:B cells have important functions in the pathogenesis of systemic autoimmune rheumatic diseases (SARDs).Objectives:The purpose of the research was to study the therapeutic option of Rituximab (RTM), a chimeric anti-CD20 antibody, in SARDs such as ANCA-associated systemic vasculitis (AAV), cryoglobulinemic vasculitis (СV), systemic lupus erythematosus (SLE), systemic sclerosis (SS), primary Sjögren syndrome (pSS) and IgG4-related disease (IgG4-RD).Methods:We present data on efficacy and safety of RTM in 515 patients (pts) with SARDs. 103 pts had AAV (58- granulomatosis with polyangiitis, GPA; 35- microscopic polyangiitis, MPA and 10- eosinophilic granulomatosis with polyangiitis, EGPA), 21 pts had CV, 167- SLE, 90- SS, 100- pSS, 34- IgG4-RD. Characteristics of pts and results of RTM treatment are present in Table. Mean follow-up duration after initiation of RTM was 25- 58 months.Results:The average cumulative RTM dose in all groups exceeded 2.4 g, 71% of pts received repeated RTM courses (0.5-1.0 g) every 4 – 12 months. Complete (good) clinical response was achieved in 70-93% pts, except for the SLE (49%- complete response, 32- incomplete and 19%- no response). Usage of repeated RTM courses increased the clinical efficacy and reduced the risk of recurrence. Despite the fact that the study population included a high percentage of pts with severe or refractory SARDs, total mortality rate was about 6% during the follow-up period, highest in CV and AAV (14-11%). In AAV and SLE infections constitute a significant proportion of serious adverse reactions (10-11%). Late-onset neutropenia was only in pts with AAV (12%) and SLE (3%).Conclusion:Treatment with RTM was highly effective in SARDs. In certain SARDs RTM safety profile of should be considered during treatment planning. Further studies of the targeted anti-B-cell therapy, including RTM efficacy and safety in SARDs, clarification of the indications and optimal RTM regimens are needed.Table.ParametersАAVCVSLESSpSSIgG4-RDGPA, MPAEGPAN pts9310211679010034Age, years41(16-67)50(24-71)53,6 + 2941(18-52)47(17-71)42 + 12,247,4 + 15,9Percentage of females56%90%52%92%75%97%60%Duration of disease, months*14(1-288)11(1-180)72(3-96)18(2-47)70(7-264)90(36-168)24(6-60)Cumulative RTM dose, g*3 (0,5-8)3 (1,5-5,5)4,7 + 3,82,4 (1,8±0,8)2,9(0,5-6)5,5 + 1,54 + 1,5Follow-up duration after the first RTM course, month*37(1–96)36(14-94)52(6-108)38(12-67)27(12-42)58(24-96)25(3-60)Clinical response, %Complete (good)93%90%71%49%70%92,5%77%Incomplete response6%10%29%32%24%6,5%23%No response1%0%-19%6%1%-Relapse8%30%--nd--Glucocorticoids dose, mg/day*:Before RTMAfter RTM30(5–60)5(0-10)20(7,5-50)7,5(5-10)4,4(0-24)1,5(0-4)28(15-40)7,5(5-15)12(0-25)9(0-15)7,5(0-40)1,2510(2,5-40)0,5Immunosuppressants% pts before RTM72%90%38%65%43%44%40%% pts after RTM43%70%5%46%50%8%10%Infusion-related reactions,9%20%24%4%2%10%3%including severe-10%-0,6%1%1%-Pts with serious adverse reactions,26%40%5%14%2%5%3%including: infections,11%10%-10%2%5%3%neutropenia10%20%-3%---Deceased pts during the follow-up11%-14%5%6%2%-*Data are provided in the following format: median & min-max range in the bracketsDisclosure of Interests:None declared
BackgroundEfficacy and good tolerability of Rituximab (Rtm) in some refractory to standard care systemic autoimmune rheumatic diseases (SARD) has been demonstrated in several registers (1-3). Although, available evidence is not yet sufficient, thus RTM is used as an off label therapy in systemic lupus erythematosus (SLE), systemic sclerosis (SSc), primary SjÖgren's syndrome (pSS) and polydermatomyositis (PDM).ObjectivesTo evaluate efficacy and tolerability of Rtm in patients with severe SARD when standard of care (SOC) therapy is ineffective or contraindicated, or not tolerated – as it happens in real life clinical setting.MethodsProspective study included 229 pts with SARD: 97 (42,4%) SLE pts; 50 (21,8%) ANCA-associated systemic vasculitis (SV) pts; 40 (17,5%) SSc pts, 23 (10%)- pSS and 19 (8,3%) - PDM. All pts were administered Rtm and conventional therapy consisting of glucocorticoids (GC) and/or immunosuppressants (IS). Median follow up period after first Rtm administration was 23 mo (1-60). The groups were compared based on response to treatment, classified as: complete response, partial response, no response (1).ResultsTotally participating pts received 1-5 Rtm courses during the follow up period. Average Rtm dose received varied from 1,6±0,84 to 3,1±1,75. Improvement was documented in 80,6% pts, complete response was achieved in 50,6% pts and partial response in 30%. The greatest proportion of non-responders was seen in SLE and DMP cohorts (18% and 16%, respectively). GCs were tapered following patients' improvement and/or immunosuppressants were discontinued. Rtm demonstrated accumulation of effect and enhancing efficacy with longer duration of therapy (i.e. repeated courses). In SLE patients repeated Rtm administration allowed to improve the responder's rate, as compared to a single Rtm course (p=0,05). Repeated Rtm course allowed to decrease the relapse rate in ANCA-SV pts (p =0,002). Rtm efficacy in SSc pts inversely correlated with disease duration. Adverse drug reactions (ADRs) were registered in 101 (44%) pts, and the majority of them (73 pts) were coming from SLE and ANCA-SV cohorts. Infectious complications were the most common ADRs, including severe infections (from 2,5% in SSc cohort to 17% in pSS cohort). There were 20 deaths out of 229 participants (8,7%), caused by progression of the disease or infectious complications.ConclusionsComplete or partial response to Rtm therapy was achieved in 80% of SARD patients, refractory to standard of care therapy or having contraindications to SOC. Repeated Rtm courses resulted in sustainable and long term efficacy of therapy allowing to taper or even discontinue conventional therapy agents. Rtm tolerability was satisfactoryReferencesTony HP, Burmester G, Schulze-Koops H et al. Arthritis Res Ther 2011;13:R75.Mariette X, Gottenberg JE, Ravaud P, Combe B. Rheumatology (Oxford). 2011;50:222-9.Ramos-Casals M, García-Hernández FJ, de Ramόn E et al. Clin Exp Rheumatol. 2010; 28: 468-76.Disclosure of InterestNone declared
Purpose of the study. To study the characteristics and frequency of lymphomas in patients with Sjogren's disease (SD) and anticentromere antibodies (ACA); to evaluate the predictors of the development of lymphoproliferative diseases (LPD) in this group of patients. Material and methods. Over the period from 1998 till 2019, 131 ACA-positive patients were under medical supervision at the Research Institute of Rheumatology named after Nasonova V.A. Isolated SD was diagnosed in 82 patients (62.6%), isolated limited form of SSc — in 12 patients (9.2%), combination of SD and limited form of SSc — in 37 patients (28.2%). Lymphoproliferative diseases (LPD) were diagnosed in 20 ACA-positive patients: in 15 — with SD, in 5 — with SD and SSc; no lymphomas were found in the group of patients with isolated SSc. All lymphomas were diagnosed on the basis of histological, immunohistochemical and PCR examination with of B-cell clonality determination in the tissue, and were classified on the base of haematopoietic and lymphoid tissue tumors classification by the World Health Organization. Further analysis included 15 ACA-positive patients with isolated SD and lymphomas. Results. In our study, 18.3% of patients with isolated ACA-positive SD were diagnosed with LPD, represented by MALT lymphomas of the salivary glands (subsequent transformation into aggressive diffuse large B-cell lymphoma (DLBCL) was noted in one patient) in most cases. The course of SD before the diagnosis of LPD was characterized by a gradual progression of dental manifestations of SD with the development of late stages of parenchymal parotitis, severe xerostomia, and significant enlargement of the salivary glands with a minimum number of systemic manifestations of the disease. Significant enlargement of salivary glands, severe infiltration of minor salivary glands, severe xerostomia, decreased level of C4-complement component, monoclonal secretion, low content of CD19+B-cells in peripheral blood, positive B-cell clonality in biopsy material were the main signs of LPD in this study. When diagnosing MALT lymphomas, a focal damage of the salivary glands with no signs of dissemination, no symptoms of B-cell intoxication, and minimal changes in laboratory assessment were found in patients with ACA-positive SD. Conclusion. The natural course of ACA-positive SD and the absence of pathogenetic therapy at an early stage contribute to the development of salivary gland lymphomas in the first 10 years of the disease. Persistent enlargement of the salivary glands in SD, especially in the presence of other predictors of lymphoproliferation, is a direct indication for biopsy followed by the research to exclude the presence of lymphoma.
The detection in serum of monospecifc antibodies that induce a dense fne-speckled fluorescence when interacting with the DFS70 / LEDGF / p75 nuclear antigen is negatively associated with the development of systemic autoimmune rheumatic diseases (SARD) and increases the diagnostic specifcity of the screening study of antinuclear antibodies (ANA) using indirect immunofluorescence on HEp-2 cells (IIF-HEp-2). The results of assessing the clinical signifcance of anti-DFS70 antibodies vary depending on the test systems and the selection of patient groups. The aim of this work is to study the frequency of detection of monospecifc anti-DFS70 antibodies in blood serum in healthy individuals and patients with SARD. Sera of 74 healthy donors and 59 patients with SARD were studied (27 – systemic lupus erythematosus – SLE, 15 – Sjogren's syndrome – SjS, 17 – rheumatoid arthritis – RA). Classical antinuclear antibodies (ANA) and anti-DFS70 antibodies were determined by IIF using a mixture of standard and genetically engineered DFS70-KO HEp-2 cells that do not express DFS70 / LEDGF / p75 as a substrate. 14.9% of healthy donors and 83.1% of SARD patients (96.3% – SLE, 100.0% – SS, 47.1% – RA) were seropositive for antinuclear factor (ANF). Classical ANA with homogeneous, speckled, nucleolar, cytoplasmic, mixed types of fluorescence and the absence of anti-DFS70 antibodies were found in all ANF-positive patients with SARD and in 8.1% of healthy donors. Monospecifc anti-DFS70 antibodies without classical ANA were detected in 6.8% of healthy individuals and were absent in SARS. Among ANF-positive healthy donors, the frequency of isolated detection of anti-DFS70 antibodies was 45.5%. The detection of monospecifc anti-DFS70 antibodies can be considered as a potential predictive marker for excluding the diagnosis of SARD in ANF-positive patients with no or unclear clinical signs of these diseases.
Introduction:The adverse experience in childhood (parental deprivation mostly) (AEC) has an important role in predisposing to mood and immuno-inflammatory rheumatic disorders in adults via chronic stress mechanisms. The primary Sjögren's Syndrome (SS) - a chronic, systemic autoimmune disease, which has some common pathogenic links with stress-related mental disorders.Objectives/Aims:To evaluate the AEC and MD presentation in SS patients.Methods:80 inpatients (mean age 46,2+12,3 yrs) suffering SS were enrolled in the study. MD were diagnosed in accordance with ICD-10 criteria. The severity of depression, anxiety, stress were measured with HADS, MADRS, HAM-A, PSS-10.Results:The AEC had 78,7% of SS patients (recurrent events – 32,5%). Patients with AEC had an increased risk of developing dysthymia (OR=1,34; 95% CI=0,26–6,83) and depressive episode (OR=1,75 (0,35–8,65)) in adults. Recurrent depression was not revealed in patients with ACE. However, patients with AEC had no reliable differences in the MADRS, HAM-A, HADS, PSS-10 compared to patients without AEC. Patients with AEC had an increased risk of suicide attempts (OR=2,15; (0,25–37,2)) and suicidal thoughts (OR=4,58; (0,25–18,5)). The reliable correlations of the severity of SS symptoms (dry eyes/mouth, lymphoma) and AEC have not been confirmed. Patients with AEC had early onset SS (33,6±13,0 vs 38,1±14,2) and MD (28,4±12,6 vs 34,1±13,5) than patients without AEC.Conclusion:AE? is a significant risk factor for depression and suicidal thoughts and attempts in patients suffering SS.
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