The findings results confirm the important role of STAT4 gene in the predisposition to SSC and its phenotypes, such as DF, ILD, CI, and ATA in the Russian population.
Background Individual response to biological treatment is highly variable and potentially subject to genetics influence. There is a need for biomarkers that are able to predict clinical response to rituximab (RTX) treatment. Objectives To examine whether there are genetic polymorphisms associated with response to RTX therapy. Methods 53 RA patients receiving RTX therapy were included in this pharmacogenetic prospective study (mean age 51±15 years and mean disease duration 8.2±6.2 years). Response to RTX therapy was evaluated using the EULAR criteria (DAS28-ESR) at 6 months after the first RTX course (two intravenous infusions at weeks 0 and 2). The following gene polymorphisms (SNPs) were genotyped: IL-6 (rs1800795), IL-6RA (rs8192284), TNFA (rs1800629), TNFAIP3 (rs675520, rs6920220, rs10499194), MCP-1/CCL2 (rs1024611), CTLA4 (rs3087243), PTPN22 (rs2476601). Comparison of responses for the following groups (good responders vs moderate/non responders, and good responders vs moderate responders) was evaluated using logistic regression, and the results were expressed as ORs with 95% CI. Results After the 1st RTX course a good response was achieved in 18 (40,0%) patients. 29 (54,7%) patients were defined as moderate responders and 6 (11,3%) patients as non-responders. A SNP at TNFAIP3 locus (rs675520) tended to be associated with the response to RTX treatment in both groups of responders vs moderate/non responders (OR 4,6, 95% CI 0,9-23,6, p=0,06) and responders vs moderate responders (OR 4,8, 95% CI 0,9-25,5, p=0,062). The patients with homozygous genotype CC had the worse results than patients with CT and TT genotypes in the swollen joint count (p=0,036), tender joint count (p=0,034), DAS28 (p=0,01) and HAQ (p=0,01) at 6 months after the first course of treatment. No evidence for association was detected at the other SNPs tested Conclusions Our preliminary results suggest the TNFAIP3 SNP (rs675520) may possibly influence the response to RTX therapy. This finding requires replication in additional patients groups. Disclosure of Interest None Declared
BackgroundAutoantibodies against intracellular antigens are a serological hallmark of ANA-associated systemic autoimmune rheumatic diseases (AARD) such as SLE. IIF on HEp-2 cells for ANA remains the “gold standard” but it has very low positive predictive value. Up to 20% of serum samples from HI have been reported to have a positive ANA IIF test, the majority of them due to the presence of anti-dense fine speckled 70 (anti-DFS70) antibodies. Monospecific anti-DFS70 antibodies represent a biomarker that can be used to discriminate AARD patients (pts) from HI in ANA IIF positive subjects. Recognition of the DFS70 ANA IIF pattern can be challenging. The DFS-KO Hep-2 cells inhibit anti-DFS70 antibodies reactions, providing clear differentiation of the DFS pattern from classical ANA patterns.ObjectivesTo evaluate the utility of a novel HEp-2/DFS70-KO IIF substrate for the detection of anti-DFS70 antibodies in HI and SLE pts.MethodsWe studied 45 HI (36 F/9 M; age 50.4 [24.0–72.0] years, median [interquartile range 25–75%]) and 12 pts with SLE (ACR criteria, 1997) (10 F/2M, age 38.9 [17.0–65.0] years; disease duration 100.3 [4.0–432.0] months; SLEDAI 2K score 11.7 [2–30]; SLICC damage index score 1.28 [0–4]). Serum samples were tested for classical ANA and anti-DFS70 antibodies by IIF technique with a mixture of standard HEp-2 cells and DFS70-KO HEp-2 cells (“Trinity Biotech”, Bray, Ireland) as a substrate. Fluorescence titers ≥1: 160 were considered as positive for ANA patterns.ResultsANA were present in 7/45 (15.6%) of HI and in 12/12 (100%) of SLE pts. All SLE pts and 3/45 (6.7%) of HI showed classic ANA patterns (homogeneous, speckled, and mixed) in the absence of DFS70 pattern. 4/45 (8.9%) of HI had classic ANA negative/anti-DFS70 antibodies positive IIF results. Isolated anti-DFS70 antibodies were found in 57% of ANA IIF positive HI. Among HI classic ANA and anti-DFS70 antibodies were detected in the low- to medium-titer range (1:160–1:320). The frequency of anti-DFS70 antibodies did not correlated with age.ConclusionsThe detection of isolated anti-DFS70 antibodies may be regarded as an exclusion criterion for the diagnosis of SLE. The testing for anti-DFS70 antibodies in a single step by HEp-2/DFS70-KO IIF method should be included into a modified ANA diagnostic algorithm. Additional investigations are required to evaluate the clinical relevance of anti-DFS70 autoantibodies.Disclosure of InterestNone declared
ObjectivesTo assess the efficacy of a rituximab and belimumab combination therapy in pts with active SLE and dynamics of CD19+ B-lymphocytes count in treated pts.MethodsThe study included 7 SLE pts (1M/6F) with high (SLEDAI2K≥10 – 4pts.) and moderate (SLEDAI2K<10- 2pts.) disease activity; out of them 1 patient had lupus nephritis, 1- vasculitis, and remaining 5 had predominantly mucocutaneous and articular manifestations of SLE. The dose of oral GCs at baseline did not exceed 20 mg/day, two pts were treated with prednisone 5 mg/day. The damage index at baseline was 0 in 3 pts,≤1 in 3pts, and ≥1 – in 1 patient. Rituximab (RTM) was administered at 500–1000 mg, with subsequent adding of Belimumab (BLM) 3 months later at a standard dosing regimen 10 mg/kg once a month during 9mo. CD19+ B- lymphocytes counts were obtained before initiation RTM (0), and subsequently after 3, 6, 9, and 12mo. Depletion of CD19+ B- lymphocytes after RTM was assessed as the decrease of B-cell counts after 3mo<0,01 10*9/l, where 0 10*9/l was categorised as complete depletion, from 0001 to 0,01 10*9/l – partial depletion, and >0,011 10*9/l – absence of depletion. The comparison group included 20 pts receiving a single 500–2000 mg dose of RTM.Results6 pts demonstrated the decrease in clinical and laboratory SLE activity, starting from 3mo of follow-up (SLEDAI-2K 0 mo–Me 10, 9;16 3mo-Me 8, 4;86mo–Me 4, 2;6 9mo–Me 5,4;10 12mo–Me 2 2;6) with RTM+BLM combination therapy. The oral GCs dose was reduced to 7,5 5;10mg/day by 12mo, none of the patient required prednisone dose escalation during follow-up. There were no cases of severe infection. The damage index did not increase by 12mo. The combination therapy reduced the absolute counts of CD19+. B-cells. RTM therapy resulted in complete depletion in 2 pts, in partial depletion – in 3; in 1 patient the depletion was not documented. Addition of BLM resulted in slowing down of CD19+ B-cell repopulation (figure 1) among pts with complete and partial depletion (0mo–Me 0,11 × 109/l[0,1;0,28], 12mo -Me 0,01 × 109/l[0,0085; 0025]) vs pts receiving RTM monotherapy (0mo–Me 0,1 × 109/l[0,06;0,2], 12mo -Me 0,03 × 109/l[0,008; 0,08]). The decrease in CD19+ B-cell counts after RTM was also documented in the patient who didn’t develop depletion initially (0mo–0,5 10*9/l, 12mo-0,04 10*9/l). RTM and BLM combination failure, as well as failure of standard GCS and cytostatic based therapy, was documented in one patient with cutaneous, articular and haematological SLE.Abstract FRI0313 – Figure 1Dynamics in CD19+ B-lymphocytes in pts treated RTM and RTM+BLM combination therapyConclusionsCombination therapy allows to gain control over disease activity in short time, due to the effect of RTM, while added BLM provides further prolongation of the effect achieved, minimising the risk of exacerbation. This combination may be used as a method of choice in pts with severe SLE involving vital organs, and in persistent cutaneous-articular disease and high immunological activity. Of notice is the fact, that use of RTM and BLM combi...
Иммуногенетические аспекты раннего ревматоидного артрита Изучено распределение аллелей гена HLA-DRB1 у больных ранним ревматоидным артритом и здоровых лиц контрольной группы российской популяции и оценена их значимость в качестве молекулярно-генетических маркеров предрасположенности и протекции ревматоидного артрита. Определена сила ассоциативной связи аллелей гена HLA-DRB1 с продукцией антител к циклическим цитруллинированным пептидам и ревматоидному фактору класса М. В исследовании проведено сравнение методов высоко-и низкоразрешающего генотипирования аллелей HLA-DRB1. У больных ранним ревматоидным артритом обнаружены аллели гена HLA-DRB1, являющиеся маркерами риска и протекции ревматоидного артрита, детерминирующие продукцию антител к циклическим цитруллинированным пептидам, но не ассоциированные с антителами класса M к ревматоидному фактору. Полученные данные могут свидетельствовать о различных аутоиммунных механизмах патогенеза ревматоидного артрита. Ключевые слова: ревматоидный артрит, HLA-DRB1, shared epitope, антитела к циклическим цитруллинированным пептидам, ревматоидный фактор.
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