Background:A sound experience has been accumulated up to date with the use of rituximab (RTХ) for treatment of systemic sclerosis (SSc). Some studies reported improvement of skin fibrosis following treatment with RTХ, but long-term follow-ups are really few.Objectives:to evaluate the effect of RTХ on the manifestations of skin fibrosis in patients (pts) with SSc in the long-term follow-up.Methods:This prospective study included 71 pts aged 46 years (17-66) on average, 59 (83%) pts were females, mean disease duration was 5,6±4,4 years, and mean follow-up - 42 months (12-72) (mo). Diffuse SSc was established in 42 (59%) pts. All pts received glucocorticoids in low doses. 45% of pts were receiving immunosuppressants at study entry. The following parameters were evaluated: Rodnan skin score (mRSS), interdigital space(IDS) (the distance between the tips of 1 and 5 fingers at maximum extension), oral aperture (OAp) and activity index (EScSG-AI) over the periods: 12-18 mo, 24-30 mo, 36-42 mo, 48-54 mo and 60-72 mo after initiation of RTX therapy. The results are presented as: mean values, delta (Δ), median, upper and lower quartiles.Results:RTX therapy resulted in significant decrease of disease activity index, which statistically significantly correlated with decrease of mRSS - the main indicator of the severity of skin fibrosis (r=0,39;p=0,001). Changes in parameters by follow-up periods are presented in the Table 1.Table 1.Changes in clinical and instrumental parameters at RTX treatment (delta; median; lower quartile; upper quartile).Parameters12-18 mo (n=71)24-30 mo (n=55)36-42 mo (n=36)48-54 mo (n=24)60-72 mo (n=17)ΔmRSS3,32 [3.3; 0; 8]5,4 [3; 0; 10]5,1 [3,5; 0; 9]5,3 [3; 0; 10]7,3 [5; 1; 14]p=0,001p=0,001p=0,001p=0,001p=0,001ΔOAp, cm0,24 [0,1; 0; 0,5]0,26 [0,1; 0; 0,6]0,39 [0,2; 0; 0,8]0,31 [0.3; 0; 0,7]0,36 [0,2; 0; 0,8]p=0,0009p=0,0006p=0,004p=0,006p=0,009ΔActivity index (EScSG-AI)1,49 [1,5; 0; 2,5]1,64 [1,5; 0; 2,5]1,11 [1; 0; 2]2 [2; 1; 3]2,17 [2; 1,5; 2]p=0,001p=0,001p=0,0001p=0,0001p=0,0001Cumulative dose of RTX, g1,43±0,62,97±0,83,45±1,33,96±1,15,15±1,7Decreasing of mRSS statistically significantly correlated with increasing cumulative dose of RTX (r=0,29;p=0,01). Decreasing disease activity index correlated with increasing cumulative dose of RTX (r=-0,37; p=0,01). IDS improvement was documented at all assessment time periods, although statistically insignificant.Conclusion:The results of this study confirm reported positive effect of RTX on the reduction of skin fibrosis in SSc. Long-term follow-up demonstrated steadily decreasing skin fibrosis and improvement of microstomia with increasing oral aperture in parallel with a decrease of the disease activity index and increasing cumulative dose of RTX.Disclosure of Interests:None declared

Background:Patients with systemic sclerosis positive for anti-U1RNP have special clinical picture and disease progression. The autoimmune profile in this group is poorly understood.Objectives:The purpose of our work was to study the level of major autoantibodies in patients with systemic sclerosis positive for anti-U1RNP.Methods:The study included 80 patients (71 women and 9 men, mean age 44,5±14 years) positive for antibodies to RNP and meeting the criteria of the systemic sclerosis (ACR/EULAR 2013). Patients were examined for autoantibodies: RF, ACCP, ACA, anti-Scl70, anti-RNAP-III, anti-Ro, anti-La, anti-dsDNA, anti-Sm, ACL, anti-Jo1. 44 patients were examined in dynamics in 24 months.Results:In the study group the clinical picture was dominated by inflammatory musculoskeletal lesions (synovitis and myopathy), skin manifestations were poorly expressed. Interstitial lung disease was detected in 68% of cases. Overlaps (34%) with other rheumatic diseases (rheumatoid arthritis, systemic lupus erythematosus) and combination with Sjogren’s syndrome (32.5%) were frequently noted. Other antibodies were often detected: commonly - RF (31%), anti-Ro (38%), anti-dsDNA (42%), rarely - anti-Sm (11%), ACCP (8%), anti-La (8%), ACA (6%), anti-Scl70 (6%), AKL (2%). Anti-Jo1 and anti-RNAP-III were not detected at all. In patients with systemic sclerosis highly-positive for anti-U1RNP (more than 2 upper normal limits) RF, anti-Ro, anti-dsDNA were significantly more common in comparison with low-positive(p=0.00). In dynamics 80% of patients maintained anti-U1RNP, while other autoantibodies were detected with the same frequency. In patients with initially low titer of anti-U1RNP, their disappearance was noted.Conclusion:Patients with systemic sclerosis positive for anti-U1RNP differ in the predominance of inflammatory musculoskeletal manifestations and frequent combination with Sjogren’s syndrome and overlaps. Highly positivity for anti-U1RNP is accompanied by a persistent increase in RF, anti-Ro, anti-dsDNADisclosure of Interests:None declared

Background:Interstitial lung disease (ILD) frequently complicates SSc and can be a debilitating disorder with a poor prognosis. Several risk factors for progressive SSc-ILD have been identified and prognostic scoring systems have identified predictors of mortality. It’s important to develop treatment recommendation.Objectives:To use the discrimination function for pts with SSc-ILD and highlight pts with different prognosis.Methods:It was a longitudinal study involving 140pts with SSc-ILD. The mean age was 46.7±13.9ys, females 82%, SSc duration 6.2±5.8ys, diff subset-54%. The mean duration of follow up was 73,2±27,8months. All pts received low- and moderate-dose glucocorticoids (Gc), RTM (the mean dose 3,14±2,38g) and 77 pts had received parenteral CyP(mean dose 15,9±15,6g).We have got the discrimination function that included: ground glass opacities (GGO)(1–the absents of GGO; 2–the presents of GGO); index EScSG(the digital value); FVC(FVC≥75=0, FVC<75=1); the maximum daily dose of Gc (the digital value,mg); Gamma globulins (the digital value,%); cyclophosphamide (CYC) (the absence of CyP=0, the treatment of CYC =1);DLco(DLco<52% =0, DLco≥52=1). We assessed all parameters at the entry in the study except DLco evaluated after one year of follow up. Based on this analysis the equation was developed.The equation of prognosis is 3.14GGO+0,70index EScSG–1,326 FVC-0,1 the maximum daily dose of glucocorticoids+0,136 Gamma globulins+1.066 CYP–1.075DLCO≤5,8.Value of equation of prognosis to 5.8 corresponds to stabilization or good prognosis and value after 5.8 corresponds to poor prognosis.Results:Оn results of discrimination function pts were distributed in the following order: 22 pts(16%) were into zone of stabilization(Group 1) and 118(84%) - in zone of poor prognosis, among which 13pts died during the study. That`s why pts in zone of poor prognosis were divided into group 2 - survived pts (n=105(75%)) and group 3– died pts(n=13 (9%)).So we have got 3groups; the age, SSc duration, gender proportion and SSc forms, were similar in the all groups(p>0,05).Table 1.Baseline characteristics of the groupsParametersGroup 1 (n=22)M±SDGroup 2 (n=105)M±SDGroup 3 (n=13)M±SDCRP mg/ml9,4±10,411,5±23,421,5±27,1ME [25‰/75‰] 7,5 [1,9;11,2]5 [1,6;10,4]9,9 [5;32,8]ESR mm/h17±16,3523,6±1722,9±14,3a-Scl-70 u/ml62,5±85*118,6±93,09*102,1±96Skin score9,63±7,711,5±9,99±9,23Index EScSG1,9±1,7**3,4±1,9**2,9±1,1Mean PAP mm hg31,9 ±7β ββ35±11,9 β47,5±23,3ββCumulative dose of CyP g1,5±3γ γγ11,4±14,4γ18,9±23,3γγME [25‰/75‰]0 [0;2]4,9 [0;17]4 [0;46,5]Сumulative dose of RTM, g3,15±1,62,63±1,362,2±1,5* - p=0,01; **p=0,0008; β - p=0,006; ββ - p=0,03; γ- p=0,002; γγ - p=0,0018Mean level a-Scl-70, Index EScSG were significantly lower in group 1 vs group 2. Mean value of PAP and dose of CyP were significantly increased in group 3. It should be noted that pts with good prognosis have had low level of all parameters and high dose of RTM.Conclusion:The discrimination function is a proposed screening algorithm for pts with SSc-ILD who could develop progression disease. Usage of discrimination function revealed that 84% pts with ILD-SSc have got poor prognosis and 9% of them have got fatal outcome. Usage the equation of prognosis is very useful to choice of treatment and observation pts SSc-ILD.Disclosure of Interests:None declared.

Background:Systemic Sclerosis (SSc) overlap syndromes (SSc with polymyositis / dermatomyositis (PM/DM), rheumatoid arthritis (RA), etc.) still remain a group of very heterogenous and not very well studied clinical variants of SSc that are characterized by certain clinical and immunological features.Objectives:Identify clinical and immunological features of the SSc-overlap syndromesMethods:80 pts with SSc-PM/DM and 35 pts with SSc-RA undergoing standard clinical examination and laboratory immunological evaluation.Results:ANA Hep2 was positive in 98% of SSc-PM/DM pts; a-Scl-70 was in 34%, a - PM-Scl and RF were in 20%. ACA (6%), a-RNP (9%), and a - Jo-1 (5%) were significantly less common. Correlation analysis showed significant prevalence of conduction abnormalities in pts with a-Scl-70- (p<0.03); PM-Scl was rarely associated with cardiac arrhythmia (p<0.02) and pericarditis (p<0.03), but there was an association between ACA and presence of digital ischemia (p<0.04). Three pts with limited skin had Scl-70 and PM-Scl antibodies, two of them manifested clinical features of DM. A-Jo-1 was found in 3 pts with a longstanding disease (14,10 and 7 years), and one of these pts was also positive for a-Scl-70. All pts had limited skin and two had interstitial lung disease with FVC values of 79% and 74.8%.ANA Hep2 was positive in 96% of SSc-RA pts; a-Scl-70 – in 28%, and a-RNP - in 30%. RF-positivity was in 72% of pts, and Anti-CCP - in 27%. Simultaneous Anti-CCP and a-Scl-70 was found in one case, and Anti-CCP - anti-RNP – in another, both were associated with low RF titers. All pts had early joint involvement which became prevailing in subsequent years, and onset of the disease between 30 and 36 years. There was a correlation between laboratory signs of inflammatory activity and immunological disorders: ESR and a-Scl-70 (p<0.03). Anti-CCP and a-Scl-70 co-positivity was a significantly less frequent phenomenon (p<0.04). There was a remarkable 28% proportion of a-Scl-70 cases in SSc-RA with limited cutaneous which is usually characterized by ACA-positivity.Conclusion:SSc-PM/DM and SSc-RA appear to be an active disease from the immunological point of view, confirming therefore an important role of immune alterations in disease progression. Laboratory findings display specific pathogenetic features of SSc-overlap syndromes; laboratory abnormalities can be used to measure the activity and specify characteristics of the pathological process.Disclosure of Interests:None declared

Background:Rituximab (RTX) has been used for the treatment of systemic sclerosis (SSc) for a long time, but data on tolerance and long-term adverse events (AE) are insufficient.Objectives:To assess the tolerability and safety of RTX in the patients (pts) with SSc in long-term prospective follow-up.Methods:Data on the safety and tolerability of RTX were evaluated in 149 SSc pts who received at least one RTX infusion in a long-term open-label prospective observational study. The mean age was 48±13,5 years (17-74), women - 122 (82%), diffuse cutaneous subset of the disease had 52%, limited-37% and overlap-11%. The mean disease duration was 6,4±5,8 years (0,5-30). The observation period was 12 years. All pts received prednisolone at a dose of 11,7±4,8mg/day, and 73 patients (49%) received immunosuppressants at inclusion. The indications for the appointment of RTX were ineffectiveness or impossibility of standard therapy and a severe course of the disease with high activity and unfavorable prognosis factors. AE were assessed and recorded by a physician at a hospital immediately after the infusion of RTX, then by patient reported outcome during the observation period. Severe AE were defined as those that required hospitalization for more than 24 hours, exacerbation of the disease requiring therapy, malignancies, life-threatening situations. All causes of death were considered, regardless of treatment.Results:The mean follow-up period after the first infusion of RTX was 5,6±2,6 years [834,4 patient-years (PY)]. Pts received a mean of 3,4 courses of RTX (1–10). The cumulative mean dose of RTX was 3,2±2,4 gr (0,5-11). AE were reported in 77 patients (52%), the overall frequency of AE was 9,3/100 PY (95% Confidence Interval (CI) 8-11). The highest frequency of all AE was observed in the first 2-6 months after the first infusion of RTX, however these were mainly mild AE (71%). There was a decrease of AE in the follow-up period (3,4/100 PY, 95% CI 2,4-4,9 – at the period from 3 to 10 course of RTX). The overall incidence of serious AE was 2,22/100 PY (95% CI 1,4–3,5). The specter of serious AE included: pneumonia in 7 pts, infusion reactions in 5, as well as in one case: cerebral ischemia, acute pancreatitis, allergic pneumonitis, lymphoma of pharynx, purulent arthritis, lower limb vein thrombosis, pulmonary embolism of small arteries. The most frequent AE were infections (n=53), with no serious opportunistic infections reported. The overall incidence of all infections was 6,4/100 PY (95% CI 4,9-8,3), serious infections – 1,32/100 PY (95% CI 0,7-2,4). The level of immunoglobulin G during follow-up period decreased from 12,9±4,9 to 10,1±3,4g/l (p=0,0001), but remained within normal limits. Infusion reactions occurred in 15 pts (1,8/100 PY, 95% CI 1-3). Other AE were observed in 9 pts (6%) (1,1/100 PY, 95% CI 0,53-2,12). Sixteen deaths were recorded – 10,7% or 1,91/100 PY, 95% CI 1,2-3,1. In most cases, pts died from the progression of the major organ failure. The causes of death were: progression of the interstitial lung disease (ILD) in 4 pts, heart failure associated with SSc cardiomyopathy (2), renal crisis (4), pulmonary arterial hypertension and ILD (2), pneumonia (2), sepsis after tooth extraction (1), acute pulmonary embolism (1).Conclusion:In our study, we considered the overall safety profile of RTX in SSc as favorable. It was similar to the AE profile in other autoimmune diseases treated with RTX. With an increase of the cumulative dose of RTX, there was no increase in AE. RTX could be considered as a relatively safe drug for the complex therapy of SSc when standard therapy is ineffective or impossible.Disclosure of Interests:None declared