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In systemic sclersis (SSc), different types of renal involvement occur. Their severity can range from asymptomatic deterioration of renal function to life-threatening damage, which is a complex therapeutic problem. Rituximab (RTM) has been used in the treatment of SSc and other autoimmune diseases with promising results, but its effect on renal function has not been adequately studied. Objective: to evaluate the renal function during complex therapy, including RTM, in patients with SSc over a long-term follow-up (at least 1 year). Material and methods. The study included 90 patients with SSc who were examined at least twice – before and 1–3.5 years after initiation of RTM treatment. Renal function was assessed by glomerular filtration rate (GFR) calculated according to the CKD-EPI formula. The stages of chronic kidney disease (CKD), blood pressure, daily proteinuria, skin score, activity, and indicators of lung function – forced vital capacity and diffusing capacity of the lungs – were also determined. Results and discussion. Against the background of complex therapy with RTM, there was a statistically significant decrease in GFR in the entire group of patients at the end of observation. On the other hand, renal function remained stable in the majority of patients with initially preserved GFR and there was a 25 % decrease – from 20 to 15 patients – in the number of patients with CKD. In more than half of the patients who initially had CKD, GFR increased (n = 11) or stabilized (n = 2) after therapy, and it decreased in a statistically insignificant manner in only 7 patients, whereas the development of a more advanced stage of CKD was observed in only 2 cases. The results of the treatment of 2 patients who had previously experienced scleroderma renal crisis (SRC) are reviewed in detail. Conclusion. In this study, there was no significant effect of RTM treatment on GFR and grade of CKD. Most patients had stable renal function; patients with an initial low grade of CKD showed a tendency toward stabilization of renal function. A significant decrease in GFR during long-term therapy noted in the entire patient group appears to be explained by an increase in renal insufficiency in patients with initially severe scleroderma renal damage, particularly due to SRC. Further studies on the effects of RTM therapy on renal function in patients with SSc are needed.

Introduction. The possibilities of modern therapy for systemic sclerosis (SSc) remains limited, since most of the used drugs do not have a diseasemodifying effect. This encourages the study of new approaches that potentially affect the fundamental pathological processes underlying the disease. One example is anti-B cell therapy, in particular rituximab (RTX). Until now RTX do not have a registration for the treatment of SSc, but there is a large positive experience of its use, which is reflected in recent meta-analyses and clinical recommendations. Complicated and expensive methods for obtaining genetically engineered biological preparations have contributed to the emergence of more accessible biosimilars, one of which is the RTX biosimilar, Acellbia (Biocad, Russian Federation). The “biosimilar” versions of RTX might reduce the cost of therapy and increase patients accessibility to this treatment option. The RTX biosimilar Acellbia (ACB) has received approval in Russian Federation in 2014 for all indications held by reference RTX (including rheumatoid arthritis and ANCA-associated vasculitis).The aim of this study was to investigate the efficacy and safety of Acellbia in patients with systemic sclerosis.Material and methods. Our prospective uncontrolled study included 20 patients (14 women) aged 50±14 years, with a disease duration of 3.5±2.7 years. Indications for the prescribing of ACB were high disease activity and the presence of risk factors for progression. All patients had radiological signs of interstitial lung disease, 13 (65%) were positive for antibodies to topoisomerase 1. None of the patients had previously been treated with biological therapy. All patients received glucocorticoids in low doses and 15 (75%) patients were not on concomitant immunosuppressants during the study. ACB was administered in doses of 2 g (two doses of 1 g with a weekly interval) at inclusion of the study and after 6–8 months according to the same scheme, cumulative dose – 4 g. An assessment of basic measurements was obtained at baseline (Point 0), before the second course (after 7.2±1.7 mo, Point 1) and at the end of follow-up (13.4±1.6 mo, Point 2). The results are presented in the form of mean values and standard deviations.Results. There was a positive effect on the main manifestations of the disease, which accompanied by stable depletion of CD19+ B lymphocytes in the peripheral blood. At the intermediate assessment (between points 0–1), no significant changes were observed, with the exception of the skin score. At the end of the study, most of the parameters showed a significant improvement between points 0–2. The activity of the disease (EScSG-AI) decreased, and the skin score decreased from 12.8±11 to 6.2±5.6 (p=0.002). The forced vital capacity (% of predicted) increased from 89±18.2 to 98.26±16.13% (p=0.0002), and the diffusion capacity of the lungs (% of predicted) increased from 56.8±15.7 to 61.9±17.2% (p

Introduction. Rituximab (RTX) has been used for the treatment of systemic sclerosis (SSс) for a long time and has shown good efficacy for skin fibrosis and interstitial lung disease. However, data on tolerability and long-term adverse events (AEs) during RTX therapy in SSc are insufficient.Objective. The aim of this study was to assess the tolerability and safety of RTX in patients with SSс in a long-term prospective follow-up.Materials and methods. Our open-label prospective study included 151 SSс patients who received at least one RTX infusion. The mean age of the patients was 47.9±13.4 years; the majority of them were women (83%). The mean disease duration was 6.4±5.8 years. The mean follow-up period after the first RTX infusion was 5.6±2.6 years (845.6 patient-years (PY)). All patients received RTX in addition to ongoing therapy with prednisone and/or immunosuppressants. AEs were assessed and recorded by a doctor in the hospital immediately after RTX infusion, then by patient reported outcome during the observation period. All causes of death were considered, regardless of treatment.Results. A total of 85 (56%) AEs were registered, the overall incidence of AEs was 10/100 PY (95% confidence interval (95% CI): 8–12). The highest frequency of all AEs was observed in the first 2–6 months after the first course of RTX, however, these were mainly mild and moderate AEs (71%). The most frequent AEs were infections, they were observed in 40% of cases, with no serious opportunistic infections reported. The overall incidence of all infections was 7.1/100 PY (95% CI: 5.5–9), serious infections – 1.5/100 PY (95% CI: 0.9–2.6). Infusion reactions occurred in 8% of patients. Other AEs were noted in 3% (0.6/100 PY; 95% CI: 0.3–1.4). The overall incidence of serious AEs was 18% (3.2/100 PY; 95% CI: 2.2–4.6). There was a significant decrease of the immunoglobulin G (IgG) during follow-up, however, its average values remained within normal limits. There were 17 (11%) deaths (2/100 PY; 95% CI: 1.3–3.2). In most cases, patients died from the progression of the major organ failure, which arose before RTX treatment.Conclusions. In our study, the safety profile of RTX in SSс was assessed as favorable. It was similar to the AE profile in other autoimmune diseases treated with RTX. With an increase in the cumulative dose of RTX, no increase in AEs was observed. The mortality is comparable to the other severe autoimmune diseases in observational studies. Monitoring of Ig G may be useful for patients with SSс on RTX therapy for early detection of the risk of developing infectious complications. RTX could be considered as a relatively safe drug for the complex therapy of SSс when standard therapy is ineffective or impossible.

Background. Systemic sclerosis-related interstitial lung disease (SSc-ILD) is the leading cause of death in SSc. Predictors of the outcomes of ILD in SSc are under investigation.Objective – to assess association of the digital ulcers with dynamics of forced vital capacity (FVC) and diffusing capacity for carbon monoxide (DLco) in patients with SSc-ILD.Methods. It was a longitudinal study involving 77 pts with SSc-ILD (mean age was 46±13.2; 69% have limited subset of the disease; 93% were female). The mean duration of follow up was 58.9±11.3 months. At the end of the study a number of pts with digital ulcers (DUs) was 27 (35%). Additionally 77 pts with SSc-ILD were investigated with HRCT and were divided into 3 groups; The group 1 (16 pts) with improvement; group 2 (39 pts) without any changes and group 3 (22 pts) with worsening of fibrosis. PFT (measurement of forced vital capacity (FVC) and diffusion lung capacity (DLco)) were made.Results. 27 (35%) pts with SSc-ILD had DUs at the end of the study. The most pts with DUs was in groups 2 and 3 (14 and 9) accordingly at the end of the study. After 5 years of follow up FVC increased significantly in all pts without DUs (n=54) from 88.5±19 to 96±23% (p0.05). The mean value of FVC in all pts with DUs didn’t change (88±14 and 86±16%; p>0.05) with tendency to decreasing in group 3 (from 83±12.5 to 74±13%; p>0.05). After 5 years of follow up DLco declined significantly in all pts with or without DUs, however in the 1st group decline of DLco wasn’t significant. The decreasing of DLCO was more prominent in group 3 than in group 2. Therefore, in group 2 in patient without DU (n=24) – from 65±16 to 60±11% (p˂ 0.05) and in patients with DU (n=14) DLCO changed from 61±15 to 57±14% (p 0.05). In group 3 in patients without DU (n=13) DLCO decreased from 55±15 to 48±15% (p˂ 0.05) and in patients with DU (n=9) – from 50±20 to 44.5±15% (p˂ 0.05).Conclusions. In patients without DUs significant increasing of FVC during 5 years long follow up was observed. The worsening of fibrosis on HRCT in pts with DUs was associated with the lowest value of FVC and DLco at the entry and at the end of the study.

Objective. To evaluate the ovarian reserve in women with systemic sclerosis (SSc) and to analyze the relationship of the concentration of anti-Müllerian hormone (AMH) with the main manifestations of the disease and therapy. Material and methods. The study included 74 SSc patients aged 18 to 40 years; the control group consisted of 32 healthy women, matched by age. The concentration of follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin, estradiol (E2) and testosterone was determined by enzyme immunoassay (ELISA), AMH quantitatively using standard chemiluminescent analysis on paramagnetic particles in blood serum. The AMG level of 1.0– 10.6 ng/ml was taken as normative values. Values

In systemic sclerosis (SSc), interstitial lung disease (ILD) is common (>80%) and worsens the prognosis of the disease, but severe progressive damage develops only in 8–10% of cases. Interstitial changes in the lungs occur early (within the first 3–5 years of the disease). The histological manifestations are similar to those of idiopathic ILD.The main tool for screening and diagnosing of ILD associated with SSc is high-resolution computed tomography of the lungs, resulting data influence the choice of therapy. In most patients a relatively intact and stable forced vital capacity of the lungs is recorded for a long time, but the diffusion capacity of the lungs decreases early and steadily. Pulmonary functional tests have prognostic value.The choice of the optimal therapy for SSc with lung lesions is based on general disease activity (the severity of inflammation and fibrosis) and the its severity, rate of progression of the disease in general and the leading pathology – interstitial pneumonia (IP) – in particular. In patients with SSc and severe or progressive IP, treatment with mycophenolate mofetil (MMF), cyclophosphamide, nintedanib, or nintedanib in combination with MMF if appropriate, should be considered. If this therapy is ineffective, rituximab may be used.

Autologous hematopoietic stem cell transplantation (auto-HSCT) is presently the only disease-modifying strategy for the treatment of systemic sclerosis (SSs) that has Level A evidence, the effectiveness of which has been proven in three controlled clinical trials: ASSIST, ASTIS, and SCOT. Despite the positive results obtained with the use of this treatment option, the issues related to its tolerability and safety remain unresolved. The complications caused by obvious immunosuppression and higher frequency of infections are the main causes of death after autoHSCT for autoimmune diseases and occur mainly in the first month after treatment. Overall, the studies performed confirm the overall assessment of auto-HSCT as an effective and relatively safe treatment for severe SSs.

The aim of our study was to assess the relationship between the changes of antinuclear autoantibodies (ANA) and autoantibodies to topoisomerase 1 (anti-Topo 1) in systemic sclerosis (SSc) patients on rituximab (RTX) therapy.Materials and methods. The prospective study included 88 patients (73 women) with a mean age of 47 (17– 71) years. The mean disease duration was 5.9±4.8 years. The mean follow-up period was more than 2 years (27 (12–42) months).Results. We documented a statistically significant change in skin score, the disease activity index, improvement of pulmonary function and reduction of mean dose of prednisolone after RTX treatment. There was a significant decrease in the number of patients with high levels of ANA and overall decrease of the ANA and anti-Topo 1 levels. A moderate positive statistically significant correlation was found between ANA and anti-Topo 1 (r=0.403). In the group of patients positive for anti-Topo 1 there were a more pronounced depletion of B lymphocytes, significantly higher increase in forced vital capacity and diffusion capacity, decrease in the disease activity index, compared with a patients negative for anti-Topo 1.Conclusions. We observed the decline in the level of ANA and anti-Topo 1 in SSc patients after RTX therapy and it was correlated by an improvement of the main outcome parameters of the disease. Therefore, anti-Topo 1 positivity could be considered as a predictor of a better response to RTX treatment, especially in SSc patients with hyperproduction of anti-Topo 1.

Diffuse cutaneous systemic sclerosis (SSc) characterized by an acute, rapidly progressive course and severe damage to the internal organs has an unfavorable prognosis, while the treatment of this often fatal type of the disease has not been sufficiently developed. This paper reviews an update on an autologous hematopoietic stem cell transplantation (auto-HSCT) procedure, transplantation stages, and conditioning modes in patients with SSc. It presents the characteristics of auto-HSCT studies conducted in 2005 to 2016. The inclusion and exclusion criteria used in these studies are described and their outcomes compared. The results of three randomized controlled trials concerning auto-HSCT are analyzed separately. These findings confirm that auto-HSCT is currently more effective than standard immunosuppressive therapy. Auto-HSCT produces better results that can provide a more favorable long-term prognosis of SSc; it can prevent worsening of organ damages and improve skin scores and lung function. Patients with early diffuse SSc, a rapidly progressive course, and poor prognostic factors in the first 4–5 years of the disease before the development of functional insufficiency of the vital organs can be considered most promising for auto-HSCT.

Objective. To evaluate B-cell counts in circulation of SS patients prior to initiation and one year after completion of RTM therapy.Subjects and methods. The study included 71 patients. Median follow up was 13,2±2,0 months (11-18 Mo.). Average cumulative RTM dose during the follow up period was 1,43±0,60 g, with 48 patients receiving < 2 g RTM (Group 1, mean dose 1,1±0,1 g) and 23 patients receiving ≥ 2 g RTM (Group 2, mean dose 2,2±0,6 g). CD19+ lymphocyte counts in peripheral blood were determined using flow cytometry in PSS patients and 20 healthy volunteers matched by sex and age. In SS patients B-cell counts were obtained before initiating RTM, within first month after first administration, then after 6 months and at the end of this study.Results. Baseline absolute and proportional В-lymphocyte counts in peripheral blood was almost similar in SS patients and healthy subjects. Highest counts were observed in SS patients with

The conclusion of the Expert Council presents the results of discussing the diagnosis and therapy of interstitial lung diseases in systemic scleroderma. The reason for this discussion was the emergence of new data on the use of nintedanib in this category of patients.

In anti-U1-ribonucleoprotein (anti-U1-RNP) antibody positive patients with systemic scleroderma (SSD), the clinical picture and course of the disease have specific features: there is a preponderance of its limited form; inflammatory damage to the joints and muscles comes to the fore; and cutaneous manifestations are mild. Moreover, a high frequency (68%) of interstitial lung disease is found. At the same time, the autoimmune profile in this group has been little studied.Objective: to investigate the level of major autoantibodies (autoAbs) in anti-U1RNP antibody positive patients with SSD and to compare the frequency of the autoAbs in this group and in the groups of patients with SSD phenotypes associated with anti-centromere antibodies (ACA) and anti-topoisomerase I (anti-Scl70) antibodies.Patients and methods. The investigation enrolled a total of 144 patients meeting the 2013 ACR/EULAR SSD classification criteria. Forty-four anti-U1RNP antibody positive patients were found to have autoAbs, rheumatoid factor (RF), anti-cyclic citrullinated peptide (ACCP), anti-Ro, anti-La, anti-double-stranded DNA (anti-dsDNA), anti-Smith (anti-Sm), anti-cardiolipin (aCL), anti-histidyl tRNA synthetase (anti-Jo1), anti-Scl70, and anti-RNA polymerase III (anti-RNAP-III) antibodies, and ACA in two points. The study group (anti-U1RNP antibody positive patients with SSD) and the comparison groups (anti-Scl70 and ACA positive patients) were comparatively analyzed.Results and discussion. Anti-U1RNP antibody positive patients with SSD were commonly observed to have overlaps (34%) with rheumatoid arthritis and systemic lupus erythematosus, as well as concurrence with Sjögren’s syndrome (SS) (32.5%). The study group was found to have frequently RF (27%), anti-Ro (41%), anti-dsDNA (50%) antibodies, rarely anti-Sm (9%), ACCP (9%), anti-La (7%), ACA (11%), anti-Scl70 (9%), and aCL (2%) antibodies. Anti-Jo1 and anti-RNAP-III antibodies were not detected in any patient. SSD patients who were highly positive for anti-U1RNP antibodies (more than 2 upper limits of the reference range) significantly more frequently exhibited RF, anti-Ro and anti-dsDNA antibodies (p

Various clinical and immunological phenotypes of systemic sclerosis (SS) differ in the frequency and severity of manifestations of the disease, the progression of damage to internal organs, and prognosis. The detection rate of anti-U1-ribonucleoprotein (RNP) (anti-U1RNP) antibodies in SSD ranges from 5 to 30%. They are found in various rheumatic diseases (SS, systemic lupus erythematosus, rheumatoid arthritis, polymyositis, and Sjo gren’s syndrome) and are associated with a more favorable course, a good response to treatment (in particular, that with glucocorticoids), and a good prognosis. In SS, the clinical and laboratory associations of anti-U1RNP have been insufficiently investigated.Objective: to compare clinical, laboratory, and instrumental findings in patients with SS positive for anti-U1RNP, anti-topoisomerase-I (anti-Scl70), and anticentromere antibodies (ACA).Subjects and methods. Sixty-five anti-U1RNP antibody-positive patients were selected for a study group (Group 1) from the general database of patients who met the 2013 ACR/EULAR criteria for SS and who were followed up at the V.A. Nasonova Research Institute of Rheumatology in 2012 to 2017. The comparison groups included 50 anti-Scl70 antibody-positive patients with SS (Group 2) and 50 ACA-positive ones (Group 3). Anti-U1RNP negativity was confirmed in patients of the comparison groups.Results and discussion. Most patients in Groups 1 and 3 had the limited type of SS (88 and 94%, respectively) and a chronic course of the disease (82 and 94%) while Group 2 patients showed an acute and subacute course (52%) and predominantly the diffuse type of SS (58%). All the patients with SS had a higher level of antinuclear factor. The feature of the anti-U1RNP positive group was a preponderance of the limited type of the disease with minimal skin damage concurrent with a more frequent involvement of the musculoskeletal system (damages to the joints (65%) and muscles (43%), as well as with the high rate of damage to internal organs (in particular, the lung, heart, and gastrointestinal tract). The patients of this group exhibited high inflammatory and immunological activities, hematological disorders (hypocomplementemia (15%) and leukopenia (14%)). Sjo gren’s syndrome was detected in one-third of these patients.Conclusion. Further study of anti-U1RNP-positive SS will be able to create a management algorithm and to more clearly define the risks and prognosis of the disease for this group of patients.

Among the patients fulfilling the criteria for systemic sclerosis (SS), there is a subgroup without SS-specific antinuclear antibodies, but positive for anti-ribonucleoprotein (anti-U1 RNP) antibodies. The clinical significance of this type of antinuclear antibodies in SS is not clear. The presence of anti-U1 RNP antibodies is of great interest, since they are not only present in other rheumatic diseases, but are also considered as a marker for mixed connective tissue disease. Objective: to reveal the frequency of anti-U1RNP antibodies in patients with SS and to provide the clinical and laboratory characteristics of patients positive for these antibodies.Subjects and methods. 330 patients who fulfilled the 2013 ACR/EULAR criteria for SS and had been followed at the V.A. Nasonova Research Institute of Rheumatology from 2012 to 2017 were included. Anti-U1 RNP were determined by enzyme immunoassay (reference values: 0–25 U/ml).Results and discussion. Anti-U1RNP were detected in 65 (19.7%) patients with SS (85% of patients were highly positive; 15% were low-positive). The group included 8 men and 57 women; their mean age was 46±14 years. The disease duration was 11±7.9 years. Skin lesions were minimal; 59 (91%) patients had a limited form of the disease with swelling in the hands (scleredema) in 40% of cases and sclerodactyly in 60%. Raynaud's phenomenon was present in all the patients. One-half of the cases were observed to have peripheral ischemic disorders: digital scars and/or sores (43%), as well as necroses and ulcers of other sites, which were relatively rare (8%). Interstitial lung disease (ILD) was identified in 63% of cases. Elevated pulmonary artery systolic pressure (PASP) ≥40 mm Hg, as shown by echocardiography, was detected in 26% of cases and was associated mainly with the presence of ILD; pulmonary arterial hypertension was confirmed in three patients. Esophageal lesions were found in 61% of patients. One-third of patients had signs of scleroderma cardiopathy. The feature of the group was the common involvement of the locomotor system: joints with arthralgia and/or synovitis in 65% and muscles with mild and moderate myopathy in 43%. Erythrocyte sedimentation rate (ESR) and C-reactive protein levels were frequently elevated. The concurrence with Sjö gren's syndrome was common (in one-third of patients). None case of scleroderma renal disease was recorded; the mean values of kidney function were within the normal range; however, the glomerular filtration rate was lower than 80 ml/min/m2 in 17% of patients. All the patients were positive for antinuclear factor (HEp-2); in addition, there was rheumatoid factor (22%), antibodies against Ro/SS-A (41%), La/SS-B (18%), double-stranded DNA (42%), Scl70 (7%), and anticentromere antibodies (9%); 39 out of the 55 (71%) patients who were highly anti-U1 RNP-positive fulfilled the mixed connective tissue disease criteria proposed by R. Kasukawa et al. (1987).Conclusion. The investigation allows one to discuss of the presence of a special phenotype of SS, which is characterized by peculiar clinical manifestations in the presence of anti-U1 RNP overproduction.

The choice of drugs for the treatment of interstitial lung disease (ILD) associated with systemic sclerosis (SS) is currently very limited. Data from a number of studies show that rituximab (RTM) can improve lung function and reduce the severity of skin fibrosis in patients with SS.Objective: to evaluate the efficiency of RTM in a cohort of patients with SS-associated ILD after one-year follow-up. The indications for prescribing RTM were: 1) the inefficiency of standard therapy with glucocorticoids and immunosuppressants (ISs) or the impossibility of their use; 2) the early stage (first 3 years of the disease) with signs of poor prognosis, such as diffuse form, high skin scores (>14), male gender, rapid progression with a significant initial decline in forced vital capacity (FVC) and/or diffusion lung capacity (DLC), and a high anti-Scl-70 antibody positivity.Subjects and methods. The investigators selected a group of patients who had at least two assessment points at a 12-to-18 month interval (the mean follow-up period of 13±2 months) and took at least 1 g of RTM during this period. The investigation included 71 patients with a valid diagnosis of SS. Multi-slice spiral computed tomography (MSCT) revealed ILD in 90% of patients. The disease duration was 5.6±4.4 years. The presence of anti-Scl-70 antibodies was detected in 73% of patients. The mean cumulative dose of RTM was 1.43±0.6 g; 48 patients in Group 1 received ≤2 g of RTM (the mean dose, 1.1±0.1 g) and 23 patients in Group 2 took ≥2 g of RTM (mean dose, 2±0.6 g). Before starting treatment with RTM, all the patients received concomitant therapy with prednisone and 45% - with immunosuppressants.Results and discussion. The results assessed by a physician showed that good and moderate effects of the therapy were observed in 52 (73.2%) and 16 (22.6%) patients, respectively; no effect was seen in 3 (4.2%) patients. Overall, 95.8% of patients reported various degrees of improvement. There were significant changes as reductions in the disease activity index, skin scores, C-reactive protein and IgG levels, the number of patients with a high antinuclear antibody level, and the mean dose of prednisolone as well as increases in an oral aperture size, left ventricular ejection fraction, and 6-minute walk test scores. There were no changes in pulmonary artery systolic pressure and the HAQ DI. FVC increased from 77.35±19.9 to 82.6±20.7% (p=0.001). A minimal clinically significant increase in FVC ≥5% was noted in 41 (57.7%) people. The overall improvement in FVC (ΔFVC) reached 5.24%, while the changes were more significant in Group 2 (ΔFVC 8.98%) than in Group 1 (ΔFVC 3.75%; p=0.01). DLC remained stable, but there were significant group differences: ΔDLC was 3.75% in Group 2 and, conversely, decreased in Group 1 (1.6%; p=0005). The safety profile of the therapy was regarded as good and quite comparable with both the safety profile of ISs and the use of RTM in other trials. Infectious complications were recorded to be most common in 11 (15%) people. Of these, upper respiratory tract infections developed in 7 patients; plantar phlegmon occurred in one case; urinary tract infection and herpes zoster were detected in two and one cases, respectively.The results of this study confirm data from other studies that have demonstrated that RTM exerts a positive effect on SS-associated ILD. We were the first to show the association of positive changes in the measures of pulmonary function tests with the dose of RTM.

As of now, there has been a great body of data on the use of rituximab (RTM) in systemic sclerosis (SS), mainly on its positive effect on skin fibrosis and lung injury. However, information is still scarce about the effect of RTM on other organs and systems, namely the heart affected by SS.Objective: to assess the time course of changes in the signs of heart involvement in SS patients one year after initiation of RTM therapy.Subjects and methods. The paper gives data on changes in cardiac disorders in 71 patients with SS one year after the prescription of RTM.Results and discussion. The rate of cardiac rhythm and conduction disorders and diastolic dysfunction was unchanged. At the same time, a significant increase in left ventricular ejection fraction (EF) and a reduction in the severity of dyspnea was achieved, which correlated with improved lung function (a significant rise in forced vital capacity). The results of treatment in three patients with predominant heart involvement associated with SS (coronary heart disease and hypertension were ruled out) were considered in detail. These patients displayed pronounced positive changes as increased EF, less severe cardiac arrhythmias, reduced chronic heart failure, better quality of life, as well as the synchronicity of lower disease activity, less skin induction, improved lung function, and stabilized pulmonary artery systolic pressure.Conclusion. RTM in combination with traditional therapy can be considered as a potentially effective drug for the treatment of heart involvement in SS.

Multi-slice spiral computed tomography (MSCT) of the chest is the gold standard for confirming interstitial changes in the lung; but the role of this technique in evaluating the efficiency of therapy for systemic sclerosis (SSc) has not been fully defined.Objective: to assess the time course of changes in the lung according to chest MSCT findings and pulmonary function test (PFT) results in SSc patients and interstitial lung disease (ILD) during of active treatment.Subjects and methods. The investigation enrolled 42 patients with a reliable diagnosis of SSc who had signs of ILD, confirmed by chest MSCT. The patients’ mean age was 48±2 years; the male-to-female ratio was 1:6; that of diffuse-to-localized SSc patients was 1.5:1 (25 and 17); the mean duration of SSc was 6.6±5.9 years. Over time during therapy, forced lung capacity (FVC) and lung diffusing capacity (LDC) were studied and chest MSCT was performed in all the patients at the time of inclusion in the study and after an average of 29±15.3 months (9 to 70 months). A 10% or more change in PFT results was considered to be of clinical significance. During the follow-up period, the patients were treated with rituximab (RTM) at a mean total dose of 2.5±1.3 g (500 mg to 5 g) in combination with glucocorticoids at a mean dose of 11.7±3.9 mg calculated with reference to prednisolone; 10 (24%) patients also received immunosuppressants.Chest MSCT data were analyzed at 5 levels. The magnitude of changes following the pattern seen in frosted glass, honeycomb, and reticular alterations was estimated using a 4-point (0–3 points) scale at each level. The time course of changes in these parameters and PFT results was separately assessed in patients with less and more than 20% of lung tissue injury in Group A (n=13 (31%) and in Group B (n=29 (69%).Results and discussion. Semiquantitative assessment of changes as evidenced by chest MSCT in SSc patients with ILD did not reveal any changes in their total scores. According to a radiologist’s subjective assessment, there were positive and negative MSCT changes in 8 (19%) and 11 (26%) patients, respectively; the changes were present in 23 (55%) patients. A 10% and more increase in FVC was observed in 16 (38%) patients; its decrease was seen in 3 (7%). Positive and negative LDC changes were found in 5 (12%) and 1 (2.4%) patients, respectively. On average, the group showed a significant FVC increase from 73.2±18.8 to 82±21.8% (p=0.000031) and LDC stabilization. None of the patients with positive MSCT changes exhibited FVC deterioration. During therapy, Groups A and B had positive MSCT changes in 5 (38%) and 3 (10%) cases, respectively (p=0.08); no negative changes were noted in Group A while Group B had negative changes in 11 (38%) cases. FVC increased clinically significantly in 6 (46%) patients in Group A and in 10 (34%) in Group B; this decreased in 1 (8%) and 2 (7%) patients, respectively. FVC was significantly higher in Group A than that in Group B both at the time of study inclusion (88.8±18.6 and 65.4±14.5%, respectively; p=0.0002) and in the long-term period (103.3±15.9 and 74.1±18.5%; p=0.0009), while during therapy this increased statistically significantly in both groups (p=0.016 and p=0.0014, respectively). In Groups A and B, the median FVC increments were 10.2 (4.7; 21.9)% and 5.9 (2.75; 14.7)% , respectively (p>0.05). The mean frosted glass score was significantly lower in Group A than that in Group B both at the time of study inclusion (2.9±2.3 and 6.6±2.7; p=0.01) and in the long-term period (1.6±1.4 and 6.4±3.0, respectively; p=0.000006) and this tended to decrease during therapy. A similar pattern was observed with reticular alterations(4.3±2.7 and 8.7±3.2 (p=0.001) and 3.1±2.5 and 8.8±2.0 (p20% of lung tissue injury. During active therapy, the entire group displayed an increase in FVC, as well as LDC stabilization, and their median increments were higher in the patients with an ILD area of

The FAS antigen (Apo-1/CD95) is a key molecule of apoptosis in most cell types, including activated immune cells and fibroblasts. The FAS gene promoter region contains a single-nucleotide polymorphism (-670A/G) associated with a substitution of the nucleotide arginine for guanine, which is associated with the predisposition to systemic lupus erythematosus, multiple sclerosis, sarcoidosis, and autoimmune hepatitis.Objective: to test the hypothesis that the FAS -670А/G polymorphism may predispose to systemic sclerosis (SS), its clinical and autoimmune phenotypes in a Russian patient sample.Subjects and methods. The instigation enrolled 90 SS patients who were classified according to clinical and autoimmune phenotypes. A control group consisted of 152 apparently healthy unrelated individuals matched for sex and age. The FAS -670А/G polymorphism was studied by polymerase chain reaction, followed by restriction fragment length polymorphism analysis.Results and discussion. A relatively small sample of Russian patients showed no statistically significant association of the studied FAS -670 A/G polymorphism with the predisposition to SS as a whole and the majority of its clinical and immunological phenotypes. There was a statistically significant positive association of the G allele (the FAS -670 GG+GA genotype) with the presence of digital ulcers and the chronic course of the disease. The G allele (the FAS -670 GG+ GA) was detected less frequently in patients with interstitial lung disease (ILD) than in those without ILD.Conclusion. The findings show that the FAS -670A>G polymorphism plays a role in the predisposition to some clinical phenotypes of SS in Russian patients.

Objective: to estimate frequency of autoantibodies in a cohort of Russian patients with systemic sclerosis (SS) and to investigate clinical associations of these autoantibodies.Subjects and methods. In 2012 to 2015, the investigation enrolled 300 patients (58 men and 242 women) who fulfilled the American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) SS criteria. All patients underwent immunological examination including determination of antinuclear antibodies, anti-topoisomerase I (anti-Scl-70) antibodies, anti-centromere antibodies (ACA), anti-U1-ribonucleoprotein antibodies (anti-U1 RNP), and anti-RNP III antibodies.Results and discussion. The vast majority of patients were middle-aged females with moderate disease duration. There was a preponderance of patients with limited cutaneous form (55.3%); 37.4% patients had diffuse SS; 5.9% had overlap syndrome; and

Systemic sclerosis (SS) is a systemic disease, the basis for which is microcirculatory disorders, inflammation, and generalized fibrosis. Interstitial lung disease (ILD) is one of the primary manifestations of SS. Assessment of SS activity and severity is hindered as it is very difficult to differentiate fibrous and inflammatory changes that are mostly interrelated and have a similar picture.Objective: to estimate activity index (AI) and total severity index (TSI) for the follow-up of SS patients with different variants of ILD. Subjects and methods. The investigation enrolled 77 patients with SS and ILD, who were followed up at the V.A. Nasonova Research Institute of Rheumatology; their mean age at inclusion was 46±13 years. All the patients underwent high-resolution computed tomography (HRCT) of the chest and determination of TSI and AI scores at baseline and after an average of 59±12 months. According to the time course of HRCT revealed pulmonary changes over a 5-year follow-up, the patients were divided into 3 groups: 1) patients with improvement (n=16); 2) those without changes (n=39); 3) those with deterioration (n=22). The disease was regarded as active with AI scores of ≥3.Results and discussion. The mean AI scores for the entire patient cohort were low and substantially unchanged during the follow-up period, amounting to 2.1±1.55 and 2.37±1.55 (p > 0.05) at the start and at the end of the investigation, respectively. Following 5 years, only Group 3 showed AI scores of > 3. At inclusion, the groups did not differ in AI scores; however, 5 years later AI became significantly higher in Group 3 than that in Groups 1 and 2 (p = 0.004 and p=0.03, respectively). During the follow-up, TSI remained substantially unchanged and averaged 6.5±2.5 and 6.9±2.3 at inclusion and at the end of the investigation, respectively. Moreover, TSI tended to decline in Groups 1 and 2; but it significantly increased in Group 3 (p = 0.006) and at the end of the investigation it was significantly higher than that in Group 1 (p = 0.002). There was a direct correlation between AI and TSI in the total cohort of patients both at baseline and 5 years later (R = 0.57 and R = 0.53; p < 0.05). Direct correlations were found between the indices within Groups 2 (R = 0.51 and R = 0.37) and 3 (R = 0.67 and R = 0.71) at baseline and at the end of the follow-up, respectively; p < 0.05).Conclusion. In our investigation, AI and TSI reflected the course of ILD in patients with SS. ILD progression, as evidenced by HRCT, was followed by a significant increase in AI and TSI scores; they directly correlated between. Thus, AI and TSI may be used for monitoring progression of the disease.

Systemic sclerosis (SS) is a progressive connective tissue disease, the prognosis of which largely depends on the time of adequate therapy initiation. Low sensitivity of the 1980 American College of Rheumatology (ACR) SS classification criteria for identifying patients with early stage of the disease, and with its limited form in particular, has necessitated revision of existing SS diagnostic standards and elaboration of more sensitive criteria that allow to establish the diagnosis when the first sign of the disease appear.Objective: to compare the sensitivity of the novel SS criteria of ACR and European League against Rheumatism (ACR/EULAR) 2013 and the 1980 ACR criteria in different stages of the disease.Subjects and methods. The investigation enrolled 302 patients who had been diagnosed by experts as having SS and followed up at the V.A. Nasonova Research Institute of Rheumatology in 2007–2013. The patients’ mean age was 49±13 years (18 to 80 years); male to female ratio – 1:9 (31 and 271), that of patients with diffuse and limited SS – 1:2 (105 and 197); mean duration of the disease from the first non-Raynaud’s syndrome was 8.2±7.0 years (6 months to 36 years). Physical examination, nailfold capillaroscopy, chest radiography or computed tomography, echocardiography for the determination of pulmonary artery systolic pressure and SS-specific antibodies evaluation were performed.Results. 273 (90%) patients fulfilled the novel ACR/EULAR 2013 SS criteria. 76 (25%) patients had skin thickening above the metacarpophalangeal (MPC) joints in both hands; 263 (87%) – finger skin thickening [70 (23%) – finger swelling, 192 (64%) – thickening of all fingers distal to the MPC joints], 141 (47%) – digital ischemia [79 (26%) – digital pitting scars, 20 (7%) – digital ulcers, 42 (14%) – digital pitting scars and ulcers], 134 (44%) – telangiectasias, 276 (91%) – capillaroscopic changes, 225 (78%) – pulmonary hypertension (PH) or interstitial lung disease (ILD) [15 (5%) – PH 185 (61%) – ILD, 35 (12%) – ILD and PH], 301 (99%) – Raynaud’s phenomenon, and 185 (61%) – SS autoantibodies [138 (46%) – anti-Scl-70 antibodies (a-Scl-70), 42 (14%) – anti-centromere antibodies (ACA), 5 (1.7%) – ACA and a-Scl-70]. 216 (72%) patients fulfilled 1980 ACR SS criteria, and all of them met the novel criteria. With the latter, SS could be additionally diagnosed in 57 more (18%) patients.Conclusion. The 2013 ACR/EULAR SS classification criteria have much higher sensitivity than the 1980 ACR criteria. The sensitivity of the novel criteria remained at the level of 90% in all, including the earliest, stages of the disease while the ACR criteria allowed to confirm diagnosis of SS in only half of patients with a disease duration of less than 1 year.

Objective: to assess the efficacy and tolerability of Rituximab treatment in patients with serious immune inflammatory rheumatic diseases (IRD) like systemic lupus erythematosus (SLE), systemic sclerosis (SS), systemic vasculitis (SV), Sjogren syndrome (SjS), dermatomyositis/polymyositis (DM/PM).Subjects and methods. The clinical efficacy has been analyzed in 229 patients with IRD: SLE (n=97), SV (n=50), SS (n=40), SjS (n=23) and DM/PM (n=19). Rituximab treatment was accompanied by administration of glucocorticoids and/or immunosuppressive drugs. Most patients demonstrated resistance to or low tolerability of standard therapy. Efficacy of treatment was analyzed in each group with the criteria relevant for each disease. To compare clinical response to the treatment between the groups we used gradations accepted by international registries: complete (good) response, partial response, no response. Average duration of monitoring comprised 72 (1–288) weeks after the first introduction of Rituximab. Average Rituximab dose administered to patients over the period of monitoring was low and varied from 1.6±0.84 in DM/PM to 3.1±1.75 in SV. About 80% of patients received one or two courses of Rituximab except for patients with SS (half of them received three and more courses).Results. «Complete response» was observed in 50.6%, «partial response» – in 35% of patients. Rituximab courses provided positive dynamics in clinical scores and allowed to reduce supportive dose of glucocorticoids and to lower the dose or withdraw of immune-stimulating drugs. Multiple Rituximab courses provided stable and longlasting effect. Recurrences were observed less frequently, whereas efficacy of the therapy increased during a year and longer. Occurrence of adverse events and mortality rate were comparable to data of other national Rituximab registries.Conclusion. The results of the study may prove administration of Rituximab in patients with resistance to standard therapy

Systemic scleroderma (SSD) is a clinically heterogeneous disease characterized by obliterating microangiopathy, autoimmune activation, and fibrosis of the skin and viscera. Interstitial lung fibrosis (ILF) is a characteristic visceral injury in SSD and considered to be a main cause of disability and death. The diagnosis of SSD-associated ILF is made on the basis of a cluster of symptoms, physical examination, external respiratory function changes, and high-resolution computed tomography. Pulmonary fibrosis is included in the 1980 American College of Rheumatology (ACR) classification criteria and in the joint ACR and 2013 European League against Rheumatism diagnostic criteria. According to the definition given in these criteria, pulmonary fibrosis in SSD isdescribed as bilateral changes, most pronounced in the basal lung segments, which are not a sign of primary lung disease. The paper describes a case of a SSD patient with a complete spectrum of characteristic signs of unilateral pulmonary fibrosis. This case is the first description of unilateral ILF in SSD and shows the need for ruling outconnective tissue diseases, primarily SSD, when such lung changes concurrent with extrapulmonary manifestations are detected.