Antineutrophil  cytoplasmic antibody-associated systemic vasculitides (ANCA-SV) are characterized  by multiple organ failure, clinical and immunological heterogeneity,  and a variety of manifestations and require a high-quality interaction between the patient and the physician at all stages. Rational and personalized maintenance of a delicate balance between the use of an evidence-based  treatment protocol,  which is sufficient to secure sustainable suppression of the activity of ANCA-SV, and the simultaneous containment of the risk of treatment adverse events are the mainstay for successful therapy.

In response to the increased need for improved approaches to managing patients with ANCA-SV, the V.A. Nasonova Research Institute of Rheumatology has elaborated a National  Registry of patients with ANCA-SV, which is a regularly updated electronic database for patient follow-up and should be regarded as an innovative personalized induction and maintenance therapy tool that corresponds with the current treat-to-target concept. The main objective of the registry is to permanently  reproduce the goals of therapy for ANCA-SV, as well as to maintain  a sustainable remission, to reduce the incidence of treatment adverse events, to monitor comorbidity,  and to achieve a high quality of life. Further  development of the Russian National  Registry of patients with ANCA-SV as a federal program may play a key role in enhancing  the effectiveness of health care for patients with rare and severe diseases, contribute to the development of information  and telecommunication medical technologies for the provision of ANCA-SV patients with emergency counseling and medical assistance at the expert centers and for that of continuity at different treatment stages, to a reduction  in pharmacoeconomic expenses.

The article considers the results of an international multicenter randomized clinical trial of the efficacy and safety of the brand-name drug rituximab (MabThera), a monoclonal antibody against CD20 antigen of B cells, and its biosimi-lar drug (Acellbia®) (the BIORA study) in patients with rheumatoid arthritis (RA) refractory to therapy with tumor necrosis factor-а inhibitors.

Objective: to provide evidence for the therapeutic equivalence of Acellbia® and MabThera® and also to assess their interchangeability.

Subjects and methods. The trial enrolled adult patients with active seropositive RA, who were randomized into two groups (1:1): 1) the patients who received Acellbia® 1000 mg intravenously on days 1 and 15; 2) those who had MabThera® in a similar way. When RA activity persisted at 24 weeks, there was re-randomization (1:1) with a partial overlap: Group 1 patients were randomized into group AA (the drug of the second therapy cycle was Acellbia®) or Group AM (that was MabThera®), the similar methodology was followed in Group 2 (Groups MM and MA). Throughout the study, the patients received methotrexate at a stable dose of 7.5—25 mg/week and folic acid at a dose of 5 mg/week. The follow-up lasted 48 weeks.

Results and discussion. 24 weeks after treatment initiation, the ACR20 response was observed in 84.1% of the patients in the Acellbia® group (95% CI, 74.75—90.50) and in 87% in the MabThera® group (95% CI, 77.71—92.79%; p = 0.773), which suggests that the drugs are therapeutically equivalent. In the second phase of the study, the efficiency of therapy remained high; there were no differences in Groups AA/MM, AA/AM and MM/MA. In both phases, the safety profile of the drugs was comparable; the immunogenicity of treatment remained low. The findings suggest that the brand-name MabThera® and its biosimilar drug Acellbia® are equivalent. Switching from the biosimilar drug to the brand-name one and vice versa has no negative impact on treatment outcomes. 

The article presents the data of international registries and cohort studies of systemic lupus erythematosus (SLE). It justifies the purpose and objectives of the international registry of SLE patients, a Eurasian cohort (RENAISSANCE), which was launched in 2012 and amalgamated the leading rheumatology centers of the Russian Federation (V.A. Nasonova Research Institute of Rheumatology; Department of Rheumatology,  Pacific State Medical University), Kazakhstan (Department of Rheumatology,  S.D. Asfendiyarov Kazakh National  Medical University), and Kyrgyzstan (Academician M. Mirrakhimov  National  Center for Cardiology and Therapy), which mainly concentrate patients with the acute course of this disease. The first data of the registry are given.

Osteoporosis in ankylosing spondylitis (AS) may exacerbate pain and functional disorders and increases the risk of fractures. The mechanisms  of its development in AS have not been adequately studied.

Objective: to study bone mineral density (BMD)  and its regulation in patients with AS.

Subjects and methods. 70 patients (mean age, 43.2±9.2 years) with a documented diagnosis of AS (mean disease duration, 17.1±7.8 years) and a control group of 30 healthy individuals were examined. All the patients underwent estimation of BMD and the serum concentrations of osteocalcin,  CrossLaps, and key regulators of osteoclastogenesis, such as osteoprotegerin (OPG)  and a receptor activator of nuclear factor kappa-B ligand (RANKL) by an enzyme immunoassay. Results and discussion. In patients with AS, bone metabolism was characterized  by a decrease in bone formation and by some increase in bone tissue degradation especially in high AS activity. These patients showed the elevated levels of the major blocker of osteoclastogenesis OPG and the OPG/RANKL ratio, which can cause the process of ossification characteristic  of AS.

Objective: to estimate the changes of bone mineral density (BMD)  at the femoral neck and lumbar spine during fouryear combination  therapy with rituximab (RTM)  and methotrexate (MT) in postmenopausal women with rheumatoid arthritis (RA).

Subjects and methods. 79 postmenopausal women with a documented diagnosis of RA were followed up. They were divided into two groups according to the basic treatment:  1) 44 patients received combination  therapy with RTM and MT; 2) 36 patients had MT monotherapy. BMD was assessed by dual-energy X-ray absorptiometry using an Excell XR-46 stationary dual-energy X-ray bone densitometer  (Norland, USA) once per year (over 48 months).

Results and discussion. The group of patients receiving RTM and MT achieved a statistically significant increase in femoral neck BMD after 36 months of therapy. Statistically significant changes in femoral neck BMD were not revealed in the patients who had MT monotherapy. Lumbar spine BMD was decreased during MT monotherapy, but it remained stable in the RTM + MT group throughout  the 48-month follow-up.

Conclusion. Thirty-six-month combination  treatment with RTM and MT provides positive changes in femoral neck BMD, which persists within 48 months after treatment initiation.  Lumbar spine BMD remained stable in the patients receiving RTM and MT.

The damage of the respiratory system is a quite common  extra-articular manifestation  of rheumatoid  arthritis (RA). It is important  to note that its clinical symptoms occur in only 20–30% of patients; however, subclinical forms identified by active screening are observed in 70–80% of patients.

Objective: to compare the significance of pulmonary complaints,  the results of physical examination, and the data of instrumental  studies for the detection  of lung injury in patients with RA.

Subjects and methods. The study enrolled 70 RA patients (63 women and 7 men) aged 24 to 83 years. Only 10% of them had clinically evident lung injury associated with RA. Patients with other pulmonary diseases, such as asthma, chronic obstructive pulmonary disease, etc., were excluded. Physical examination, radiography/fluoroscopy, high-resolution computed  tomography (HRCT), single-photon emission computed  tomography (SPECT) of the lung, and lung function testing (LFT) with the determination of lung diffusion capacity.

Results and discussion. The data of physical examination  were nonspecific and unconvincing.  Pulmonary  complaints (dyspnea, cough, expectoration) were seen in 65% of the patients; an objective assessment revealed changes (vesiculotympanitic resonance,  harsh breathing, and pleural friction rub) in 40%. The X-ray films/fluorograms  displayed abnormalities (pulmonary fibrosis, focal changes) in only 10% of cases. 92% of the patients had lung HRCT  changes including moderate (bronchial  obstruction (40%), rheumatoid  nodules (10%), ground glass opacities (60%), bronchial thickening (20%), pleural effusion (10%), tree-in-bud opacities (3%)) and severe (pulmonary hypertension  (10%), bronchiectasis (10%), emphysema (5%) and lung tissue fibrotic changes as the honeycomb lung (2%)) ones. SPECT showed local hypoperfusion in the mantle and mediastinal parts of the lungs in 80% of cases. LFT analysis demonstrated reduced lung diffusion capacity in 41% of the patients, restrictive disorders in 30%, and bronchial obstruction in 70%.

Conclusion. Comparing the clinical and instrumental  findings permits one to diagnose subclinical lung injury in patients with RA. Thus, the early detection  of pulmonary involvement in RA requires the use of more sensitive methods.

One of the most common  causes of rapidly progressive glomerulonephritis (GN)  is the so-called pauci-immune crescentic GN that is characterized  by no luminescence  in kidney tissue samples during immunofluorescence microscopy and by the hyperproduction of antineutrophil cytoplasmic antibodies (ANCA). At the same time, serum ANCAs are absent in a number of cases of pauci-immune GN. Based on their own experience, the authors present the clinical and morphological characteristics of patients with ANCA-negative  pauci-immune GN and analyze the data available in the literature.

Subjects and methods. This retrospective study included 8 patients with ANCA-negative  pauci-immune GN,  who were followed up at two Russian centers (the Center of Nephrology and the Center of Rheumatology) in 2011 to 2015. Results and discussion. According to our data, ANCAs are not detectable in 6% of the patients with ANCA-associated systemic vasculitis (SV) with renal involvement and/or pauci-immune GN.  The mean age at onset of the disease in the ANCA-negative  patients was 50±18 years (range 19 to 74 years); the male/female  ratio was 1:1. Four (50%) cases were diagnosed with microscopic polyangiitis; 2 cases had granulomatosis with polyangiitis; isolated renal injury was present in other 2 patients. The Birmingham SV activity index averaged 19.6±7.9.  Hematuria  was observed in all cases and it was massive in 4. The mean daily urinary protein level was 3.4±2.7 g; three (38%) patients were observed to have nephrotic  syndrome. The blood creatinine  level averaged 704±405 μmol/l;  GN was characterized  by a rapidly progressive course in 6 (75%) patients; hemodialysis was needed in 5. A morphological study of the kidney determined  crescents (in on an average of 52 glomeruli) in the majority of cases and glomerulosclerosis in one patient. All the patients were observed to have varying degrees of interstitial fibrosis. Three (38%) treated patients achieved remission. The mortality rates were 38%. Interestingly,  the data from our group as well those obtained by the study of European  cohorts were slightly different from those of the studies conducted  in Asia, according to which a renal biopsy more frequently revealed glomerular crescents; the levels of protein in the urine were higher and renal survival was worse.

Thus, serum ANCAs are absent in 3–39% of cases of pauci-immune crescentic GN,  but the clinical and morphological picture corresponds to ANCA-associated  SV. A kidney biopsy helps establish the correct diagnosis, timely use induction  treatment, and improve prognosis.

Numerous  clinical observations show that the human genetic background plays an important  role in predisposition to many diseases.

Objective: to investigate a possible relationship of the polymorphisms in 19 A/G leptin (LEP) gene, in the interleukin (IL)-1  receptor antagonist (IL-1RA) gene VNTR (variable number of tandem repeats), and in the -174G/C IL-6 gene to the risk of developing the clinical phenotypes of panniculitis (PN), clinical and laboratory parameters.

Subjects and methods. The study enrolled 54 patients (48 women and 6 men) aged 15 to 76 years with a documented diagnosis of PN who had been treated at the V.A. Nasonova Research Institute  of Rheumatology.  Group  1 of 46 patients with erythema nodosum  (EN)  and Group  2 of 8 with Weber-Christian panniculitis  (WCP) were formed for genetic study. The genotyping data on 197 healthy unrelated  individuals were used as a control.  Clinical and laboratory information  was available from 39 patients for genotyping 19A/G  LEP gene polymorphism, that from 43 patients for -174G/C IL-6  gene polymorphism, and that from 46 patients for IL-1RA polymorphism. Genotyping  was performed by a polymerase chain reaction-restriction fragment length polymorphism  (PCRRFLP)  analysis.

Results and discussion. The frequencies of the LEP 19 GG genotype and the LEP G allele in patients with EN and WCP were significantly higher than those in the controls (48.7 and 18.2%, p = 0.0004; 50.0 and 18.2%, p = 0.053; and 70.5 and 45.4%, p = 0.0002, respectively). The frequencies of the A1A1 genotype and A1 allele of IL-1RA  gene VNTR polymorphism in EN group were significantly higher than those in the controls (67.4 and 44.2%, p=0.011; 80.4 and 61.6%, p = 0.002, respectively). The frequency of IL-6 -174GC  polymorphism was also higher in the EN group than that in the controls (58.1 and 34.7%, p = 0.008).

The -174G/C polymorphism showed a significant association with the site of erythema (p = 0.028). In patients with a single lesion of erythema on the body, the frequency of the -174 GC genotype was significantly higher than that in those with multiple foci of erythema (72.0 and 31.2%, respectively; p = 0.025). In the WCP group, analysis of variance showed an association of IL-1RA  gene VNTR polymorphism with the intensity of pain, assessed by the visual analogue scale. The carriers of the A1A1 genotype had more severe pain than those of the A1A2 genotype (83.3±11.5 and 20.0±18.2 mm, respectively; p = 0.008).

Conclusion. The findings suggest that genetic testing can be used to predict the clinical course of PN.

The lecture considers the present trends in the strategy of pharmacotherapy for rheumatoid  arthritis (RA) in the light of the guidelines by the European  League Against Rheumatism, the American College of Rheumatology and the All-Russian Public Organization  "The Association of Rheumatologists  of Russia". It emphasizes the most important  role of the treat-to-target RA treatment strategy, the key place of which is occupied by early controlled  active therapy with methotrexate (MT).  The therapeutic  place of glucocorticoids  and especially biologic agents, the rational use of which in combination  with MT allows a remission to be achieved in most patients,  is discussed.

Apremilast (AP) is a new phosphodiesterase  4 inhibitor for the treatment of psoriasis and psoriatic arthritis (PsA). Treatment  with AP reduces the level of proinflammatory cytokines and the activity of inflammatory changes.

The positive impact of AP treatment on the course of psoriasis has been proven in a number of clinical trials, for example ESTEEM  1 (Efficacy and Safety Trial Evaluating the Effects of apreMilast in psoriasis), in which the treatment with AP has led to a decrease in PASI scores in patients with moderate and severe psoriasis en plaque: after 16 weeks, a 75% PASI improvement  was significantly more common  in patients taking AP 30 mg twice daily (33%) than in those who used placebo (PL) (5%) (p = 0.0001). In the PALACE 1 trial, the PsA patients were given AP at a dose of 20 or 10 mg twice daily. At 16 weeks, the patients who used AP at doses 20 and 30 mg twice daily, more frequently showed a 20% improvement  according to the American College of Rheumatology (ACR) response criteria (ACR20) than those who received PL (in 30.4, 38.1, and 19% of cases; p = 0.0166 and p = 0.0001, respectively). Following 52 weeks of AP treatment, ACR20 was achieved by 63.0% of the patients who took the drug at 20 mg twice daily, and by 54.6% of those who used 30 mg twice daily. The PALACE 1, PALACE 2, and PALACE 3 trials demonstrated that the most common  adverse events (AE) were diarrhea,  nausea, headache,  upper respiratory tract infections, and nasopharyngitis. Most AE were mild and moderate;  and the rate of therapy discontinuation due to AE was low.

The review presents the data available in the literature on the clinical manifestation, diagnostic methods,  histological features, prognosis, and response to therapy of various lung injuries in systemic lupus erythematosus (SLE). The authors give their own data on the spectrum of pulmonary diseases in patients with SLE and describe a clinical case. 

Osteoarthritis  (OA) is a chronic disease associated with pain, stiffness, limited mobility and joint inflammation, as well as articular cartilage destruction.  Recent studies have shown the importance  of chondrocyte  differentiation (hypertrophy) as one of the mechanisms  of cartilage degradation in OA. This suggests that chondrocyte  metabolism undergoes the profound changes during cartilage resorption,  which are due to dysregulation of cell function. One of the major cellular metabolic regulators is the protein mTOR (mechanistic target of rapamycin) that controls cell growth, proliferation, protein biosynthesis and integrates extracellular signals from growth factors and hormones with amino acid availability and intracellular energy status. The importance  of mTOR activity for articular cartilage destruction  in OA

Cogan's syndrome is a rare disease from a group of systemic vasculitides with variable vascular involvement. It is a concurrence of ophthalmic  symptoms and audiovestibular disorders (Meniere's disease and sensorineural hearing loss). There is often fever, arthralgia or arthritis; neurological disorders and aortitis with the development of aortic aneurysms are encountered. Hearing loss is frequently irreversible. Changes in the organ of vision usually occur favorably.

The paper describes a case of Cogan's syndrome in a 33-year-old  patient. The disease is manifested by papilledema, conjunctivitis, acute sensorineural deafness with rapid loss of hearing, and microfocal changes in the brain, as detected by computed  tomography. Pulse therapy with glucocorticoids  and cyclophosphamide led to a rapid and obvious regression of all symptoms. The case is of interest due to the rare occurrence  of the disease and to the success of performed therapy. The description stresses the importance  of a rheumatologist's  consultation  and the need for the collective management of young patients with clinical presentations  of acute sensorineural hearing loss.

The paper discusses the possibilities of administering hyaluronic acid in osteoarthritis.  It is noted that the therapeutic efficacy of this drug class has been demonstrated in experimental and clinical studies and confirmed by the practical activities of specialists dealing with issues of arthrology. Along with the use of foreign hyaluronic acid solutions, Russian rheumatologists  can prescribe high-quality Russian analogues that include INTRAJECT®. The authors pres ent their own clinical observations that confirm that the drug may be administered.  The paper is illustrated with photos and radiographs.