Throughout the history of rheumatology, the attitude to pain has changed significantly. In the XIX and early XX centuries, pain was considered only as one of the symptoms, the control of which is secondary to the etiotropic and pathogenetic therapy of rheumatic diseases (RD). However, already in the 30–40s years of the XX century, the treatment of pain becomes an independent task, and for this purpose a wide range of medications and non-pharmacological methods are used. Rheumatologists in Europe and the USA in those years discussed the topic of “neurogenic” and “psychogenic” pain in RD, including “fibrositis”. The works of Russian rheumatologists of 50–60s years demonstrate a different attitude to pain relief in RD: some experts considered it a necessary component of treatment; others attributed it to auxiliary methods that are significantly inferior in importance to pathogenetic therapy.

In the 70s, rheumatologists have at their disposal a large arsenal of painkillers, primarily nonsteroidal anti-inflammatory drugs (NSAIDs). In parallel with the study of their therapeutic capabilities and safety, an active study of the problem of pain in RD begins. Since that time, pain relief issues have been among the main topics of the V.A. Nasonova Research Institute of Rheumatology; its employees organize their own and participate in international projects to study new analgesic drugs. Pain control is beginning to be considered among the priorities of anti-rheumatic therapy. Currently, the rheumatology community is very interested in the problem of “non-inflammatory” pain associated with autoimmune dysfunction of the nociceptive system, central sensitization and fibromyalgia – as a factor determining the insufficient response to anti-rheumatic therapy and poor quality of life of patients with RD.

The V.A. Nasonova Research Institute of Rheumatology, in collaboration with neurologists and algologists, is actively involved in the study of this pathology, studying the phenotypes of pain in different RD, the role of immunological, genetic and psychoemotional factors in nociception, as well as the influence of modern anti-rheumatic therapy (genetically engineered biological drugs and JAK inhibitors) on the main manifestations of RD.

In modern rheumatology, comorbid infections have a significant impact on morbidity and mortality, especially in immuno-inflammatory rheumatic diseases (IIRD). One of the ways to solve this problem is the study and active use of various vaccines. This article analyzes the recommendations for vaccination of patients with acute respiratory infections, proposed in 2022 by experts of the American College of Rheumatology (ACR). The safety and immunogenicity of vaccination associated with the prevention of various infections in patients with IVR are discussed. It is emphasized that the decision to suspend taking the drug before or after vaccination should be made taking into account the existing IIRD, its activity and the risk of vaccine-controlled infection. A key component of any vaccination strategy (especially for conditional recommendations) is decision-making together with the patient. The main directions of future research on the problem under consideration are outlined.

The problem of prevention of coronavirus disease 2019 (COVID-19) in patients with immune-mediated inflammatory rheumatic diseases (IMRD) remains highly relevant. The presence of IRD is associated with a high risk of disease and severe course of COVID-19 during immunosuppressive treatment, primarily anti-B cell therapy with rituximab (RTX), and a low level of post-vaccination response in such patients. A new strategy for the prevention and treatment of COVID-19 are virus-neutralizing monoclonal antibodies to coronavirus; currently, combined long-acting monoclonal antibodies tixagevimab and cilgavimab (Evusheld) are registered for prevention in the world and the Russian Federation. . Tixagevimab and cilgavimab (TC) show neutralizing activity against SARS-CoV-2, including the Omicron strain, primarily its variants BA.4, BA.5, BA.2.75 ("Centaur").

Objective – to evaluate the efficacy and safety of TC for pre-exposure prophylaxis of COVID-19 in rheumatic patients receiving RTX, based on a prospective observational study.

Materials and methods. The main group included 86 patients with various IMRD receiving RTX: 50 of them had ANCA-associated systemic vasculitis (AAV), 15 – rheumatoid arthritis, 9 – Sjogren’s syndrome (SS), 4 – IgG4-related disease, 3 – systemic lupus erythematosus (SLE), 3 – dermatomyositis (DM), 2 – systemic scleroderma (SSD). Median age was 59 (19–82) years; male : female ratio – 1:1,8. From March 26 to August 30 2022, patients received a single intramuscular injection of TC in a total dose of 300 mg, mainly after RTX (in 52% of cases, in 28% on the next day after RTX). The control group included 42 patients with AAV (median age – 45 (35–71) years; male : female ratio – 1:1), also treated with RTX, who did not receive pre-exposure prophylaxis of TC. The duration of observation was 7 months, until November 1 2022. At this time, 98% of confirmed cases of coronavirus in the Russian Federation were Omicron. A telephone and/or online survey of patient has been conducted to detect cases of COVID-19 and adverse reactions.

Results. In the TC group, confirmed coronavirus infection have been detected in 17 (20%) patients (AAV – 10, SS – 3, SSD – 2, SLE – 1, DM – 1), with fever in 7 (8%), only in one case hospitalization was required (lung damage was not detected in computed tomography), in two cases, according to CT mild lung damage (CT 1–2), there were no deaths. Good TC’s tolerability was noted, signs not associated with COVID-19 or progression of IMRD after administration of TC were observed in 8 (9%) patients (GPA – 3 MPA – 1, RA – 2, SLE – 1, IgG4-related disease – 1), adverse reactions definitely associated with the use of TC were not found. The most serious event not associated with coronavirus infection was the progression of polyneuropathy in a patient with RA. In the control group, 3 (7%) patients were diagnosed with COVID-19, one with severe lung injury (CT 3, pulmonary embolism) and death.

Conclusions. The data of clinical studies and our own clinical experience evidence the effectiveness of the use of a combination of long-acting monoclonal antibodies TC (Evusheld), registered for indications for pre-exposure prophylaxis and treatment of COVID-19. Patients with IMRD treated with RTX have a favorable safety profile of TC. The introduction of virus-neutralizing monoclonal antibodies, a new drug class for the prevention and treatment of infectious diseases, opens significant prospects for improving the prognosis of patients with IRD.

Rheumatoid arthritis (RA) is an immunoinflammatory rheumatic disease (IMRI) characterized by chronic erosive arthritis and systemic damage to internal organs, leading to early disability and reduced life expectancy in patients. Thanks to the progress in the study of the mechanisms of the development of the IVRI and industrial biotechnology, new anti-inflammatory drugs have been created, the use of which has significantly increased the effectiveness of the pharmacotherapy of RA. However, the possibilities of pharmacotherapy for RA are limited, since all biologics, regardless of the mechanism of action, have approximately the same effectiveness in achieving remission. It is believed that the relatively unsatisfactory results of RA therapy are due to the heterogeneity of the mechanisms of inflammation and pain. The significance of the Th17 type of immune response in the pathogenesis of RA, the results of controlled studies of IL-17 inhibitors, and the advisability of further studying the effectiveness of these drugs in patients with certain RA phenotypes are discussed.

Objective – to evaluate the long-term outcomes of HCV eradication with direct-acting antivirals (DAAs) in patients with hepatitis C-associated cryoglobulinemic vasculitis (HCV-CV)

Materials and methods. We retrospectively assessed 48 patients with HCV-CV treated with DAAs. The activity of HCV-CV was assessed by using Birmingham Vasculitis Activity Score version 3 (BVAS v. 3). In patients with HCV-CV the rate of sustained virologic (defined as undetectable HCV-RNA levels 12 weeks after treatment cessation) and immunological (defined as absence of circulating cryoglobulins, rheumatoid factor and normal C4 level) response; and the rate of complete (defined by a BVAS v. 3 score of 0) and partial (defined as BVAS v. 3 score <50% of the baseline score) clinical response were evaluated. Immunosupressants were given before or after DAAs therapy if clinically needed.

Results. Median time of follow-up from treatment cessation were 26,5 (11,5–62,3) months. All 48 (100%) patients achieved sustained virologic response. Elimination of cryoglobulins were reported in 20 (41,7%) patients, complete immunological response-in 4 (8,3%) cases. Complete and partial clinical responses were observed in 13 (27,1%) and 19 (39,6%) patients, respectively. BVAS v. 3 score <4 at baseline was independently associated with complete clinical response (ОR=7,58; 95% CI: 1,42–40,48; р=0,018). 3 (6,3%) patients demonstrated HCV-CV relapse.

Conclusion. Patients with HCV-CV require a long-term follow-up period even after reaching the SVR. The use of BVAS v. 3 score before the DAAs therapy can facilitate the planning of therapeutic approach, particularly, when identifying the patients in whom the immunosupressive therapy should be considered after viral eradication.

Background. Interleukin (IL) 6 plays an important role in the pathogenesis of comorbid rheumatoid arthritis (RA) depression, and IL-6 inhibitors (i) used to treat RA patients may have an antidepressant effect.

Objective – to evaluate the effectiveness of Russian iIL-6 olokizumab (OKZ) in reducing symptoms of depression in patients with moderate/high RA activity.

Material and methods. To date, 49 RA patients have been included, of which 43 (87.7%) are women, with an average age of 47.8±12.8 years; with a predominant high activity of RA according to DAS28 (CRP) indices (89.8%), SDAI (79.6%) and CDAI (75.5%) and inefficacy of stable 12-week therapy of сDMARDs. In all patients, a psychiatrist, in accordance with ICD-10, diagnosed depression (chronic or recurrent) of varying severity during a semi-structured interview. At week 0, all patients were randomized by the method of sequential numbers in a ratio of 1:1:1 to one of the 3 study groups: group 1 – cDMARDs+OKZ 64 mg subcutaneously once every 4 weeks (n=18); group 2 – cDMARDs+OKZ 64 mg subcutaneously once every 4 weeks + psychopharmacotherapy (PPT) (n=26); group 3 – cDMARDs+PPT (n=5). The duration of the study is 24 weeks. The dynamics of depression severity was assessed on the PHQ-9, MADRS scales; anxiety – HAM-A; experimental psychological projective techniques were also used.

Results. After 12 and 24 weeks of therapy, there was a significant decrease in the severity of depression and anxiety in all groups of patients. However, the difference between the final and initial values of all scales was statistically significantly greater (p<0.05) in the groups of patients receiving PPT: cDMARDs+OKZ+PPT (Δ_{PHQ-9 24–0} =–6.75±3.91; Δ_{MADRS 24–0} =–22.5±4.83; Δ_{HAM-A 24-0} =–14.6±5.37) and cDMARDs+PPT (Δ_{PHQ-9 24–0} =–15.5±3.53; Δ_{MADRS 24–0} =–25.0±1.41; Δ_{HAM-A 24-0} =–18.5±3.53), compared with the cDMARDs+OKZ group (Δ_{PHQ-9 24–0} =–4.00±3.89; Δ_{MADRS 24-0} =–5.75±8.29; Δ_{HAM-A 24–0} =–8.50±8.21). According to a semi-structured interview with a psychiatrist and design experimental psychological techniques, the proportion of patients without depression after 24 weeks of therapy was significantly higher in the groups of patients receiving PPT: 90% in the group of cDMARDs+OKZ+PPT and 100% – cDMARDs+PPT, as opposed to 25% in the group of cDMARDs+OKZ. OKZ therapy contributed to the normalization of night sleep but did not lead to a decrease in the frequency and severity of cognitive disorders (CD).

Conclusions. OKZ has an antidepressant effect in RA patients, leads to a decrease in the frequency of sleep disorders, but a com[1]plete regression of depression symptoms is possible because of the appointment of OKZ without PPT only in 25% of RA patients, mainly in patients with mild depression. Optimal for the complete regression of depression, anxiety and a decrease in the frequency and severity of CD is a combination of OKZ and PPT.

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.

The aim of the study was to study the features of the clinical picture of the disease in patients with ACPA-negative and ACPA-positive variants of rheumatoid arthritis.

Materials and methods. The study included patients with a reliable diagnosis of rheumatoid arthritis (RA) according to the criteria of ACR/EULAR 2010. Depending on the values of the ACPA, two groups of patients were recruited: ACPA-positive and ACPA-negative, comparable in gender, age, duration of the disease and therapy. The nature of the onset and course of the disease, the activity of RA were evaluated (according to the DAS28, SDAI, CDAI indices).

Results and discussion. The study included 79 patients with ACPA-negative variant of RA and 79 with ACPA-positive. Age of patients (Me [IR], in years) with the ACPA(–) variant was 52 [39; 62], with the ACPA(+) – 54 [42; 62], the duration of the disease (in months) is 59 [23; 122] and 48 [17; 84] respectively. In ACPA(+) patients, higher disease activity was determined by the indices DAS28-CRP, DAS28-ESR, SDAI, CDAI, values of C-reactive protein and erythrocyte sedimentation rate, a greater number of painful and swollen joints (p<0.05). According to the localization of the involved joints, arthritis of the proximal interphalangeal, metacarpal, wrist and shoulder joints was more often determined in ACPA(+) patients. Systemic manifestations of RA at the time of examination and in the anamnesis were statistically significantly more common in ACPA(+) (32.9%) than in ACPA(–) (17.7%). Of the systemic manifestations, rheumatoid nodules were more common in ACPA(+) patients, a tendency to a higher frequency of neuropathy, scleritis and episcleritis was revealed in ACPA(–) patients.

Conclusion. In patients with ACPA(–) subtype, clinical signs of joint damage and the inflammatory component are less pronounced compared to ACPA(+). However, the mixed picture of manifestation, the less “bright” course of the disease, the absence of characteristic immunological biomarkers necessitate long-term and careful monitoring of this group of patients. At the same time, the subjective severity of the disease and dysfunction due to ankylosing joints do not differ from the ACPA(+) variant of RA.

Central sensitization (CS) is a condition characterised by (associated with) neuroplastic changes in nociceptive neurons, sub-threshold afferent input, pain hypersensitivity and development widespread pain. Insufficient response to disease-modifying antirheumatic drugs (DMARDs) can be caused by CS.

Objective – to evaluate the features of clinical manifestations of RA in patients with ineffective antirheumatic therapy, depending on the presence of signs of CS.

Material and methods. The study group included 509 patients diagnosed with RA (according to ACR/EULAR classification criteria, 2010) with moderate or high disease activity (DAS28-CRP≥3.2) and ineffectiveness or intolerance of conventional synthetic DMARDs, biological DMARDs and JAK inhibitors. Disease activity in patient with RA was assessed by DAS28-CRP. Our study did not include an examination by a neurologist to detect signs of CS, so the Central Sensitization Inventory (CSI) (part one) was used. The BPI questionnaire was used for assessing clinical pain intensity. The PainDETECT, FSS, FIRST, HAQ questionnaires were used for screening neuropathic pain symptoms (NPS), fatigue, fibromyalgia signs and functional impairment, respectively. The HADS questionnaire was recommended for early diagnosis anxiety and depression disorders.

Results. Signs of CS (CSI≥40), with a median of 42 [32; 53], were found in 57.2% of the examined patient. Patients with signs of CS were established to have poorer health measure (PGA – 64.6±13.5 and 53.5±16.8; p=0.001), higher pain intensity in all BPI scales, longer morning stiffness – 90 [30; 180] and 60 [20; 120] minutes (p=0.001), more painful joints – 8 [5; 12] and 7 [4; 10] (p=0.005), worse functional status in HAQ (1.65±0.7 and 1.08±0.5; p=0.001) and higher disease activity in DAS28-CRP (4.9±1.0 and 4.6±0.9; p=0.001) compared to patients without signs of CS. There was also direct correlation between CS and a high frequency of having an NPS (PainDETECT>18) – 34.5% and 10.3% (p=0.001), significant anxiety and depression (HADS>11) – 29,0% and 5.1% (p=0.001) and 26.3% and 4.2% (p=0.001) respectively, fatigue (FSS) – 96.5% and 70.4% (p=0.001), signs of fibromyalgia (FIRST≥5) – 38.4% and 6.1% (p=0.001).

Conclusion. The presence of signs of CS in patient with RA significantly enhance many symptoms of disease, being associated with higher pain intensity, fatigue, impaired function, higher incidence of NPS, depression and anxiety, and fibromyalgia.

Avascular necrosis (AN) of bone tissue is a common pathology that affects people of any age, more often young and able-bodied. The disease leads to rapid destruction of the subchondral bone and collapse, followed by the development of secondary osteoarthritis (OA) of the affected joint.

The purpose of this review article is to present the accumulated knowledge about the prevalence of AN, the most commonly affected joints, risk factors and pathogenesis of the disease. Since most of the world’s literature sources present knowledge about the individual parts and facts that make up the pathogenesis of AN, this article analyzes all known paths of the development of the disease from the onset of ischemia to collapse and the development of secondary OA and the pathogenesis is presented in chronological order. Based on the results of the article, a definition of the term AN was proposed, and the stages of the disease within the pathogenesis, the most promising for conservative methods of treatment, were identified.

Along with familial Mediterranean fever (FMF), it is now considered an autoinflammatory disease and gout. The commonality of the basic mechanisms of inflammation underlying the pathogenesis of FMF and gout predetermines the possibility of using similar therapies aimed at stopping and preventing seizures (colchicine and IL-1 inhibitors). A clinical case is presented describing the presence of a combination of FMF and gout in a patient. The patient was prescribed anakinra, which proved to be effective both as a treatment for FMF and gout. The appointment of an IL-1 inhibitor fully justified expectations: already after the first injection of anakinra, the intensity of swelling and pain in the joints decreased in the patient.