Systemic lupus erythematosus (SLE) is a multifactorial disease caused by complex interactions between the genetic and environmental factors underlying various innate and adaptive immunity disorders, including cytokine hyperproduction, abnormal B cell activation, impaired intracellular T-cell signaling, and defective apoptotic and necrotic cell clearance. A broad spectrum of genetic disorders associated with susceptibility to the disease and/or its definite variants has been identified. Our knowledge concerning the mechanisms of polyclonal B cell activation in SLE has advanced substantially. Various defects in the T cells regulating a B cell immune response have been detected. The development of genetic, epigenomic, transcriptomic, and proteomic technologies could identify a group of pathogenetically relevant cytokines, including BLyS (the B-lymphocyte stimulator is the most important component of cytokine-mediated regulation of B cell function, proliferation, and differentiation), interleukin (IL) 6, 17, 18, type 1 interferon, and tumor necrosis factor-α, which are involved in the development of visceral inflammation and damage.

Large-scale clinical trials of different medications, primarily biological agents (BA), were conducted in patients with SLE. Rituximab (RTM) is the first BA to be used to treat this disease. Despite its official registration for the therapy of SLE, RTM is included in the EULAR, ACR, and Russia's Association of Rheumatologists guidelines for its treatment. Belimumab, a fully human recombinant IgG1λmonoclonal antibody, specially designed to treat SLE, prevents the interaction of pBLyS with the receptors of autoreactive transitional and naive B cells, giving rise to the suppression of B cell hyperresponsiveness, autoantibody synthesis in particular. In addition, BLyS block may cause decreased survival of B cells in the germinal centers of lymphoid organs, differentiation of memory B cells into autoantibody-producing cells, and synthesis of proinflammatory cytokines (IL-21, IL-17, and others) that play an important role in the immunopathogenesis of SLE. Despite its moderate efficacy, belimumab will be able to improve pharmacotherapy for this disease.

In patients with ankylosing spondylitis (AS), uveitis is its most common extraarticular manifestation (it occurs in 20–40% of cases).

Objective: to study the specific features of diagnosis of AS in the presence of uveitis in persons of different sex.

Subjects and methods. The study included 94 patients with AS. The rate of uveitis, patient age at its first episode, in the clinical manifestations of AS (inflammatory dorsalgia, arthritis, and enthesis), and in making a diagnosis, as well as disease activity were estimated in patients of different sex in the presence and absence of uveitis.

Results. Uveitis as an extraskeletal manifestation of AS was stablished to more common in women (40%) than in men (15.8%). In female patients, the presence of uveitis is associated with early-onset AS as compared to those without uveitis. At the same time the diagnosis of AS was made in the women with uveitis 7 years later than in those without this condition. In one fifth of the patients, uveitis occurred before or concurrently with the appearance of the symptoms of locomotive lesion.

Conclusion. Uveitis is more common in women with AS than in men and associated with the late detection of locomotive pathology.

Interleukin (IL) 1βis a major mediator of cryopyrin-associated periodic syndrome (CAPS). In this connection, the experience with IL-1 inhibitors used in patents with CAPS is being accumulated worldwide. Canakinumab was approved by FDA and EMEA in 2009 to treat CAPS and registered in the Russian Federation for this in 2011. The drug has been shown to be highly effective and well tolerated by patients with CAPS.

Objective: to present Russia's experience in using the IL-1 inhibitor canakinumab in children with CAPS.

Subjects and methods. The trial enrolled 6 CAPS patients, including 4 with Muckle-Wells Syndrome (MWS) and 4 with chronic infantile onset neurologic cutaneous articular/neonatal onset multisystem inflammatory disease (CINCA/NOMID), among whom there were 5 female patients aged 3.5 to 40 years and 1 male patient aged 17 years. Two patients (a 17-year-old daughter and her 40-year-old mother) were stated to have a familial MWS case. The duration of the disease was 3.5 to 33 years. All the patients underwent a molecular genetic analysis for mutations in the NLRP3 (CIAS1) gene. Four patients with MWS were found to have Thr436Ile and Thr438Ile mutations; the mother and her daughter had Thr350Met mutations; no mutations were detected in 2 patients with CINCA/NOMID. At the study, one female patient with MWS took gluco-corticoids (GC) in a dose of 0.1 mg/kg; the others received symptomatic therapy with nonsteroidal antiinflammatory drugs. Canakinumab was injected subcutaneously every 8 weeks in a dose of 4 mg/kg for patients with a body weight of <15 kg and in a dose of 2 mg/kg for those with a body weight of >15 kg. By now, 2 patients with MWS received 7 injections of the drug (a 48-week follow-up); 2 patients with CINCA/NOMID had its 6 injections (a 40-week follow-up) and 2 patients with MWS had 2 injections (a 10-week follow-up).

Results. All the patients showed a significant clinical improvement: recovery; elimination of fever, rash, and eye symptoms; and a reduction in the levels of acute-phase markers. The effect retained throughout the follow-up. GC could be completely discontinued in the female patient with MWS. No adverse events were observed in any case.

Conclusion. The experience in using canakinumab in the patients with CAPS showed the high efficacy and good tolerability of the drug. The decrease in acute-phase markers was slower in the patients with CINCA/NOMID, the most severe form of CAPS.

Education programs are an important part of the management of patients with rheumatoid arthritis (RA).

Objective: to develop a unified model of an education program for RA patients and to evaluate its efficiency at the early stage of the disease.

Material and methods. A group education program was worked out with the support of the All-Russian public organization of the disabled “The Russian rheumatology organization “Nadezhda” (Hope)” and encompassed 4 daily classes lasting 90 min. All information was presented by a multidisciplinary team of specialists (rheumatologists, a cardiologist, a psychologist, a physiotherapist, and a physical trainer). The study included 55 patients with early RA (89.1% of women aged 18 to 62 years; the duration of the disease was 2 to 22 months); of them 25 were taught using the education program (a study group); 30 received drug therapy only (a control group). Following 3 and 6 months, the number of tender and swollen joints, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and pain were determined applying a 100-ml VAS, DAS28, HAQ, and RAPID3. Adherence to non-drug treatments was assessed employing a special patient questionnaire.

Results. Three and six months after being taught, two patient groups showed increases in adherence to joint protection methods by 13 and 10 times (p<0.01), regular physical training by 4 and 3.25 times (p<0.01), uses of orthoses for the wrist joint by 2 times and 75% (p<0.01) and knee orthoses by 33.3 and 50.0% (p<0.01), and orthopedic insoles by 71.4 and 57.1% (p<0.01), respectively. Following 6 months, there were statistically significant differences between the two groups in most parameters (p<0.05), except for ESR, CRP, and DAS28 (p>0.05). Further more, a good response to treatment was significantly more common in these periods, as shown by the EULAR response criteria (DAS28): 56.3% versus 40% in the control group (p<0.05).

Conclusion. The education program decreases the intensity of pain syndrome and improves the functional status and quality of life of patients with early RA within 6 months. Patient education enhances adherence to non-drug treatments. The highest positive result was achieved just 3 months later; it slightly tailed off at 6 months. This necessitates re-education in succeeding 3–6 months.

Objective: to study the possible chondroprotective effect of the viscoelastic agent synvisc, by applying the developed methodological and classification approaches to evaluating the intraarticular cartilage by arthroscopy and magnetic resonance imaging (MRI).

Subjects and methods. Eighty six patients with knee arthrosis were examined and divided into 2 groups: a study group of 64 patents and a control one of 22 patients. Synvisc was injected into the affected joint in the study group; methylprednisolone acetate in the control group. Arthroscopic and MRI criteria were used to evaluate the articular cartilage. Arthroscopy and MRI were performed before and 6 and 12 months after treatment.

Results. The developed methodological approaches are distinguished for their high sensitivity (89.7%) and specificity (95.2%), which could estimate changes in arthrosis just at the stage of hyperhydration and dechondral changes and monitor long the chondroprotective effect of synvisc. The agent was noted to have a positive effect at the stage of hyperhydration and dechondral changes and in grade I–II intrachondral changes and to be able to prevent or stop the progression of OA in later (II–III) X-ray stages. The effect of synvisc did not depend on disease duration and patient age, but it decreased in the presence of marked articular anatomic and morphological changes. The administration of the agent could reduce or preclude the use of nonsteroidal anti-inflammatory drugs or intraarticular glucocorticoids n 96% of cases.

Conclusion. Arthroscopy and MRI make possible to recognize arthrosis in its earliest stage and to monitor the effect of drugs on the cartilage. The use of synvisc in early-stage gonarthrosis allows a long-term symptomatic effect and some structure-modifying activity.

The annual incidence of adult-onset Still's disease (AOSD) worldwide is 0.16 cases per 100,000 persons. Its leading symptoms are joint involvement, fever, skin rash, and neutrophilic leukocytosis in the absence of rheumatoid factor and anticyclic citrullinated peptide antibodies in serum and synovial fluid. In its initial stage, there may be monoarthritis more commonly of the wrist, hip, or knee. Then the lesion assumes the pattern of oligo- or polyarthritis. Musculoskeletal involvement appearing as arthralgia, arthritis, and myalgia is noted in all patients. In the majority of patients, articular involvement progresses and destructive polyarthritis develops. Symmetric involvement of the carpophalangeal and distal interphalangeal joints is frequently detected. Skin lesion manifests itself as maculopapular or roseolous rashes on the chest, back, shoulders, occasionally on the legs, or in the areas of mechanical irritation. A sore throat with the signs of pharyngitis is a characteristic early symptom of the disease. There may be involvements of the liver, cardiovascular system, lung, as well as lymphadenopathy, or splenomegaly. The chronic course of the disease is more frequently noted.

The paper describes two cases of AOSD. One case demonstrates that the physician has no experience in diagnosing and managing patients with AOSD, resulting in the misinterpretation of the increase in disease activity when the subclinical doses of methotrexate (MT) are used, which has been regarded as a therapeutic complication. The use of the adequate dose of MT could achieve a clinical and laboratory remission and discontinue glucocorticoids (GC).

In the other case of recurrent AOSD and mild clinical symptoms, the unreasonable use of high GC doses gave rise to adverse reactions.

Systemic vasculitides (SVs) are characterized by inflammation of the blood vessels wall; the spectrum of their clinical manifestations depends on the type, extent, and location of affected vessels and the activity of systemic inflammation. The etiology of most primary SVs is unknown. Antineutrophil cytoplasmic antibodies (ANCAs) are implicated in its pathogenesis. The presence of ANCAa in patients' serum and the correlation of their level with the severity of clinical manifestations served as a basis for identifying a subgroup of systemic necrotizing vasculitides associated with ANCA synthesis: granulomatosis with polyangiitis (GPA), microscopic polyangiitis, and Churg – Strauss syndrome. GPA is characterized by systemic granulomatous necrotizing vasculitis involving the small vessels of the upper respiratory tract, lung, and kidney.

The paper describes a case of difficult diagnosis and successful rituximab (RTM) treatment of generalized GPA in a 45-year-old female patients. The disease occurred with local damage to the upper respiratory tract, granulomatous inflammation of the pulmonary vessels to form multiple infiltrates with lung tissue destruction elements and necrotizing glomerulonephritis. Despite intensive immunosuppressive treatment, there was a rapid GPA progression with the further development of respiratory failure, which had been induced by stenotic laryngitis subglottica leading to tracheostoma. Damage to the organ of vision could lead to severe complications, including amaurosis. RMT was shown to be effective in treating generalized GPA with a poor prognosis.

Rheumatoid arthritis (RA) is a systemic autoimmune rheumatic disease of unknown etiology, characterized by chronic erosive arthritis and extraarticular manifestations. Pulmonary involvement is one of the common extraarticular manifestations of RA and may show itself as bronchial tree lesions, rheumatoid nodules, Caplan's syndrome, and lesions in the pleura or pulmonary interstitium (interstitial lung involvement (ILI)). High-resolution computed tomography allows the diagnosis of ILI in RA in nearly 70% of cases although the incidence of ILI may be lower (4 to 30%) depending on diagnostic methods and patient selection criteria. There are several histopathological types of ILI, the differential diagnosis of which can be troublesome. Usual interstitial pneumonia (UIP) and nonspecific interstitial pneumonia are major types of RA-associated ILI. UIP-pattern ILI has a more severe course than ILI with other histological patterns. The clinical presentation of ILI may be complicated by the likely toxic effect of a number of disease-modifying antirheumatic drugs (DMARDs) used to treat RA, such as methotrexate and leflunomide, and biological agents (BAs), tumor necrosis factor-α (TNF-α) inhibitors. The pathogenesis of pulmonary involvement in RA and the role of synthetic DMARDs and BAs in the development of ILI call for further investigations.

An extraarticular manifestation, such as ILI, affects the choice of treatment policy in patients with RA.

The relevance of a study of ILI is beyond question. The paper discusses the state-of-the-art of investigations in this area.

Pain is a major problem in patients with rheumatoid arthritis (RA). It produces a serious psychological discomfort, causes sleep disorders, and drastically limits physical activity. Pain is one of the main signs of inflammation and its intensity correlates with inflammatory activity. The early use of disease-modifying antirheumatic drugs, regular monitoring, and timely correction of therapy in accordance with the treat-to-target principle make it possible to effectively monitor the activity of RA and to delay its progression. However, despite a marked decrease in RA activity, pain does not go away completely and may increase with time in a number of cases. Pain occurring in patients with RA is always far short of being caused by arthritis. It may be also related to comorbidity, osteoarthritis or fibromyalgia in particular. Pain induced by comorbidity may seriously distort the result of assessment of inflammatory activity and a physician's decision made to correct drug therapy in accordance with the treat-to-target principle.

Nonsteroidal antiinflammatory drugs (NSAIDs) are in most common use for the symptomatic therapy of RA. In spite of a significant reduction in pain and stiffness during therapy with NSAIDs, they do not affect the progression of X-ray changes. Virtually all NSAIDs may relieve pain when used in doses substantially smaller than those required to suppress inflammation. NSAIDs are an essential component of combination therapy for RA. They are given just at the early stage of the disease, by taking into account the gastrointestinal tract, kidney, and cardiovascular system. The National Institute for Health and Clinical Excellence in the United Kingdom proposes to administer analgesics (paracetamol and codeine) to reduce needs for NSAIDs in RA. For the time being, the use of analgesics in RA has, however, a weak evidence base.

Different trials have also studied the efficiency of monotherapy with weak opioids, but it has proven to be also low. It is well, where possible, to avoid the long-term use of opioids.

Along with NSAIDs and paracetamol, the recent guidelines of the International Expert Group of Pain Pharmacotherapy to use tricyclic antidepressants as additional agents to treat joint inflammatory diseases, which may be effective in some cohort of patients, such as those with RA and comorbid depressive disorders.

Besides drug therapy, nonpharmacological methods are also successfully used in the treatment of pain in RA. The effective suppression of pain makes it possible not only to considerably reduce existing discomfort in a patient, but also to more correctly choose treatment policy in each specific case.

The paper discusses the mechanisms of destructive processes in rheumatoid arthritis (RA). At the present stage, in addition to suppress inflammation, the goals of treatment are to prevent cartilage and bone destruction in the affected joints. Prediction of destructive processes in RA plays an important role as the irreversibility of functional changes in RA directly correlates with the degree of joint injury. The paper discusses the mechanisms of articular cartilage and bone destruction and the significance of different biochemical markers for estimating the degree of injury and for predicting further destruction of small hand and foot joints. In RA, the investigators identify not only clinical (activity indicators), but also biological (bone, cartilage, and synovium damage markers) predictors for joint injury: CТXII is a marker for cartilage degradation (collagen type II) and CTXI is a marker for bone degradation (collagen type I) and their trends over 4–12 or more weeks. Although the occurrence of erosions is considered to be a major manifestation of joint destruction progression in RA, the functional activity in its early stages is shown to depend on the estimate of joint space narrowing (cartilage degradation) to a greater extent than on that of erosions when evaluating the destruction by the modified Sharp method. Several randomized placebocontrolled studies (RPCSs) have assessed the association of patients' functional capacity with joint space narrowing or with the number of erosions. In RA, cartilage degradation has been demonstrated to play a larger role in irreversible function loss than bone destruction.

The possibility of suppressing cartilage degradation, which is indicated in RPCSs of the efficacy of adalimumab, correlates with a better functional outcome in patients with RA. Serum markers for cartilage metabolism may be not only predictors for further radiographic progression, but also be used to evaluate therapeutic effectiveness.

Endoprosthetic replacement is a widely used treatment for joint disease worldwide. In the past few decades, the rate of endoprosthetic replacement of different joints has substantially increased – about 1.5 million operations yearly. The paper considers the problems of endoprosthetic joint replacement in patients with rheumatoid arthritis (RA) receiving biological agents (BAs). The latter are extensively used to treat not only the early, but also late stages of the disease when there are already indications for endoprosthetic joint replacement, but the activity of the disease cannot be diminished by standard therapy with disease-modifying antirheumatic drugs. BA therapy can enhance the efficiency of monitoring the activity of RA in its different stages and improve functional parameters. There is an increase in the number of patients requiring endoprosthetic joint replacement and receiving BAs. Data on the safety of BAs used in the perioperative period are given. Endoprosthestic joint replacement during this therapy makes it possible to decrease the degree of pain syndrome, to improve the function of an operated joint and the quality of life in patients, to affect the course of RA, to lower disease activity, and to improve their monitoring.

The tumor necrosis factor-α (TNF-α) golimumab (GLM), that is a fully human monoclonal anti-body, was registered in Russia in 2012 to treat rheumatic diseases, such as rheumatoid arthritis (RA), ankylosing spondylitis, and psoriatic arthritis. Its distinguishing characteristics are a high affinity for TNF-α and easiness-to-use: the drug as a 0.5-ml solution is injected subcutaneously once monthly. The registration of the medication was followed by the implementation of a massive program of clinical trials. The randomized placebo-controlled GO-FORWARD, GO-BEFORE, and GO-AFTER studies have indicated that GLM is effective in patients with RA from different subgroups and has a favorable safety profile as compared to that of the entire class of biological agents. According to the data of these studies, GLM had a positive effect on the functional status and quality of life in patients with RA: there was a significantly greater decrease in HAQ scores in both the early and long open treatment phases (to 5 years) and in fatigability than in the control group (p=0.032), physical and mental health improvements, as shown by the SF-36 questionnaire, and a significant reduction in disability.

Ankylosing spondylitis (AS) is a chronic systemic disease with predominant axial skeleton injury, peripheral articular and entheseal involvements, and extra-skeletal manifestations. 8–10 years elapse since the first manifestations of AC to its diagnosis, leading to delays in adequate therapy, to the progression of structural and functional impairments in the axial skeleton and peripheral joints and to the development of complications. According to the international and Russia's Association of Rheumatologists guidelines, nonsteroidal anti-inflammatory drugs (NSAIDs) are an important component of AS therapy. It is necessary to carefully choose the safest NSAID for these patients, by taking into consideration that AS therapy should be long-term and continuous.

The trial previously performed by the authors evaluated comorbidity in 220 AS patients long receiving nimesulide. Its long-term administration was shown to cause no increase in the level of liver enzymes. Esophagogastroduodenoscopy revealed antral gastritis in 23.6% of the patients, gastric mucosal erosions in 13, and gastric ulcer disease without an exacerbation in 3.6%. It was noted that the physicians had not prescribed gastroprotectors to the patients. Nimesulide caused no blood pressure (BP) elevation even in patients who had baseline hypertension. Elevated BP occurred in 2.5% of the patients. There was no clear association of higher BP with nimesulide intake since the patients had previously used other NSAIDs, mainly diclofenac, to treat severe pain syndrome. These findings suggest that in addition to its analgesic activity, nimesulide shows good tolerability in patients with AS, which permits its long-term use, but in this case the gastrointestinal tract and BD should be carefully monitored, which will be able to prevent the possible adverse events characteristic of the entire group of NSAIDs.

Diacerein (DR) is a medication from a group of symptomatic slow-acting agents (chondroprotectors), which has an original mechanism of action and is widely used in Russia and many countries in the world to treat osteoarthrosis (OA). The ability of DR to affect its major symptoms and progression has been shown in a series of well-organized clinical trials. However, the supervisory health bodies of the European Union have presently made a decision to restrict the use of DR, which is associated with the fact that the viewpoint of this drug's safety level has been changed. The case in point is gastrointestinal complications (diarrhea) and hepatotoxic reactions, which may be caused by DR treatment. This review considers the results of the most known clinical trials of DR, gives basic data on its adverse reactions, and assesses prospects for using its new generic drugs.

The Expert Council for Tofacitinib (TOFA) and two symposiums on New Possibilities for Targeted Therapy of Rheumatoid Arthritis and on Success Factor of Biological Therapy for Rheumatic Diseases were held within the annual scientific-and-practical conference of the V.A. Nasonova Research Institute of Rheumatology on Comorbidity in Rheumatic Diseases in Moscow on 14–15 October 2014.