Vol 92, No 5 (2020)

Thrombotic microangiopathy in rheumatology: a link between thrombosis and autoimmunity
Nasonov E.L., Reshetnyak T.M., Alekberova Z.S.

Uncontrolled hypercoagulation and inflammation (“thromboinflammation”), which are both independent and closely related and amplifying each other pathological processes, form the basis for pathogenesis of a wide range of diseases and complications, including immuno-inflammatory (autoimmune) rheumatic diseases, with the development of potentially fatal injuries of internal organs. Thrombotic microangiopathy is one of the most prominent prototypes of “thromboinflammatory” pathological conditions. The close link between environmental factors, hemostasis genetic defects and the complement system, inflammation and autoimmunity as pathogenetic mechanisms of microthrombosis draws particular attention to studying thrombotic microangiopathy in immuno-inflammatory rheumatic diseases, primarily systemic lupus erythematosus, antiphospholipid syndrome and scleroderma renal crisis. In future, these studies may be important for expanding the idea of the role of autoimmune mechanisms in pathogenesis of “critical” hemostasis disorders in human diseases, and for developing new approaches to therapy. Recently, special attention has been paid to the treatment of systemic lupus erythematosus and antiphospholipid syndrome with eculizumab, which is humanized monoclonal IgG2/4k antibody that blocks the complement component C5a and the membrane attack complex (C5b-9) formation, and which is registered for the treatment of atypical hemolytic uremic syndrome, paroxysmal nocturnal hemoglobinuria, as well as severe forms of myasthenia gravis and neuromyelitis optica. Further studies in this direction will create prerequisites for improving the prognosis not only in patients with orphan disorders, but also for widespread human diseases.

Terapevticheskii arkhiv. 2020;92(5):4-14
Original articles
Frequency of sarcopenia and factors associated with lean mass in women with rheumatoid arthritis
Toroptsova N.V., Dobrovolskaya O.V., Nikitinskaya O.A., Demin N.V., Feklistov A.Y.

Aim. To evaluate the frequency of sarcopenia (SP) according to EWGSOP2 criteria and factors associated with low lean mass in women with rheumatoid arthritis (RA).

Materials and methods. 79 women (aged 40–75 years) with RA were enrolled in the study. We analyzed clinical data: age, body mass index (BMI), disease duration, methotrexate use, glucocorticoid use, anthropometric measurements, C-reactive protein level, disease activity score in 28 joints-erythrocyte sedimentation rate, bone mineral density (BMD) of the lumbar spine, femur neck, total hip and body composition by Dual energy X-ray absorptiometry. Also, muscle strength and functional tests were performed. We analyzed the correlation between disease parameters and low lean mass with the Spearman method.

Results. 73 (92%) patients had low muscle strength, 20 (25%) patients had low muscle strength and low lean mass, among them 9 (11%) – also had functional disability. There was no correlation between the age of patients and the presence of SP, while the duration of RA in women with SP was significantly greater (p=0.006). There were significant correlations between lean mass and body mass index, glucocorticoids used, methotrexate doses, creatinine and urea acid serum concentration, bone mineral density and falls number.

Conclusion. According EWGSOP2 confirmed sarcopenia was found in 25% RA patients, among them 11% women had severe sarcopenia. Lean mass correlated with the factors related to the disease itself and some general clinical parameters, which requires further study.

Terapevticheskii arkhiv. 2020;92(5):15-21
Depression and severity of articular destruction in patients with rheumatoid arthritis
Abramkin A.A., Lisitsyna T.A., Veltishchev D.Y., Seravina O.F., Kovalevskaya O.B., Glukhova S.I., Nasonov E.L.

Aim. To assess the influence of anxiety and depressive disorders on joint destruction in patients with rheumatoid arthritis (RA).

Materials and methods. 128 RA-patients were included, 87% were women with a mean age of 47.4±11.3 years and a median of RA duration – 96 [48; 228] months. At the inclusion most patients had moderate (n=56, 43.7%) and severe (n=48, 37.5%) disease activity according to DAS28. Joint destruction was classified as maximal in patients with radiographic stage III, IV and/or osteonecrosis) and minimal in patients with stage I, II and no osteonecrosis. Pain intensity was measured with the BPI (Brief Pain Inventory) scale, severity of fatigue – with fatigue severity scale (FSS), clinically important fatigue was diagnosed in patients with FSS≥4. Anxiety and depressive disorders (ADD) were diagnosed by a licensed psychiatrist in 123 (96.1%) of RA-patients in accordance with ICD-10 in semi-structured interview. Severity of depression and anxiety was evaluated with Montgomery-Asberg Depression Rating Scale (MADRS) and Hamilton Anxiety Rating Scale (HAM-A). RA-patients with ADD were divided into the following treatment groups: 1 – сDMARDs (n=39), 2 – сDMARDs+PPT (sertraline or mianserine), n=43, 3 – сDMARDs+bDMARDs (n=32), 4 – сDMARDs+bDMARDs+PPT (sertraline or mianserine), n=9. Biologics treatment duration varied from 1 to 6 years, antidepressants – from 6 to 96 weeks. 83 (67.5%) RA patients were assessed at five-years follow-up. Linear regression analysis was conducted to determine factors associated with maximal join destruction.

Results. According to linear regression analysis, maximal joint destruction at 5 years follow-up was associated with higher baseline BPImax, longer RA and ADD duration, clinically important fatigue at baseline, baseline extraarticular RA manifestations, recurrent depressive disorder at 5-years follow-up and treatment with cDMARDs only.

Conclusion. Recurrent depressive disorder without antidepressant treatment is an important predictor of progression of joint destruction in patients with rheumatoid arthritis.

Terapevticheskii arkhiv. 2020;92(5):22-32
Panniculitis in modern rheumatology
Egorova O.N., Belov B.S., Glukhova S.I., Radenska-Lopovok S.G.

Aim. To study clinical and laboratory features of panniculitis (Pn) in modern rheumatology.

Materials and methods. The study included 690 patients with Pn (615 women and 75 men, average age – 39.4±10.26) with the prevailing referral diagnosis of Erythema nodosum (59.2%), Pn (27.5%), Rheumatic disease – Rd (9%), other diseases (4.4%),who had been on outpatient and/or inpatient treatment for 10 years. All patients were examined according to our diagnostic algorithm: general clinical, immunological and histological examinations, computed tomography of the chest organs, tuberculin tests.

Results. Pn with Rd was diagnosed in 140 patients (118 women and 22 men, average age 40.21±14.87), average disease duration 31.06 [0.1; 541] months. In most cases (49%) patients had idiopathic lobular Pn which belongs to the group of systematic lesions of connective tissue (M35.6), as well as systemic lupus erythematosus and Behcet disease (13% each), rheumatoid arthritis (8%), dermatomyositis (6.4%), etc. Matching of the referral and final diagnoses was 35% in case of Rd. Among the examined patients prevailed those with a moderate (51.07%) degree of activity of the underlying disease. Within the study group Pn was represented by all forms, but mainly by nodular form (64.02%). Mesenteric form was characteristic only for idiopathic lobular Pn. The main features of Pn associated with Rd were identified. In modern clinical practice the type of Pn and the activity of the underlying disease determine the approaches to treatment.

Terapevticheskii arkhiv. 2020;92(5):33-38
Survival of bDMARDs in bionaive patients with rheumatoid arthritis: data from a retrospective 12-month follow-up
Aronova E.S., Lukina G.V., Glukhova S.I., Gridneva G.I., Kudryavtseva A.V.

Aim. Analysis of survival on biological therapy in previously bionaive patients with rheumatoid arthritis (RA) during the first year of therapy in real clinical practice.

Materials and methods. The retrospective study included 204 adult patients with RA. In the hospital, patients were first prescribed therapy with various biological disease-modifying antirheumatic drugs (bDMARDs): infliximab, adalimumab, etanercept, certolizumab pegol, tocilizumab, abatacept (ABA), rituximab (RTM). Patients were divided by age in accordance with the classification adopted by WHO. Clinical forms of RA were presented: RA, seropositive for rheumatoid factor, RA, seronegative for rheumatoid factor, RA with extra-articular manifestations, adult-oneset Still’s disease, juvenile RA. The reasons for the cancellation of bDMARD during the first year of treatment were: insufficient effectiveness (including primary inefficiency), adverse events, administrative reasons, clinical and laboratory remission, death.

Results. A year after being included in the study, treatment was continued in 92 (45%) patients and was discontinued in 112 patients. The average time of treatment amounted to 0.75±0.33 years. The longest duration of treatment was in the RTM and ABA groups (0.92±0.22 and 0.83±0.29 years, respectively). In 56 (50%) patients, bDMARD was canceled due to insufficient effectiveness (including primary inefficiency), 28 patients (25%) – due to the development of adverse reactions, 19 (17%) patients – for administrative reasons, 7 (6.25%) patients – due to drug remission. During the first year of therapy, there were 2 (1.75%) deaths due to severe comorbid conditions in patients, one of whom received RTM, the other – tocilizumab.

Conclusion. Study showed that 45% of patients with RA continue treatment with first-time bDMARD for more than 12 months. The most common reason for discontinuation of therapy was its lack of effectiveness. The best survival rate of bDMARDs was observed in RTM and ABA. When selecting bDMARD in each case, it is necessary to take into account the continuity at all stages of treatment.

Terapevticheskii arkhiv. 2020;92(5):39-45
The efficacy and safety of intra-articular application of a combination of sodium hyaluronate and chondroitin sulfate for osteoarthritis of the knee: a multicenter prospective study
Alekseeva L.I., Kashevarova N.G., Taskina E.A., Sharapova E.P., Anikin S.G., Strebkova E.A., Raskina T.A., Zonova E.V., Otteva E.N., Rodionova S.S., Torgashin A.N., Buklemishev U.V., Shmidt E.I., Shesternya P.A., Naumov A.V., Zagorodniy N.V., Lila A.M.

in 3 mL on patients with knee osteoarthritis (OA) in a multicenter prospective study.

Materials and methods. 79 outpatients (predominantly females – 81.0%) from 5 RF constituent territories with primary tibiofemoral Kellgren–Lawrence score grade II or III knee OA, ≤40 mm pain intensity during walking on visual analogue scale (VAS), requiring NSAIDs intake (for at least 30 days during 3 months prior to enrollment) were included into the study after signing the informed consent form. Mean age was 60.3±8.7 years, mean BMI – 29.2±4.7 kg/m2, disease duration – 6 (3–10) years. Grade II OA was documented in 68.4% of patients, Grade III – in 31.6%. The study lasted for 6 months. Efficacy and safety evaluations were made based on VAS pain assessment, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) – [WOMAC pain (0–500), WOMAC function (0–1700), WOMAC stiffness (0–200)], VAS patients’ health status, EQ-5D-based assessment of patients’ quality of life, global physician’s and patient’s efficacy assessment, and daily NSAIDs requirements.

Results. Obtained results demonstrate statistically significant VAS pain reduction during walking already in 1 week after intra-articular injection of the combination [respectively, 62 (55–72) and 41 (32–51) mm, р<0.0001]. Moreover, pain continued to subside during all 3 months of follow up [in 1 month – 28 (20–42), in 3 month – 22 (14–37) mm]. A significant pan reduction achieved at Mo 3 persisted until Mo 6 – 20 (14–42) mm, without documented pain increase. Similar trends were observed with total WOMAC score [1125 (899–1540) – at baseline, and 552 (309–837) mm – by the end of the study, p<0.0001], and all WOMAC sub-scores [268 (189–312) – baseline WOMAC pain, 91 (48–171) mm – by the end of the study p<0.0001; stiffness – 101 (59–130) and 40 (20–61) mm, p<0.0001; function – 802 (647–1095) and 402 (191–638) mm, p<0.0001, respectively]. Median time to the onset of therapeutic effect was 7 (5–18) days. Statistically significant improvement of patients’ quality of life by EQ-5D and general health status was observed during all follow up period [respectively, 0.52 (-0.02–0.59) and 0.69 (0.59–0.80), р<0.0001; 48 (30–60) and 72 (60–80) mm, р<0.0001]. One injection of the drug resulted in dose reduction or discontinuation of NSAIDs therapy: at baseline 76 patients (96.2%) were taking NSAIDs, in one week 31 (39.2%) patients discontinued NSAIDs, in 1 month – 72.2%, in 3 months – 73.4%, and by the end of the study at Mo 6 – 54.4% were not taking NSAIDs. These data were consistent with physician’s and patient’s global assessment of the efficacy of treatment, who stated “significant improvement” and “improvement” in the majority of cases, with only few “no effect” or “worsening” cases documented in analyzed population. Adverse events, such as worsening of pain and/or swelling of the joint, were documented in 8 patients (10.1%); they resolved spontaneously or following NSAIDs intake.

Conclusion. These results suggest that intra-articular injections of hyaluronic acid plus chondroitin sulfate in patients with knee OA are efficient and safe. A single injection of the drug resulted in statistically significant reduction of pain and stiffness, reduction in NSAIDs intake, as well as improvement in patients’ quality of life and function.

Terapevticheskii arkhiv. 2020;92(5):46-54
Clinicopatological variants and risk factors for chronic kidney disease in rheumatoid arthritis
Chebotareva N.V., Gulyaev S.V., Androsova T.V., Popova E.N., Gurova D.V., Novikov P.I., Milovanova L.Y., Moiseev S.V.

Recent studies have shown a high risk of chronic kidney disease and associated cardiovascular complications in patients with rheumatoid arthritis (RA), which determines the prognosis. However, the prevalence of chronic kidney disease (CKD) in RA has not been established in the Russians.

Aim. Study was to examine the prevalence, risk factors and histological variants of CKD in RA.

Materials and methods. 180 patients with rheumatoid arthritis were observed in the Tareev clinic of nephrology, for the period from 2014 to 2019 years. Age, gender, duration of RA, drug therapy, ESR, CRP, DAS28, renal function, proteinuria, histological variants were analyzed. Of the common population risk factors for CKD arterial hypertension, weight index, serum lipids and glucose levels were also assessed.

Results. The prevalence of CKD in RA was 19.7%. Age, presence and stage of arterial hypertension, an increase in body mass index, as well as high rates of disease activity – ESR, CRP, DAS28 score and duration of RA were risk factors of CKD in RA. Age, duration of the disease, stage of AH and hypercholesterolemia were risk factors in multifactorial regression analysis. Amyloidosis was the most common histologic pattern (50.0%), followed by chronic glomerulonephritis (30.4%) and tubulo-interstitial nephritis (19.6%). Among chronic glomerulonephritis mesangial glomerulonephritis was the most frequent. Renal amyloidosis was associated with a duration of RA, presence of systemic symptoms and CRP level. An isolated decrease in GFR of less than 60 ml/min was detected in 31 (36.0%) out of 86 patients.

Сonclusion. The risk factors for CKD in patients with RA are activity and duration of the disease In addition to common population factors. Amyloidosis was the most common histologic pattern associated with duration of RA and inflammatory proteins levels.

Terapevticheskii arkhiv. 2020;92(5):55-60
Assessment of the safety, tolerability and effectiveness of first Russian generic aceclofenac in patients with undifferentiated peripheral inflammatory arthritis
Zavodovsky B.V., Sivordova L.E., Polyakova Y.V., Akhverdyan Y.R., Papichev E.V.

Aim. To evaluate the effectiveness and tolerability of the drug in patients with undifferentiated peripheral inflammatory arthritis (UPIA).

Materials and methods. We observed 60 patients (39 women and 21 men) met G. Hazlewood et al., UPIA criteria, 2011. Patients were divided into 3 groups: with monoarthritis, oligoarthritis and polyarthritis. They took aceclofenac 100 mg twice day for 3 weeks.

Results. We noted significant decreasing in pain level according to visual analogue scale: in patients with monoarthritis – by 69.3 mm (p<0.001); in oligoarthritis group – by 47.5 mm (p<0.001), in patients with polyarthritis – by 30 mm (p<0.001). The life quality by the EQ-5D-5L index was improved too in all groups from 0.616 to 0.829 (p<0.001). The satisfaction with the therapy was: in monoarthritis patients (80% of patients and 93% of doctors noted good results), in oligoarthritis group (53% and 39% accordingly) and polyarthritis (74% and 64% respectively). We suppose the difference was due to the fact that mono- and oligoarthritis patients suffered from initial forms of seronegative spondylarthropathy, in which the effectiveness of NSAIDs is traditionally higher; polyarthritis patients probably had debut of rheumatoid arthritis. Adverse events of therapy were mild. We noted gastrointestinal tract symptoms (dyspepsia) and increased ALT in 10 patients and increased blood pressure – in 1 patient. The symptoms did not require discontinuation of therapy.

Сonclusion. Post-registration observational study of first Russian generic aceclofenac (“Alental”, Vertex, Russia) was conducted. In UPIA patients aceclofenac therapy was most effective in mono- and oligoarthritis patients. The first Russian generic aceclofenac (“Alental”, Vertex, Russia) has good efficacy, tolerability and safety and can be recommended for arthritis treatment.

Terapevticheskii arkhiv. 2020;92(5):61-68
Control of pain in the early post-traumatic period in the outpatient practice. Results of the multi-center observational study RAPTOR (Rational Analgesia PostTraumatic: an Observational Research)
Karateev A.E., Lila A.M., Zagorodnii N.V., Amirdzhanova V.N., Pogozheva E.L., Filatova E.S., Nesterenko V.A.

Aim. Evaluate the frequency, nature and course of PTP, as well as the effectiveness and safety of NSAIDs in PTP in real clinical practice.

Materials and methods. The assessment of the condition and need for NSAIDs (original meloxicam) in 1115 outpatient patients who suffered a fracture of the radius (32.2%), injury to the knee (35.2%) or ligaments of the ankle (32.6%); women/men 51.5 and 48.5%, average age 46.9±15.5 years. We evaluated the dynamics of pain intensity (on a numerical rating scale – NRS 0–10) at rest and during movement, the preservation of moderate and severe pain, as well as the development of adverse drugs reactions (ADR) to NSAIDs 4–8 weeks after injury.

Results. The average intensity of pain during movement decreased from 7.03±1.66 to 2.21±1.38 (p<0.001), at rest – from 4.46±2.07 to 0.71±0.989 (p<0.001). The number of people with pain severity ≥4 in the NRS in 4–8 weeks after the radius fracture, injury of the knee and ligaments of ankle was 21.0, 16.9 and 11.9%, with moderate or severe impairment of the injured limb – 40.4, 26.2 and 16.3%, respectively. The need for taking NSAIDs up to 7 days was noted in 43.3%, 7–14 days-in 41.8%, more than 2 weeks or constantly in 14.9% of patients. Weak or moderate ADR were observed in 20.8% of patients, mainly dyspepsia and hypertension. Discontinuation of NSAIDs due to ADR was required in only 2.6% of patients. Pain retention ≥4 in NRS was associated with initially expressed pain (>7 in NRS) – OR 2.75 (95% CI 0.83–4.13; p<0.001) and the presence of osteoarthritis of knee and/or hip – OR 1.56 (95% CI 1.03–2.34; p=0.039).

Conclusion. PTP decreases rapidly in most patients after a radius fracture, injury of the knee, and ankle ligament injury while taking the original meloxicam. However, in a significant part of patients, moderate or severe PTP persists after 4–8 weeks, which requires prolonged analgesic therapy and active rehabilitation.

Terapevticheskii arkhiv. 2020;92(5):69-77
Clinical observation
Idiopathic multicentric Castleman’s disease
Vasilyev V.I., Palshina S.G., Pavlovskaya A.I., Kokosadze N.V., Chaltsev B.D., Shornikova L.A.

Idiopathic multicentric Castleman’s disease is a rare lymphoproliferative disorder that has many similar laboratory, radiological, clinical and pathological manifestations with various conditions, including IgG4-related disease. Increased activity of cytokines, especially interleukin-6, leads to systemic inflammatory symptoms with the development of lymphadenopathy and rarely extranodal lesions. Histological changes in the lymph nodesin hyaline vascular and plasma cell variants of Castleman’s disease are hardly distinguishable from the pattern of reactive, tumor and IgG4-related lymphadenopathy. Idiopathic multicentric Castleman’s disease can be diagnosed only when infection with human herpesvirus-8 type and human immunodeficiency virus is excluded. In the article, the authors describe two cases of idiopathic multicentric Castleman’s disease, including the first world literature description of extranodal damage of the hip muscle in this disorder. In addition, the authors gave a review of the literature on the main clinical, laboratory and morphological manifestations, which allow confirming the diagnosis of Castleman’s disease.

Terapevticheskii arkhiv. 2020;92(5):78-84
Possibility of complex medicamental and endovascular treatment of pulmonary hypertension in Takayasu arteritis with predominant pulmonary arteries’ lesion
Маrtynuk T.V., Aleevskaya A.M., Gramovich V.V., Danilov N.M., Korobkova I.Z., Matchin U.G., Solodovnikova L.V., Beketova T.V.

Takayasu arteritis (TA) is a systemic vasculitis with predominatly lesions of aorta and its large branches. In some cases pulmonary arteries (PA) are involved in the pathological inflammatory process and lead to the formation of pulmonary hypertension and significantly worse the prognosis. Timely development of lesion of PA, appointment of adequate therapy and surgical treatment can prevent irreversible damage of blood vessels and improve the prognosis. Perioperative administration of interleukin-6 inhibitor inhibitor (tocilizumab) in at patients with indications for vascular surgery, including angioplasty PA, should be considered as a promising approach to control the inflammatory activity of TA, reduce the dose of glucocorticoids and the risk of postoperative complications. We present the clinical experience of significant improvement in the patient’s condition was achieved by using two-stage balloon angioplasty on the background of control of the disease activity with interleukin-6 tocilizumab intravenously and specific therapy with riociguat and iloprost.

Terapevticheskii arkhiv. 2020;92(5):85-91
Mental disorders and cognitive impairment in patients with antiphospholipid syndrome
Borisova A.B., Lisitsyna T.A., Veltishchev D.Y., Reshetnyak T.M., Seravina O.F., Kovalevskaya O.B., Krasnov V.N., Nasonov E.L.

Mental disorders (mainly anxiety and depressive disorders) and cognitive impairment are often found in patients with antiphospholipid syndrome (APS), but their prevalence, structure, and mechanisms of occurrence are not well researched. The review provides literature data on the frequency, spectrum and possible causes of mental disorders and cognitive impairment in patients with APS, the pathogenetic mechanisms of these disorders (in particular, the important role of antiphospholipid antibodies, stress factors, chronic inflammation), the relationship between APS, mental disorders and as well as cognitive impairment is examined. Special attention is paid to the influence of mental disorders and cognitive impairment on patients’ adherence to treatment, their quality of life, as well as the particularities of psychopharmacotherapy of mental disorders in patients with APS. The aim of the review is to actualize the interdisciplinary problem of mental disorders and cognitive impairment in patients with APS and the need to introduce a partnership model of care.

Terapevticheskii arkhiv. 2020;92(5):92-103
IgG4-related disease: what do we know after 20 years
Sokol E.V.

IgG4-related disease is immunomediated fibroinflammatory condition, characterized by tumefective lesions in different organs with distinctive pathomorphological features and IgG4 hypersecretion in serum and tissues in the majority of patients. IgG4-RD has been established as a separate clinical in the early 2000s. In the review we focus on the evolution of views on ethiopathogenesis of the disease, therapeutic and diagnostic options and classification of the disease.

Terapevticheskii arkhiv. 2020;92(5):104-109
Advantages of therapy with sodium glucose cotransporter type 2 inhibitors in patients with type 2 diabetes mellitus in combination with hyperuricemia and gout
Panevin T.S., Eliseev M.S., Shestakova M.V., Nasonov E.L.

Currently, only two drugs for reducing uric acid (UA), allopurinol and febuxostat, are registered in the Russian Federation, but their use does not allow to achieve the target level of UA in all cases. According to the results of numerous randomized trials, hyperuricemia and gout are associated with the corresponding components of the metabolic syndrome, including diabetes mellitus. The influence of factors is due to the need to search for new drugs that have a complex effect on several components of metabolic syndrome at once. Potentially attractive in this regard is a new group of drugs for the treatment of type 2 diabetes mellitus – inhibitors of the sodium-glucose cotransporter of type 2, which, in addition to the main hypoglycemic actions, showed positive effects on the cardiovascular system, kidneys, as well as lowering UA.

Terapevticheskii arkhiv. 2020;92(5):110-118
Anniversary of the honored scientist professor Sergey Nikolaevich Tereshchenko
Therapeutic archive B.

April 23, 2020 marks the 60th anniversary of a prominent national cardiologist Sergey Nikolaevich Tereshchenko

Terapevticheskii arkhiv. 2020;92(5):119

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