Vol 47, No 5 (2019)

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Full Issue


Musculoskeletal pain: determination of clinical phenotypes and the rational treatment approach

Karateev A.E.


Personalized treatment is one of the basic principles of modern medicine. When administering a treatment, one should consider individual patient characteristics, comorbidities and, what is most important, the prevailing symptoms, as well as the clinical phenotype of a disease. This is directly related to chronic musculoskeletal pain (MSP), which occurs with underlying most prevalent joint and vertebral disorders. At present, MSP is considered to be an independent clinical syndrome.
Predominant mechanisms of MSP pathophysiology allow for determination of its special phenotypes: “inflammatory”, “mechanical”, related to enthesopathy and central sensitization. Treatment strategies for MSP phenotypes should obviously be differentiated and based on a tailored and pathophysiologically sound of medical agents and non-medical measures with different mechanisms of pharmacological effects. Effective treatment of the “inflammatory” phenotype requires the use of non-steroidal anti-inflammatory drugs, topical glucocorticoids, disease modifying anti-inflammatory agents. The “mechanical” phenotype necessitates the correction of biomechanical abnormalities, the use of hyaluronic acid containing agents, whereas the “enthesopathic” phenotype is treated with local therapy. Treatment of the phenotype with central sensitization is performed with agents effective for neuropathic pain (anticonvulsants, anti-depressants).

Almanac of Clinical Medicine. 2019;47(5):445-453
pages 445-453 views

Mixed connective tissue disease, undifferentiated connective tissue disease and overlap syndromes

Alekperov R.T.


Systemic lupus erythematosus, systemic sclerosis, inflammatory myopathy and rheumatoid arthritis are systemic connective tissue disorders which are characterized by heterogeneous clinical symptoms and variable course. To date, updated diagnostic criteria for early diagnosis of each of the diseases of this group have been proposed. At the same time, a proportion of patients already have at the onset of the disease or over time, a combination of signs characteristic of different diseases. Such conditions are referred to as mixed connective tissue disease, undifferentiated connective tissue disease or overlap-syndrome, whose nosological identity remains the subject of discussion. Formerly there has been a kind of terminological confusion and similar conditions were described under different names, depending on the author's preferences. It was also believed that these conditions were an early stage or a clinically "incomplete" form of a connective tissue disease. However, as the observations of large patient groups have shown, whose disease was represented by a number of individual signs of several connective tissue diseases, the clinical manifestation remains unchanged for many years in the majority of them. To recognize the right for nosological independence, one should account for the fact that only for a mixed connective tissue disease various authors and research groups have proposed four variants of diagnostic criteria. These criteria have small differences in the number of clinical signs; however, all criteria include a mandatory sign, i.e. the presence of antibodies to U1-ribonucleoprotein in high titers. Clinical signs common to all these diagnostic criteria include the Raynaud's syndrome, arthritis, myositis and finger swelling or sclerodactyly. Another patient category includes those with mono- or oligosymptomatic manifestations characteristic of systemic connective tissue diseases, but without any specific immunological markers. Some of these patients in a fairly short time, usually from several months to 1–2 years, develop other clinical symptoms and signs corresponding to a reliable diagnosis of a connective tissue disease. At the same time, a significant part of patients with the oligosymptomatic course demonstrate a long-term stability without any further evolution of the disease. Such cases are defined as an undifferentiated connective tissue disease. To avoid the erroneous diagnosis of the transient form or an early stage of any connective tissue disease, the proposed classification criteria, along with the inclusion criteria, also embrace clinical and serological exclusion criteria. A separate category consists of patients with a combination of clinical signs sufficient for a definitive diagnosis of at least two systemic connective tissue diseases. These patients are diagnosed with the overlap-syndrome with indication of the components of connective tissue diseases in each individual case, as it largely determines the individual treatment and prognosis. The possibility of such clinical variants of systemic connective tissue diseases is becoming increasingly justified due to the concept of polyautoimmunity, which has attracted great interest of researchers in the last few years.

Almanac of Clinical Medicine. 2019;47(5):435-444
pages 435-444 views

Extracorporeal photopheresis as a non-specific immune therapy of autoimmune diseases and skin T-cell lymphoma (a review of the literature and own studies)

Kil'dyushevskiy A.V., Molochkov V.A., Mitina T.A., Moysyuk Y.G., Molochkov A.V.


Aim: To present well-known and disputable mechanisms of the effects of extracorporeal photopheresis (ECP) in heterogeneous clinical conditions, as well as to demonstrate its advantages over conventional hormonal, immunosuppressive and cytostatic treatments, with a recommendation to widely implement it into practical management of autoimmune disease and cutaneous T-cell lymphomas (CTCLs).

Key points: Despite convincing evidence of the ECP efficacy in the treatment of T-cell mediated disorders, a unifying concept of its mechanism has not been established so far. In this review, we attempted to determine the value of multiple, sometimes contradictory and equivocal points of view to immunobiochemical processes underlying the restoration of mechanism of immune tolerance in some autoimmune diseases and CTCLs. We focused our attention on our own clinical and immunological data obtained during a 20-years' experience with the use of ECP in clinical departments of MONIKI (Russia). Based on this, we have shown that ECP is more effective in autoimmune diseases than conventional treatment approaches with hormones, immunosuppressants and cytostatics. Unlike them, ECP is selectively targeted to auto-aggressive T-cells without induction of systemic immunosuppression. The leading role is played by the transformation of activated (immunogenic) myeloid dendrite cells (DC) into tolerogenic cell associated with their synthesis of inhibitor cytokines. The interplay of the cytokines with an antigen results in polarization of CD4+ Т lymphocytes via the Th2 pathway with restoration of the Th1/Th2 balance and their cytokine production. ECP triggers regulatory anti-clonotypic effector memory cells at the end stage of CD3+/CD8+/CD27-/CD28-/CD62L+ differentiation, that provide and maintain the peripheral immune tolerance, by deletion of the clone of auto-reactive cytotoxic lymphocytes and inducing their apoptosis. In autoimmune disorders, ECP results in reduction of the expression of integrin adhesion molecules on auto-reactive cell membranes with subsequent loss of their ability to migrate through the endothelium to their target cells. In its turn, it leads to decreasing immunoinflammatory response in the lesion. Both clinical and experimental data indicate that the mechanism of ECP action against CTCLs is characterized by activation of tumor cell apoptosis, unblocking of co-activation receptors on the antigen-presenting DC providing the functioning of the second signaling pathway for T lymphocyte activation. This results in proliferation of anti-tumor effector cells pool, production of DC activating cytokines that participate in the CD4+ polarization via Th1 pathway. In addition, this review considers the mechanism of the immunomodulating effect of ECP in the context of its influence at the levels of transcription and translation of proteins contributing to the pathophysiology of the disorders, based on molecular immunogenetic studies. Thus, ECP is able to induce antigen-specific immunological tolerance through the transformation of antigen-presenting cells, modulation of cytokine profile, adhesion and activation molecules, as well as through formatting of the regulatory T cells (Tregs).

Conclusion: Undoubtedly, the immunobiological ECP technique has significant advantages over well-known conventional hormonal, immunosuppressive, and cytostatic therapies of autoimmune diseases and CTCLs.

Almanac of Clinical Medicine. 2019;47(5):419-434
pages 419-434 views

Anatomical and ultrasound navigation of intra joint injections

Knyazeva L.A., Damjanov N., Knyazeva L.I., Khardikova E.M., Meshcherina N.S., Stepchenko M.A., Goryainov I.I.


Optimization of joint syndrome treatment methods, including those based on the intra- and periarticular drug administration and invasive diagnostic techniques, remains high on the agenda of modern clinical rheumatology. The implementation and quite widely spread use of ultrasonographic visualization has been an impetus to the development of this type of treatment for joint diseases. Without any doubt, the quality of intraarticular injection performance mainly depends on the professional level of the specialist and his/hers procedural skills. However, here comes a predictable question: are these conditions sufficient to enable maximal precision, safety, and efficacy of intraarticular interventions? From this perspective, it is interesting to study the possibilities to improve the results of local treatments for the joint syndrome by means of the ultrasound navigation technique. Based on data presented in the literature review, we compared a “blind” invasive treatment method to the ultrasound navigation-guided intra- and periarticular interventions in patients with skeletomuscular and connective tissue disorders. The authors of the studies published point to higher safety, efficacy, procedure precision, and diagnostic quality of the information obtained by the ultrasound navigation. Its important advantages include wider possibilities and availability of this method in outpatient settings, due to its rather low costs and patients' safety. The information from the current literature review reflects an initial stage of studies on the evaluation of the role, significance, determination of potential of the ultrasound navigation to enhance the quality of diagnosis and invasive treatment in patients with joint syndromes of various origins and to minimize adverse effects.
Almanac of Clinical Medicine. 2019;47(5):454-460
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New possibilities of drug therapy for rheumatoid arthritis: focus at sarilumab

Karateev D.E., Luchikhina E.L.


Rheumatoid arthritis (RA) is one of the most prevalent autoimmune diseases in humans and is a serious medical and social problem in the Russian Federation. Current synthetic and biological agents acting through specific molecular targets, play a significant role in the treatment of RA. Over the last few years, inhibitors of the biological effects of interleukin-6 (IL-6) have attracted increasing attention, being positioned as the first choice agents among the biologicals, especially if there is a need in monotherapy. IL-6 is a pleiotropic cytokine with a broad range of biological effects on immune cells, such as B and T lymphocytes, on hepatocytes, hematopoietic cells, vascular endothelial cells, and many others. In this regard, IL-6 is a good therapeutic target in RA. For several years, the group of inhibitors of IL-6 biological effects has been represented by one drug only, i.e. tocilizumab. The new drug of this group, sarilumab, is a human monoclonal antibody (IgG1 subtype) to the IL-6 receptor. Sarilumab binds specifically to both soluble and membrane IL-6 receptors (IL-6Rα), and inhibits IL-6-mediated signal transduction involving signal protein glycoprotein 130 (gp130) and signal proteins STAT-3. There is evidence that sarilumab has a higher affinity to the IL-6 receptor, and binds the receptor in a more stable manner than tocilizumab. Sarilumab has been approved for treatment of RA with moderate or high activity in adult patients with inadequate response or intolerability to one or several synthetic basic drugs, at a dose 150 mg or 200 mg subcutaneously biweekly in combination with methotrexate (MTX). It also can be prescribed as monotherapy in case of MTX intolerability or if treatment with MTX is inexpedient. Sarilumab is a highly active therapeutic agent with proven superiority in monotherapy over adalimumab. Therefore, sarilumab can be positioned as a first line biological agent in patients with high inflammatory activity, as well as in those resistant to tumor necrosis factor-α inhibitors. The safety profile of sarilumab is similar to that of tocilizumab; probably there is a slightly higher risk of neutropenia, but a lower risk of dyslipidemia, reactions at the injection site and gastrointestinal perforation for sarilumab than for tocilizumab.
Almanac of Clinical Medicine. 2019;47(5):461-469
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The use of subcutaneous methotrexate from various manufacturers in real clinical practice: a comparative study

Karateev D.E., Luchikhina E.L., Gridneva G.I., Demidova N.V.


Background: Methotrexate is the main synthetic disease-modifying antirheumatic drug for the treatment of rheumatoid arthritis (RA), psoriatic arthritis (PsA) and other immunoinflammatory conditions. In the recent years, the subcutaneous form of methotrexate (SC MTX), particularly as ready-to-use syringes, has been increasingly used worldwide. Currently, several generics of SC MTX from different manufacturers are available. In literature we could not find any publications on the comparison of SC MTX generics.

Aim: To evaluate the possibility to effectively use various SC MTXs for the treatment of RA and PsA in real clinical practice.

Materials and methods: Patients older than 18 years old with a diagnosis of RA by ACR 1987 or ACR / EULAR 2010 criteria or diagnosis of PsA by CASPAR criteria with indications for SC MTX were included in this open-label 6-month observational study “Therapy of Rheumatoid Arthritis with Methotrexate in the Subcutaneous Form in Clinical Practice (TRAMPLIN)”. TRAMPLIN included two study periods: 1) a retrospective study of the safety of SC MTX from various manufacturers in clinical practice, according to patients' medical records; 632 patients (67.2% female, 32.8% male) on SC MTX were identified, and the number of adverse reactions recorded in the documentation (spontaneous reports) was determined; 2) a prospective study of the treatment duration and the reasons for the withdrawal of SC MTX from different manufacturers, which included 69 patients with RA and PsA. SC MTXs from three manufacturers were used in this study, namely Metoject (Medac GmbH, Germany); Métortrites (S.C. Rompharm Company S.R.L., Romania); Methotrexat Ebewe (Sandoz Pharmaceuticals D.D., Slovenia).

Results: In the retrospective part of the study very few adverse events (AEs) were registered, which were related to SC MTX in the physician's opinion (41 patients, or 6.5%). Their incidence was higher in methotrexate-naïve patients. In the prospective part of the study at 3 months after the start of SC MTX therapy, 25 patients (36.2%) changed the treatment regimen (switched between the study drugs or to oral methotrexate). The main reasons for switching (20.3%) were “non-medical” events in the outpatients. AEs ranked second as a reason for the drug withdrawal (14.5%), irrespective of the manufacturer. At 6 month of the study, 38% patients were treated with Metoject, 30% with Methotrexat Ebewe, 28% with Métortrites, and 4% of patients  switched to oral methotrexate.

Conclusion: This first Russian study of SC MTX generics from three different manufacturers confirmed a good SC MTX safety profile in a large clinical sample and showed good retention rates for therapy: by the end of the observation, 96% of the patients with available follow-up data remained on SC MTX. All three SC MTXs from different manufacturers were compatible in terms of safety, tolerability, and drug survival.

Almanac of Clinical Medicine. 2019;47(5):383-392
pages 383-392 views

Serum cytokine profile in early and established rheumatoid arthritis

Novikov A.A., Aleksandrova Е.N., Lukina G.V.


Background: An important characteristic of immune pathology in rheumatoid arthritis (RA) is a B-cell tolerance defect, associated with autoantibodies production, and antigen-specific activation of Th-1 CD4+ T lymphocytes with an excess production of pro-inflammatory cytokines compared to anti-inflammatory ones. Pro-inflammatory cytokines contribute to the development of local inflammatory effects, induce bone destruction and pannus formation, and contribute to the development of autoimmune abnormalities and systemic manifestations. Anti-inflammatory cytokines are able to reduce the rate of joint destruction. There is evidence of the involvement of Th2 cytokines in the development of early RA. These facts suggest the need for a thorough investigation into the balance between the Th1 and Th2 types of immune response at different stages of the disease.

Aim: To assess the importance of сytokine profiling in the evaluation of immune abnormalities in RA.

Materials and methods: In this descriptive, controlled, retrospective study, we examined 118 patients with RA and 33 healthy donors as a control group. Serum IgM rheumatoid factor (RF) and C-reactive protein (CRP) levels were measured by immunonephelometry; anti-cyclic citrullinated peptide antibodies (anti-CCP) and anti-mutated citrullinated vimentin antibodies (anti-MCV) were determined by an enzyme immunoassay, cytokines levels with "xMAP" technique.

Results: Serum cytokine levels vary depending on RA duration. The cytokine profile in early RA, unlike that in established RA with a duration of more than 6 months, is characterized by higher levels of pro-inflammatory (MIP-1α), Th1 (IFN-γ), and Th17 (IL-17) cytokines, colony-stimulating factors (IL-7, G-CSF), and chemokines (IL-8, IP-10) (p < 0.05 for all parameters). In established RA, the levels of pro-inflammatory (IL-1β, -6, -15, TNF-α), anti-inflammatory (IL-1ra, IL-10, IL-13, IL-5), Th1 (IL-2, IL-12), Th2 (IL-9) cytokines and colony-stimulating factors (G-CSF, GM-CSF) correlate with the concentrations of IgM RF and antibodies to citrullinated proteins (antiCCP, anti-MCV) (all p < 0.05). There was also а correlation between CRP and pro-inflammatory (IL-1β, IL-6, TNF-α), Th1 (IL-12), Th2 (IL-5, IL-9) cytokine levels and between DAS28 and pro-inflammatory cytokine (IL-6) and colony-stimulating factor (G-CSF) levels (all p < 0.05). Conclusion: In RA, cytokines, chemokines and colony-stimulating factors mirror the inflammatory activity of the disease. Changes in blood concentrations of cytokines enable to get an insight into the complex interplay of numerous mediators of innate and acquired immunity.

Almanac of Clinical Medicine. 2019;47(5):393-399
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The course of chronic heart failure in patients with early rheumatoid arthritis on the anti-rheumatic therapy

Kirillova I.G., Novikova D.S., Popkova T.V., Udachkina H.V., Markelova E.I., Gorbunova Y.N., Korsakova Y.O.


Objective: To evaluate the effect of the “treat to target” anti-rheumatic therapy on the course of chronic heart failure (CHF) in patients with early rheumatoid arthritis (RA).

Materials and methods: The study included 22 patients (17, or 77% female) with CHF with valid diagnosis of RA (ACR/EULAR criteria, 2010), median (Me) age of 60 years, and median disease duration of 7 months. Ten patients (45%) were seropositive for IgM rheumatoid factor and 22 (100%) had antibodies to cyclic citrulline peptide. Their median (1st; 3rd quartiles) DAS28 was 5.6 [4.8; 6.5]. The diagnosis of CHF was confirmed in accordance with the guidelines on the diagnosis and treatment of CHF by the Russian Society of Specialists in Heart Failure (2013). NT-proBNP levels were measured by electrochemiluminescence (Elecsys proBNP II, Roche Diagnostics, Switzerland). All patients were started on subcutaneous methotrexate (MT) with rapid dose titration to 30 mg weekly. If the MT was insufficiently effective, a biological disease-modifying antirheumatic drug (bDMARD) was added to the therapy after 3 months, mainly a TNF-alpha inhibitor. After 18 months, 10 (45%) patients were in remission and had low disease activity, 6 (60%) patients underwent MT therapy in combination with bDMARDs.

Results: At baseline, 21 (95%) patients were diagnosed with CHF with preserved ejection fraction and one patient had CHF with reduced ejection fraction. After 18 months there was an improvement of clinical symptoms, echocardiographic parameters (reduction of the left atrium diameter and the left atrium end-systolic volume index, IVRT, E'LV), and diastolic function of the left ventricle (LV). No episodes of acute CHF deterioration were registered. LV diastolic function normalized in 7 (32%) patients who reached the target level of blood pressure, remission (n=5) and low disease activity (n=2), mainly under the treatment with MT and bDMARDs. In patients with RA and CHF, the NT-proBNP levels decreased from 192.2 [151.4; 266.4] to 114.0 [90.4; 163.4] pg/ml (p<0.001) and became normal in 16 of 22 (73%) patients (p<0.001) with remission or low RA activity. In 5 (22%) patients, clinical CHF manifestations resolved, LV diastolic function and NT-proBNP levels were normalized.

Conclusion: In the patients with early RA and CHF anti-rheumatic therapy improves the clinical course of CHF, LV diastolic function and reduces NT-proBNP levels.

Almanac of Clinical Medicine. 2019;47(5):400-409
pages 400-409 views

Is anemia a clinical marker of NSAIDs-induced upper gastrointestinal lesions in patients with spondyloarthritis?

Safarova K.N., Dorogoykina K.D., Rebrov A.P.


Background: Anemia is a frequent comorbid conditions in patients with spondyloarthritis (SpA). Its development is associated with the activity of the underlying disorder, and in some cases can be a complication of medical treatment. Investigation into the particulars of the anemia, its prevalence in SpA patients is of considerable interest due to the long-term inflammatory process, on the one hand, and high frequency of non-steroidal anti-inflammatory drugs (NSAIDs) usage, on the other.

Aim: To assess the incidence of NSAID-induced lesions of upper gastrointestinal tract in patients with SpA and anemia.

Materials and methods: This cross-sectional observational study included 107 patients with proven SpA (mean age, 44 [36; 53] years; SpA duration, 16 [9; 21] years; men, 61.9%) who were treated in the Department of Rheumatology, Saratov Regional Clinical Hospital, from 2017 to 2018. We assessed their blood cell counts, C-reactive protein levels, iron kinetic parameters (serum iron, transferrin, ferritin, transferrin saturation). Anemia was diagnosed according to the World Health Organization criteria. Two groups were formed depending on the presence of absolute iron deficiency: group 1, 13 patients with anemia of chronic disease (ACD), group 2, 3 patients with iron deficiency anemia (IDA) and 26 patients with ACD + IDA. Esophagogastroduodenoscopy (EGDS) was performed to assess mucous membranes of the upper gastrointestinal tract in patients with anemia.

Results: Anemia was found in 42 (39.3%) patients, 38 (90.5%) of them had mild anemia. The increase in the activity of the underlying disorder judged by changes in the laboratory markers of systemic inflammation (erythrocyte sedimentation rate and C-reactive protein levels) significantly correlated with a decrease in hemoglobin concentration (r = -0.5715 and r = -0.3498 respectively, p<0.05). At EGDS, NSAIDs-induced erosions in the esophagus and/or stomach were found detected in 1 (7.7%) patient of the group 1 and in 1 (3.4%) patient of the group 2. A past episode of NSAIDs-induced erosions in the stomach and duodenum was noted in 4 (13.8%) patients of the group 2, whereas at the time of the study no mucous membranes defects were found at EGDS.

Conclusion: Anemia was found in more than one third of SpA patients, with 29 of them (69%) having laboratory signs of iron deficiency, but only 1 (3.4%) patient had NSAIDs-induced gastropathy confirmed at EGDS. NSAIDs-associated enteropathy could be the cause of iron deficiency in these patients that would require additional patient examination. The development of iron deficiency can be pathophysiologically associated to prolonged inhibition of alimentary iron absorption against the background of persistent systemic inflammation and depletion of the iron pool in the absence of gastrointestinal blood losses.

Almanac of Clinical Medicine. 2019;47(5):410-418
pages 410-418 views


Rowell syndrome in dermatological practice (a clinical case)

Taganov A.V., Tamrazova O.B., Gureeva M.A.


Rowell syndrome is a  rare cluster of symptoms characterized by clinical manifestation of lupus erythematosus and erythema multiforme (EM). About 100  cases of the syndrome have been reported in medical publications during the last 100 years. This may be related to misinterpretation of the symptoms and subsequent incorrect diagnosis due to its EM-like manifestations. Important clues for the diagnosis of Rowell syndrome are findings of positive rheumatoid factor, anti-nuclear antibodies and other erythematoid markers, as well as additional investigations, in particular, direct immunofluorescence technique. The paper describes a  clinical case of Rowell syndrome in a 16-year old male patient. The diagnosis was challenging due to EM-like skin manifestations and required additional laboratory work-up, as well as the patient's follow-up. The diagnosis of Rowell syndrome was based on the clinical manifestations and on such diagnostic criteria as positive rheumatoid factor and anti-nuclear antibodies, as well as histological and laboratory abnormalities characteristic of the erythematosis. The patient was hospitalized and received the following treatment: prednisolone infusion (2.5 mg/kg/daily for 7 days), chloropyramine (1 mL i.m. twice daily for 5  days), hydroxychloroquine (6.5  mg/kg daily for 5  days), magnesium asparaginate/potassium asparaginate (one tablet (166.3  mg/175  mg) 3  times daily for 7  days), topical methylprednisolone aceponate cream 1% (once daily for 7 days). The treatment resulted in positive changes in the skin lesion and improvement of his general state. This clinical observation gives an example of classic Rowell syndrome proven both by lab and clinical signs, taking into account skin symptoms of lupus erythematosus and EM-like rash.
Almanac of Clinical Medicine. 2019;47(5):470-476
pages 470-476 views

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