Vol 47, No 5 (2019)

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).

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.

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.

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.

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 (1^st; 3^rd 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.

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.