RU2696285C1 - Method of vasomotor endothelial dysfunction correction and arterial rigidity in patients with rheumatoid arthritis - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to rheumatology and cardiology, and concerns correction of vasomotor dysfunction of endothelium and arterial rigidity in patients with rheumatoid arthritis. For this purpose, after diagnosing a patient with active course of rheumatoid arthritis and ineffectiveness of previous therapy with methotrexate or presence of contraindications to its use as a basic anti-inflammatory therapy orally prescribed tofacitinib 10 mg a day constantly.

EFFECT: method provides effective correction of functional state of endothelium and morphofunctional properties of vascular wall in this category of patients due to the fact that along with immunomodulating (immunosuppressive) and anti-inflammatory effects tofacitinib has vasoprotective action both on large vessels of elastic type (reduced indices of augmentation and stiffness), and large (increased value of phase shift between channels) and small arteries of muscle type (increased index of occlusion by amplitude and reduced index of reflection).

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Description

The invention relates to medicine, in particular to rheumatology and cardiology.

, K.P. Liao, D.H. Solomon // Rheumatology. - 2016. - Vol. 55, Issue 5 - P. 809-816.), несмотря на «благоприятный» липидный профиль (Динамика липидных параметров крови у больных ранним ревматоидным артритом на фоне противоревматической терапии, проводимой по принципу «Лечение до достижения цели» (по данным 18-месячного наблюдения) / Е.В. Удачкина, Д.С. Новикова, Т.В. Попкова и др. // Научно-практическаяревматология. - 2016. - Том 54, №2. - С. 164-170).Rheumatoid arthritis is currently regarded as a disease with high cardiovascular risk due to the fact that up to 50-60% of premature mortality in this pathology is due to cardiovascular complications due to the early development and rapid progression of atherosclerotic vascular disease (Cardiovascular risk factor management in patients with RA compared to matched non-RA patients / E. Alemao, H. Cawston, F. Bourhis, M. Al, MPMH Rutten-van

, KP Liao, DH Solomon // Rheumatology. - 2016. - Vol. 55, Issue 5 - P. 809-816.), Despite the “favorable” lipid profile (Dynamics of blood lipid parameters in patients with early rheumatoid arthritis on the background of antirheumatic therapy conducted on the principle of “Treatment to achieve the goal” (according to the 18-month-old observations) / E.V. Udachkina, D.S. Novikova, T.V. Popkova et al. // Scientific and Practical Rheumatology. - 2016. - Volume 54, No. 2. - S. 164-170).

Currently, it is becoming increasingly important to determine the integral indicators of cardiovascular risk, which include subclinical vascular markers of cardiovascular diseases, such as endothelial dysfunction, increased stiffness of arterial vessels, augmentation of central aortic pressure, decreased ankle-brachial index, calcification of coronary arteries, thickening of the intima-media complex in the carotid arteries (Expert consensus document on the measurement of aortic stiffness in daily practice using carotid-femoral pulse wave velocity / LM Van Bortel, S. Laurent, P. Boutouyrie, et al. // J. Hypertens. - 2012 .-- Vol. 30, No. 3. - P. 445-8.).

The results of the studies indicate a multifactorial genesis of endothelial dysfunction and arterial stiffness in rheumatoid arthritis, which includes a whole range of mechanisms, among which along with traditional risk factors are discussed “disease-associated” associated with persistent autoimmune inflammation, accompanied by overproduction of numerous mediators and “immune” cells (pro-inflammatory cytokines, leukocyte adhesion molecules, metalloproteinases, growth factors, autoantibodies: rheumatoid fact p, antibodies to citrulline proteins, etc.) (Rheumatoid arthritis is sufficient to cause atheromatosis but not arterial stiffness or hypertrophy in the absence of classical cardiovascular risk factors / A. Arida, E. Zampeli, G. Konstantonis, et al. // Clin. Rheumatol. -2015. - Vol. 34, No. 5. - P. 853-859; Libby P. Role of inflammation in atherosclerosis associated with rheumatoid arthritis // Am J Med. - 2008. - Vol. 121 (10 Suppl 1). - P. S21-31.). Therefore, an important scientific and practical aspect of this problem is to study the effect of disease-modifying antirheumatic drugs on the functional state of the endothelium and arterial stiffness, which will allow us to develop a set of preventive and therapeutic measures aimed at reducing the risk of cardiovascular complications and creating a system of dynamic control and monitoring of progression atherosclerosis in PA (Atherosclerosis is not accelerated in rheumatoid arthritis of low activity or remission, regardless of antirheumatic treatment modalities / A. Arida, E. Zampeli, G. Konstantonis , etal. // Rheumatology (Oxford). - 2017. - Vol. 56, No. 6. - P. 934-939.)

As a prototype of the proposed method for the correction of endothelial dysfunction and arterial stiffness in rheumatoid arthritis, one can consider the use of standard disease-modifying antirheumatic drugs (methotrexate, leflunomide) and genetic engineering biological preparations, primarily inhibitors of tumor necrosis factor a (infliximab, etanercept, adalimumab and etc.) (Cardiovascular diseases in patients with rheumatoid arthritis during long-term therapy with methotrexate / E.V. Gerasimova, T.V. Popkova, D.S. N Vikova, E.L. Nasonov // Therapeutic Archive. - 2014. - No. 5. - P. 26-31. Infliximab improves vascular stiffness in patients with rheumatoid arthritis / M. Wong [et al.] // Ann. Rheum. Dis. - 2009. - Vol. 68, N 8. - P. 1277-1284; Maki-Petaja, KM Anti-inflammatory drugs and statins for arterial stiffness reduction / KM Maki-Petaja, IB. Wilkinson // Curr. Pharm. Des. - 2009. - Vol. 15, N 3. - P. 290-303; Rheumatoid arthritis is associated with increased aortic pulse-wave velocity, which is reduced by anti-tumor necrosis factor-alpha therapy / KM. Maki-Petaja [et al] // Circulation. - 2006. - Vol. 114. - P. 1185-1192; TNF-alpha antagonists reduce arterial stiffness in patients with rheumatoid arthritis and related arthropaties: a controlled study / K. Angel [et al] // Ann. Rheum. Dis. - 2008. - Vol. 67 (Suppl. 21). - P. 160 .; Meshcherina, N.S. Approaches to correcting the activity of immune inflammation and remodeling of the cardiovascular bed in patients with rheumatoid arthritis by genetic engineering biological preparations; autoref. dis. ... Dr. honey. Sciences: 14.03.09 / N.S. Meshcherin. - Kursk, 2014 .-- 46 s).

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- 2016. - Vol. 31 (n.6). - P. 162-175.).A number of positive effects have been established both of standard disease-modifying antirheumatic drugs (methotrexate, leflunomide), and tumor necrosis factor inhibitors and on the risk of manifestation of cardiovascular complications in rheumatoid arthritis, reduction of stiffness of the arterial wall and the thickness of the CMM of the carotid arteries, as development mechanisms which the authors indicate a decrease in the activity of systemic inflammation (The relationship of cardiovascular risk factors with arterial stiffness in women with high activity rheumatoid arthritis / D.S. Novikova, T.V. Popkova, A.N. Gerasimov, A.V. Volkov, E.L. Nasonov // Rational Pharmacotherapy in Cardiology. - 2012. - T. 8, No. 6. - S. 756-765; Tumor necrosis factor antagonists and the risk of cardiovascular disease in patients with rheumatoid arthritis: a systematic literature review / Sarah L. Westlake [et al] // Rheumatology. 2011.- Vol. 50 (5). - P. 518-531; Changes in the endothelial function and stiffness of the arterial bed in patients with rheumatoid arthritis during treatment with leflunomide / Knyazeva L.A., Knyazeva L.I., Mescherina N.S., Goryainov N.I., Ponkratov V .AND. // Kursk scientific and practical bulletin Man and his health. - 2016. - No. 2. - S. 20-28; Effect of subcutaneous form of methotrexate on structural-functional state of the vascular wall in patients with rheumatoid arthritis / Knyazeva LA, Meshcherina NS, Knyazeva LI, Goryainov 1.1., Stepchenko MA, Ponkratov VI. //

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- 2016. - Vol. 31 (n.6). - P. 162-175.).

At the same time, the prototype under discussion has a number of limitations due to available data on the pro-atherogenic effect of tumor necrosis factor a inhibitors on the blood lipid spectrum (Impact of TNF inhibition on insulin resistance and lipids levels in patients with rheumatoid arthritis / LS Tarn [et al] // Clin. Rheumatol. - 2007. - Vol. 26, N9.-P. 1495-1498; Insulin resistance in rheumatoid arthritis: the impact of the anti-TNF-alpha therapy / MA Gonzalez-Gay [et al] // Ann. NY. Acad. Sci. - 2010. - Vol. 1193. - P. 153-159; Modulation of lipoprotein plasma concentration during long-term anti-TNF therapy in patients with active rheumatoid arthritis / C. Popa [et al] // Ann. Rheum. Dis. - 2007. - Vol. 66, N11. - P 1503-1507; Randomized, double blind, placebo-controlled, pilot trial of infliximab, a chimeric monoclonal antibody to tumor necrosis factor-alpha, in patients with moderate-to-severe heart failure: results of the anti-TNF Therapy Against Congestive Heart Failure [AT TACH] trial / E.S. Chung [et al] // Circulation. - 2003. - Vol 107. - P. 3133-3140.), An increased risk of cardiovascular mortality due to the use of these drugs and the absence of an effect on the thickness of the intima-media complex of carotid arteries and arterial stiffness in patients with rheumatoid arthritis already having cardiovascular diseases ( Methotrexate and the risk of cardiovascular complications in rheumatoid arthritis / TV Popkova, EV Gerasimova, DS Novikova, EL Nasonov // Scientific and Practical Rheumatology. - 2012. T. 50, Mb. - S 70-79 .; Genetically engineered biologicals in the treatment of rheumatoid arthritis. a / under the editorship of E.L. Nasonov. - M .: IMA-PRESS, 2013. - 552 pp., ill .; Novikova, D.S., Painless myocardial ischemia, autonomic regulation of cardiac activity and elastic properties of arteries in women with rheumatoid arthritis: abstract of thesis ... doctor of medical sciences: 01/14/22, 01/14/05 / D.S. Novikova. - M., 2013. - 58 p .; Gonzalez-Gay, MA Insulin resistance in rheumatoid arthritis : the impact of the anti-TNF-alpha therapy / MA Gonzalez-Gay, C. Gonzalez-Juanatey, TR Vazguez-Rodriguez // Ann. N. Y. Acad. Sci. - 2010 .-- Vol. 1193, N 1. - P. 153-159; The association between functional and morphological assessments of endothelial function in patients with rheumatoid arthritis: a cross-sectional study [Electronic resource] / A. Sandoo [et al] // Arthritis Res. Ther. - 2013 .-- Vol. 15. - P. R107.), And related to the lack of effectiveness or poor tolerance of synthetic disease-modifying antirheumatic (methotrexate, leflunomide, etc.) and genetic engineering biological drugs on average from 40 to 60% of cases, the presence of contraindications for them prescription (Balabanova PM Efficacy and safety of the drug leflunomide (Arava) for rheumatic diseases. Russian Medical Journal. - 2010. - Volume 18, No. 11. - P. 744-746; Simsekl. Predictors of response to TNF inhibitors in rheumatoid arthritis - do we have new tools for personalized medicine? // Bull. NY. U. Hosp. Jt. Dis .. - 2012. - Vol. 70. - P 187-190; So PP. A personalized medicine approach to biologic treatment of rheumatoid arthritis: a preliminary treatment algorithm // Rheumatology (Oxford). - 2012. - No. 51. - P. 600-609).

Under these conditions, to implement the TREAT TO TARGET strategy, a new category of drugs is proposed as an alternative, aimed at cytoplasmic protein kinases, the so-called targeted disease-modifying antirheumatic drugs, the only one registered for use in the Russian Federation, the representative of which is tofacitinib, proved in a randomized placebo-controlled trials high clinical efficacy, good tolerance and safety in quality monotherapy and in combination with methotrexate (Nasonov EL New approaches to pharmacotherapy of rheumatoid arthritis: // tofacitinib Scientific practical rheumatology - 2014. - Vol 52, №2 - pp 209-221...).

It should be emphasized that there is practically no data on the effect of tofacitinib on reducing cardiovascular risk. The research results indicate a dose-dependent increase in the concentration of total cholesterol, high and low density lipoproteins (without a significant increase in the atherogenicity index), which, however, did not lead to an increase in the frequency of cardiovascular catastrophes (Effects of tofacitinib and other DMARDs on lipid profiles in rheumatoid arthritis: implications for the rheumatologist / C. Charles-Schoeman, MA Gonzalez-Gay, I. Kaplan, et al. // Seminars in Arthritis and Rheumatism. - 2016 .-- Vol. 46, Issue 1. - P. 71-80. https : //doi.Org/10.1016/j.semarthrit.2016.03.03.004). Along with this, an increase in the level of “anti-atherogenic” factors (lecithin-cholesterol acetyltransferase and paraoxonase) and a decrease in “atherogenic” mediators (SSA and low density lipoprotein associated with SAA) (Effects of tofacitinib on lipid biomarkers in patients with active rheumatoid arthritis Mclnes, I. Kaplan, M. Boy, et al. // Ann. Rheum. Dis. - 2013 .-- Vol. 72, Suppl. - P. 3: 416.). In addition, only two cohort studies demonstrated a decrease in arterial stiffness, estimated using the vascular CAVI index and augmentation index, and the thickness of the intima-media complex in patients with rheumatoid arthritis with a decrease in disease activity during combination therapy with tofacitinib and methotrexate (Kite K, Atapo K, Yamada S. Tofacitinib Improves Arterial Stiffness with Methotrexate Resistant Active Rheumatoid Arthritis. A Cohort Study. // Annals of the Rheumatic Diseases. - 2014. - No. 73 (Suppl 2). - P. 961; DOI: 10.1136 / annrheumdis- 2014-eular. 1019; Tofacitinib improves atherosclerosis despite up-regulating serum cholesterol in patients with active rheumatoid arthritis: a cohort study / K Kume, K. Amano, S. Yamada, et al. // Rheumatol. Int. - 2017. - Vol. 37, No. 12. - P. 2079-2085. doi: 10.1007Vs00296- 017-3844-9.).

However, to date, there is no reliable evidence of the effect of tofacitinib monotherapy on the early manifestations and severity of atherosclerotic vascular lesions in rheumatoid arthritis, which does not allow a final judgment on the effect of the drug on the functional state of the endothelium and morpho-functional parameters of the vascular wall.

The technical result of the invention is the development of a method for the correction of vasomotor dysfunction of the endothelium and arterial stiffness in patients with rheumatoid arthritis.

The technical result is achieved by the fact that in order to improve the functional state of the endothelium and the morpho-functional properties of the vascular wall to a patient with an active course of rheumatoid arthritis and the ineffectiveness of previous therapy with methotrexate or the presence of contraindications for its use, tofacitinib is administered orally as a basic anti-inflammatory therapy at a dose of 10 mg per day constantly, which along with immunomodulatory (immunosuppressive) and anti-inflammatory effects, has a vasoprotective effect thyroid, both on large vessels of the elastic type (a decrease in augmentation and stiffness indices), and on large (an increase in the phase shift between channels) and small arteries of a muscle type (an increase in the occlusion index in amplitude and a decrease in the reflection index).

The method is as follows: after a diagnosis has been made to a patient with an active course of rheumatoid arthritis and the ineffectiveness of previous therapy with methotrexate or the presence of contraindications for its use, tofacitinib is constantly prescribed as a basic anti-inflammatory therapy at a dose of 10 mg per day.

Clinical testing of the proposed method was carried out in 26 patients with rheumatoid arthritis without cardiovascular complications. Among the examined patients there were 18 women and 8 men, the average age of which was 41.2 [33.6; 49.3] years, the average duration of the disease was 14.8 [8.6; 22.4] months. DAS28 disease activity was moderate in 3 patients and high in 23 patients. In 46.1% (n = 12) of patients, II took place, and in 53.9% (n = 14), there was III radiological stage according to Steinbrocker. In 10 patients, there was an RF / ACCP-seronegative subtype of the disease, 16 patients with rheumatoid arthritis were seropositive in the Russian Federation and / or ACCP. Prior to inclusion in the study, patients received previous therapy for HDPE: methotrexate - 69.2% (n = 18), sulfasalazine - 7.7% (n = 2), leflunomide - 23.1% (n = 6), as well as non-steroidal anti-inflammatory drugs - 46.1% (n = 12) and glucocorticoids - 31% (n = 8). Systemic manifestations of the disease were identified in 24 (92.3%) patients, among which rheumatoid nodules (n = 9) and amyotrophic syndrome (n = 16) were most common, anemia (n = 5) and capillaritis (n = four). Among the patients included in the study, 8 (30.7%) patients had a family history of cardiovascular disease; a moderate (n = 18) or low (n = 8) cardiovascular risk was determined by the modified SCORE scale.

The control group consisted of 26 healthy individuals aged 38.8 [31.6; 46.7] years (of which 19 (73%) were women and 7 (27%) were men).

The study of endothelial function and arterial stiffness included assessing the pulse wave contour analysis and conducting a test with reactive hyperemia on the AngioScan-01 apparatus (AngioScan-Electronics LLC, Russia) in accordance with the requirements for the preparation of the test subject and the test procedure (Parfenov, A .S. Express diagnostics of cardiovascular diseases / A.S. Parfenov // World of measurements. - 2008. - No. 6. - S. 74-82.).

Study protocol: a pulse wave contour analysis and an occlusal test were performed in a darkened room after 15 minutes of rest, in the morning, on an empty stomach, in a comfortable sitting position with fixed hands with photoplethysmographic sensors on the tip phalanges of the index fingers.

When evaluating the function of the endothelium, the occlusal cuff freely inflated a finger into the gap between the cuff and the skin of the shoulder before inflation, was located on the forearm, 2-3 cm below the elbow. 24 hours before the study, caffeine, alcohol and other stimulants, physical activity and smoking were excluded.

Based on the results of the pulse wave contour analysis, such parameters as stiffness index (SI, stiffness index), reflection index (RI, reflection index), augmentation index (Alp, augmentation index), central systolic pressure - prognosis (Spa, SystolicPressureAortic - prognosis) were analyzed. )

During the performance of the occlusal test, the amplitude occlusion index and phase shift between the channels were analyzed.

Analysis of the effectiveness of the intervention was based on intermediate "surrogate" criteria. EULAR criteria based on the dynamics of the DAS28 index were used to evaluate the clinical efficacy of therapy. The vasomotor function of the endothelium and the morphological and functional parameters of the vascular wall in patients with RA were evaluated twice: before treatment and after 6 months of tofacitinib therapy.

Against the background of the use of tofacitinib, a significant decrease in DAS28 was recorded already after 1 month of therapy, by the end of the observation, clinical improvement (good / moderate effect according to EULAR criteria) was determined in 69.2% of patients (n = 18), remission was achieved in 30.8% patients with rheumatoid arthritis (n = 8).

Assessment of the dynamics of the parameters of the functional state of the endothelium in patients with rheumatoid arthritis on the background of 6 months of treatment with tofacitinib showed an increase in the occlusion index in amplitude, which did not statistically significantly differ from the control values, and the magnitude of the phase shift between the channels was on average 1.8 times (p = 0.008) in comparison with the initial indicator (table.).

Note: the results are presented in the form of a median (Me) with an interquartile range of 25-75 percentile ([25Q; 75QJ); p - in comparison with the initial values (according to the Wilcoxon test), NS differences are not statistically significant.

The study of the characteristics of the contour analysis of the pulse wave after treatment with tofacitinib in patients with rheumatoid arthritis showed a 4-fold (p = 0.001) and 1.3-fold (p <0, 0) comparison with the initial augmentation index (Alp) and rigidity index (SI). 01), respectively, while maintaining statistically significant differences with control values. Also, after 6 months of tofacitinib therapy, normalization of the reflection index (RI) indicators was established, which characterizes the tone of small muscle arteries and determines the presence of spasm, which is an important component of the pathogenesis of cardiovascular diseases (table).

Clinical example. Patient A., born in 1978, considers herself sick since December 2015, when she began to notice swelling of the wrist joints and small joints of both hands, limitation of movement in them, morning stiffness that persists until noon; unmotivated weight loss, severe weakness, an increase in body temperature in the evening to 37.6 ° C. In March 2016 she was hospitalized in the rheumatology department, during the examination of CRP - 45 mg / l, ATsPP - 102.9 IU / ml (N≤5 IU / ml), RF - 382 IU / ml (N≤20 IU / ml) . In the general blood test: hematocrit - 36.7%, hemoglobin - 10.9 g / dl, erythrocytes - 3.31 million / μl, MCV - 65.9 fl, RDW - 15.6%, SIT - 23.3 pg , platelets - 320 thousand / μl, leukocytes - 7.8 thousand / μl, neutrophils - 56%, eosinophils - 3%, lymphocytes - 35%, monocytes - 6%, ESR - 38 mm / h. When radiography of the hands and feet: periarticular osteoporosis, cracks in the wrist joints narrowed, single cystic enlightenment in the styloid processes of the radial, ulnar bones, in the bones of the wrist. Diagnosis: Rheumatoid arthritis, seropositive for the Russian Federation and ACCP, activity III (DAS28 - 6.53), early stage, non-erosive variant, stage II according to Steinbrocker, with systemic manifestations: anemia, fever, FC P. Oral therapy of methotrexate at a dose of 15 was started. mg / week, further in view of the lack of effectiveness and poor tolerance (nausea) transferred to the subcutaneous form of 25 mg / week. Against the background of 6 months of therapy, objective signs of high activity of rheumatoid arthritis persisted (swelling of the metacarpophalangeal and proximal interphalangeal joints of the hands on both sides, a positive symptom of lateral compression of the hand; rheumatoid nodules on the extensor surface of the forearm on the left), unfavorable prognosis factors (high levels of RF and ADC ), an increase in functional insufficiency was observed, changes in the biochemical analysis of blood were revealed: total. bilirubin - 34 μmol / l, ACT - 112 units / liter, ALT - 108 units / liter, and therefore treatment with methotrexate was canceled.

As part of the testing of the method:

- Contour analysis of the pulse wave: heart rate - 90 beats / min, the age of the vascular system - 59 years, the type of curve - A: 65%; B: 35%, Alp - 12.4%, SI - 10.6 m / s, RI - 31.8%, Spa - 125 mmHg

- Occlusion test: occlusion index in amplitude - 1.2; the phase shift between the channels before and after occlusion is 8.8 ms, which corresponds to pronounced dysfunctions of the endothelial function both in the microcirculation system and in the arteries of the muscle type.

As a basic therapy, tofacitinib was prescribed at a dose of 5 mg 2 times a day orally.

Against the background of tofacitinib therapy, after 6 months there was a statistically significant decrease in blood serum ESR from 38 mm / h to 10 mm / h and CRP from 45 mg / l to 1.5 mg / l, the level of ACCP decreased to 10 IU / ml, RF up to 36 U / ml.

Starting from the 4th week of treatment, there was a persistent decrease in DAS28, by the end of the observation, low activity of rheumatoid arthritis was achieved (DAS28 = 2.17).

In the contour analysis of the pulse wave: heart rate - 82 beats / min, the age of the vascular system - 44 years, the type of curve - A: 20%, B: 40%; C: 40%, Alp - -7.8%, SI - 7.6 m / s, RI - 22.7%, Spa - 124 mmHg

According to data obtained during the performance of the occlusion test, the increase in the amplitude of the signal oscillations was 2.8; phase shift between channels before and after occlusion - 11.2 ms.

Thus, the given clinical example demonstrates that along with the immunomodulatory (immunosuppressive) and anti-inflammatory effects, tofacitinib has a vasoprotective effect, realized both on the large vessels of the elastic type (decrease in augmentation and stiffness indices) and on large ones (increase in the phase shift between channels ) and small arteries of the muscle type (increase in the occlusion index in amplitude and a decrease in the reflection index). The achieved decrease in the signs of vasomotor endothelial dysfunction and arterial stiffness under the influence of tofacitinib therapy is potentially associated with a decrease in the risk of cardiovascular complications against the background of adequate control of the course of the immuno-inflammatory process in rheumatoid arthritis, which determines future preventive strategies aimed at improving the prognosis and quality of life of this category of patients.

Claims (1)

A method for correcting vasomotor endothelial dysfunction and arterial stiffness in patients with rheumatoid arthritis, including evaluating the vasoprotective effect of disease-modifying antirheumatic drugs, characterized in that a patient with an active course of rheumatoid arthritis and the ineffectiveness of previous therapy with methotrexate or having contraindications for its use as a basalt Tofacitinib is prescribed at a dose of 10 mg per day constantly.