rspНаучно-практическая ревматологияRheumatology Science and Practice1995-44841995-4492IMA-PRESS, LLC10.14412/1995-4484-2016-145-154rsp-2203Research ArticleОРИГИНАЛЬНЫЕ ИССЛЕДОВАНИЯORIGINAL RESEARCHКлиническое значение концентраций лигандов BAFF и APRIL при системной красной волчанкеCLINICAL VALUE OF BAFF AND APRIL CONCENTRATIONS IN SYSTEMIC LUPUS ERYTHEMATOSUSПанафидинаТ. А.PanafidinaT. A.

115522 Москва, Каширское шоссе, 34А

34A, Kashirskoe Shosse, Moscow 115522

panafidina@inbox.ruСоховаМ. А.SokhovaM. A.

115522 Москва, Каширское шоссе, 34А

34A, Kashirskoe Shosse, Moscow 115522

ПопковаТ. В.PopkovaT. V.

115522 Москва, Каширское шоссе, 34А

34A, Kashirskoe Shosse, Moscow 115522

ЧеркасоваМ. В.CherkasovaM. V.

115522 Москва, Каширское шоссе, 34А

34A, Kashirskoe Shosse, Moscow 115522

НовиковА. А.NovikovA. A.

115522 Москва, Каширское шоссе, 34А

34A, Kashirskoe Shosse, Moscow 115522

АлександроваЕ. Н.AleksandrovaE. N.

115522 Москва, Каширское шоссе, 34А

34A, Kashirskoe Shosse, Moscow 115522

НасоновЕ. Л.NasonovE. L.

Институт профессионального образования

кафедра ревматологии 

115522 Москва, Каширское шоссе, 34А

119991 Москва, ул. Трубецкая, 8, стр. 2 

Department of Rheumatology, Institute of Professional Education

34A, Kashirskoe Shosse, Moscow 115522

8, Trubetskaya St., Build. 2, Moscow 119991 

ФГБНУ Научно- исследовательский институт ревматологии им. В.А. Насоновой, МоскваРоссияV.A. Nasonova Research Institute of Rheumatology, MoscowRussian FederationФГБНУ Научно- исследовательский институт ревматологии им. В.А. Насоновой, Москва; ГБОУ ВПО «Первый Московский государственный медицинский университет им. И.М. Сеченова» Минздрава России, МоскваРоссияV.A. Nasonova Research Institute of Rheumatology, Moscow; I.M. Sechenov First Moscow State Medical University, Ministry of Health of Russia, MoscowRussian Federation201618072016542145154Copyright © Панафидина Т.А., Сохова М.А., Попкова Т.В., Черкасова М.В., Новиков А.А., Александрова Е.Н., Насонов Е.Л., 20162016Панафидина Т.А., Сохова М.А., Попкова Т.В., Черкасова М.В., Новиков А.А., Александрова Е.Н., Насонов Е.Л.Panafidina T.A., Sokhova M.A., Popkova T.V., Cherkasova M.V., Novikov A.A., Aleksandrova E.N., Nasonov E.L.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://rsp.mediar-press.net/rsp/article/view/2203

Системная красная волчанка (СКВ) характеризуется патологической активацией и дифференцировкой В-лимфоцитов. Стимулятор В-лимфоцитов (BLyS, также известный как BAFF) и его гомолог APRIL относятся к числу лигандов семейства фактора некроза опухоли (ФНО) и играют ключевую роль в селекции и выживаемости В-лимфоцитов.

Цель – определить концентрацию BAFF и APRIL в сыворотке крови больных СКВ и зависимость клинических и лабораторных показателей болезни от уровня этих цитокинов.

Материал и методы

Материал и методы. В исследование включено 73 пациента с СКВ (62 женщины и 11 мужчин), медиана возраста 30,0 [28,0; 46,0] года, длительности болезни – 5,0 [1,5; 11,0] года, с высокой активностью (медиана SLEDAI-2K – 8 [2; 13] баллов). Поражение почек выявлено в 40% случаев, суставов – в 36%, гематологические нарушения – в 38%, антинуклеарный фактор (АНФ) – в 94,5% и антитела к двуспиральной ДНК – в 77%. Сопутствующий антифосфолипидный синдром обнаружен у 15% больных. Глюкокортикоиды (ГК) принимали 66% (медиана дозы в пересчете на преднизолон 10 [0; 15] мг/сут), цитотоксические препараты (циклофосфан, микофенолата мофетил, азатиоприн) – 42%, генно-инженерные биологические препараты (ГИБП) использовались у 12% больных, 31,5% пациентов на момент включения в исследование не получали терапию. Концентрацию BAFF и APRIL определяли в сыворотке крови методом иммуноферментного анализа.

Результаты и обсуждение

Результаты и обсуждение. Концентрации BAFF и APRIL у пациентов с СКВ и в группе контроля существенно не различались: медиана уровня BAFF – 0,02 [0,01; 0,64] и 0,02 [0,01; 0,03] нг/мл, APRIL – 2,09 [0,01; 3,80] и 0,01 [0,01; 4,16] нг/мл соответственно. Повышенная концентрация BAFF (>0,82 нг/мл) определялась у 5,5% больных СКВ, APRIL (>5,96 нг/мл) – у 4,1%. Выявлена положительная корреляция между концентрацией BAFF и уровнем гематурии (r=0,261; p<0,05), отрицательная – с концентрацией гемоглобина (r=-0,289; p<0,05), длительностью болезни (r=-0,261; p<0,05) и значением SLICC/DI (r=-0,286; p<0,05). Отмечалась положительная корреляция уровня APRIL со значением SLEDAI-2K (r=0,323; p<0,01), титром АНФ (r=0,256; p<0,05) и концентрацией ионов К+ (r=0,322; p<0,05), отрицательная – с уровнем гемоглобина (r=-0,299; p<0,05), лейкоцитов (r=-0,253; p<0,05) и скоростью клубочковой фильтрации (СКФ; r=-0,299; p<0,05). Обнаружено повышение концентрации как BAFF, так и APRIL у пациентов с волчаночным нефритом в сравнении с пациентами без него (р<0,05). Пациенты с гематологическими нарушениями, обусловленными СКВ, имели большую концентрацию APRIL (р<0,05), чем пациенты без гематологических нарушений; в отношении уровня BAFF группы оказались сопоставимы. С нарастанием активности СКВ (SLEDAI-2K ≥8 баллов) выявлено повышение концентрации обоих лигандов (р<0,05).

Отдельно была проанализирована подгруппа больных СКВ (n=26), которые не получали ГК или других иммуносупрессивных препаратов и ГИБП. У этих пациентов концентрация APRIL была выше, чем в контрольной группе: 3,06 [2,09; 4,05] и 0,01 [0,01; 4,16] нг/мл (р<0,05), различий уровня BAFF не отмечалось. Обнаружена положительная корреляция между уровнем APRIL и концентрацией креатинина (r=0,635; p<0,001), мочевины (r=0,574; p<0,01), мочевой кислоты (r=0,633; p<0,001), отрицательная – с уровнем лейкоцитов (r=-0,437; p<0,05), лимфоцитов (r=-0,497; p<0,05) и СКФ (r=-0,663; p<0,001). Концентрация BAFF положительно коррелировала с уровнем гематурии (r=0,591; p<0,01), значением SLEDAI-2K (r=0,413; p<0,05) и СОЭ (r=0,394; p<0,05), отрицательно – с концентрацией гемоглобина (r=-0,2488; p<0,05) и СКФ (r=-0,473; p<0,05).

Выводы

Выводы. Концентрации BAFF и APRIL у пациентов с СКВ и здоровых доноров были сопоставимы. Повышенные уровни как BAFF, так и APRIL ассоциированы с высокой активностью болезни (SLEDAI-2K ≥8 баллов), волчаночным нефритом, APRIL – с гематологическими нарушениями. Иммуносупрессивная терапия (ГК, цитостатические препараты, ГИБП) снижает концентрацию APRIL в сыворотке крови больных СКВ. 

Systemic lupus erythematosus (SLE) is characterized by the pathological activation and differentiation of B lymphocytes. The B-lymphocyte stimulator (BLyS), also known as B cell-activating factor of the tumor necrosis factor family (BAFF), and its homologue, a proliferation-inducing ligand (APRIL), belong to the ligands of the tumor necrosis factor (TNF) family and play a key role in B-lymphocyte selection and survival.

Objective

Objective: to determine serum BAFF and APRIL concentrations in patients with SLE and a relationship of the clinical and laboratory parameters of the disease to the level of these cytokines.

Subjects and methods

Subjects and methods. The investigation enrolled 73 patients (62 women and 11 men; median age, 30.0 [28.0; 46.0] years) with SLE (disease duration, 5.0 [1.5; 11.0] years) and its high activity (the median SLEDAI-2K scores of 8 [2; 13]).

Involvement of the kidneys and joints were found in 40 and 36% of cases, respectively; there were hematologic disorders in 38%, antinuclear factor (ANF) in 94.5%, and anti-double stranded DNA antibodies in 77%. The concurrent antiphospholipid syndrome was detected in 15% of the patients. 66% of the patients took glucocorticoids (GCs) (the median dose was 10 [0; 15] mg/day, calculated with reference to prednisolone), 42% received cytotoxic drugs (cyclophosphamide, mycophenolate mofetil, azathioprine); 12% used biological agents (BAs); 31.5% received no therapy at enrolment in the investigation. Serum BAFF and APRIL concentrations were estimated using an enzyme immunoassay.

Results and discussion

Results and discussion. The concentrations of BAFF and APRIL did not differ essentially in the patients with SLE and in the controls: the median level of BAFF was 0.02 [0.01; 0.64] and 0.02 [0.01; 0.03] ng/ml; that of APRIL was 2.09 [0.01; 3.80] and 0.01 [0.01; 4.16] ng/ml, respectively. The elevated concentration of BAFF (>0.82 ng/ml) was revealed in 5.5% of the patients with SLE and that of APRIL (>5.96 ng/ml) in 4.1%. There was a positive correlation between the concentration of BAFF and the level of hematuria (r = 0.261; p < 0.05) and a negative correlation with hemoglobin concentrations (r = -0.289; p < 0.05), disease duration (r = -0.261; p < 0.05), and SLICC/DI scores (r = -0.286; p < 0.05). There was a positive correlation of APRIL levels with SLEDAI-2K scores (r = 0.323; p < 0.01), ANF titer (r = 0.256; p < 0.05), and K+ concentrations (r = 0.322; p < 0.05) and a negative correlation with hemoglobin levels (r = -0.299; p < 0.05), white blood cell count (r = -0.253; p < 0.05), and glomerular filtration rate (GFR) (r = -0.299; p < 0.05). The elevated concentrations of both BAFF and APRIL were found more often in patients with lupus nephritis compared to those without this condition (p < 0.05). The patients with SLE-induced hematological disorders had a higher APRIL concentration (p < 0.05) than those without these disorders; the groups proved to be comparable in BAFF levels. As SLE activity increased (SLEDAI-2K scores of ≥8), there was a rise in the concentration of both ligands (p < 0.05).

A subgroup of SLE patients (n = 26) who had received neither GCs nor other immunosuppressants or BAs was separately analyzed. In these patients, the concentration of APRIL was higher than that in the control group: 3.06 [2.09; 4.05] and 0.01 [0.01; 4.16] ng/ml (p < 0.05), there were no differences in the level of BAFF. There was a positive correlation between the level of APRIL and the concentration of creatinine (r = 0.635; p < 0.001), urea (r = 0.574; p < 0.01), and uric acid (r = 0.633; p < 0.001) and a negative correlation with the level of white blood cells (r = -0.437; p < 0.05), lymphocytes (r = -0.497; p < 0.05) and GFR (r = -0.663; p < 0.001). The BAFF concentrations correlated positively with hematuria levels (r = 0.591; p < 0.01), SLEDAI-2K scores (r = 0.413; p < 0.05), and erythrocyte sedimentation rate (r = 0.394; p < 0.05) and negatively with hemoglobin concentrations (r = -0.2488; p < 0.05) and GFR (r = -0.473; p < 0.05).

Conclusion

Conclusion. The concentrations of BAFF and APRIL were comparable in the patients with SLE and healthy donors. The elevated levels of both BAFF and APRIL were associated with high disease active (SLEDAI-2K scores of ≥ 8) and lupus nephritis; those of APRL are related to hematological disorders. Immunosuppressive therapy (GCs, cytostatic drugs, BAs) decreased the serum concentration of APRIL in patients with SLE. 

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The authors declare that there are no conflicts of interest present.