rspНаучно-практическая ревматологияRheumatology Science and Practice1995-44841995-4492IMA-PRESS, LLC10.14412/1995-4484-2019-265-273rsp-2724Research ArticleОРИГИНАЛЬНЫЕ ИССЛЕДОВАНИЯORIGINAL RESEARCHВлияние ритуксимаба на проявления активности и легочную функцию у больных системной склеродермией: оценка после года наблюденияEffect of rituximab on the manifestations of activity and pulmonary function in patients with systemic sclerosis: one-year follow-up evaluationАнаньеваЛ. П.AnanyevaL. P.

115522, Москва, Каширское шоссе, 34А.

34A, Kashirskoe Shosse, Moscow, 115522.

lpana@yandex.ruКоневаО. А.KonevaO. A.

115522, Москва, Каширское шоссе, 34А.

34A, Kashirskoe Shosse, Moscow, 115522.

ДесиноваО. В.DesinovaO. V.

115522, Москва, Каширское шоссе, 34А.

34A, Kashirskoe Shosse, Moscow, 115522.

ГарзановаЛ. А.GarzanovaL. A.

115522, Москва, Каширское шоссе, 34А.

34A, Kashirskoe Shosse, Moscow, 115522.

ГлуховаС. И.GlukhovaS. I.

115522, Москва, Каширское шоссе, 34А.

34A, Kashirskoe Shosse, Moscow, 115522.

СтаровойтоваМ. Н.StarovoitovaM. N.

115522, Москва, Каширское шоссе, 34А.

34A, Kashirskoe Shosse, Moscow, 115522.

ОвсянниковаО. Б.OvsyannikovaO. B.

115522, Москва, Каширское шоссе, 34А.

34A, Kashirskoe Shosse, Moscow, 115522.

ВолковА. В.VolkovA. V.

115522, Москва, Каширское шоссе, 34А.

34A, Kashirskoe Shosse, Moscow, 115522.

АлексанкинА. П.AleksankinA. P.

115522, Москва, Каширское шоссе, 34А.

34A, Kashirskoe Shosse, Moscow, 115522.

НасоновЕ. Л.NasonovE. L.

115522, Москва, Каширское шоссе, 34А.

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

34A, Kashirskoe Shosse, Moscow, 115522.

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

ФГБНУ «Научно-исследовательский институт ревматологии им. В.А. Насоновой»РоссияV.A. Nasonova Research Institute of RheumatologyRussian FederationФГБНУ «Научно-исследовательский институт ревматологии им. В.А. Насоновой»; ФГАОУ ВО «Первый Московский государственный медицинский университет им. И.М. Сеченова» Минздрава России (Сеченовский Университет)РоссияV.A. Nasonova Research Institute of Rheumatology; I.M. Sechenov First Moscow State Medical University, Ministry of Health of Russia (Sechenov University)Russian Federation201908072019573265273Copyright © Ананьева Л.П., Конева О.А., Десинова О.В., Гарзанова Л.А., Глухова С.И., Старовойтова М.Н., Овсянникова О.Б., Волков А.В., Алексанкин А.П., Насонов Е.Л., 20192019Ананьева Л.П., Конева О.А., Десинова О.В., Гарзанова Л.А., Глухова С.И., Старовойтова М.Н., Овсянникова О.Б., Волков А.В., Алексанкин А.П., Насонов Е.Л.Ananyeva L.P., Koneva O.A., Desinova O.V., Garzanova L.A., Glukhova S.I., Starovoitova M.N., Ovsyannikova O.B., Volkov A.V., Aleksankin A.P., 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/2724

Выбор препаратов для лечения интерстициального поражения легких (ИПЛ), ассоциированного с системной склеродермией (ССД), в настоящее время очень ограничен. Данные ряда исследований показывают, что ритуксимаб (РТМ) может улучшить функцию легких и уменьшить выраженность фиброза кожи у пациентов с ССД.

Цель данного исследования заключалась в оценке эффективности лечения РТМ после года наблюдения в когорте пациентов с ССД-ассоциированным ИПЛ. Показаниями для назначения РТМ были: 1) неэффективность стандартной терапии ГК и иммуносупрессантами (ИС) или невозможность их применения, 2) ранняя стадия (первые 3 года болезни) с признаками неблагоприятного прогноза, такими как диффузная форма, высокий кожный счет (>14), мужской пол, быстрое прогрессирование со значительным исходным снижением форсированной жизненной емкости легких (ФЖЕЛ) и/или диффузионной способности легких (ДСЛ), высокая позитивность по антителам к Scl-70.

Материал и методы

Материал и методы. Была отобрана группа больных, имеющих не менее двух точек оценки с интервалом от 12 до 18 мес (средний период наблюдения 13±2 мес) и получивших за этот период не менее 1 г РТМ. В исследование был включен 71 пациент с достоверным диагнозом ССД. У 90% больных выявлялось интерстициальное поражение легких по данным МСКТ. Продолжительность заболевания составила 5,6±4,4 года. Позитивность по антителам к Scl-70 выявлена у 73% больных. Средняя кумулятивная доза РТМ составила 1,43±0,6 г, 48 пациентов получили ≤2 г РТМ (группа 1, средняя доза 1,1±0,1 г) и 23 пациента ≥2 г РТМ (группа 2, средняя доза 2,2±0,6 г). До начала лечения РТМ все пациенты получали сопутствующую терапию преднизолоном и 45% – иммуносупрессанты.

Результаты и обсуждение

Результаты и обсуждение. При оценке результатов врачом хороший эффект терапии отмечался у 52 (73,2%) пациентов, удовлетворительный – у 16 (22,6%), не было эффекта у 3 (4,2%) пациентов. В целом 95,8% больных отметили улучшение разной степени. Достоверные изменения наблюдались в снижении индекса активности заболевания, кожного счета, уровней С-реактивного белка и IgG, числа пациентов с высоким титром антинуклеарного фактора, средней дозы преднизолона, а также в увеличении размера ротовой апертуры, фракции выброса левого желудочка, теста 6-минутной ходьбы. Не было изменений уровня систолического давления в легочной артерии и индекса HAQ. ФЖЕЛ увеличилась с 77,35±19,9 до 82,6±20,7% (p=0,001). Минимально клинически значимое увеличение ФЖЕЛ ≥5% наблюдалось у 41 человека (57,7%). Общее улучшение ФЖЕЛ (ΔФЖЕЛ) достигло 5,24%, при этом изменения были более значимы в группе 2 (ΔФЖЕЛ 8,98%), чем в группе 1 (ΔФЖЕЛ 3,75%; p=0,01). ДСЛ осталась стабильной, но между группами были значимые различия: ΔДСЛ составила 3,75% в группе 2 и, наоборот, уменьшилась в группе 1 (1,6%; p=0005). Профиль безопасности терапии был расценен как хороший и вполне сравнимый как с профилем безопасности иммуносупрессантов, так и с применением РТМ в других исследованиях. Наиболее частыми были инфекционные осложнения, зарегистрированные у 11 человек (15%). Из них инфекции верхних дыхательных путей развились у 7, в одном случае возникла флегмона стопы, в двух случаях – мочевая инфекция и в одном – Herpes zoster.

Заключение

Заключение. Результаты этого исследования подтверждают данные других работ, которые продемонстрировали положительный эффект РТМ на ИПЛ, ассоциированное с ССД. Нами впервые была продемонстрирована связь позитивной динамики показателей легочных тестов с дозой РТМ.

The choice of drugs for the treatment of interstitial lung disease (ILD) associated with systemic sclerosis (SS) is currently very limited. Data from a number of studies show that rituximab (RTM) can improve lung function and reduce the severity of skin fibrosis in patients with SS.

Objective

Objective: to evaluate the efficiency of RTM in a cohort of patients with SS-associated ILD after one-year follow-up. The indications for prescribing RTM were: 1) the inefficiency of standard therapy with glucocorticoids and immunosuppressants (ISs) or the impossibility of their use; 2) the early stage (first 3 years of the disease) with signs of poor prognosis, such as diffuse form, high skin scores (>14), male gender, rapid progression with a significant initial decline in forced vital capacity (FVC) and/or diffusion lung capacity (DLC), and a high anti-Scl-70 antibody positivity.

Subjects and methods

Subjects and methods. The investigators selected a group of patients who had at least two assessment points at a 12-to-18 month interval (the mean follow-up period of 13±2 months) and took at least 1 g of RTM during this period. The investigation included 71 patients with a valid diagnosis of SS. Multi-slice spiral computed tomography (MSCT) revealed ILD in 90% of patients. The disease duration was 5.6±4.4 years. The presence of anti-Scl-70 antibodies was detected in 73% of patients. The mean cumulative dose of RTM was 1.43±0.6 g; 48 patients in Group 1 received ≤2 g of RTM (the mean dose, 1.1±0.1 g) and 23 patients in Group 2 took ≥2 g of RTM (mean dose, 2±0.6 g). Before starting treatment with RTM, all the patients received concomitant therapy with prednisone and 45% - with immunosuppressants.

Results and discussion

Results and discussion. The results assessed by a physician showed that good and moderate effects of the therapy were observed in 52 (73.2%) and 16 (22.6%) patients, respectively; no effect was seen in 3 (4.2%) patients. Overall, 95.8% of patients reported various degrees of improvement. There were significant changes as reductions in the disease activity index, skin scores, C-reactive protein and IgG levels, the number of patients with a high antinuclear antibody level, and the mean dose of prednisolone as well as increases in an oral aperture size, left ventricular ejection fraction, and 6-minute walk test scores. There were no changes in pulmonary artery systolic pressure and the HAQ DI. FVC increased from 77.35±19.9 to 82.6±20.7% (p=0.001). A minimal clinically significant increase in FVC ≥5% was noted in 41 (57.7%) people. The overall improvement in FVC (ΔFVC) reached 5.24%, while the changes were more significant in Group 2 (ΔFVC 8.98%) than in Group 1 (ΔFVC 3.75%; p=0.01). DLC remained stable, but there were significant group differences: ΔDLC was 3.75% in Group 2 and, conversely, decreased in Group 1 (1.6%; p=0005). The safety profile of the therapy was regarded as good and quite comparable with both the safety profile of ISs and the use of RTM in other trials. Infectious complications were recorded to be most common in 11 (15%) people. Of these, upper respiratory tract infections developed in 7 patients; plantar phlegmon occurred in one case; urinary tract infection and herpes zoster were detected in two and one cases, respectively.

The results of this study confirm data from other studies that have demonstrated that RTM exerts a positive effect on SS-associated ILD. We were the first to show the association of positive changes in the measures of pulmonary function tests with the dose of RTM.

системная склеродермияинтерстициальное поражение легкиханти-В-клеточная терапияритуксимабsystemic sclerosisinterstitial lung diseaseanti-B cell therapyrituximabReferencesBosello S, De Luca G, Tolusso B, et al. B cells in systemic sclerosis: a possible target for therapy. Autoimmun Rev. 2011;10(10):624-30. doi: 10.1016/j.autrev.2011.04.013Bosello S, De Luca G, Tolusso B, et al. B cells in systemic sclerosis: a possible target for therapy. Autoimmun Rev. 2011;10(10):624-30. doi: 10.1016/j.autrev.2011.04.013Yoshizaki A, Sato S. Abnormal B lymphocyte activation and function in systemic sclerosis. Ann Dermatol. 2015;27:1-9. doi: 10.5021/ad.2015.27.1.1Yoshizaki A, Sato S. Abnormal B lymphocyte activation and function in systemic sclerosis. Ann Dermatol. 2015;27:1-9. doi: 10.5021/ad.2015.27.1.1Sakkas LL, Dimitrios P, Bogdanos DP. The Role of B cells in the Pathogenesis of systemic sclerosis. IMAJ. 2016;18:516-8.Sakkas LL, Dimitrios P, Bogdanos DP. The Role of B cells in the Pathogenesis of systemic sclerosis. IMAJ. 2016;18:516-8.Yoshizaki A. Pathogenic roles of B lymphocytes in systemic sclerosis. Immunol Lett. 2018;195:76-82. doi: 10.1016/j.imlet.2018.01.002Yoshizaki A. Pathogenic roles of B lymphocytes in systemic sclerosis. Immunol Lett. 2018;195:76-82. doi: 10.1016/j.imlet.2018.01.002Lafyatis R, Kissin E, York M, et al. B cell depletion with rituximab in patients with diffuse cutaneous systemic sclerosis. Arthritis Rheum. 2009;60(2):578-83. doi: 10.1002/art.24249Lafyatis R, Kissin E, York M, et al. B cell depletion with rituximab in patients with diffuse cutaneous systemic sclerosis. Arthritis Rheum. 2009;60(2):578-83. doi: 10.1002/art.24249Bosello S, De Santis M, Lama G, et al. B cell depletion in diffuse progressive systemic sclerosis: safety, skin score modification and IL-6 modulation in an up to thirty-six months follow-up openlabel trial. Arthritis Res Ther. 2010;12(2):54. doi: 10.1186/ar2965Bosello S, De Santis M, Lama G, et al. B cell depletion in diffuse progressive systemic sclerosis: safety, skin score modification and IL-6 modulation in an up to thirty-six months follow-up openlabel trial. Arthritis Res Ther. 2010;12(2):54. doi: 10.1186/ar2965Smith V, van Praet JT, Vandooren B, et al. Rituximab in diffuse cutaneous systemic sclerosis: an open-label clinical and histopathological study. Ann Rheum Dis. 2010;69(1):193-7. doi: 10.1136/ard.2008.095463Smith V, van Praet JT, Vandooren B, et al. Rituximab in diffuse cutaneous systemic sclerosis: an open-label clinical and histopathological study. Ann Rheum Dis. 2010;69(1):193-7. doi: 10.1136/ard.2008.095463Smith V, Piette Y, van Praet JT, et al. Two-year results of an open pilot study of a 2-treatment course with rituximab in patients with early systemic sclerosis with diffuse skin involvement. J Rheumatol. 2013;40(1):52-5. doi: 10.3899/jrheum.120778Smith V, Piette Y, van Praet JT, et al. Two-year results of an open pilot study of a 2-treatment course with rituximab in patients with early systemic sclerosis with diffuse skin involvement. J Rheumatol. 2013;40(1):52-5. doi: 10.3899/jrheum.120778Giuggioli D, Lumetti F, Colaci M, et al. Rituximab in the treatment of patients with systemic sclerosis. Our experience and review of the literature. Autoimmun Rev. 2015;14(11):1072-8. doi: 10.1016/j.autrev.2015.07.008Giuggioli D, Lumetti F, Colaci M, et al. Rituximab in the treatment of patients with systemic sclerosis. Our experience and review of the literature. Autoimmun Rev. 2015;14(11):1072-8. doi: 10.1016/j.autrev.2015.07.008Ананьева ЛП, Соловьев СК, Бекетова ТВ и др. Анти-В-клеточная терапия при системных аутоиммунных ревматических заболеваниях: эффективность и переносимость у 229 больных. Научно-практическая ревматология. 2014;52(5):495-506 [Ananieva LP, Soloviyov SK, Beketova TV, et al. Anti-B-cell therapy at immune inflammatory rheumatic diseases: efficacy and tolerability in 229 patients. Nauchno-Prakticheskaya Revmatologiya = Rheumatology Science and Practice. 2014;52(5):495-506 (In Russ.)]. doi: 10.14412/1995-4484-2014-495-506Ананьева ЛП, Соловьев СК, Бекетова ТВ и др. Анти-В-клеточная терапия при системных аутоиммунных ревматических заболеваниях: эффективность и переносимость у 229 больных. Научно-практическая ревматология. 2014;52(5):495-506 [Ananieva LP, Soloviyov SK, Beketova TV, et al. Anti-B-cell therapy at immune inflammatory rheumatic diseases: efficacy and tolerability in 229 patients. Nauchno-Prakticheskaya Revmatologiya = Rheumatology Science and Practice. 2014;52(5):495-506 (In Russ.)]. doi: 10.14412/1995-4484-2014-495-506Elhai M, Meune C, Avouac J, et al. Trends in mortality in patients with systemic sclerosis over 40 years: a systematic review and meta-analysis of cohort studies. Rheumatol (Oxford). 2012;51:1017-26. doi: 10.1093/rheumatology/ker269Elhai M, Meune C, Avouac J, et al. Trends in mortality in patients with systemic sclerosis over 40 years: a systematic review and meta-analysis of cohort studies. Rheumatol (Oxford). 2012;51:1017-26. doi: 10.1093/rheumatology/ker269Van den Hoogen F, Khanna D, Fransen J, et al. 2013 classification criteria for systemic sclerosis: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Ann Rheum Dis. 2013;72(11):1747-55. doi: 10.1136/annrheumdis-2013-204424Van den Hoogen F, Khanna D, Fransen J, et al. 2013 classification criteria for systemic sclerosis: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Ann Rheum Dis. 2013;72(11):1747-55. doi: 10.1136/annrheumdis-2013-204424Walker UA, Tyndall A, Czirjak L, et al Clinical risk assessment of organ manifestations in systemic sclerosis: a report from the EULAR Scleroderma Trials And Research group database. Ann Rheum Dis. 2007;66(6):754-63. doi: 10.1136/ard.2006.062901Walker UA, Tyndall A, Czirjak L, et al Clinical risk assessment of organ manifestations in systemic sclerosis: a report from the EULAR Scleroderma Trials And Research group database. Ann Rheum Dis. 2007;66(6):754-63. doi: 10.1136/ard.2006.062901Gazi H, Pope JE, Clements P, et al. Outcome measurements in scleroderma: results from a delphi exercise. J Rheumatol. 2007;34:501-9.Gazi H, Pope JE, Clements P, et al. Outcome measurements in scleroderma: results from a delphi exercise. J Rheumatol. 2007;34:501-9.Clements PJ, Hurwitz EL, Wong WK, et al. Skin thickness score as a predictor and correlate of outcome in systemic sclerosis. Arthritis Rheum. 2000;43:2445-54. doi: 10.1002/1529-0131(200011)43:11<2445::AID-ANR11>3.0.CO;2-QClements PJ, Hurwitz EL, Wong WK, et al. Skin thickness score as a predictor and correlate of outcome in systemic sclerosis. Arthritis Rheum. 2000;43:2445-54. doi: 10.1002/1529-0131(200011)43:11<2445::AID-ANR11>3.0.CO;2-QKhanna D, Furst DE, Hays RD, et al. Minimally important difference in diffuse systemic sclerosis: results from the D-penicillamine study. Ann Rheum Dis. 2006;65:1325-9. doi: 10.1136/ard.2005.050187Khanna D, Furst DE, Hays RD, et al. Minimally important difference in diffuse systemic sclerosis: results from the D-penicillamine study. Ann Rheum Dis. 2006;65:1325-9. doi: 10.1136/ard.2005.050187Vallentini G, Della Rossa A, Bombardier S, et al. European multicentre study of define disease activity variables and development of preliminary activity indexes. Ann Rheum Dis. 2001;60:592-8. doi: 10.1136/ard.60.6.592Vallentini G, Della Rossa A, Bombardier S, et al. European multicentre study of define disease activity variables and development of preliminary activity indexes. Ann Rheum Dis. 2001;60:592-8. doi: 10.1136/ard.60.6.592Behr J, Furst DE. Pulmonary function tests. Rheumatology (Oxford). 2008;47(5):65-7. doi: 10.1093/rheumatology/ken313Behr J, Furst DE. Pulmonary function tests. Rheumatology (Oxford). 2008;47(5):65-7. doi: 10.1093/rheumatology/ken313Khanna D, Seibold J, Goldin J, et al. Interstitial lung disease points to consider for clinical trials in systemic sclerosis. Rheumatology (Oxford). 2017;56(5):27-32. doi: 10.1093/rheumatology/kex203Khanna D, Seibold J, Goldin J, et al. Interstitial lung disease points to consider for clinical trials in systemic sclerosis. Rheumatology (Oxford). 2017;56(5):27-32. doi: 10.1093/rheumatology/kex203Kafaja S, Clements PJ, Wilhalme H, et al. Reliability and minimal clinically important differences of forced vital capacity: Results from the Scleroderma Lung Studies (SLS-I and SLS-II). Am J Respir Crit Care Med. 2018;197(5):644-52. doi: 10.1164/rccm.201709-1845OCKafaja S, Clements PJ, Wilhalme H, et al. Reliability and minimal clinically important differences of forced vital capacity: Results from the Scleroderma Lung Studies (SLS-I and SLS-II). Am J Respir Crit Care Med. 2018;197(5):644-52. doi: 10.1164/rccm.201709-1845OCATS statement: guidelines for the six-minute walk test. Am J Respir Crit Care Med. 2002;166(1):111-7. doi: 10.1164/ajrccm.166.1.at1102ATS statement: guidelines for the six-minute walk test. Am J Respir Crit Care Med. 2002;166(1):111-7. doi: 10.1164/ajrccm.166.1.at1102Dass S, Rawstron AC, Vital EM, et al. Highly sensitive B cell analysis predicts response to rituximab therapy in rheumatoid arthritis. Arthritis Rheum. 2008;58:2993-9. doi: 10.1002/art.23902Dass S, Rawstron AC, Vital EM, et al. Highly sensitive B cell analysis predicts response to rituximab therapy in rheumatoid arthritis. Arthritis Rheum. 2008;58:2993-9. doi: 10.1002/art.23902Kowal-Bielecka O, Landewe R, Avouac J, et al. EULAR recommendations for the treatment of systemic sclerosis a report from the EULAR Scleroderma Trials and Research group (EUSTAR). Ann Rheum Dis. 2009;68(5):620-9. doi: 10.1136/ard.2008.096677Kowal-Bielecka O, Landewe R, Avouac J, et al. EULAR recommendations for the treatment of systemic sclerosis a report from the EULAR Scleroderma Trials and Research group (EUSTAR). Ann Rheum Dis. 2009;68(5):620-9. doi: 10.1136/ard.2008.096677Khanna D, Distler JHW, Sandner P, et al. Emerging strategies for treatment of systemic sclerosis. J Scleroderma Relat Disord. 2016;1:186-93. doi: 10.5301/jsrd.5000207Khanna D, Distler JHW, Sandner P, et al. Emerging strategies for treatment of systemic sclerosis. J Scleroderma Relat Disord. 2016;1:186-93. doi: 10.5301/jsrd.5000207Sakkas LI, Bogdanos DP. Systemic sclerosis: New evidence reinforces the role of B cells. Autoimmune Rev. 2016;15:155-61. doi: 10.1016/j.autrev.2015.10.005Sakkas LI, Bogdanos DP. Systemic sclerosis: New evidence reinforces the role of B cells. Autoimmune Rev. 2016;15:155-61. doi: 10.1016/j.autrev.2015.10.005Daoussis D, Liossis SN, Tsamandas AC, et al. Effect of long-term treatment with rituximab on pulmonary function and skin fibrosis in patients with diffuse systemic sclerosis. Clin Exp Rheumatol. 2012;30(2 Suppl 71):17-22.Daoussis D, Liossis SN, Tsamandas AC, et al. Effect of long-term treatment with rituximab on pulmonary function and skin fibrosis in patients with diffuse systemic sclerosis. Clin Exp Rheumatol. 2012;30(2 Suppl 71):17-22.Jordan S, Distler JH, Maurer B, et al; EUSTAR Rituximab study group. Effects and safety of rituximab in systemic sclerosis: an analysis from the European Scleroderma Trial and Research (EUSTAR) group. Ann Rheum Dis. 201;74(6):1188-94. doi: 10.1136/annrheumdis-2013-204522Jordan S, Distler JH, Maurer B, et al; EUSTAR Rituximab study group. Effects and safety of rituximab in systemic sclerosis: an analysis from the European Scleroderma Trial and Research (EUSTAR) group. Ann Rheum Dis. 201;74(6):1188-94. doi: 10.1136/annrheumdis-2013-204522Lepri G, Avouac J, Airo P, et al. Effects of rituximab in connective tissue disorders related interstitial lung disease. Clin Exp Rheumatol. 2016;34 Suppl 100(5):181-5.Lepri G, Avouac J, Airo P, et al. Effects of rituximab in connective tissue disorders related interstitial lung disease. Clin Exp Rheumatol. 2016;34 Suppl 100(5):181-5.Boonstra M, Meijs J, Dorjee AL, Marsan NA. Rituximab in early systemic sclerosis. RMD Open. 2017;3(2):384. doi: 10.1136/rmdopen-2016-000384. eCollection 2017.Boonstra M, Meijs J, Dorjee AL, Marsan NA. Rituximab in early systemic sclerosis. RMD Open. 2017;3(2):384. doi: 10.1136/rmdopen-2016-000384. eCollection 2017.Bosello SL, De Luca G, Rucco M, et al. Long-term efficacy of B cell depletion therapy on lung and skin involvement in diffuse systemic sclerosis. Semin Arthritis Rheum. 2015;44(4):428-36.Bosello SL, De Luca G, Rucco M, et al. Long-term efficacy of B cell depletion therapy on lung and skin involvement in diffuse systemic sclerosis. Semin Arthritis Rheum. 2015;44(4):428-36.Daoussis D, Melissaropoulos K, Sakellaropoulos G, et al. A multicenter, open-label, comparative study of B-cell depletion therapy with Rituximab for systemic sclerosis-associated interstitial lung disease. Semin Arthritis Rheum. 2017;46(5):625-31.Daoussis D, Melissaropoulos K, Sakellaropoulos G, et al. A multicenter, open-label, comparative study of B-cell depletion therapy with Rituximab for systemic sclerosis-associated interstitial lung disease. Semin Arthritis Rheum. 2017;46(5):625-31.Adler S, Huscher D, Siegert E, et al. Systemic sclerosis associated interstitial lung disease – individualized immunosuppressive therapy and course of lung function: results of the EUSTAR group. Arthritis Res Ther. 2018;20:17. doi: 10.1186/s13075-018-1517Adler S, Huscher D, Siegert E, et al. Systemic sclerosis associated interstitial lung disease – individualized immunosuppressive therapy and course of lung function: results of the EUSTAR group. Arthritis Res Ther. 2018;20:17. doi: 10.1186/s13075-018-1517Lee JJ, Pope JE. Diagnosis and management of systemic sclerosis: a practical approach. Drug. 2016;76:203-13. doi: 10.1007/s40265-015-0491-xLee JJ, Pope JE. Diagnosis and management of systemic sclerosis: a practical approach. Drug. 2016;76:203-13. doi: 10.1007/s40265-015-0491-xSchioppo T, Ingegnoli F. Current perspective on rituximab in rheumatic diseases. Drug Des Devel Ther. 2017;11:2891-904. doi: 10.2147/DDDT.S139248Schioppo T, Ingegnoli F. Current perspective on rituximab in rheumatic diseases. Drug Des Devel Ther. 2017;11:2891-904. doi: 10.2147/DDDT.S139248Насонов ЕЛ, редактор. Российские клинические рекоменда- ции. Ревматология. Москва: ГЭОТАР-Медиа; 2017. 464 с. [Nasonov EL, editor. Rossiiskie klinicheskie rekomendatsii. Revmatologiya. [Russian clinical guidelines. Rheumatology]. Moscow: GEOTAR-Media; 2017. 464 p. (In Russ.)].Насонов ЕЛ, редактор. Российские клинические рекоменда- ции. Ревматология. Москва: ГЭОТАР-Медиа; 2017. 464 с. [Nasonov EL, editor. Rossiiskie klinicheskie rekomendatsii. Revmatologiya. [Russian clinical guidelines. Rheumatology]. Moscow: GEOTAR-Media; 2017. 464 p. (In Russ.)].Merkel PA, Silliman NP, Clements P, et al. Patterns and predictors of change in outcome measures in clinical trials in scleroderma: an individual patient meta-analysis of 629 subjects with diffuse cutaneous systemic sclerosis. Arthritis Rheum. 2012;64:3420-9. doi: 10.1002/art.34427Merkel PA, Silliman NP, Clements P, et al. Patterns and predictors of change in outcome measures in clinical trials in scleroderma: an individual patient meta-analysis of 629 subjects with diffuse cutaneous systemic sclerosis. Arthritis Rheum. 2012;64:3420-9. doi: 10.1002/art.34427Penn H, Howie AJ, Kingdon EJ, et al. Scleroderma renal crisis: patient characteristics and long-term outcomes. QJM. 2007;100:485-94. doi: 10.1093/qjmed/hcm052Penn H, Howie AJ, Kingdon EJ, et al. Scleroderma renal crisis: patient characteristics and long-term outcomes. QJM. 2007;100:485-94. doi: 10.1093/qjmed/hcm052Thiebaut M, Launay D, Riviere S, et al. Efficacy and safety of rituximab in systemic sclerosis: French retrospective study and literature review. Autoimmun Rev. 2018;17(6):582-7. doi: 10.1016/j.autrev.2017.12.010Thiebaut M, Launay D, Riviere S, et al. Efficacy and safety of rituximab in systemic sclerosis: French retrospective study and literature review. Autoimmun Rev. 2018;17(6):582-7. doi: 10.1016/j.autrev.2017.12.010Hoyles RK, Ellis RW, Wellsbury J, et al. A multicenter, prospective, randomized, double-blind, placebo-controlled trail of corticosteroids and intravenous cyclophosphamide followed by oral azathioprine for treatment of pulmonary fibrosis in scleroderma. Arthritis Rheum. 2006;54(12):3962-70. doi: 10.1002/art.22204Hoyles RK, Ellis RW, Wellsbury J, et al. A multicenter, prospective, randomized, double-blind, placebo-controlled trail of corticosteroids and intravenous cyclophosphamide followed by oral azathioprine for treatment of pulmonary fibrosis in scleroderma. Arthritis Rheum. 2006;54(12):3962-70. doi: 10.1002/art.22204Tashkin DP, Elashoff R, Clements PJ, et al. Cyclophosphamide versus placebo in scleroderma lung disease. N Eng J Med. 2006;354(25):2655-66. doi: 10.1056/NEJMoa055120Tashkin DP, Elashoff R, Clements PJ, et al. Cyclophosphamide versus placebo in scleroderma lung disease. N Eng J Med. 2006;354(25):2655-66. doi: 10.1056/NEJMoa055120Tashkin DP, Roth MD, Clements PJ, et al. Mycophenolate Mofetil versus Oral Cyclophosphamide in Scleroderma-related Interstitial Lung Disease: Scleroderma Lung Study II (SLS-II), a doubleblind, parallel group, randomized controlled trial. Lancet Respir Med. 2016;4(9):708-19. doi: 10.1016/S2213-2600(16)30152-7Tashkin DP, Roth MD, Clements PJ, et al. Mycophenolate Mofetil versus Oral Cyclophosphamide in Scleroderma-related Interstitial Lung Disease: Scleroderma Lung Study II (SLS-II), a doubleblind, parallel group, randomized controlled trial. Lancet Respir Med. 2016;4(9):708-19. doi: 10.1016/S2213-2600(16)30152-7Morgan C, Knight C, Lunt M, et al. Predictors of end stage lung disease in a cohort of patients with scleroderma. Ann Rheum Dis. 2003;62:146-50. doi: 10.1136/ard.62.2.146Morgan C, Knight C, Lunt M, et al. Predictors of end stage lung disease in a cohort of patients with scleroderma. Ann Rheum Dis. 2003;62:146-50. doi: 10.1136/ard.62.2.146Bouros D, Wells AU, Nicholson AG, et al. Histopathologic subsets of fibrosing alveolitis in patients with systemic sclerosis and their relationship to outcome. Am J Respir Crit Care Med. 2002;165:1581-6. doi: 10.1164/rccm.2106012Bouros D, Wells AU, Nicholson AG, et al. Histopathologic subsets of fibrosing alveolitis in patients with systemic sclerosis and their relationship to outcome. Am J Respir Crit Care Med. 2002;165:1581-6. doi: 10.1164/rccm.2106012Colp CR, Riker J, Williams MH Jr. Serial changes in scleroderma and idiopathic interstitial lung disease. Arch Intern Med. 1973;132(4):506-15. doi: 10.1001/archinte.1973.03650100028006Colp CR, Riker J, Williams MH Jr. Serial changes in scleroderma and idiopathic interstitial lung disease. Arch Intern Med. 1973;132(4):506-15. doi: 10.1001/archinte.1973.03650100028006Greenwald GI, Tashkin DP, Gong H, et al. Longitudinal changes in lung function and respiratory symptoms in progressive systemic sclerosis. Prospective study. Am J Med. 1987;83(1):83-92. doi: 10.1016/0002-9343(87)90501-8Greenwald GI, Tashkin DP, Gong H, et al. Longitudinal changes in lung function and respiratory symptoms in progressive systemic sclerosis. Prospective study. Am J Med. 1987;83(1):83-92. doi: 10.1016/0002-9343(87)90501-8Schneider PD, Wise RA, Hochberg MC, Wigley FM. Serial pulmonary function in systemic sclerosis. Am J Med. 1982;73:385-94. doi: 10.1016/0002-9343(82)90732-XSchneider PD, Wise RA, Hochberg MC, Wigley FM. Serial pulmonary function in systemic sclerosis. Am J Med. 1982;73:385-94. doi: 10.1016/0002-9343(82)90732-XSteen VD, Conte C, Owens GR, Medsger TA Jr. Severe restrictive lung disease in systemic sclerosis. Arthritis Rheum. 1994;37:1283-9. doi: 10.1002/art.1780370903Steen VD, Conte C, Owens GR, Medsger TA Jr. Severe restrictive lung disease in systemic sclerosis. Arthritis Rheum. 1994;37:1283-9. doi: 10.1002/art.1780370903Assassi S, Sharif R, Lasky RE, et al. Predictors of interstitial lung disease in early systemic sclerosis: a prospective longitudinal study of the GENISOS cohort. Arthritis Res Ther. 2010;12:166. doi: 10.1186/ar3125Assassi S, Sharif R, Lasky RE, et al. Predictors of interstitial lung disease in early systemic sclerosis: a prospective longitudinal study of the GENISOS cohort. Arthritis Res Ther. 2010;12:166. doi: 10.1186/ar3125Man A, Davidyock T, Ferguson LT, et al. Changes in forced vital capacity over time in systemic sclerosis: application of group-based trajectory modelling. Rheumatology (Oxford). 2015;54(8):1464-71. doi: 10.1093/rheumatology/kev016Man A, Davidyock T, Ferguson LT, et al. Changes in forced vital capacity over time in systemic sclerosis: application of group-based trajectory modelling. Rheumatology (Oxford). 2015;54(8):1464-71. doi: 10.1093/rheumatology/kev016Khanna D, Tseng CH, Farmani N, et al. Clinical course of lung physiology in patients with scleroderma and interstitial lung disease: analysis of the Scleroderma Lung Study Placebo Group. Arthritis Rheum. 2011;63(10):3078-85. doi: 10.1002/art.30467Khanna D, Tseng CH, Farmani N, et al. Clinical course of lung physiology in patients with scleroderma and interstitial lung disease: analysis of the Scleroderma Lung Study Placebo Group. Arthritis Rheum. 2011;63(10):3078-85. doi: 10.1002/art.30467Fernandez-Codina A, Walker KM, Pope JE. Scleroderma Algorithm Group. Treatment Algorithms for Systemic Sclerosis According to Experts. Arthritis Rheum. 2018;70(11):1820-8. doi: 10.1002/art.40560. Epub 2018 Sep 17.Fernandez-Codina A, Walker KM, Pope JE. Scleroderma Algorithm Group. Treatment Algorithms for Systemic Sclerosis According to Experts. Arthritis Rheum. 2018;70(11):1820-8. doi: 10.1002/art.40560. Epub 2018 Sep 17.Kowal-Bielecka O, Fransen J, Avouac J, et al. Update of EULAR recommendations for the treatment of systemic sclerosis. Ann Rheum Dis. 2017;76(8):1327-39. doi: 10.1136/annrheumdis-2016-209909Kowal-Bielecka O, Fransen J, Avouac J, et al. Update of EULAR recommendations for the treatment of systemic sclerosis. Ann Rheum Dis. 2017;76(8):1327-39. doi: 10.1136/annrheumdis-2016-209909Saunders P, Tsipouri V, Keir GJ, et al. Rituximab versus cyclophosphamide for the treatment of connective tissue disease associated interstitial lung disease (RECITAL): study protocol for a randomized controlled trial. Trials. 2017;18:275-86. doi: 10.1186/s13063-017-2016-2Saunders P, Tsipouri V, Keir GJ, et al. Rituximab versus cyclophosphamide for the treatment of connective tissue disease associated interstitial lung disease (RECITAL): study protocol for a randomized controlled trial. Trials. 2017;18:275-86. doi: 10.1186/s13063-017-2016-2

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