Заболевания, протекающие с увеличением больших слюнных желез, поражением органов орбит, носа и придаточных пазух в практике ревматолога

Objective: to analyze the nosological spectrum, demographic, clinical and laboratory characteristics of diseases with a significant enlargementof major salivary (SG) / lacrimal glands, and/or accessory organs of the eye and paranasal sinuses lesions in rheumatological practice.Patients and methods. This work includes 73 patients who underwent a complex clinical and laboratory, imaging, pathomorphological and histomolecular examination, which was necessary to establish a nosological diagnosis. In all cases, the diagnosis was confirmed pathomorphologically.Results and discussion. Sjogren's syndrome (SjS) was diagnosed in 30 (41%) patients (14 of them developed lymphoproliferative disorder, LPD, as a complication), granulomatosis with polyangiitis (GPA) – in 12 (16.4%), IgG4-related disease (IgG4-RD) – in 10 (13.7%), sarcoidosis – in 6 (8.2%), non Langerhans cell histiocytosis – in 2 (2.7%), AL-amyloidosis – in 1 (1.4%), Warthin's tumor – in 1 (1.4%), chronic atrophic rhinitis – in 1 (1.4%), infectious lesions – in 3 (4.1%) (HIV-associated – in 2, dirofilariasis – in 1), idiopathic inflammatory pseudotumor – in 6 (8.2%). In 1 (1.4%) patient, the diagnosis could not be established.A massive increase of major SG was observed in 46 patients, more often (in 28 cases) with SjS with LPD or without it, with IgG4-RD (in 7) and sarcoidosis (in 6). Orbital lesions were observed in 18 patients: in 7 with IgG4-RD, in 5 with idiopathic inflammatory pseudotumor, in 2 with sarcoidosis, in 2 with GPA, and in 1 each with non Langerhans cell histiocytosis and dirofilariasis. Nasal lesions in the form of chronic rhinosinusitis with or without nasal septum perforation, were found in 18 patients, 12 of whom suffered GPA and 6 – IgG4-RD.Two algorithms, that can facilitate the choice of additional studies and the direction of diagnostic search have been proposed for practicing rheumatologists.Conclusion. Taking into account the possible similarity of clinical manifestations of the diseases with the formation of mass-like tissue, the differential diagnosis should be based on pathomorphological study.Цель исследования – анализ нозологического спектра, а также демографичеcких и клинико-лабораторных особенностей заболеваний, протекающих со значительным увеличением больших слюнных (СЖ) / слезных желез, поражением придаточного аппарата глаза и параназальных синусов в ревматологической практике.Пациенты и методы. В настоящую работу включено 73 пациента, которым проведено комплексное клинико-лабораторное, визуализационное, патоморфологическое и гистомолекулярное исследование, необходимое для установления нозологического диагноза. Во всех случаях диагноз подтвержден патоморфологически.Результаты и обсуждение. Болезнь Шёгрена (БШ) диагностирована у 30 (41%) пациентов (у 14 из них возникло осложнение в виде лимфопролиферативного заболевания, ЛПЗ), гранулематоз с полиангиитом (ГПА) – у 12 (16,4%), IgG4-связанное заболевание (JgG4-СЗ) – у 10 (13,7%), саркоидоз – у 6 (8,2%), нелангергансоклеточный гистиоцитоз – у 2 (2,7%), AL-амилоидоз – у 1 (1,4%), опухоль Уортина – у 1 (1,4%), хронический атрофический ринит – у 1 (1,4%), инфекционные поражения – у 3 (4,1%; ВИЧ-ассоциированное – у 2, дирофиляриоз – у 1), идиопатический воспалительный псевдотумор – у 6 (8,2%). У 1 (1,4%) больной диагноз установить не удалось.Массивное увеличение больших СЖ имелось у 46 пациентов, чаще (в 28 случаях) при БШ с ЛПЗ или без него, при IgG4-CЗ (в 7) и саркоидозе (в 6). Поражение орбит отмечалось у 18 пациентов: у 7 – с IgG4-CЗ, у 5 – с идиопатическим воспалительным псевдотумором, у 2 – с саркоидозом, еще у 2 – с ГПА и по 1 – с нелангергансоклеточным гистиоцитозом и дирофиляриозом. Поражение носа в виде хронического риносинусита выявлено у 18 пациентов с перфорацией носовой перегородки или без нее, 12 из которых страдали ГПА и 6 – IgG4-CЗ.На основании анализа нозологий, проявляющихся увеличением больших СЖ, органов орбит и поражением ЛОР-органов, предложено два алгоритма, которые могут облегчить выбор дополнительных исследований и направление диагностического поиска для практикующих ревматологов.Заключение. Учитывая возможную схожесть клинических проявлений заболеваний, протекающих с формированием «плюс»-ткани, основой их дифференциальной диагностики должно быть патоморфологическое исследование

Трансформированный вариант диффузной В-клеточной крупноклеточной лимфомы желудка у пациентки с сочетанием болезни Шегрена и системной склеродермии (описание случая и обзор литературы)

This article describes a case of a transformed diffuse large B-cell lymphoma of the stomach in a patient with Sjogren’s disease (SjD) and systemic sclerosis (SSc), as well as a brief review of the literature on lymphoproliferative diseases in SjD and SSc.Представлены описание случая трансформированного варианта диффузной В-клеточной крупноклеточной лимфомы желудка у пациентки с болезнью Шегрена (БШ) и лимитированной системной склеродермией (ССД), а также краткий обзор литературы, посвященной лимфопролиферативным заболеваниям при БШ и ССД. Обсуждаются связи между указанными состояниями

Характеристика клинических, лабораторных и иммунологических проявлений у пациентов с болезнью Шёгрена, ассоциированной с антицентромерными антителами

Objective: to study clinical and laboratory features in patients with anticentromere antibody (ACA)-positive SjЪgren's disease (SD), as well as the sensitivity of different methods for determination of ACA, and to elaborate an algorithm for differential diagnosis in ACA-positive patients.Patients and methods. The V.A. Nasonova Research Institute of Rheumatology followed up 136 patients who were highly positive for ACA. The investigators used the 2001 Russian criteria for the diagnosis for SD; the 2013 ACR/European League Against Rheumatism (EULAR) criteria for that of scleroderma systematica (SDS); the guidelines of the American Association for the Study of Liver Diseases, the Russian Gastroenterological Association, and the Russian Society for the Study of the Liver for that of primary biliary cholangitis (PBC)/biliary duct epitheliitis in the presence of SD. Lymphomas were diagnosed by biopsies of affected organs according to the WHO classification. SD was diagnosed in 119 patients; SDS in 49 cases (37 with SDS concurrent with SD and 12 with isolated SDS), PBC/biliary duct epitheliitis in 23 (all cases with PBC/biliary duct epitheliitis concurrent with SD and/or SDS); 5 patients were excluded from the investigation. Further analysis included 131 ACA-positive patients. The patients were divided into three groups: SD (n=82 or 62.6%); SD+SDS (n=37 or 28.24%); SDS (n=12 or 9.16%).Results and discussion. Autoantibodies to centromere peptide (CENP) A and CENP-B in the same titers were detected in all ACA-positive patients, regardless of diagnosis. Comparative analysis of three patient groups revealed no statistically significant differences in the frequency of laboratory deviations. The signs characteristic of classical SD (rheumatoid factor (RF)), anti-Ro and anti-La antibodies, leukopenia, higher ESR values, hypergammaglobulinemia, and elevated IgG/IgA levels) were found in a small proportion of patients. The frequency and severity of glandular manifestations did not differ in SD and SD + SDS. PBC/biliary duct epitheliitis was present in 17.5% of ACA-positive patients (in most antimitochondrial antibody-positive cases); no statistically significant differences in its frequency were found between the groups. Other extraglandular manifestations in SD and SD + SDS were identified in a smaller number of patients. All sclerodermic spectrum manifestations were more common in SD and SD + SDS than in BS. Pulmonary arterial hypertension was not diagnosed in any patient from the SD group. MALT lymphomas were detected in 19 ACA-positive patients. Those were present only in BS patients and absent in the SDS group. MALT lymphomas developed in the first 10 years after the onset of SD. The transformation of MALT lymphoma into diffuse large B-cell lymphoma was observed in 2 patients. The main signs of lymphomas in SD patients were persistent parotid salivary gland enlargement, decreased levels of complement C4 and peripheral blood CD19+ cells, as well as cryoglobulinemic vasculitis, serum monoclonal secretion, lymphoid infiltration in the minor salivary glands (a focus score of >4), and severe damage to the salivary and lacrimal glands.Conclusion. ACA-associated SD is an independent disease subtype characterized by an increased risk for SDS, PBC, and MALT lymphomas and by a low frequency of the systemic manifestations and laboratory signs characteristic of classical SD. Regardless of the detected type of antibodies and the presence or absence of extraglandular manifestations, damage to the salivary and lacrimal glands progresses in SD, which often leads to lymphomas; therefore, the therapy that may prevent this complication should be initiated as soon as possible after SD diagnosis. The lymphoproliferation signs identified in this investigation should be taken into account in all ACA-positive patients with SD for the early diagnosis of lymphoid tumors before therapy is prescribed. An algorithm for differential diagnosis in seropositivity for ACA is presented. Determination of autoantibodies to CENP-A and CENP-B does not allow the differential diagnosis in ACA-positive patients.Цель исследования – изучение клинических и лабораторных особенностей у пациентов с болезнью Шёгрена (БШ), позитивных по антицентромерным антителам (АЦА), а также чувствительности разных методов определения АЦА, разработка алгоритма дифференциальной диагностики у АЦА-позитивных пациентов.Пациенты и методы. В ФГБНУ «Научно-исследовательский институт ревматологии им. В.А. Насоновой» под наблюдением находилось 136 высокопозитивных по АЦА пациентов. Для диагностики БШ использовались отечественные критерии 2001 г., системной склеродермии (ССД) – критерии ACR/EULAR 2013 г., первичного билиарного холангита (ПБХ)/эпителиита билиарных протоков в рамках БШ – рекомендации Американской ассоциации по изучению заболеваний печени, Российской гастроэнтерологической ассоциации и Российского общества по изучению печени. Диагностика лимфом осуществлялась на основании исследований биоптатов пораженных органов согласно классификации ВОЗ. БШ диагностирована у 119 пациентов, ССД – у 49 (у 37 в сочетании с БШ и у 12 – изолированная ССД), ПБХ/эпителиит билиарных протоков – у 23 (во всех случаях в сочетании с БШ и/или ССД), 5 пациентов были исключены из исследования. В дальнейший анализ вошел 131 АЦА-позитивный пациент. Больные были разделены на три группы: БШ (n=82, или 62,6%); БШ + ССД (n=37, или 28,24%); ССД (n=12, или 9,16%).Результаты и обсуждение. Аутоантитела к центромерному пептиду (CENP) A и CENP-B в одинаковых титрах выявлены у всех АЦА-позитивных пациентов независимо от диагноза. При сравнительном анализе трех групп пациентов статистически значимых различий в частоте лабораторных отклонений не выявлено. Характерные для классической БШ признаки – ревматоидный фактор (РФ), антитела к Ro и La, лейкопения, повышение СОЭ, гипергаммаглобулинемия, увеличение уровня IgG/IgA – обнаружены у незначительной части пациентов. Частота и выраженность железистых проявлений при БШ и БШ + ССД не различались. ПБХ/эпителиит билиарных протоков имелся у 17,5% АЦА-позитивных пациентов (в большинстве случаев позитивных по антимитохондриальным антителам), статистически значимых различий в его частоте между группами не обнаружено. Другие внежелезистые проявления при БШ и БШ + ССД выявлены у меньшего числа пациентов. Все проявления склеродермического спектра при ССД и БШ + ССД встречались чаще, чем при БШ. Легочная артериальная гипертензия не диагностирована ни у одного пациента из группы БШ. MALT-лимфомы обнаружены у 19 АЦА-позитивных пациентов. Они встречались только у пациентов с БШ, в группе ССД лимфом не было. MALT-лимфомы развивались в первые 10 лет после начала БШ. Трансформация MALT-лимфомы в диффузную В-клеточную крупноклеточную лимфому наблюдалась у 2 пациентов. Основными признаками лимфом у пациентов с БШ были: стойкое увеличение околоушных слюнных желез, снижение уровня С4-компонента комплемента, а также CD19+ клеток в периферической крови, криоглобулинемический васкулит, моноклональная секреция в сыворотке крови, лимфоидная инфильтрация малых слюнных желез >4 фокуса, а также тяжелое поражение слюнных и слезных желез.Заключение. БШ, ассоциированная с АЦА, является самостоятельным субтипом заболевания, отличающимся повышенным риском возникновения ССД, ПБХ и MALT-лимфом, низкой частотой характерных для классической БШ системных проявлений и лабораторных признаков. При БШ, независимо от выявляемого типа антител и наличия или отсутствия внежелезистых проявлений, прогрессирует поражение слюнных и слезных желез, что нередко приводит к развитию лимфом, поэтому терапия, способная предотвратить возникновение данного осложнения, должна быть инициирована сразу после установления диагноза БШ. Выявленные в настоящем исследовании признаки лимфопролиферации должны учитываться у всех АЦА-позитивных пациентов с БШ для ранней диагностики лимфоидных опухолей до назначения терапии. Приведен алгоритм дифференциальной диагностики при серопозитивности по АЦА. Определение аутоантител к CENP-A и CENP-B не позволяет осуществлять дифференциальную диагностику у АЦА-позитивных пациентов

Синдром VEXAS: на рубеже смены представлений об известных заболеваниях

This article presents the first case of VEXAS syndrome identified in the Russian Federation as well as characteristics of currently known clinical manifestations and treatment approaches. The clinical observation described is an impressive example of how the identification of a new pathogenic mutation can change the understanding of the classification, diagnosis and treatment of previously known immunoinflammatory diseases. Thus, in refractory forms of relapsing polychondritis, neutrophilic dermatosis, atypical forms of vasculitis, inflammatory joint diseases or undifferentiated systemic inflammatory syndrome, especially when associated with macrocytic anemia and myelodysplastic syndrome, VEXAS syndrome should be suspected and genetic testing should be performed to exclude the autoinflammatory nature of the existing condition.В статье приведен первый случай синдрома VEXAS, выявленный в Российской Федерации, а также характеристика известных на настоящий момент клинических проявлений и подходов к его терапии. Описанное клиническое наблюдение является ярким примером того, как выявление новой патогенной мутации может изменить представление о классификации, диагностике и терапии ранее известных иммуновоспалительных заболеваний. Так, при рефрактерных формах рецидивирующего полихондрита, нейтрофильного дерматоза, нетипичных формах васкулита, воспалительных заболеваний суставов или недифференцированном системном воспалительном синдроме, особенно при ассоциации с макроцитарной анемией и миелодиспластическим синдромом, необходима настороженность в отношении синдрома VEXAS и проведение генетического исследования для исключения аутовоспалительной природы имеющегося состояния

PRIMARY SJOGREN'S SYNDROME ASSOCIATED WITH ANTICENTROMERE ANTIBODIES

Anti-centromere antibody (ANCA) seropositivity is generally regarded by rheumatologists as a sign of systemic sclerosis (SS) in clinical practice. However, the literature describes many cases of ANCA-associated primary Sjogren's syndrome (PSS) that is the subtype of this disease, which differs from the classic type in a number of laboratory and clinical manifestations. According to the literature, even a long-term follow-up indicates that only one quarter of patients with ANCA-positive PSS develop documented SS. This fact raises the question of whether it is necessary to include ANCA into the list of autoantibodies pathogenetically related to PSS

CLINICAL AND LABORATORY FEATURES OF ANTICENTROMERE ANTIBODY-POSITIVE SJö GREN’S SYNDROME

Objective: to study the clinical and laboratory features of patients with anticentromere antibody (ACA) positive Sjö gren’s syndrome (SjS); to assess the spectrum of autoantibodies in patients of this group; to determine the frequency with which the SjS patients who are highly positive for ACA, meet the international classification criteria for SjS and systemic sclerosis (SS); to reveal the incidence of MALT lymphomas in this patient group; to estimate the incidence of primary biliary cirrhosis (PBC)/biliary lesions as part of autoimmune epithelitis in SjS in this patient group.Material and methods. A total of 83 patients with ACA positive SjS were comprehensively examined at the V.A. Nasonova Research Institute of Rheumatology during the period 2012 to 2018. The inclusion criteria were con formity to the 2001 Russian SjS criteria and a high ACA level. MALT lymphomas were diagnosed on the basis of histological and immunohistochemical studies and polymerase chain reaction-based determination of B-cell clonality in the biopsy samples of affected organs according to the World Health Organization classification of Hematopoietic Tumors. The diagnosis of PBC/biliary lesions was made on the basis of histological and immunohistochemical studies of liver biopsy specimens.Results and discussion. The investigation revealed low detection rates for anti-Ro antibodies (32.5%), anti-La antibodies (7.2%) and rheumatoid factor (RF) (21.7%), which were typical for the classical SjS immunophenotype), increased ESR (14%), leukopenia (7%), hypergammaglobulinemia (17.6%), elevated levels of IgG (9.5%) and IgA (18.7%), and hypocomplementemia (16.1%) in the ACA positive SjS patients. Despite the low detection rate of RF, 15 (18%) patients in this group developed MALT lymphomas: 14 patients had salivary gland MALT lymphoma and one patient had tonsil MALT lymphoma with peripheral lymph node involvement (generalized marginal zone lymphoma). Also, the patients of this group showed high detection rates for AMA antibodies (34.6%), increased IgM level (29.7%) and a higher risk for PBC/biliary lesions as a manifestation of autoimmune epithelitis in SjS (14.5%). AMA-antibodies were absent in only two patients who were diagnosed with liver disease according to biopsy specimens. Nervous system and renal lesions, antiphospholipid syndrome, rheumatoid arthritis, hypergammaglobulinemic purpura, and cryoglobulinemic vasculitis were much less common and sporadic. Also ACA-positive SjS patients often have Raynaud’s phenomenon (54.9%) with scleroderma-type capillaroscopic changes (68%) and a limited form of SS (24%) according to the 2013 ACR criteria.Conclusion. ACA-positive SjS is a subtype of the disease, which is significantly different from the classic one in a number of clinical and laboratory signs and characterized by an increased risk for SS, MALT lymphomas, and PBC/biliary lesions as a manifestation of autoimmune epithelitis in SjS which in some cases leads to the underdiagnosis of SjS. ACA should be considered as pathogenetically related to SjS autoantibodies; and all patients who are seropositive for ACA should be examined for SjS and PBC/biliary lesions as a manifestation of autoimmune epithelitis in SjS regardless of whether they have SS or not, as well as complaints of dry mouth and eyes. Patients with significantly enlarged salivary glands should undergo biopsy to rule out or confirm MALT lymphoma before initiating hormonal, antilymphoproliferative, and anti-B-cell therapy

Characteristics of clinical, laboratory, and immunological manifestations in patients with anticentromere antibody-associated Sjögren's disease

Objective: to study clinical and laboratory features in patients with anticentromere antibody (ACA)-positive SjЪgren's disease (SD), as well as the sensitivity of different methods for determination of ACA, and to elaborate an algorithm for differential diagnosis in ACA-positive patients.Patients and methods. The V.A. Nasonova Research Institute of Rheumatology followed up 136 patients who were highly positive for ACA. The investigators used the 2001 Russian criteria for the diagnosis for SD; the 2013 ACR/European League Against Rheumatism (EULAR) criteria for that of scleroderma systematica (SDS); the guidelines of the American Association for the Study of Liver Diseases, the Russian Gastroenterological Association, and the Russian Society for the Study of the Liver for that of primary biliary cholangitis (PBC)/biliary duct epitheliitis in the presence of SD. Lymphomas were diagnosed by biopsies of affected organs according to the WHO classification. SD was diagnosed in 119 patients; SDS in 49 cases (37 with SDS concurrent with SD and 12 with isolated SDS), PBC/biliary duct epitheliitis in 23 (all cases with PBC/biliary duct epitheliitis concurrent with SD and/or SDS); 5 patients were excluded from the investigation. Further analysis included 131 ACA-positive patients. The patients were divided into three groups: SD (n=82 or 62.6%); SD+SDS (n=37 or 28.24%); SDS (n=12 or 9.16%).Results and discussion. Autoantibodies to centromere peptide (CENP) A and CENP-B in the same titers were detected in all ACA-positive patients, regardless of diagnosis. Comparative analysis of three patient groups revealed no statistically significant differences in the frequency of laboratory deviations. The signs characteristic of classical SD (rheumatoid factor (RF)), anti-Ro and anti-La antibodies, leukopenia, higher ESR values, hypergammaglobulinemia, and elevated IgG/IgA levels) were found in a small proportion of patients. The frequency and severity of glandular manifestations did not differ in SD and SD + SDS. PBC/biliary duct epitheliitis was present in 17.5% of ACA-positive patients (in most antimitochondrial antibody-positive cases); no statistically significant differences in its frequency were found between the groups. Other extraglandular manifestations in SD and SD + SDS were identified in a smaller number of patients. All sclerodermic spectrum manifestations were more common in SD and SD + SDS than in BS. Pulmonary arterial hypertension was not diagnosed in any patient from the SD group. MALT lymphomas were detected in 19 ACA-positive patients. Those were present only in BS patients and absent in the SDS group. MALT lymphomas developed in the first 10 years after the onset of SD. The transformation of MALT lymphoma into diffuse large B-cell lymphoma was observed in 2 patients. The main signs of lymphomas in SD patients were persistent parotid salivary gland enlargement, decreased levels of complement C4 and peripheral blood CD19+ cells, as well as cryoglobulinemic vasculitis, serum monoclonal secretion, lymphoid infiltration in the minor salivary glands (a focus score of >4), and severe damage to the salivary and lacrimal glands.Conclusion. ACA-associated SD is an independent disease subtype characterized by an increased risk for SDS, PBC, and MALT lymphomas and by a low frequency of the systemic manifestations and laboratory signs characteristic of classical SD. Regardless of the detected type of antibodies and the presence or absence of extraglandular manifestations, damage to the salivary and lacrimal glands progresses in SD, which often leads to lymphomas; therefore, the therapy that may prevent this complication should be initiated as soon as possible after SD diagnosis. The lymphoproliferation signs identified in this investigation should be taken into account in all ACA-positive patients with SD for the early diagnosis of lymphoid tumors before therapy is prescribed. An algorithm for differential diagnosis in seropositivity for ACA is presented. Determination of autoantibodies to CENP-A and CENP-B does not allow the differential diagnosis in ACA-positive patients