Повреждение легких при антифосфолипидном синдроме

Functional lesions of organs depend on the size of a diseased vessel and frequently require the use of intensive therapy methods. The commonest manifestation of antiphospholipid syndrome (APS) is deep vein thrombosis of the leg and pulmonary thromboembolism (PTE).Objective: to estimate the frequency of lung lesions in primary APS (PAPS), secondary (in the presence of systemic lupus erythematosus (SLE)) and catastrophic APS and to assess a relationship between lung pathology and other clinical and laboratory manifestations of the disease.Subjects and methods. The study covered 372 patients followed up at the Institute of Rheumatology, Russian Academy of Medical Sciences, since 1990, of whom 290 and 82 patients had SLE and PAPS, respectively. Among the 290 patients with SLE, there were 96 males and 194 females. At the moment of the study, the patients’ age was 31.2±11.1 years and the duration of the disease was 8.6±7.2 years. The group of patients with PAPS comprised 20 males and 62 females. Their mean age was 35.6±9.9 years and the duration of the disease was 11.9±8.5 years. Thrombotic events were verified only by instrumental studies. Lung pathology was instrumentally confirmed; all the patients underwent lung X-ray study, if required, scintigraphy and computed tomography.Results. Lung lesion associated with the pathology of vessels was revealed in 28% of the examined patients (105/372). There were prevalent patients with PTE, followed by the development of lung infarcts, which was present in 96 (91%) of the 105 patients with pulmonary vascular pathology. Autopsy revealed pulmonary microangiopathy was in 12 patients, which was concurrent with focal pneumonia in 7 of them, with pneumonitis and exudative pleuritis in 5. Hemorrhagic alveolitis detected at autopsy in combination with occlusions of the pulmonary arterioles was in 3 patients who had been diagnosed as having thromboembolism of small branches of the pulmonary artery. Thrombosis of the pulmonary arterial trunk was detectable in 2 patients, both patients died from respiratory failure. All 105 patients with pulmonary vascular pathology had blood serological markers of APS. There was a combination of elevated levels of aKL and VA in 61% of cases and in 28.5% in the group of patients without pulmonary vascular pathology (OR = 3.92; [2.38-6.48]). The rate of vascular lung pathology increased in the presence of both blood aKL isotopes (IgG and IgM). The number of patients position in both aKL isotopes was 48% whereas in Group 2, that was 19.5% (OR = 3.76; [2.24-6.31]).Conclusion. More than a fourth of the patients with SLE and PAPS have pulmonary vascular pathology. The spectrum of pulmonary vascular diseases in SLE is broad and varies from thrombosis of the pulmonary arterial trunk to occlusive vascular lesion of the microcirculatory bed of the lung, and it is associated with aFL.Функциональные повреждения органов зависят от калибра пораженного сосуда и часто требуют применения методов интенсивной терапии. Наиболее частым проявлением АФС является тромбоз глубоких вен голеней и тромбоэмболии легочных артерий.Цель: оценить частоту поражения легких при первичном АФС, вторичном (на фоне СКВ) и катастрофическом АФС и связь между патологией легких и другими клинико-лабораторными проявлениями заболевания.Материал и методы. В исследование включены 372 больных, наблюдавшихся в Институте ревматологии РАМН с 1990 г., из которых 290 имели СКВ и 82 — ПАФС. Среди больных СКВ 96 из 290 были мужчины и 194 женщины. Возраст больных на момент исследования составлял 31,2±11,1 лет и длительность заболевания 8,6±7,2 лет. Группу больных с ПАФС составляли 20 мужчин и 62 женщины. Средний возраст был 35,6±9,9 лет и длительность заболевания — 11,9±8,5 лет. Тромботические исходы верифицировались только при инструментальном их подтверждении. Легочная патология подтверждалась инструментально, всем больным проводилась рентгенография легких, при необходимости сцинтиграфия и компьютерная томография легких.Результаты. Поражение легких, связанное с патологией сосудов, было выявлено у 28% (105 из 372) обследованных больных. Преобладало число больных с ТЭЛА и последующим развитием инфаркта легких, которая имела место у 96 из 105 (91%) больных c сосудистой патологией легких. Легочная микроанги-опатия была выявлена при аутопсии у 12 больных и у 7 из них она сочеталась с очаговой пневмонией, у 5 — с пневмонитом и экссудативным плевритом. Геморрагический альвеолит, выявленный на аутопсии, в сочетании с окклю-зиями артериол легких — у 3 больных, при жизни у них диагностировалась тромбоэмболия мелких ветвей легочной артерии. Тромбоз ствола легочной артерии определялся у 2 больных, оба пациента умерли из-за легочной недостаточности. Все 105 больных с сосудистой легочной патологией имели в крови серологические маркеры АФС. Сочетание повышенных уровней аКЛ и ВА отмечено в 61% случаев, тогда как в группе больных без сосудистой легочной патологии — в 28,5% (OR=3,92; [2,38—6,48]). Частота сосудистой патологии легких возрастала при наличии в крови обоих изотипов аКЛ (IgG; IgM). Число больных позитивных по обоим изотипам аКЛ в первой группе составило 48%, тогда как во второй — 19,5% (OR=3,76; [2,24—6,31]).Заключение. более одной четверти больных СКВ и ПАФС имеют патологию сосудов легких. Спектр легочной сосудистой патологии СКВ широк и варьирует от тромбоза ствола легочной артерии до окклюзивного поражения сосудов микроциркуляторного русла легких и ассоциируется с аФЛ

Varfarin in the complex treatment of antiphospholipid syndrome: preliminary results

Objective. To assess efficacy and tolerance of varfarin in prophylaxis and therapy of thrombotic complications in patients with antiphospholipid syndrome (APS). Methods. 20 pts with APS (5 male and 15 female) received varfarin during a year. 8 of them had primary APS (PAPS) and 12 -systemic lupus erythematosus with APS (SLE+APS). 2 other pts (I with SLE+APS and I with PAPS) received varfarin during the last 4 years. Nobody from 9 pts with PAPS received corticosteroids (CS). In SLE+APS pts CS dose varied from 4 to 20 mg/day and was not increased during follow up. During the study prothrombine time (PT) was examined with thromboplastin ( manufactured by Renam) having international sensitivity index 1,2 and international normalization relation (INR). Depending on treatment scheme APS pts were divided into 3 groups. Group 1 included 8 pts with INR<2,0, Group 2-7 with INR >3,0, group 3 - 7 pts with INR<2,0 receiving as additional treatment thrombo ASS 100 mg/day and vasonit from 600 to 1200 mg/day. Results. Two pts with INR = 1,8 had thrombosis recurrence (due to leg thrombophlebitis). There were no recurrences in other groups. 2 from 22 pts had "large" bleedings. "Small" bleedings episodes were noted in 7 from 22 pts. Largely that were subcutaneous bleedings (in 4 pts) no more than 5 cm of size. Two pts receiving varfarin with INR 1,8 and 2,4 had renal colic. Conclusion. Our preliminary results prove the necessity of inclusion of varfarin in the treatment of pts with APS and thrombosis but intensive anticoagulant effect is not always desired

VEGFR1 and VEGFR2 Involvement in Extracellular Galectin-1- and Galectin-3-Induced Angiogenesis

Aim:Accumulating evidence suggests that extracellular galectin-1 and galectin-3 promote angiogenesis. Increased expression of galectin-1 and/or galectin-3 has been reported to be associated with tumour progression. Thus, it is critical to identify their influence on angiogenesis.Methods:We examined the individual and combined effects of galectin-1 and galectin-3 on endothelial cell (EC) growth and tube formation using two EC lines, EA.hy926 and HUVEC. The activation of vascular endothelial growth factor receptors (VEGFR1 and VEGFR2) was determined by ELISA and Western blots. We evaluated the VEGFR1 and VEGFR2 levels in endosomes by proximity ligation assay.Results:We observed different responses to exogenous galectins depending on the EC line. An enhanced effect on EA.hy926 cell growth and tube formation was observed when both galectins were added together. Focusing on this enhanced effect, we observed that together galectins induced the phosphorylation of both VEGFR1 and VEGFR2, whereas galectin-1 and -3 alone induced VEGFR2 phosphorylation only. In the same way, the addition of a blocking VEGFR1 antibody completely abolished the increase in tube formation induced by the combined addition of both galectins. In contrast, the addition of a blocking VEGFR2 antibody only partially inhibited this effect. Finally, the addition of both galectins induced a decrease in the VEGFR1 and VEGFR2 endocytic pools, with a significantly enhanced effect on the VEGFR1 endocytic pool. These results suggest that the combined action of galectin-1 and galectin-3 has an enhanced effect on angiogenesis via VEGFR1 activation, which could be related to a decrease in receptor endocytosis. © 2013 D'Haene et al.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Pembrolizumab plus pomalidomide and dexamethasone for patients with relapsed or refractory multiple myeloma (KEYNOTE-183): a randomised, open-label, phase 3 trial

BACKGROUND: Pomalidomide and dexamethasone is a standard of care for patients with multiple myeloma in whom bortezomib and lenalidomide treatment has failed. KEYNOTE-183 assessed efficacy and safety of pomalidomide and dexamethasone with or without pembrolizumab in patients with relapsed or refractory multiple myeloma. Here, we present the findings of an unplanned, ad-hoc interim analysis at the request of the US Food and Drug Administration (FDA). METHODS: KEYNOTE-183 was a randomised, open-label, phase 3 trial done at 97 medical centres across 11 countries (Australia, Canada, France, Germany, Israel, Italy, Japan, New Zealand, Norway, Spain, and USA). Patients aged at least 18 years with multiple myeloma, an Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1, previously treated with at least two lines of therapy (excluding pomalidomide) and refractory to the last line were randomly assigned 1:1 to the pembrolizumab plus pomalidomide and dexamethasone group or the pomalidomide and dexamethasone group via an interactive voice response or integrated web response system. Patients received oral pomalidomide 4 mg daily on days 1-21 and oral low-dose dexamethasone 40 mg on days 1, 8, 15, and 22 in 28-day cycles, with or without intravenous pembrolizumab 200 mg every 3 weeks. The dual primary endpoints were progression-free survival and overall survival. Efficacy was assessed in all randomly assigned patients and safety was assessed in patients who received at least one dose of study treatment. The trial is registered at ClinicalTrials.gov, number NCT02576977, and it is closed for accrual. FINDINGS: Between Jan 18, 2016, and June 7, 2017, 249 patients were randomly assigned to either the pembrolizumab plus pomalidomide and dexamethasone group (n=125) or the pomalidomide and dexamethasone group (n=124). On July 3, 2017, the FDA established that risks associated with the triple combination outweighed benefits and halted the study. Median follow-up was 8\ub71 months (IQR 4\ub75-10\ub79). Median progression-free survival was 5\ub76 months (95% CI 3\ub77-7\ub75) in the pembrolizumab plus pomalidomide and dexamethasone group versus 8\ub74 months (5\ub79-not reached) in the pomalidomide and dexamethasone group; progression-free survival estimates at 6 months were 48% (95% CI 37-58) versus 60% (49-69) at 6 months (hazard ratio [HR] 1\ub753; 95% CI 1\ub705-2\ub722; p=0\ub798). Median overall survival was not reached (95% CI 12\ub79-not reached) versus 15\ub72 months (12\ub77-not reached; HR 1\ub761; 95% CI 0\ub791-2\ub785; p=0\ub795); overall survival estimates at 6 months were 82% (95% CI 74-88) versus 90% (82-95). Serious adverse events occurred in 75 (63%) of 120 patients in the pembrolizumab plus pomalidomide and dexamethasone group versus 56 (46%) of 121 patients in the pomalidomide and dexamethasone group. Four (3%) treatment-related deaths occurred in the pembrolizumab plus pomalidomide and dexamethasone group (one each of unknown cause, neutropenic sepsis, myocarditis, and Stevens-Johnson syndrome); myocarditis and Stevens-Johnson syndrome were considered related to pembrolizumab. No treatment-related deaths were reported in the pomalidomide and dexamethasone group. INTERPRETATION: The results from this unplanned, FDA-requested, interim analysis showed that the benefit-risk profile of pembrolizumab plus pomalidomide and dexamethasone is unfavourable for patients with relapsed or refractory multiple myeloma. FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co (Kenilworth, NJ, USA)

Rituximab plus Lenalidomide in Advanced Untreated Follicular Lymphoma

Rituximab plus chemotherapy has been shown to be effective in patients with advanced-stage, previously untreated follicular lymphoma; nevertheless, most patients will have a relapse. Combination immunotherapy with lenalidomide and rituximab is an immunomodulatory regimen that has shown promising activity in patients with indolent B-cell non-Hodgkin's lymphoma