JAK-inhibitors are small molecules blocking the JAK-STAT pathway that have proven effective in the treatment of different immune-mediated diseases in adults and juvenile idiopathic arthritis (JIA).Aim of StudyTo evaluate the safety and efficacy of tofacitinib in children with different rheumatic diseases.Material and MethodsWe extracted information from 24 children with the following diagnosis: JIA (n = 15), undifferentiated systemic autoinflammatory diseases (SAIDs) (n = 7), and juvenile dermatomyositis (JDM) (n = 2) who have been treated with tofacitinib for a period of longer than 6 months. The treatment outcomes were classified according to the opinion of the attending physicians as having a complete response (CR), i.e., the absence of disease activity, or a partial response (PR)—a significant improvement of symptoms and disease activity, or no response (NR)—no changes in disease activity.ResultsCR was achieved in 10/24 patients; 7/15 among JIA patients, 1/2 among JDM patients, 4/7 among SAID patients, and PR in 5/15 of JIA, 1/2 of JDM, and 3/7 of SAID patients. Three non-responders with JIA discontinued tofacitinib. Corticosteroids were successfully tapered off in 11/14 patients and discontinued in 2/14 patients. Four patients had side effects not requiring treatment discontinuation: liver enzyme elevation (n = 2), hypercholesterolemia (n = 1), lymphadenitis (n = 1).ConclusionJAK-inhibitors are effective new therapies for the treatment of multiple immune-mediated diseases. Our experience has shown the best results in patients with JIA and JIA-associated alopecia, and type I interferonopathies. More data from randomized controlled clinical trials are needed to use JAK-inhibitors safely in pediatric rheumatic diseases.
Diaphanous related formins are highly conserved proteins regulated by Rho-GTPases that act as actin nucleation and assembly factors. Here we report the functional characterization of a non-inherited heterozygous FMNL2 p.L136P mutation carried by a patient who presented with severe very early onset inflammatory bowel disease (IBD). We found that the FMNL2 L136P protein displayed subcellular mislocalization and deregulated protein autoinhibition indicating gain-of-function mechanism. Expression of FMNL2 L136P impaired cell spreading as well as filopodia formation. THP-1 macrophages expressing FMNL2 L136P revealed dysregulated podosome formation and a defect in matrix degradation. Our data indicate that the L136P mutation affects cellular actin dynamics in fibroblasts and immune cells such as macrophages.
Обоснование. Гипофосфатазия-редкое наследственное заболевание, вызванное дефицитом изофермента тканенеспецифичной щелочной фосфатазы, проявляется нарушением минерализации костей и зубов, электролитными и дыхательными нарушениями, судорожным синдромом, задержкой физического развития, нефрокальцинозом. Редкость заболевания, полиморфизм клинических проявлений, неспецифичность жалоб являются причиной поздней диагностики гипофосфатазии. Для лечения тяжелых форм заболевания применяется ферментозаместительная терапия рекомбинантной щелочной фосфатазой-асфотазой альфа. Описание клинического случая. Девочка, возраст 1 год 4 мес, госпитализирована в плановом порядке с жалобами на задержку физического и психомоторного развития, деформацию нижних конечностей, грудной клетки, нарушение походки, выпадение зубов, с диагнозом «белково-калорийная недостаточность». Отмечены рахитоподобные изменения скелета, миопатический синдром, раннее выпадение неизмененных зубов, гепатомегалия. Выявлена сниженная активность щелочной фосфатазы в сыворотке крови (33 Ед/л; норма 156-369 Ед/л). Диагностирована инфантильная форма гипофосфатазии. При молекулярногенетическом исследовании в гене ALPL обнаружены патогенные варианты c.526G>A (p.Ala176Thr) и c.1375G>A (p/Val459Met) в компаунд-гетерозиготном состоянии, подтвердившие диагноз. В возрасте 1 года 10 мес была начата терапия асфотазой альфа в дозировке 2 мг/кг массы тела подкожно 3 раза в неделю. За 6 мес терапии наблюдали значительное увеличение активности щелочной фосфатазы (максимально 4400 Ед/л), массы тела (+2 кг), роста (+6 см), уменьшение выраженности костных деформаций, восстановление мышечного тонуса, нормализацию походки, повышение толерантности к физическим нагрузкам. Введение препарата переносила удовлетворительно. Редко в месте инъекции отмечали появление гиперемии до 4 см в диаметре с умеренным уплотнением, которая самостоятельно разрешалась в течение 2-3 сут. Заключение. Пациентам с рахитоподобными заболеваниями с низкой активностью щелочной фосфатазы необходима генетическая диагностика для подтверждения гипофосфатазии. Своевременная диагностика и назначение ферментозаместительной терапии может существенно улучшить качество жизни детей с гипофосфатазией. Ключевые слова: дети, гипофосфатазия, рахитоподобные заболевания, щелочная фосфатаза, асфотаза альфа, ген ALPL.
A clinical case of mitochondrial neurogastrointestinal encephalopathy (MNGIE), a rare autosomal recessive multisystem disease caused by TYMP gene mutations and thymidine phosphorylase (TP) deficiency, is presented. Authors draw the specialists’ attention to the complexity of making a diagnosis and the importance of an interdisciplinary approach in the diagnosis and management of such patients with the purpose of increasing the pediatric practitioners’ MNGIE awareness thereby reducing the time to diagnosis, which in its turn improves the prognosis for the course of the disease for the patients.
The authors present a clinical case of asymptomatic spontaneous emphysema in a child with a severe course of Crohn's disease, which is a type of inflammatory bowel disease (IBD). The emphysema was diagnosed on the occasion, during the CT scan prior to the start of the immunobiological (Anti-TNF-α) therapy. The etiopathogenetic causes for this condition, its diagnosis and relationship with the severity of the underlying disease are discussed in the paper. A retrospective analysis of the prevalence of this pathology is also given. Conclusion: in the absence of an obvious cause (perforation), the pneumomediastinum can be explained by retroperitoneal air leak through microperforations in severe colitis, which is an unfavorable prognostic criterion for a severe course of the Crohn's disease and increases the risk of surgical treatment, colectomy as usual.
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