The phenotype of TNF receptor-associated autoinflammatory syndrome (TRAPS) at presentation: a series of 158 cases from the Eurofever/EUROTRAPS international registry

Abstract

Objective To evaluate the genetic findings, demographic features and clinical presentation of tumour necrosis factor receptor-associated autoinflammatory syndrome (TRAPS) in patients from the Eurofever/ EUROTRAPS international registry. Methods A web-based registry collected retrospective data on patients with TNFRSF1A sequence variants and inflammatory symptoms. Participating hospitals included paediatric rheumatology centres and adult centres with a specific interest in autoinflammatory diseases. Cases were independently validated by experts in the disease. Results Complete information on 158 validated patients was available. The most common TNFRSF1A variant was R92Q (34% of cases), followed by T50M (10%). Cysteine residues were disrupted in 27% of cases, accounting for 39% of sequence variants. A family history was present in 19% of patients with R92Q and 64% of those with other variants. The median age at which symptoms began was 4.3 years but 9.1% of patients presented after 30 years of age. Attacks were recurrent in 88% and the commonest features associated with the pathogenic variants were fever (88%), limb pain (85%), abdominal pain (74%), rash (63%) and eye manifestations (45%). Disease associated with R92Q presented slightly later at a median of 5.7 years with significantly less rash or eye signs and more headaches. Children were more likely than adults to present with lymphadenopathy, periorbital oedema and abdominal pains. AA amyloidosis has developed in 16 (10%) patients at a median age of 43 years. Conclusions In this, the largest reported case series to date, the genetic heterogeneity of TRAPS is accompanied by a variable phenotype at presentation. Patients had a median 70 symptomatic days a year, with fever, limb and abdominal pain and rash the commonest symptoms. Overall, there is little evidence of a significant effect of age or genotype on disease features at presentation.

Treating TRAPS Syndrome with a Previously Undescribed TNF α Gene Receptor Mutation Successfully with Canakinumab

“…Наибольшее число описанных к настоящему времени мутаций в гене TNFRSF1A расположено в экзоне 04, при этом наиболее распространена мутация c.362G>A (R92Q) [12]. Ген TNFRSF1A кодирует один из рецепто-ров фактора некроза опухоли (Tumor necrosis factor, TNF) ␣ -важнейший провоспалительный цитокин, про-дуцируемый моноцитами/макрофагами, лимфоцитами, NK клетками, полиморфноядерными лейкоцитами [6,12].…”

“…Ген TNFRSF1A кодирует один из рецепто-ров фактора некроза опухоли (Tumor necrosis factor, TNF) ␣ -важнейший провоспалительный цитокин, про-дуцируемый моноцитами/макрофагами, лимфоцитами, NK клетками, полиморфноядерными лейкоцитами [6,12]. Гиперпродукция TNF ␣ играет ведущую патогенетическую роль при многих воспалительных заболеваниях, включая ревматические (ревматоидный артрит, группа серонега-тивных спондилоартритов, ювенильный артрит и др.)…”

“…Самым грозным осложнением TRAPS, приводящим к почечной или печеночной недостаточности и гибе-ли пациентов [12], является АА-амилоидоз (поражает до 25% больных). Согласно данным литературы, мута-ции, затрагивающие цистеиновые остатки в молекуле рецептора TNFR1, гораздо чаще приводят к развитию системного амилоидоза [12], тогда как мутации с низкой пенетрантностью (R92Q) обычно вовлечены в развитие хронических воспалительных процессов, а их носители имеют более мягкое течение TRAPS [12].…”

Review of International Registers of Patients with Systemic Juvenile Idiopathic Arthritis

“…Пациенты получали различные иммунодепрес-санты и ГИБП; 1674 (23%) лечились только метотрек-сатом (без ГИБП), 3025 (42%) -одним ГИБП с/без метотрексата, 1163 (16%) получали более чем одним ГИБП с/без метотрексата. Результаты анализа данных, включенных в регистр, показали, что при использова-нии комбинации ГИБП с метотрексатом увеличивается частота нежелательных явлений и серьезных инфекций [18][19][20][21].…”

A signalome screening approach in the autoinflammatory disease TNF receptor associated periodic syndrome (TRAPS) highlights the anti-inflammatory properties of drugs for repurposing

“…One such disease is TNF Receptor Associated Periodic Syndrome (TRAPS) caused by mutations in TNF receptor-1 (TNFR1) [8], resulting in spontaneous episodes of systemic inflammation causing morbidity and potential mortality [9][10][11]. Current treatment options for TRAPS include corticosteroids (with potentially major side-effects) and cytokine-blocking biologics; although the latter represent a major advance in the management of TRAPS, they are expensive, may require specialist administration, and show variable, unpredictable, limited efficacy [12,13].…”