The effect of novel polymorphisms in the interleukin-6 (IL-6) gene on IL-6 transcription and plasma IL-6 levels, and an association with systemic-onset juvenile chronic arthritis. 1998
Artrite giovanile idiopatica, bene abatacept
Nei bambini affetti da artrite giovanile idiopatica (Jia) il trattamento con abatacept migliora la qualità di vita associata allo stato di salute (HrQoL) con benefici tangibili per la vita dei piccoli pazienti e dei loro genitori/caregiver. Lo ha dimostrato uno studio placebo controllato in doppio cieco di fase III che ha arruolato pazienti con artrite in fase attiva poliarticolare e inadeguata risposta/intolleranza ad almeno un Dmard, inclusi i farmaci biologici, avviati a trattamento con abatacept (10 mg/Kg) più metotrexate per un periodo di quattro mesi in aperto (periodo A). Successivamente, i responder (Acr 30) sono stati randomizzati in un gruppo abatacept o placebo (più metotrexate) per un periodo in doppio cieco di sei mesi (periodo B). La valutazione di HrQoL ha incluso i 15 concetti per lo stato di salute del Child Health Questionnaire (Chq), gli score physical health/psychosocial summary (PhS e PsS), la scala Vas per il dolore, il Children's Sleep Habits Questionnaire e il questionario sulla partecipazione alle attività quotidiane. Nel periodo A si sono notati con abatacept sostanziali miglioramenti in tutti i domini Chq (specie per il dolore/discomfort) e nei punteggi PhS (8,3 unità ) e PsS (4,3 unità ). Al termine del periodo B, i pazienti trattati con abatacept hanno mostrato maggiori miglioramenti rispetto al placebo in tutti i domini Chq, a eccezione del comportamento, e negli score PhS e PsS. Simili pattern di miglioramento si sono visti sul dolore e sul sonno. Riguardo la partecipazione alle attività quotidiane, nel periodo A i responder hanno guadagnato 2,6 giorni al mese di attività usuali a scuola e 2,3 per i genitori. Ulteriori guadagni in termini di giorni dedicati alle normali attività quotidiane sono stati osservati nel periodo B: 1,9 vs 0,9 e 0,2 vs -1,3 per le attività scolastiche e parentali rispettivamente nei bambini trattati con abatacept o con placebo. Lo studio è frutto del lavoro del Pediatric Rheumatology Collaborative Study Group (Prcsg) - per la Paediatric Rheumatology International Trials Organization (Printo) - con la prima firma di Nicolino Ruperto dell'Irccs G. Gaslini, Università di Genova.
Arthritis Care Res, 2010 Jul 1. [Epub ahead of print]
Arthritis Care Res (Hoboken). 2010 Jul 1. [Epub ahead of print]
Abatacept improves health-related quality of life, pain, sleep quality and daily participation in subjects with juvenile idiopathic arthritis. 2010
Ruperto N, Lovell DJ, Li T, Sztajnbok F, Goldenstein-Schainberg C, Scheinberg M, Penades IC, Fischbach M, Orozco J, Hashkes PJ, Hom C, Jung L, Lepore L, Oliveira S, Wallace C, Alessio M, Quartier P, Cortis E, Eberhard A, Simonini G, Lemelle I, Chalom E, Sigal LH, Block A, Covucci A, Nys M, Martini A, Giannini EH; for the Paediatric Rheumatology INternational Trials Organization (PRINTO) the Pediatric Rheumatology Collaborative Study Group (PRCSG).
IRCCS G Gaslini, Pediatria II-PRINTO, Università di Genova, Genova, Italy.
Abstract
OBJECTIVE:: To assess health-related quality of life (HRQoL) in abatacept-treated children/adolescents with JIA. METHODS:: In this Phase III, double-blind, placebo-controlled trial, subjects with active polyarticular course JIA and an inadequate response/intolerance to >/=1 disease-modifying antirheumatic drug (including biologics) received abatacept 10 mg/kg plus methotrexate (MTX) during the 4-month open-label period (Period A). Subjects achieving ACR Paediatric (ACR Ped) 30 (defined 'responders') were randomized to abatacept or placebo (plus MTX) in the 6-month double-blind withdrawal period (Period B). HRQoL assessments included 15 Child Health Questionnaire (CHQ) health concepts plus physical/psychosocial summary scores (PhS, PsS); pain (100 mm VAS); Children's Sleep Habits Questionnaire; daily activity participation questionnaire. RESULTS:: 190 subjects from Period A and 122 from Period B were eligible for analysis. In Period A there were substantial improvements across all CHQ domains, (greatest improvement was in pain/discomfort) and the PhS (8.3 units) and PsS (4.3 units) with abatacept. At the end of Period B, abatacept-treated subjects had greater improvements versus placebo in all domains (except behaviour), and both summary scores. Similar improvement patterns were seen with pain and sleep. For participation in daily activities, an additional 2.6 school and 2.3 parents' usual activity days/month were gained in Period A responders with abatacept, and further gains were made in Period B (1.9 vs 0.9 [p=0.033] and 0.2 vs 1.3 [p=0.109] school and parents usual activity days/month, respectively, in abatacept vs placebo-treated subjects). CONCLUSIONS:: Improvements in HRQoL were observed with abatacept, providing real-life tangible benefits to children with JIA, and their parents/caregivers.
New Hypothesis
New gene mutations found in white blood cells in patients with rheumatoid arthritis
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Gene mutations accumulating in cells are typical of the development of cancer. Finnish researchers found that a similar accumulation of mutations occurs also in some patients with rheumatoid arthritis.
Gene mutations that accumulate in somatic cells have a significant impact on the development of cancer, yet no studies on their involvement in the pathogenesis of autoimmune diseases have previously been conducted. A research project conducted in cooperation by the University of Helsinki and the Helsinki University Central Hospital found that somatic mutations were present also in patients with rheumatoid arthritis.
Published in the Nature Communications journal, the study found mutations in genes important to the immune defence system in white cells separated from blood samples taken from patients recently diagnosed with rheumatoid arthritis.
"It may be possible that these mutations affect the regulation of the inflammatory process," says Satu Mustjoki, a research professor at the Finnish Cancer Institute and the University of Helsinki.
Altogether 85 patients with recently diagnosed rheumatoid arthritis participated in the study, in addition to which there were 20 healthy control subjects. By utilising the latest deep sequencing techniques, the researchers identified mutations in one fifth of the patients. All identified mutations were located in cells known as killer cells, or cytotoxic CD8+ T cells. No mutations were found in helper cells, or CD4+ T cells.
"One somatic mutation was found in a single healthy control subject, which means that the finding is not entirely arthritis specific," notes Professor Marjatta Leirisalo-Repo, a specialist in rheumatology.
Mutations Only Develop In Mature T Cells
The ability found in T cells to recognise countless different protein structures inherent in, for example, pathogens, is based on their versatile selection of T cell receptors. This selection is formed in the thymus, where gene stubs that code the T cell receptors found in T cells are split and rearranged into functioning receptors. Thus, the surface of each new T cell is imbued with a unique T cell receptor.
When the immune defence system is activated, T cells multiply exponentially while identical T cells form cell clones that can be identified by the rearrangement of their shared, unique T cell receptor.
Enlarged T cell clones were found in all patients with rheumatoid arthritis concomitant with somatic mutations. Further investigation proved that the mutations were limited to these enlarged cell clones.
"This indicates that mutations are formed only in mature T cells, not at the stem cell level," say BM Paula Savola and PhD Tiina Kelkka, the main authors of the article. "If mutations were formed at the earlier differentiation stage, they would have been present in CD8+ T cells and CD4+ helper cells expressing other T cell receptor types as well."
The mutations were found to be permanent, since identical clones and mutations were found in the patients' white blood cells several years after the original finding.
Are Mutations "Genomic Scars"?
"For now, there is no certainty on how these mutations affect the regulation of chronic inflammations. They may be, for lack of a better word, 'genomic scars' formed as a result of the activation of the immune defence system," says Mustjoki.
"In any case, this research project revealed a new connection on the molecular level between autoimmune diseases and cancer, which brings us one step closer to understanding these diseases."
The starting point for this project was earlier findings related to LGL leukaemia made by Mustjoki's research group. In LGL leukaemia, somatic mutations often found in the STAT3 gene and located also in the cytotoxic T cells of patients cause a slowly progressing blood disorder, in addition to which they predispose patients to autoimmune diseases. The most common autoimmune disease related to LGL leukaemia is rheumatoid arthritis.
"In the future, we intend to study the prevalence of this phenomenon in other inflammatory conditions and the practical significance of these mutations as regulators of inflammatory reactions," says Mustjoki.
Funding for the project was provided, among others, by the Academy of Finland and the European Research Council.
Article: Somatic mutations in clonally expanded cytotoxic T lymphocytes in patients with newly diagnosed rheumatoid arthritis, P. Savola, T. Kelkka, H. L. Rajala, A. Kuuliala, K. Kuuliala, S. Eldfors, P. Ellonen, S. Lagström, M. Lepistö, T. Hannunen, E. I. Andersson, R. K. Khajuria, T. Jaatinen, R. Koivuniemi, H. Repo, J. Saarela, K. Porkka, M. Leirisalo-Repo & S. Mustjoki, Nature Communications, doi: 10.1038/ncomms15869, published online 21 June 2017.
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Source: University of Helsinki
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Knowledge Center
Somatic mutations in clonally expanded cytotoxic T lymphocytes in patients with newly diagnosed rheumatoid arthritis
- Somatic mutations contribute to tumorigenesis. Although these mutations occur in all proliferating cells, their accumulation under non-malignant conditions, such as in autoimmune disorders, has not been investigated. Here, we show that patients with newly diagnosed rheumatoid arthritis have expanded CD8+ T-cell clones; in 20% (5/25) of patients CD8+ T cells, but not CD4+ T cells, harbour somatic mutations. In healthy controls (n=20), only one mutation is identified in the CD8+ T-cell pool. Mutations exist exclusively in the expanded CD8+ effector-memory subset, persist during follow-up, and are predicted to change protein functions. Some of the mutated genes (SLAMF6, IRF1) have previously been associated with autoimmunity. RNA sequencing of mutation-harbouring cells shows signatures corresponding to cell proliferation. Our data provide evidence of accumulation of somatic mutations in expanded CD8+ T cells, which may have pathogenic significance for RA and other autoimmune diseases.
