R Sighart1, J Rech2, A Hueber2, N Blank3, S Löhr1, A Reis1, H Sticht4, U Hüffmeier5. 1. Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Schwabachanlage 10, 91052, Erlangen, Germany. 2. Department of Internal Medicine 3 and Institute of Clinical Immunology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany. 3. Division of Rheumatology, Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany. 4. Bioinformatics, Institute of Biochemistry, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany. 5. Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Schwabachanlage 10, 91052, Erlangen, Germany. ulrike.hueffmeier@uk-erlangen.de.
Abstract
OBJECTIVE: Adult onset Still's disease (AOSD) is a severe, autoimmune disease that can be challenging to treat with conventional therapeutics and biologicals in a considerable number of cases. Therefore, there is a high need to understand its pathogenesis better. As major clinical symptoms overlap between AOSD and hereditary periodic fever syndromes (HPFS), we analysed four known HPFS genes in AOSD. METHODS: We performed Sanger sequencing and quantitative analysis of all coding regions of MEFV, TNFRSF1A, MVK and NLRP3 in 40 AOSD patients. All rare coding variants (n = 6) were evaluated for several aspects to classify them as benign to pathogenic variants. Statistical analysis was performed to analyse whether variants classified as (likely) pathogenic were associated with AOSD. RESULTS: We identified three rare variants in MEFV, one previously not described. Association to the three likely pathogenic MEFV variants was significant (p c = 2.34E- 03), and two of the three carriers had a severe course of disease. We observed strong evidence for significant association to mutations in TNFRSF1A (p c = 2.40E- 04), as 5% of patients (2/40) carried a (likely) pathogenic variant in this gene. Both of them received a biological for treatment. CONCLUSION: Our results indicate TNFRSF1A as a relevant gene in AOSD, especially in patients with a more challenging course of disease, while causal variants remain to be identified in the majority of patients.
OBJECTIVE: Adult onset Still's disease (AOSD) is a severe, autoimmune disease that can be challenging to treat with conventional therapeutics and biologicals in a considerable number of cases. Therefore, there is a high need to understand its pathogenesis better. As major clinical symptoms overlap between AOSD and hereditary periodic fever syndromes (HPFS), we analysed four known HPFS genes in AOSD. METHODS: We performed Sanger sequencing and quantitative analysis of all coding regions of MEFV, TNFRSF1A, MVK and NLRP3 in 40 AOSD patients. All rare coding variants (n = 6) were evaluated for several aspects to classify them as benign to pathogenic variants. Statistical analysis was performed to analyse whether variants classified as (likely) pathogenic were associated with AOSD. RESULTS: We identified three rare variants in MEFV, one previously not described. Association to the three likely pathogenic MEFV variants was significant (p c = 2.34E- 03), and two of the three carriers had a severe course of disease. We observed strong evidence for significant association to mutations in TNFRSF1A (p c = 2.40E- 04), as 5% of patients (2/40) carried a (likely) pathogenic variant in this gene. Both of them received a biological for treatment. CONCLUSION: Our results indicate TNFRSF1A as a relevant gene in AOSD, especially in patients with a more challenging course of disease, while causal variants remain to be identified in the majority of patients.
Authors: S Papin; S Cuenin; L Agostini; F Martinon; S Werner; H-D Beer; C Grütter; M Grütter; J Tschopp Journal: Cell Death Differ Date: 2007-04-13 Impact factor: 15.828
Authors: Martin A Kriegel; Ulrike Hüffmeier; Elisabeth Scherb; Christina Scheidig; Thomas Geiler; Joachim R Kalden; André Reis; Hanns-Martin Lorenz Journal: Arthritis Rheum Date: 2003-08