A new functional assay for the diagnosis of X-linked inhibitor of apoptosis (XIAP) deficiency.

X-linked inhibitor of apoptosis (XIAP) deficiency, caused by mutations in BIRC4, is an immunodeficiency associated with immune dysregulation and a highly variable clinical presentation. Current diagnostic screening tests such as flow cytometry for XIAP expression or lymphocyte apoptosis assays have significant limitations. Based on recent evidence that XIAP is essential for nucleotide-binding and oligomerization domains (NOD)1/2 signalling, we evaluated the use of a simple flow cytometric assay assessing tumour necrosis factor (TNF) production of monocytes in response to NOD2 stimulation by muramyl dipeptides (L18-MDP) for the functional diagnosis of XIAP deficiency. We investigated 12 patients with XIAP deficiency, six female carriers and relevant disease controls. Irrespective of the diverse clinical phenotype, the extent of residual protein expression or the nature of the mutation, the TNF response was severely reduced in all patients. On average, L18-MDP induced TNF production in 25% of monocytes from healthy donors or female carriers, while fewer than 6% of monocytes responded in affected patients. Notably, the assay clearly discriminated affected patients from disease controls with other immunodeficiencies accompanied by lymphoproliferation, hypogammaglobulinaemia or inflammatory bowel disease. Functional testing of the NOD2 signalling pathway is an easy, fast and reliable assay in the diagnostic evaluation of patients with suspected XIAP deficiency.

[The importance of biologicals in the treatment of SoJIA]. / Die Bedeutung von Biologika bei der Therapie der SoJIA (Morbus Still).

Systemic onset juvenile idiopathic arthritis (SoJIA) remains difficult to treat. In addition to conventional antirheumatic therapy with non-steroidal antirheumatic drugs (NSARDs), steroids or disease-modifying antirheumatic drugs (DMARDs), biologicals offer a new therapeutic approach for this disease in that they are able to target pathogenically relevant cytokines and effector cells. Some biologicals are already approved for use in children with rheumatic disease.In order to assess the currently available data on the use of biologicals in SoJIA, we performed a Medline search for the period 2005 to March 2010, including the MeSH terms "SoJIA", "systemic juvenile idiopathic arthritis" and"biologicals", as well as an NIH study registry search. At Present there are scant and unconvincing data on the use of Etanercept or Adalimumab for the treatment of SoJIA. No results are published on the use of Infliximab or other new TNF-alpha inhibitors. The inhibition of IL-1 or IL-6 shows promising results. Data on the efficacy of Abatacept is limited due to very low numbers of SoJIA patients in the studies.Further studies on the use of biologicals in SoJIA while taking individual factors into consideration are required. The long-term safety of all biologicals should be investigated in prospective registers.