Autoinflammatory syndromes with an emphasis on anakinra treatment

Contains fulltext : 96661.pdf (Publisher’s version ) (Open Access)Radboud Universiteit Nijmegen, 16 december 2011Promotores : Drenth, J.P.H., Meer, J.W.M. van der Co-promotor : Simon, A

Effect of etanercept and anakinra on inflammatory attacks in the hyper-IgD syndrome: introducing a vaccination provocation model.

Contains fulltext : 48588.pdf (publisher's version ) (Open Access)BACKGROUND: Hyper-IgD and periodic fever syndrome (HIDS) is an hereditary autoinflammatory syndrome, characterised by recurrent inflammatory attacks. Treatment of HIDS is difficult, although simvastatin is beneficial and etanercept might be effective. Studying the treatment of a rare periodic syndrome is complicated by the varying frequency and severity of symptoms and low prevalence. Our aim was to develop a system of clinical observations to evaluate effectiveness of treatment-on-demand. METHODS: Seven fever episodes in three HIDS patients were monitored, with and without administration of etanercept or anakinra. We developed a clinical score, which includes 12 symptoms. In one patient, inflammatory attacks were provoked by vaccination. RESULTS AND CONCLUSIONS: At the onset of an attack, all patients reported a clinical score between 20 and 25. The score was used to quantify severity and define the end of an attack. Reproducible monitoring of inflammatory episodes was difficult, even in this pilot study. The effect of early administration of etanercept was variable. In one patient, a fever episode could be readily provoked within 12 to 24 hours by vaccination. In this patient, the IL-1ra analogue anakinra was more successful in aborting the inflammatory attack than etanercept. We propose that this vaccination model will allow evaluation of treatment-on-demand in a controlled setting

[A Dutch family with the hereditary periodic fever or tumour necrosis factor receptor-associated periodic syndrome (TRAPS)],Een Nederlandse familie met het erfelijke periodieke koortssyndroom 'tumornecrosisfactor receptor-associated periodic syndrome' (TRAPS).

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Complete remission of severe idiopathic cold urticaria on interleukin-1 receptor antagonist (anakinra).

Contains fulltext : 81758.pdf (publisher's version ) (Closed access)A 62-year-old patient had suffered from severe cold intolerance with an urticarial rash and oropharyngeal angio-oedema upon cold exposure since early childhood. This could be provoked by the ice cube test and by exposure in a cold room. Her family history was negative, and she did not carry any mutations in the NRLP3 gene. Treatment with IL-1 receptor antagonist anakinra resulted in complete resolution of these symptoms, with a radical beneficial change in her quality of life. In recent years this patient had developed progressive neurological symptoms leading to a diagnosis of amyotrophic lateral sclerosis (ALS), which seems unrelated to the idiopathic cold urticaria. The neurological symptoms did not respond to anakinra treatment and were eventually fatal. Conclusion: We describe the first case of IL-1RA treatment in idiopathic cold urticaria with good response. Anakinra had no effect on the progression of her symptoms of ALS

Schnitzler syndrome: beyond the case reports: review and follow-up of 94 patients with an emphasis on prognosis and treatment.

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Complete remission of severe idiopathic cold urticaria on interleukin-1 receptor antagonist (anakinra).

A 62-year-old patient had suffered from severe cold intolerance with an urticarial rash and oropharyngeal angio-oedema upon cold exposure since early childhood. This could be provoked by the ice cube test and by exposure in a cold room. Her family history was negative, and she did not carry any mutations in the NRLP3 gene. Treatment with IL-1 receptor antagonist anakinra resulted in complete resolution of these symptoms, with a radical beneficial change in her quality of life. In recent years this patient had developed progressive neurological symptoms leading to a diagnosis of amyotrophic lateral sclerosis (ALS), which seems unrelated to the idiopathic cold urticaria. The neurological symptoms did not respond to anakinra treatment and were eventually fatal. Conclusion: We describe the first case of IL-1RA treatment in idiopathic cold urticaria with good response. Anakinra had no effect on the progression of her symptoms of ALS

Two patients with recurrent fever and wine red discolouration of the eyelids.

Contains fulltext : 59192.pdf (publisher's version ) (Closed access

Response to "Schnitzler's Syndrome: A True Auto-Inflammatory Disorder?"

Contains fulltext : 71145.pdf (publisher's version ) (Closed access

Crystals of monosodium urate monohydrate enhance lipopolysaccharide-induced release of interleukin 1 beta by mononuclear cells through a caspase 1-mediated process.

Contains fulltext : 79577.pdf (publisher's version ) (Closed access)OBJECTIVE: Recent studies suggest that crystals of monosodium urate (MSU), deposited in joints of patients with acute gouty arthritis, activate the NACHT domain, leucine-rich repeat and pyrin domain-containing protein (NALP)3 inflammasome. In the present study we have investigated whether production of proinflammatory cytokines by crystals was exacerbated during costimulation with Toll-like receptor (TLR) ligands. METHODS: Mononuclear cells of 22 healthy donors were stimulated by various concentrations of MSU crystals in the absence or presence of lipopolysaccharide (LPS), Pam3Cys and flagellin. Production of tumour necrosis factor alpha (TNFalpha), interleukin (IL)1 beta and IL6, as well as the intracellular concentrations of proIL1 beta were measured by ELISA. mRNA transcripts of TNFalpha and IL1 beta were assessed by real-time PCR. Stimulation experiments were also performed with peripheral blood mononuclear cells (PBMCs) of one patient carrying a NALP3 mutation. RESULTS: MSU induced a moderate release of IL1 beta and IL6, but not of TNFalpha. Urate crystals amplified IL1 beta production stimulated by the TLR4 ligand LPS, while no synergy was apparent for IL6 production. In addition, no synergy between urate crystals and Pam3Cys (TLR2 ligand) or flagellin (TLR5 ligand) was apparent. The synergy between urate crystals and LPS was directed at the level of the NALP3 inflammasome, as it was present only when active IL1 beta was measured, but not at the level of IL1 mRNA or proIL1 beta. The synergy between LPS and MSU crystals ceased to exist in the presence of a caspase 1 inhibitor. CONCLUSIONS: MSU crystals act in synergy with LPS for the induction of enhanced release of IL1 beta. Increased cleavage of proIL1 beta by urate-activated caspase 1 is proposed as the underlying mechanism

On-demand anakinra treatment is effective in mevalonate kinase deficiency

Contains fulltext : 98172.pdf (publisher's version ) (Closed access)BACKGROUND: Mevalonate kinase deficiency (MKD) is a hereditary autoinflammatory syndrome marked by recurrent attacks of fever and inflammation. Severe enzyme deficiency results in mevalonic aciduria (MA) and milder deficiency in hyperimmunoglobulin D syndrome (HIDS). Treatment remains a challenge. OBJECTIVE: To observe the effect of the recombinant interleukin-1 receptor antagonist anakinra in patients with MKD. METHODS: A prospective observational study was undertaken. Two patients with MA started continuous treatment with anakinra (1-2 mg/kg/day) and nine patients with HIDS chose between continuous treatment and on-demand treatment (starting at first symptoms of attack, 100 mg/day or 1 mg/kg/day for 5-7 days). RESULTS: Anakinra induced partial remission in one patient with MA but there was no response in the other patient with MA. In one patient with HIDS continuous treatment induced complete remission for 7 months but was stopped because of side effects. Eight patients with HIDS preferred on-demand treatment from the start. This induced a clinical response (>/=50% reduction in duration) in 8 of 12 treated attacks without a change in attack frequency. Anakinra prevented fever attacks due to vaccination without inhibiting antibody induction. No major side effects were seen. CONCLUSIONS: On-demand treatment with anakinra in HIDS decreases the duration and severity of fever attacks. Because of the burden of daily injections and relatively long asymptomatic intervals of HIDS, all patients with HIDS preferred on-demand treatment