Guenther E Dannecker

Introduction: Muckle-Wells syndrome (MWS) is an inherited autoinflammatory disease characterized by fever, rash, arthralgia, conjunctivitis, sensorineural deafness and potentially life-threatening amyloidosis. The NLRP3/CIAS1 E311K mutation caused a heterogeneous phenotype of MWS in a large family. This study analyzes the clinical spectrum, patterns of inflammatory parameters and reports on response to treatment. Methods: A total of 42 patients and family members were screened for the presence of the NLRP3 mutation. Clinical symptoms were reviewed in all family members. Classical (erythrocyte sedimentation rate (ESR, C-reactive protein (CRP)) and novel MWS inflammatory markers (serum amyloid A (SAA), cytokines, cytokine receptor levels) were determined. Patients were treated with the IL-1 inhibitors Anakinra or Canakinumab. Results: All 13 clinically affected patients were heterozygous carriers of the amino acid substitution p.Glu311Lys/E311K encoded by exon 3 of the NLRP3 gene, but none of the healthy family members. Disease manifestations varied widely. Except for one child, all carriers suffered from hearing loss and severe fatigue. TNF-α, IL-6, TNF-RI, and TNF-RII levels as well as SAA were elevated in three, two, one, six and ten patients, respectively. Both clinical and laboratory parameters responded quickly and sustainedly to treatment with Anakinra or Canakinumab. Conclusion: The NLRP3 E311K mutation is associated with a heterogeneous clinical spectrum, which may expand the view on MWS presentation. The leading symptom was hearing loss. Pericarditis, a rare but severe clinical feature of MWS, was diagnosed in three patients. One patient had a severe course, which led to renal failure secondary to amyloidosis. IL-1 inhibition leads to rapid and sustained improvement of symptoms.

Background: The term juvenile idiopathic arthritis (JIA) describes a clinically heterogeneous group of arthritides. The onset in all subgroups is before 16 years of age, but each group presents with different clinical signs and symptoms. The cause of the disease is unknown, but both genetic and environmental factors are believed to be involved. Management of the disease has greatly improved in recent years due to advances in pharmacologic treatment options (especially with new biologic agents) and the prognosis for patients is better than ever before. However, none of the available drugs has a curative potential. This review provides an overview on the classification and the clinical symptoms of the defined subgroups of JIA as well as pharmacotherapies for it. Conclusions: Treatment of children with JIA is challenging and complex. Since lengthy therapy might be necessary, a multidisciplinary pediatric rheumatology team is crucial for optimal treatment. Although a cure is unknown at this time, adequate treatment aims to preserve function of the joints as well as normal childhood development.