Caroline Galeotti

Kawasaki disease: aetiopathogenesis and therapeutic utility of intravenous immunoglobulin.

Abstract Kawasaki disease (KD) is an acute febrile childhood vasculitis, associated with the development of coronary artery abnormalities in 25–30% of untreated patients. The aetiopathogenesis is not well known but it is accepted that an undefined infectious trigger in genetically predisposed individuals results in the disease. KD is characterized by an endothelial cell injury, which could be due to abnormal cytokine production and to generation of cytotoxic antibodies against the endothelial cells. Intravenous immunoglobulin IVIG is an effective treatment in preventing the occurrence of coronary artery abnormalities in KD. Several mechanisms may explain the anti-inflammatory effects of IVIG in this disease. They include modification of the cytokine balance, and alteration on both the differentiation and the function of monocytes/macrophages, neutrophils and lymphocytes.

Inherited CARD9 Deficiency in 2 Unrelated Patients With Invasive Exophiala Infection

BACKGROUND Exophiala species are mostly responsible for skin infections. Invasive Exophiala dermatitidis disease is a rare and frequently fatal infection, with 42 cases reported. About half of these cases had no known risk factors. Similarly, invasive Exophiala spinifera disease is extremely rare, with only 3 cases reported, all in patients with no known immunodeficiency. Autosomal recessive CARD9 deficiency has recently been reported in otherwise healthy patients with severe fungal diseases caused by Candida species, dermatophytes, or Phialophora verrucosa. METHODS We investigated an 8-year-old girl from a nonconsanguineous Angolan kindred, who was born in France and developed disseminated E. dermatitidis disease and a 26 year-old woman from an Iranian consaguineous kindred, who was living in Iran and developed disseminated E. spinifera disease. Both patients were otherwise healthy. RESULTS We sequenced CARD9 and found both patients to be homozygous for loss-of-function mutations (R18W and E323del). The first patient had segmental uniparental disomy of chromosome 9, carrying 2 copies of the maternal CARD9 mutated allele. CONCLUSIONS These are the first 2 patients with inherited CARD9 deficiency and invasive Exophiala disease to be described. CARD9 deficiency should thus be considered in patients with unexplained invasive Exophiala species disease, even in the absence of other infections.

Evidence-based recommendations for genetic diagnosis of familial Mediterranean fever

Familial Mediterranean fever (FMF) is a disease of early onset which can lead to significant morbidity. In 2012, Single Hub and Access point for pediatric Rheumatology in Europe (SHARE) was launched with the aim of optimising and disseminating diagnostic and management regimens for children and young adults with rheumatic diseases. The objective was to establish recommendations for FMF focusing on provision of diagnostic tools for inexperienced clinicians particularly regarding interpretation of MEFV mutations. Evidence-based recommendations were developed using the European League against Rheumatism standard operating procedure. An expert committee of paediatric rheumatologists defined search terms for the systematic literature review. Two independent experts scored articles for validity and level of evidence. Recommendations derived from the literature were evaluated by an online survey and statements with less than 80% agreement were reformulated. Subsequently, all recommendations were discussed at a consensus meeting using the nominal group technique and were accepted if more than 80% agreement was reached. The literature search yielded 3386 articles, of which 25 were considered relevant and scored for validity and level of evidence. In total, 17 articles were scored valid and used to formulate the recommendations. Eight recommendations were accepted with 100% agreement after the consensus meeting. Topics covered were clinical versus genetic diagnosis of FMF, genotype–phenotype correlation, genotype–age at onset correlation, silent carriers and risk of amyloid A (AA) amyloidosis, and role of the specialist in FMF diagnosis. The SHARE initiative provides recommendations for diagnosing FMF aimed at facilitating improved and uniform care throughout Europe.

Tolerance and efficacy of off-label anti-interleukin-1 treatments in France: a nationwide survey

BackgroundDespite their limited licensed indications, anti–interleukin-1 (anti–IL-1) agents are often used in clinical practice for an increasing number of auto-inflammatory diseases. We conducted a national cross-sectional observational study from January 2011 to January 2013 to record the off-label use of such agents in France. We aimed to estimate the off-label use of anti–IL-1 treatments in France, assess their efficacy in rare diseases, and increase the reporting of their possible side effects.MethodsPhysicians answered a questionnaire that covered patient and disease data, anti–IL-1 agent use, efficacy and adverse events. The study involved adult or paediatric patient who had received an anti–IL-1 agent after January 2005 in France.ResultsIn total, 189 patients from 38 centres were included. The main diseases were adult-onset Still’s disease (AOSD) (35), gout (28), systemic juvenile idiopathic arthritis (27), cryopyrin-associated periodic syndrome (CAPS) (21), familial Mediterranean fever (14) and mevalonate kinase deficiency (12). The main off-label used agent was anakinra, used at least once for 185 patients, with canakinumab used for 25. Anakinra was effective in most patients (90%), with higher complete clinical response rates for Schnitzler’s syndrome, gout, CAPS and AOSD. Overall, 58% of patients showed at least one adverse event, mainly minor injection-site reactions. The main reported serious adverse event was severe infection. Injection-site reactions and liver toxicity were significantly more frequent in children than adults. The main non-cutaneous adverse event was liver toxicity, significantly associated with treatment duration. Weight gain was reported in about 10% of patients and was associated with treatment duration and CAPS. Canakinumab was rarely used and showed better cutaneous tolerance than anakinra but similar rates of non-cutaneous and severe adverse events.ConclusionsAnakinra was well tolerated and effective in most patients with various inflammatory diseases. The main adverse events were mild injection-site reactions, especially in children. The survey allowed for collecting limited information on the off-label use of canakinumab.

IL-1RA agonist (anakinra) in the treatment of multifocal castleman disease: case report.

Multicentric Castleman disease (MCD), or multicentric angiofollicular lymph node hyperplasia, is an idiopathic lymphoproliferative disorder that is only seldom reported in children. The clinical and laboratory findings that characterize this peculiar disorder are thought to result from increased interleukin (IL)-6 production. We report herein the case of a 13-year-old boy with a long history of hectic fevers and abdominal pain, accompanied by stunted growth and elevated biologic markers of inflammation. Surgical biopsies of a pancreatico-splenic mass and of mesenteric lymph nodes revealed mixed-type MCD, which was diagnosed 6 years after the first clinical symptoms appeared. He received combination chemotherapy (cyclophosphamide, vinblastine) associated with a monoclonal B-cell antibody (Rituximab). This treatment was well tolerated but ineffective. Given the reported success of IL-1 blocking agents for treating Still disease, another IL-6 linked disorder, we attempted to treat him with anakinra, an IL-1RA agonist. His overall state normalized and both his clinical and biologic signs dramatically improved. This is the first report of anakinra treatment for MCD. We conclude that anti-IL-1 blocking agents could be an interesting treatment alternative for MCD, a chronic debilitating disease, which still carries a poor prognosis.

Molecular and immunological biomarkers to predict IVIg response

Some patients with autoimmune and inflammatory diseases treated with intravenous immunoglobulin G (IVIg) as a first line therapy are refractory. Identification of predictive biomarker(s) to segregate responders and non-responders to IVIg therapy remains critical. A number of biomarkers, particularly in Kawasaki disease, have shown potential for predicting response to IVIg.

Current treatment recommendations and considerations for cryopyrin-associated periodic syndrome.

Cryopyrin-associated periodic syndrome (CAPS) encompasses a spectrum of three phenotypes of increasing severity. The syndrome is due to dominant mutations in NLRP3, which encodes a key component of the innate immunity that regulates the secretion of IL-1β. CAPS manifests as systemic inflammation, which compromises quality of life and leads to serious complications and handicap. Anti-IL-1 drugs have shown remarkable efficacy in treating CAPS symptoms and have significantly changed patients’ lives. They have acceptable safety profiles but do have some differences. We review three drugs that are currently marketed for CAPS, give additional information for the practical use of these drugs, and provide some recommendations for management.

Anakinra for cryopyrin-associated periodic syndrome

Cryopyrin-associated periodic syndrome (CAPS) is a very rare auto-inflammatory syndrome, which has recently served as a pure model of IL-1β-driven diseases. CAPS is caused by mutations into the NLRP3 gene that encodes crypoyrin, which serves as a receptor of the innate immunity that senses danger signals and pathogens. Constitutive activation of cryopyrin in CAPS leads to an excessive secretion of IL-1β. CAPS patients experience symptoms of systemic inflammation, intense fatigue and have poor quality of life. In the most severe forms, they may develop serious organ damage such as visual and hearing impairment, neurological deterioration and renal insufficiency. Anti-IL-1 drugs are effective in treating symptoms of almost all CAPS patients and have radically transformed their lives. We describe the history of the ‘revival’ of CAPS patients through anti-IL-1 treatments with a special focus on anakinra, the first drug used in cohorts with variable disease severity and number of patients.

Coronary artery abnormalities in children with systemic-onset juvenile idiopathic arthritis

Stills disease (Systemic-onset Juvenile Idiopathic Arthritis: SoJIA) is characterised by high-spiking daily fevers, arthritis and evanescent rashes. Diagnosis of Stills disease is often challenging. Infectious diseases and other inflammatory conditions, especially in young children, Kawasaki disease may look similar. Clinicians often rely on echocardiographic evidence of coronary artery abnormalities to differentiate between Kawasaki disease and Stills disease. Coronary artery dilation would typically favour the diagnosis of Kawasaki disease. We present four children with Stills disease and coronary artery abnormalities who were initially misdiagnosed as Kawasaki disease. The first patient had pericarditis and an irregular wall of the left coronary artery, without dilation on echocardiography. The second patient had a left coronary artery dilatation and a pericarditis. The third patient had thickened left coronary artery walls, and the fourth patient had a hyperechogenicity of the left and right coronary arteries. They received IVIG without success. The diagnosis of Stills disease was made secondary with evidence of persistent arthritis. All but one patient finally needed biologic treatments. Coronary abnormalities may be observed during various febrile conditions and do not exclude the diagnosis of Stills disease.

Heme oxygenase-1 is dispensable for the anti-inflammatory activity of intravenous immunoglobulin

Intravenous immunoglobulin G (IVIG) is used in the therapy of various autoimmune and inflammatory conditions. The mechanisms by which IVIG exerts anti-inflammatory effects are not completely understood. IVIG interacts with numerous components of the immune system including dendritic cells, macrophages, T and B cells and modulate their functions. Recent studies have reported that heme oxygenase-1 (HO-1) pathway plays an important role in the regulation of inflammatory response in several pathologies. Several therapeutic agents exert anti-inflammatory effects via induction of HO-1. Therefore, we aimed at exploring if anti-inflammatory effects of IVIG are mediated via HO-1 pathway. Confirming the previous reports, we report that IVIG exerts anti-inflammatory effects on innate cells as shown by the inhibitory effects on IL-6 and nitric oxide production and confers protection in experimental autoimmune encephalomyelitis (EAE) model. However, these effects were not associated with an induction of HO-1 either in innate cells such as monocytes, dendritic cells and macrophages or in the kidneys and liver of IVIG-treated EAE mice. Also, inhibition of endogenous HO-1 did not modify anti-inflammatory effects of IVIG. These results thus indicate that IVIG exerts anti-inflammatory effects independent of HO-1 pathway.