Maryam Piram

Epidemiology of immunoglobulin A vasculitis (Henoch-Schönlein): current state of knowledge.

Purpose of reviewTo review the current knowledge of epidemiological features of immunoglobulin (Ig) A vasculitis (Henoch–Schönlein) and disease etiology. Recent findingsThe annual incidence of IgA vasculitis in the population is an estimated 3–26.7/100u200a000 for children and infants and 0.8–1.8/100u200a000 for adults. These may be conservative approximations of the true frequency because of skewed case-finding strategies. In children, the marked autumn–winter peak in incidence rates, the frequent occurrence after an upper respiratory tract infection and the short interval between disease onset in index cases and in other family members collectively point to a transmissible infectious process. A subset of adult IgA vasculitis could be related to preceding or concurrent malignancies. Despite several lines of evidence supporting the critical role of an exogenous factor in IgA vasculitis, recent progress has been made in understanding the genetic susceptibility to IgA vasculitis. Recent findings also lessened the suggestion that IgA vasculitis might be triggered by vaccination. SummaryIgA vasculitis is two to 33 times more common in children than adults and appears to have a strong environmental component, with possibly different risk factors in childhood and adulthood. Support is strengthening for a role of genetics in IgA vasculitis.

First Clinical Description of an Infant With Interleukin-36-Receptor Antagonist Deficiency Successfully Treated With Anakinra

YM is the first son of Tunisian consanguineous parents who developed, at 2 weeks of life, an erythematous and scaly eruption, with subsequent rapid evolution toward generalized pustular psoriasis. Afterward, cutaneous flares of diffuse erythematous rash and pustules involving the whole body appeared, with a once weekly periodicity. Intense irritability was present during flares without fever. Moreover, since 1 month of age the infant presented with diarrhea, dysphagia, and reduced feeding rate, with failure to thrive. Laboratory tests during acute flares showed marked leukocytosis, thrombocytosis, and anemia without C-reactive protein elevation. Skin biopsy and clinical presentation were consistent with pustular psoriasis; nevertheless, the patient did not respond to high-potency topical corticosteroids and retinoid acid. As the patient presented with repeated skin flares early after birth, as well as serious constitutional distress with failure to thrive, an autoinflammatory syndrome like interleukine-1-receptor antagonist deficiency or interleukin-36-receptor antagonist deficiency (DITRA) was considered. The hypothesis was reinforced by parental consanguinity, and absence of skin lesion improvement under standard topical treatment. Genetic analyses showed a homozygous mutation in the IL36RN gene (L27P), which represents the same mutation recently described in DITRA patients. At age 6 months we started treatment with the recombinant interleukin-1 receptor antagonist anakinra with efficacy both on constitutional symptoms and skin involvement. DITRA is a recently described autoinflammatory disease characterized by repeated flares of generalized pustular psoriasis, high fever, asthenia, and systemic inflammation. We report herein the first exhaustive clinical description of an infant with DITRA who was successfully treated with anakinra.

Targeting interleukin-1β in CAPS (cryopyrin-associated periodic) syndromes: what did we learn?

CAPS is the prototype of an IL-1β driven auto inflammatory disorder. Features of recurrent systemic inflammation compromises patients quality of life, and may reduce life expectancy by inducing definite organ damage. Recent treatment targeting IL-1 have shown dramatic effect on patients clinical symptoms and quality of life. Anakinra was first used successfully in treating small series of patients with all CAPS phenotypes. Two pivotal randomized placebo-controlled studies allowed licensing of rilonacept and canakinumab as orphan drugs for CAPS patients. The use of anti-IL-1 drugs in CAPS is still relatively new, and their effect on a long term is not well known. As we can suppress the clinical symptoms of patients with CAPS, important questions remain regarding the full effect of anti-IL-1 treatment on organ involvement and their potential ability to prevent them. As important variations of treatment doses and schedules appear in reaching effectiveness, pharmacologic studies are still warranted to determine a potential diffusion of anti-IL-1 drugs in the fluids and tissues. More studies evaluating the efficacy and safety of anti-IL-1 drugs given in patients before 2 years of age are warranted, since it is believed that the earliest treatment could avoid secondary CAPS complications to develop.

A preliminary score for the assessment of disease activity in hereditary recurrent fevers: results from the AIDAI (Auto-Inflammatory Diseases Activity Index) Consensus Conference

Background The systemic autoinflammatory disorders (SAID) share many clinical manifestations, albeit with variable patterns, intensity and frequency. A common definition of disease activity would be rational and useful in the management of these lifelong diseases. Moreover, standardised disease activity scores are required for the assessment of new therapies in constant development. The aim of this study was to develop preliminary activity scores for familial Mediterranean fever, mevalonate kinase deficiency, tumour necrosis factor receptor-1-associated periodic syndrome and cryopyrin-associated periodic syndromes (CAPS). Methods The study was conducted using two well-recognised consensus formation methods: the Delphi technique and the nominal group technique. The results from a two-step survey and data from parent/patient interviews were used as preliminary data to develop the agenda for a consensus conference to build a provisional scoring system. Results 24 of 65 experts in SAID from 20 countries answered the web questionnaire and 16 attended the consensus conference. There was consensus agreement to develop separate activity scores for each disease but with a common format based on patient diaries. Fever and disease-specific clinical variables were scored according to their severity. A final score was generated by summing the score of all the variables divided by the number of days over which the diary was completed. Scores varied from 0 to 16 (0–13 in CAPS). These scores were developed for the purpose of clinical studies but could be used in clinical practice. Conclusion Using widely recognised consensus formation techniques, preliminary scores were obtained to measure disease activity in four main SAID. Further prospective validation study of this instrument will follow.

Validation of the Auto-Inflammatory Diseases Activity Index (AIDAI) for hereditary recurrent fever syndromes

Objectives To validate the Auto-Inflammatory Diseases Activity Index (AIDAI) in the four major hereditary recurrent fever syndromes (HRFs): familial Mediterranean fever (FMF), mevalonate kinase deficiency (MKD), tumour necrosis factor receptor-associated periodic syndrome (TRAPS) and cryopyrin-associated periodic syndromes (CAPS). Methods In 2010, an international collaboration established the content of a disease activity tool for HRFs. Patients completed a 1-month prospective diary with 12 yes/no items before a clinical appointment during which their physician assessed their disease activity by a questionnaire. Eight international experts in auto-inflammatory diseases evaluated the patients disease activity by a blinded web evaluation and a nominal group technique consensus conference, with their consensus judgement considered the gold standard. Sensitivity/specificity/accuracy measures and the ability of the score to discriminate active from inactive patients via the best cut-off score were calculated by a receiver operating characteristic analysis. Results Consensus was achieved for 98/106 (92%) cases (39 FMF, 35 CAPS, 14 TRAPS and 10 MKD), with 26 patients declared as having inactive disease and 72 as having active disease. The median total AIDAI score was 14 (range=0–175). An AIDAI cut-off score ≥9 discriminated active from inactive patients, with sensitivity/specificity/accuracy of 89%/92%/90%, respectively, and an area under the curve of 98% (95% CI 96% to 100%). Conclusions The AIDAI score is a valid and simple tool for assessing disease activity in FMF/MKD/TRAPS/CAPS. This tool is easy to use in clinical practice and has the potential to be used as the standard efficacy measure in future clinical trials.

Effect of race/ethnicity on risk, presentation and course of connective tissue diseases and primary systemic vasculitides.

Purpose of reviewUnderstanding the effects of race/ethnicity on the risk and expression of systemic rheumatic diseases has potential clinical implications and provides insight into their etiopathogeneses. This review summarizes knowledge of the effects of race/ethnicity on the following nine conditions: antineutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV), Behçets disease, dermatomyositis/polymyositis, Henoch-Schönlein purpura, Kawasaki disease, large-vessel vasculitis (LVV), primary Sjögrens syndrome (pSS), systemic lupus erythematosus (SLE) and systemic sclerosis (SSc). Recent findingsDistinct racial/ethnic patterns have emerged for most of the conditions considered here. Areas of progress include the finding that the two AAVs, granulomatosis with polyangiitis (Wegeners) (GPA) and microscopic polyangiitis, exhibit distinct racial/ethnic susceptibilities in disease risk. In addition, nonwhites, with known high risk of SLE and SSc, may also be at a high risk for pSS and have more severe disease. Evidence is accumulating that nonwhites are rarely affected by the LVV giant-cell arteritis. Race/ethnicity-specific genetic risk factors were recently detected for GPA. SummaryEpidemiologic data have allowed discerning the racial/ethnic profiles for many of the considered systemic rheumatic conditions. Future challenges will be to unravel the genetic, environmental and/or socio-econonomic determinants of the observed racial/ethnic disparities. More research is needed to clarify the impact of race/ethnicity on the AAV Churg-Strauss syndrome, dermatomyositis/polymyositis and Takayasu arteritis.

Validation of the new paediatric criteria for the diagnosis of familial Mediterranean fever: data from a mixed population of 100 children from the French reference centre for auto-inflammatory disorders

OBJECTIVEnWe aimed to validate the new paediatric criteria for diagnosis of FMF in a mixed population of 100 French patients.nnnMETHODSnThe study group included 100 FMF children from the French reference centre for auto-inflammatory disorders. A control group of 40 patients with unexplained recurrent fever was reviewed in parallel. Both groups of patients were assessed for both the Tel Hashomer and the new paediatric criteria published by Yalcinkaya et al.nnnRESULTSnComparison of Tel Hashomer vs Yalcinkayas criteria in both groups gave a sensitivity of 99 vs 100%, a specificity of 45 vs 50%, a positive predictive value (PPV) of 81.8 vs 83.3% and a negative predictive value (NPV) of 94.7 vs 100%. However, when we used at least three Yalcinkayas criteria we obtained a sensitivity of 77% and a specificity of 95% with a PPV of 97.3% and an NPV of 62.3%. The number of mutations in the MEFV gene did not modify results for both sets of criteria.nnnCONCLUSIONnThe new paediatric Turkish criteria did not make a better contribution to FMF diagnosis than the Tel Hashomer criteria in our mixed population of French children while using an appropriate control group. However, if needed, they can be applied using at least three criteria, which slightly decreases their sensitivity but markedly increases their specificity.

Kawasaki disease in adults: Observations in France and literature review.

OBJECTIVEnKawasaki disease (KD) is a vasculitis that mostly occurs in young children and rarely in adults. We analyzed the characteristics of adult-onset KD (AKD) in France.nnnMETHODSnWe collected retrospective and prospective data for patients with a diagnosis of KD occurring after the age of 18 years. Cases were obtained via various French medical networks and identified from the international literature.nnnRESULTSnWe included 43 patients of AKD at 26 institution from 1992 to 2015, with mean (SD) age 30 (11) years (range 18-68) and sex ratio (M/F) 1.2; 34 patients met the American Heart Association criteria and 9 were incomplete AKD. The median time to diagnosis was 13 days (interquartile range 8-21). The main symptoms were fever (100%), exanthema (98%), changes in the extremities (91%), conjunctivitis (77%), oral cavity changes (89%), cervical adenitis (55%) and cardiac abnormalities (45%). Overall, 35% of patients showed large-vessel vasculitis: coronary vasculitis (26%) and coronary aneurysm (19%). Treatment was mostly intravenous immunoglobulins (79%) and aspirin (81%). Four patients showed myocardial infarction due to coronary vasculitis, but none were treated with IVIg because of late diagnosis. After a median follow-up of 5 months (range 1-117), persistent aneurysm was noted in 9% of cases. Damage was significantly lower with early treatment than late or no treatment (p=0.01).nnnCONCLUSIONnGiven the high frequency of cardiac involvement and complications in this series of AKD, diagnosis and treatment should not be delayed, and early IVIg treatment seems to improve the outcome.

The expanding spectrum of rare monogenic autoinflammatory diseases

Monogenic autoinflammatory diseases are a group of hereditary disorders characterized by a clinical and biological inflammatory syndrome in which there is little or no evidence of autoimmunity. The discovery of the first causative gene in 1997 was rapidly followed by the identification of many others from the same group. The mutated proteins can be directly or indirectly involved in the regulation of inflammation. The available literature includes numerous reviews, which address the principle diseases, but we wanted to focus on the most recent rare syndromes. A comprehensive review is thus provided, including taxonomic, genetic, and epidemiological data, along with characteristics defining positive and differential diagnoses and treatment. We believe that this update will assist physicians in correctly naming their patient’s illness. This is an essential step for the effective and targeted management of an orphan disease.Abstract in frenchLes maladies autoinflammatoires monogéniques sont un groupe de pathologies héréditaires caractérisées par un syndrome inflammatoire clinique et biologique, dans lesquelles on ne retrouve pas ou peu de signe dautoimmunité. La découverte du premier gène en 1997 a été rapidement suivie par l’identification de nombreux autres appartenant au même groupe. Les protéines mutées participent directement ou indirectement à la régulation de l’inflammation. De nombreuses revues balayant les principales entités sont disponibles dans la littérature, mais nous avons voulu mettre la lumière sur les formes rares les plus récentes. Nous proposons une revue exhaustive incluant des données taxonomiques, génétiques, épidémiologiques, ainsi que des éléments cliniques de certitude et différentiels, et de traitement. Nous espérons que cette mise à jour aidera le médecin à mettre un nom sur la maladie dont souffrent leurs patients atteints de maladie autoinflammatoire, une étape indispensable pour une prise en charge efficace et ciblée.

A restrospective survey of patients's journey before the diagnosis of mevalonate kinase deficiency

UNLABELLEDnMevalonate kinase deficiency (MKD) is an autosomic recessive auto-inflammatory disease caused by mutations of the MVK gene. MKD being a very rare disease, numerous misdiagnoses and medical referrals may precede the right diagnosis, amplifying the burden of the disease.nnnOBJECTIVESnTo evaluate the patients medical referrals between the first symptom and the diagnosis of MKD and the diagnosis delay.nnnMETHODSnA questionnaire was sent to French paediatric and adult rheumatologists to retrospectively collect information from genetically confirmed patients with MKD regarding the first symptoms of the disease, the different diagnoses made previously, the treatments received, and the disease burden evaluated mainly by the number of hospitalizations.nnnRESULTSnThirteen patients were analyzed. The mean age at onset was 9.5months (birth to 36months). The average diagnosis delay was 7.1years. Eleven of them were hospitalized at least 5 times before the establishment of the diagnosis. A wide variety of diseases had been suspected: systemic juvenile idiopathic arthritis, periodic fever aphtous stomatitis pharyngitis adenitis syndrome, other hereditary recurrent fever, vasculitis, connective tissue disease, inflammatory bowel disease, gastritis, infections and immunodeficiency. Before the right diagnosis, 9 patients received corticosteroids and 6 patients received non-steroidal-anti-inflammatory drugs. Half patients had received repeated antibiotics, one third had received intravenous immunoglobulin, and the others were treated with immunosuppressive drugs or hydroxychloroquine.nnnCONCLUSIONSnMKD is a serious disease still difficult to treat, however earlier accurate medical referral and care, by increasing physicians awareness, is critical to improve both the disease course and quality of life.