: Autoinflammatory diseases are characterised by fever and systemic inflammation, with potentially serious complications. Owing to the rarity of these diseases, evidence-based guidelines are lacking. ...In 2012, the European project Single Hub and Access point for paediatric Rheumatology in Europe (SHARE) was launched to optimise and disseminate regimens for the management of children and young adults with rheumatic diseases, facilitating the clinical practice of paediatricians and (paediatric) rheumatologists. One of the aims of SHARE was to provide evidence-based recommendations for the management of the autoinflammatory diseases cryopyrin-associated periodic syndromes (CAPS), tumour necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS) and mevalonate kinase deficiency (MKD). These recommendations were developed using the European League Against Rheumatism standard operating procedure. An expert committee of paediatric and adult rheumatologists was convened. Recommendations derived from the systematic literature review were evaluated by an online survey and subsequently discussed at a consensus meeting using Nominal Group Technique. Recommendations were accepted if more than 80% agreement was reached. In total, four overarching principles, 20 recommendations on therapy and 14 recommendations on monitoring were accepted with ≥80% agreement among the experts. Topics included (but were not limited to) validated disease activity scores, therapy and items to assess in monitoring of a patient. By developing these recommendations, we aim to optimise the management of patients with CAPS, TRAPS and MKD.
Familial Mediterranean fever (FMF) is an autoinflammatory disease caused by homozygous or compound heterozygous gain-of-function mutations in MEFV, which encodes pyrin, an inflammasome protein. ...Heterozygous carrier frequencies for multiple MEFV mutations are high in several Mediterranean populations, suggesting that they confer selective advantage. Among 2,313 Turkish people, we found extended haplotype homozygosity flanking FMF-associated mutations, indicating evolutionarily recent positive selection of FMF-associated mutations. Two pathogenic pyrin variants independently arose >1,800 years ago. Mutant pyrin interacts less avidly with Yersinia pestis virulence factor YopM than with wild-type human pyrin, thereby attenuating YopM-induced interleukin (IL)-1β suppression. Relative to healthy controls, leukocytes from patients with FMF harboring homozygous or compound heterozygous mutations and from asymptomatic heterozygous carriers released heightened IL-1β specifically in response to Y. pestis. Y. pestis-infected Mefv
FMF knock-in mice exhibited IL-1-dependent increased survival relative to wild-type knock-in mice. Thus, FMF mutations that were positively selected in Mediterranean populations confer heightened resistance to Y. pestis.
The syndrome of periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) is the most common periodic fever disease in children. However, the pathogenesis is unknown. Using a ...systems biology approach we analyzed blood samples from PFAPA patients whose genetic testing excluded hereditary periodic fevers (HPFs), and from healthy children and pediatric HPF patients. Gene expression profiling could clearly distinguish PFAPA flares from asymptomatic intervals, HPF flares, and healthy controls. During PFAPA attacks, complement (C1QB, C2, SERPING1), IL-1-related (IL-1B, IL-1RN, CASP1, IL18RAP), and IFN-induced (AIM2, IP-10/CXCL10) genes were significantly overexpressed, but T cell-associated transcripts (CD3, CD8B) were down-regulated. On the protein level, PFAPA flares were accompanied by significantly increased serum levels of chemokines for activated T lymphocytes (IP-10/CXCL10, MIG/CXCL9), G-CSF, and proinflammatory cytokines (IL-18, IL-6). PFAPA flares also manifested a relative lymphopenia. Activated CD4âº/CD25⺠T-lymphocyte counts correlated negatively with serum concentrations of IP-10/CXCL10, whereas CD4âº/HLA-DR⺠T lymphocyte counts correlated positively with serum concentrations of the counterregulatory IL-1 receptor antagonist. Based on the evidence for IL-1β activation in PFAPA flares, we treated five PFAPA patients with a recombinant IL-1 receptor antagonist. All patients showed a prompt clinical and IP-10/CXCL10 response. Our data suggest an environmentally triggered activation of complement and IL-1β/-18 during PFAPA flares, with induction of Th1-chemokines and subsequent retention of activated T cells in peripheral tissues. IL-1 inhibition may thus be beneficial for treatment of PFAPA attacks, with IP-10/CXCL10 serving as a potential biomarker.
Chronic granulomatous disease (CGD) is characterized by recurrent infections and granuloma formation. In addition, we have observed a number of diverse autoimmune conditions in our CGD population, ...suggesting that patients with CGD are at an elevated risk for development of autoimmune disorders. In this report, we describe antiphospholipid syndrome, recurrent pericardial effusion, juvenile idiopathic arthritis, IgA nephropathy, cutaneous lupus erythematosus, and autoimmune pulmonary disease in the setting of CGD. The presence and type of autoimmune disease have important treatment implications for patients with CGD.
Currently, there is no proven alternative therapy for patients with familial Mediterranean fever (FMF) that is resistant to or intolerant of colchicine. Interleukin-1 is a key proinflammatory ...cytokine in FMF.
To assess the efficacy and safety of rilonacept, an interleukin-1 decoy receptor, in treating patients with colchicine-resistant or -intolerant FMF.
Randomized, double-blind, single-participant alternating treatment study. (ClinicalTrials.gov number: NCT00582907).
6 U.S. sites.
Patients with FMF aged 4 years or older with 1 or more attacks per month.
One of 4 treatment sequences that each included two 3-month courses of rilonacept, 2.2 mg/kg (maximum, 160 mg) by weekly subcutaneous injection, and two 3-month courses of placebo.
Differences in the frequency of FMF attacks and adverse events between rilonacept and placebo.
8 males and 6 females with a mean age of 24.4 years (SD, 11.8) were randomly assigned. Among 12 participants who completed 2 or more treatment courses, the rilonacept-placebo attack risk ratio was 0.59 (SD, 0.12) (equal-tail 95% credible interval, 0.39 to 0.85). The median number of attacks per month was 0.77 (0.18 and 1.20 attacks in the first and third quartiles, respectively) with rilonacept versus 2.00 (0.90 and 2.40, respectively) with placebo (median difference, -1.74 95% CI, -3.4 to -0.1; P = 0.027). There were more treatment courses of rilonacept without attacks (29% vs. 0%; P = 0.004) and with a decrease in attacks of greater than 50% compared with the baseline rate during screening (75% vs. 35%; P = 0.006) than with placebo. However, the duration of attacks did not differ between placebo and rilonacept (median difference, 1.2 days -0.5 and 2.4 days in the first and third quartiles, respectively; P = 0.32). Injection site reactions were more frequent with rilonacept (median difference, 0 events per patient treatment month medians of -4 and 0 in the first and third quartiles, respectively; P = 0.047), but no differences were seen in other adverse events.
Small sample size, heterogeneity of FMF mutations, age, and participant indication (colchicine resistance or intolerance) were study limitations.
Rilonacept reduces the frequency of FMF attacks and seems to be a treatment option for patients with colchicine-resistant or -intolerant FMF.
U.S. Food and Drug Administration, Office of Orphan Products Development.
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