Joost Frenkel

An Autoinflammatory Disease with Deficiency of the Interleukin-1–Receptor Antagonist

BACKGROUND Autoinflammatory diseases manifest inflammation without evidence of infection, high-titer autoantibodies, or autoreactive T cells. We report a disorder caused by mutations of IL1RN, which encodes the interleukin-1-receptor antagonist, with prominent involvement of skin and bone. METHODS We studied nine children from six families who had neonatal onset of sterile multifocal osteomyelitis, periostitis, and pustulosis. Response to empirical treatment with the recombinant interleukin-1-receptor antagonist anakinra in the first patient prompted us to test for the presence of mutations and changes in proteins and their function in interleukin-1-pathway genes including IL1RN. RESULTS We identified homozygous mutations of IL1RN in nine affected children, from one family from Newfoundland, Canada, three families from The Netherlands, and one consanguineous family from Lebanon. A nonconsanguineous patient from Puerto Rico was homozygous for a genomic deletion that includes IL1RN and five other interleukin-1-family members. At least three of the mutations are founder mutations; heterozygous carriers were asymptomatic, with no cytokine abnormalities in vitro. The IL1RN mutations resulted in a truncated protein that is not secreted, thereby rendering cells hyperresponsive to interleukin-1beta stimulation. Patients treated with anakinra responded rapidly. CONCLUSIONS We propose the term deficiency of the interleukin-1-receptor antagonist, or DIRA, to denote this autosomal recessive autoinflammatory disease caused by mutations affecting IL1RN. The absence of interleukin-1-receptor antagonist allows unopposed action of interleukin-1, resulting in life-threatening systemic inflammation with skin and bone involvement. (ClinicalTrials.gov number, NCT00059748.)

Long-term follow-up, clinical features, and quality of life in a series of 103 patients with hyperimmunoglobulinemia D syndrome.

The hyperimmunoglobulinemia D and periodic fever syndrome (HIDS), one of the autoinflammatory syndromes, is caused by mutations in the gene coding for mevalonate kinase (MVK). We conducted the current study to assess the genetic, laboratory, and clinical features as well as the complications and course of disease in patients with genetically confirmed HIDS. In addition, we studied the quality of life and course of life in a selection of patients. Follow-up data were obtained by a questionnaire sent to all physicians of patients in the International HIDS Database. In addition, we assessed the course of life and quality of life in Dutch patients aged >16 years using validated quality of life instruments. Data were obtained from 103 patients from 18 different countries. The median age of first attack was 6 months (range, 0-120 mo), with a median period of 9.9 years from onset of disease to diagnosis. The most frequent symptoms that accompanied attacks of fever were lymphadenopathy, abdominal pain, arthralgia, diarrhea, vomiting, skin lesions, and aphthous ulcers. Amyloidosis was a severe but infrequent complication (2.9%). The median serum IgD level was 400 U/mL. IgD levels were normal in 22% of patients. The 4 most prevalent mutations (V377I, I268T, H20P/N, P167L) accounted for 71.5% of mutations found. The frequency of attacks decreased with the patients increasing age, although 50% of patients over the age of 20 years still had 6 or more attacks per year. Many drugs have been tried in HIDS. Some patients responded to high-dose prednisone (24.4% response). Anakinra and etanercept can also be effective (33.3% response). Quality of life was determined in a subgroup of patients (n = 28). Social functioning, general health perception, and vitality were significantly lower in patients with HIDS than in controls, as were autonomy and social development. In addition, HIDS had an adverse impact on educational achievements and employment status. In conclusion, HIDS is an early-onset disease that is accompanied by an array of inflammatory symptoms. Although the frequency of attacks decreases during the patients life, many patients continue to have frequent attacks. HIDS impairs several aspects of quality of life. Abbreviations: FMF = familial Mediterranean fever, HIDS = hyperimmunoglobulinemia D and periodic fever syndrome, MKD = mevalonate kinase deficiency, MVA = mevalonic aciduria, MVK = mevalonate kinase, RAND-36 = RAND-36 Health Survey, TAAQoL = TNOAZL Adult Quality of Life questionnaire, TRAPS = tumor necrosis factor-1 receptor-associated periodic syndrome

A Trial of Artemether or Quinine in Children with Cerebral Malaria

BACKGROUND Cerebral malaria has a mortality rate of 10 to 30 percent despite treatment with parenteral quinine, a situation that may worsen with the spread of quinine resistance. Artemether is a new antimalarial agent that clears parasites from the circulation more rapidly than quinine, but its effect on mortality is unclear. METHODS We conducted a randomized, unblinded comparison of intramuscular artemether and intramuscular quinine in 576 Gambian children with cerebral malaria. The primary end points of the study were mortality and residual neurologic sequelae. RESULTS Fifty-nine of the 288 children treated with artemether died in the hospital (20.5 percent), as compared with 62 of the 288 treated with quinine (21.5 percent). Among the 418 children analyzed at approximately five months for neurologic disease, residual neurologic sequelae were detected in 7 of 209 survivors treated with artemether (3.3 percent) and 11 of 209 survivors treated with quinine (5.3 percent, P = 0.5). After adjustment for potential confounders, the odds ratio for death was 0.84 (95 percent confidence interval, 0.53 to 1.32) in the artemether group, and for residual neurologic sequelae, 0.51 (95 percent confidence interval, 0.17 to 1.47). There were fewer local reactions at the injection site with artemether than with quinine (0.7 percent vs. 5.9 percent, P = 0.001). CONCLUSIONS Artemether is as effective as quinine in the treatment of cerebral malaria in children.

Treatment of autoinflammatory diseases: results from the Eurofever Registry and a literature review

Objective To evaluate the response to treatment of autoinflammatory diseases from an international registry and an up-to-date literature review. Methods The response to treatment was studied in a web-based registry in which clinical information on anonymised patients with autoinflammatory diseases was collected retrospectively as part of the Eurofever initiative. Participating hospitals included paediatric rheumatology centres of the Paediatric Rheumatology International Trial Organisation network and adult centres with a specific interest in autoinflammatory diseases. The following diseases were included: familial Mediterranean fever (FMF), cryopyrin-associated periodic syndromes (CAPS), tumour necrosis factor (TNF)-receptor associated periodic syndrome (TRAPS), mevalonate kinase deficiency (MKD), pyogenic arthritis pustulosis acne (PAPA) syndrome, deficiency of interleukin-1 receptor antagonist (DIRA), NLRP12-related periodic fever and periodic fever aphthosis pharyngitis adenitis (PFAPA) syndrome. Cases were independently validated by experts for each disease. A literature search regarding treatment of the abovementioned diseases was also performed using Medline and Embase. Results 22 months from the beginning of the enrolment, complete information on 496 validated patients was available. Data from the registry in combination with evidence from the literature confirmed that colchicine is the treatment of choice for FMF and IL-1 blockade for DIRA and CAPS. Corticosteroids on demand probably represent a valid therapeutic strategy for PFAPA, but also for MKD and TRAPS. Patients with poorly controlled MKD, TRAPS, PAPA or FMF may benefit from IL-1 blockade; anti-TNF treatment may represent a possible valuable alternative. Conclusions In the absence of high-grade evidence, these results could serve as a basis for therapeutic guidelines and to identify candidate drugs for future therapeutic trials.

High Incidence of NLRP3 Somatic Mosaicism in Patients With Chronic Infantile Neurologic, Cutaneous, Articular Syndrome: Results of an International Multicenter Collaborative Study

OBJECTIVE Chronic infantile neurologic, cutaneous, articular (CINCA) syndrome, also known as neonatal-onset multisystem inflammatory disease (NOMID), is a dominantly inherited systemic autoinflammatory disease. Although heterozygous germline gain-of-function NLRP3 mutations are a known cause of this disease, conventional genetic analyses fail to detect disease-causing mutations in ∼40% of patients. Since somatic NLRP3 mosaicism has been detected in several mutation-negative NOMID/CINCA syndrome patients, we undertook this study to determine the precise contribution of somatic NLRP3 mosaicism to the etiology of NOMID/CINCA syndrome. METHODS An international case-control study was performed to detect somatic NLRP3 mosaicism in NOMID/CINCA syndrome patients who had shown no mutation during conventional sequencing. Subcloning and sequencing of NLRP3 was performed in these mutation-negative NOMID/CINCA syndrome patients and their healthy relatives. Clinical features were analyzed to identify potential genotype-phenotype associations. RESULTS Somatic NLRP3 mosaicism was identified in 18 of the 26 patients (69.2%). Estimates of the level of mosaicism ranged from 4.2% to 35.8% (mean ± SD 12.1 ± 7.9%). Mosaicism was not detected in any of the 19 healthy relatives (18 of 26 patients versus 0 of 19 relatives; P < 0.0001). In vitro functional assays indicated that the detected somatic NLRP3 mutations had disease-causing functional effects. No differences in NLRP3 mosaicism were detected between different cell lineages. Among nondescript clinical features, a lower incidence of mental retardation was noted in patients with somatic mosaicism. Genotype-matched comparison confirmed that patients with somatic NLRP3 mosaicism presented with milder neurologic symptoms. CONCLUSION Somatic NLRP3 mutations were identified in 69.2% of patients with mutation-negative NOMID/CINCA syndrome. This indicates that somatic NLRP3 mosaicism is a major cause of NOMID/CINCA syndrome.

On-demand anakinra treatment is effective in mevalonate kinase deficiency

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.

Evidence-based provisional clinical classification criteria for autoinflammatory periodic fevers

The objective of this work was to develop and validate a set of clinical criteria for the classification of patients affected by periodic fevers. Patients with inherited periodic fevers (familial Mediterranean fever (FMF); mevalonate kinase deficiency (MKD); tumour necrosis factor receptor-associated periodic fever syndrome (TRAPS); cryopyrin-associated periodic syndromes (CAPS)) enrolled in the Eurofever Registry up until March 2013 were evaluated. Patients with periodic fever, aphthosis, pharyngitis and adenitis (PFAPA) syndrome were used as negative controls. For each genetic disease, patients were considered to be ‘gold standard’ on the basis of the presence of a confirmatory genetic analysis. Clinical criteria were formulated on the basis of univariate and multivariate analysis in an initial group of patients (training set) and validated in an independent set of patients (validation set). A total of 1215 consecutive patients with periodic fevers were identified, and 518 gold standard patients (291 FMF, 74 MKD, 86 TRAPS, 67 CAPS) and 199 patients with PFAPA as disease controls were evaluated. The univariate and multivariate analyses identified a number of clinical variables that correlated independently with each disease, and four provisional classification scores were created. Cut-off values of the classification scores were chosen using receiver operating characteristic curve analysis as those giving the highest sensitivity and specificity. The classification scores were then tested in an independent set of patients (validation set) with an area under the curve of 0.98 for FMF, 0.95 for TRAPS, 0.96 for MKD, and 0.99 for CAPS. In conclusion, evidence-based provisional clinical criteria with high sensitivity and specificity for the clinical classification of patients with inherited periodic fevers have been developed.

An International registry on Autoinflammatory diseases: the Eurofever experience

Objective To report on the demographic data from the first 18 months of enrollment to an international registry on autoinflammatory diseases in the context of the Eurofever project. Methods A web-based registry collecting baseline and clinical information on autoinflammatory diseases and related conditions is available in the member area of the PRINTO web-site. Anonymised data were collected with standardised forms. Results 1880 (M:F=916:964) individuals from 67 centers in 31 countries have been entered in the Eurofever registry. Most of the patients (1388; 74%), reside in western Europe, 294 (16%) in the eastern and southern Mediterranean region (Turkey, Israel, North Africa), 106 (6%) in eastern Europe, 54 in Asia, 27 in South America and 11 in Australia. In total 1049 patients with a clinical diagnosis of a monogenic autoinflammatory diseases have been enrolled; genetic analysis was performed in 993 patients (95%): 703 patients have genetically confirmed disease and 197 patients are heterozygous carriers of mutations in genes that are mutated in patients with recessively inherited autoinflammatory diseases. The median diagnosis delay was 7.3 years (range 0.3–76), with a clear reduction in patients born after the identification of the first gene associated with autoinflammatory diseases in 1997. Conclusions A shared online registry for patients with autoinflammatory diseases is available and enrollment is ongoing. Currently, there are data available for analysis on clinical presentation, disease course, and response to treatment, and to perform large scale comparative studies between different conditions.

Differentiating PFAPA syndrome from monogenic periodic fevers

OBJECTIVES: To analyze whether there were clinical differences between genetically positive and negative patients fulfilling periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome criteria and to test the accuracy of the Gaslini diagnostic score for identifying patients with PFAPA syndrome with higher probabilities of carrying relevant mutations in genes associated with periodic fevers. METHODS: Complete clinical and genetic information was available for 393 children with periodic fever; 82 had positive genetic test results, 75 had incomplete genetic test results, and 236 had negative results for MVK, TNFRSF1A, and MEFV mutations. Current diagnostic criteria for PFAPA syndrome were applied. RESULTS: Of 393 children, 210 satisfied PFAPA syndrome criteria; 43 carried diagnostic mutations (mevalonate kinase deficiency: n = 33; tumor necrosis factor receptor-associated periodic syndrome: n = 3; familial Mediterranean fever: n = 7), 37 displayed low-penetrance mutations or incomplete genotypes, and 130 demonstrated negative genetic testing results. Genetically positive patients had higher frequencies of abdominal pain and diarrhea (P < .001), vomiting (P = .006), and cutaneous rash and arthralgia (P = .01). Genetically negative patients had a higher frequency of exudative pharyngitis (P = .010). Genetically undetermined patients showed the same pattern of symptom frequency as genetically negative patients. The Gaslini diagnostic score was able to identify 91% of genetically positive patients correctly, with a global accuracy of 66%. CONCLUSION: The Gaslini diagnostic score represents a useful tool to identify patients meeting PFAPA syndrome criteria and at low risk of carrying relevant mutations in genes associated with periodic fevers.

Effective treatment of a colchicine-resistant familial Mediterranean fever patient with anakinra

Familial Mediterranean fever (FMF) is an autoinflammatory disorder, characterized by periodic fever and serosal inflammation, often complicated by systemic amyloidosis. Maintenance treatment of FMF with colchicine can reduce disease activity and prevent amyloidosis. Some patients, however, fail colchicine therapy. Many reports have recently been published concerning the effective use of a recombinant IL-1 receptor antagonist, anakinra, in several closely related disorders.1–4 These results prompted us to use anakinra in a 14-year-old FMF patient who was unresponsive to colchicine therapy (2 mg/day). A diagnosis of FMF was confirmed by analysis of the MEFV gene (pM694V, M694I). The …