Proceedings
Friday 10 December 1999
9:00 Opening Remarks - JWM van der Meer, Nijmegen, the Netherlands
Announcement of this website on hyper-IgD and periodic fever syndrome (HIDS) at
http://hids.net
Clinical session—chair: R.J. Powell, C.M.R. Weemaes
9:10 Update on Registry - JPH Drenth, Nijmegen, the Netherlands
The Nijmegen HIDS registry was initiated in 1992, and has as aims to collect new HIDS cases, unify knowledge, to give a comprehensive description of clinical features and develop diagnostic criteria, to obtain insight in prognosis, to form a central registry for research in HIDS and a database of patient addresses. To promote standardization of data, a questionnaire has been developed which can be used to enter a new case. This questionnaire can also be found at the website. The diagnosis of HIDS is made by the local physician, and data are assessed in Nijmegen.
At this moment, the registry contains data on 144 patients (female/male = 73/71). A large majority of these patients live in Europe, and about 60 of them in the Netherlands. Current mean age is 23.5 years (median 21 yr), mean age at onset 3.1 years (median 6 months). An average attack lasts 3-5 days, and occurs once per 4 weeks. The registry also generates data on the prevalence of symptoms during attacks. There is a mortality of 3,5% (5 patients).
9:40 Clinical Spectrum - JWM van der Meer, Nijmegen, the Netherlands
HIDS is characterized by attacks of spiking fever, which last 1 to 7 days, proceeded by chills and rigors, and accompanied by a number of symptoms, which are briefly described. It has to be distinguished from a number of syndromes, including Familial Mediterranean Fever, Familial Hibernian Fever, Muckle Wells syndrome and adult onset Still’s disease. It is still not known why these syndromes are paroxysmal – possibly there is a role for biorythms or hormonal influences. Attacks seem to be provoked by trivial events, e.g. vaccination, minor infection, trauma, which might indicate that they are due to an amplified stimulus, a sensitized system or deficient (negative) feedback. Now that deficiency of mevalonate kinase has been found, HIDS can be compared with classical mevalonic aciduria, in which patients have more severe clinical features and, interestingly enough, normal IgD levels. This gives rise to speculations on whether high IgD is an obligate finding. It is also not clear yet why there is no amyloidosis in HIDS.
Genetic Aspects—chair: H. Brunner, M. Delpech
10:30 HIDS - L Cuisset, Paris, France
We searched for the gene responsible for HIDS by polymorphism study (see also Drenth et al, Nature Genetics 1999;22:178 -PubMed ID 10369262). We used material from 16 families, and 46.000 PCRs. Two point linkage analysis pointed to chromosome 12q24, between D12S330 and D12S79. The gene for mevalonate kinase is located in this area. Attention was drawn to this gene because of the periodic fever which occurs in mevalonic aciduria. HIDS patients have high levels of mevalonic acid in urine during attacks; though not as high as in classical mevalonic aciduria, where urine levels of mevalonic acid are constantly elevated. The most frequently found mutations are V377I (35%), I268T (18%) and P167L (8%).
11:00 HIDS - H Waterham, Amsterdam, the Netherlands
Pediatricians in Utrecht, the Netherlands, discovered increased organic acid in urine of HIDS patients during attacks, which was found to be mevalonic acid. This raised the suggestion that HIDS might be caused by a defect in mevalonate kinase. When fibroblasts and lymphocytes of HIDS patients were studied, we found decreased activity of mevalonate kinase, but not absent activity like in mevalonic aciduria (see Houten et al, Nature Genetics 1999;22:175 PubMed ID 10369261). Both HIDS and mevalonic aciduria are caused by mutations in the mevalonate kinase gene. All 13 missense mutations identified so far affect mevalonate kinase enzyme activity. The V3771 mutation is the most common; this mutation affects both enzyme activity and stability of the mutant mevalonate kinase protein. Conclusion: HIDS is due to strongly reduced, but not fully deficient mevalonate kinase activity, and may possibly be considered as a mild presentation of mevalonic aciduria.
11:30 FMF - D Kastner, Bethesda, USA
In FMF, there is autosomal recessive inheritance, with incomplete penetrance in females (50-70%). The gene involved was found to be the MEFV gene, located on chromosome 16. So far, 19 mutations have been described. From the geographical distribution of FMF and haplotype studies it is speculated that there is a founder effect, with founders living in the Middle East in biblical times, who spread the genes to different areas. The MEFV gene has 10 exons, and most mutations are found in exon 10. All mutations are missense mutations or in-frame deletions. Also, complex alleles are found, that is, alleles with more than one mutation (e.g. E148Q and V726A), which is likely to be the result of recombination. This complicates genetic tests. There is some information on genotype-phenotype correlations: e.g. M694V homozygotes are at increased risk for systemic amyloidosis, and K695R is associated with a mild phenotype. Only in 65% of patients with FMF both mutated alleles are identified; in 30% only one mutation is found, and in the other 5% no mutation can be detected. It is possible that there are as yet unknown mutations within introns or promotor or enhancer elements, but it could be that there is a clinical phenotype associated with a single mutant allele.
12:00 FHF /TRAPS- R McIntosh, Nottingham, UK
Familial Hibernian Fever (FHF) has an autosomal dominant inheritance pattern. Genetic mapping studies, using microsatellite markers, pointed to chromosome 12q13. It was found that the gene for tumor-necrosis factor receptor-1 (TNFR1) was the one responsible in this syndrome. Because of the identification of mutations in the TNFR1 gene FHF was renamed TRAPS, i.e. TNFR1-associated periodic syndromes. A number of mutations have been described so far, most of which are cysteine residue mutations, which indicates a role for structural changes. Most mutations are located in exon 2, 3 and 4, all in the extracellular region of the protein and not at the TNF binding site. FHF patients have been shown to have low circulating levels of soluble TNFR1.
Pathophysiology of Periodic Fever
Chair: R.J.A. Wanders, J.W.M. van der Meer
14:00 Pathophysiology of FMF - D Kastner, Bethesda, USA
We are trying to discover the role of the protein product of the MEFV gene, named pyrin (or marenostrin). This can be done in several ways. In the first place, using a computational analysis of the predicted protein, looking at the structure and homologies. Secondly, by analyzing gene expression. There is MEFV expression in peripheral blood leukocytes. It is found in granulocytes, eosinophils, neutrophils and in some individuals also in monocytes / macrophages, but not in lymphocytes. In bone marrow, it is also expressed in granulocyte precursors to a lesser degree; in cultures, MEFV appears at the time of primary granules, when the cells are committed to become granulocytes. In monocytes, MEFV expression is stimulated by inflammatory mediators such as IFNg, LPS and TNF, and possibly inhibited by IL-4, IL-10 and TGFb. In the third place, by studies of the FMF protein. It has been found to be a cytoplasmic protein at subcellular level. Fourthly, we are working on yeast two-hybrid assays. And in the last place, we are working on a mouse model for FMF. The mouse (and rat) homologue gene for MEFV unfortunately does not contain the B30.2 domain, which contains the most mutations in humans. Knock-out mice for this gene survive and can reproduce; we are working on an implanted temperature chip to measure possible periodic fever in these mice. It will also be interesting to study "knock-in" mice, where the B30.2 domain is introduced in the gene, possibly also including the mutations.
14:30 Pathophysiology of FHF/TRAPS - I Todd, Nottingham, UK
During attacks in FHF, circulating levels of IL-6 and IL-1ra are clearly raised, while levels of IFNg are undetectable. The level of soluble TNFR1 (sTNFR1) is low, while the level of sTNFR2 is normal. There is an increased expression of TNFR1 on leucocytes, as the cells have defective clearance of TNFR1 from the surface. This effect is seen most markedly for monocytes, less for granulocytes. So, the mutations in TRAPS affect shedding of TNFR1; the degree of impaired shedding varies in different mutations. There does not seem to be constitutive activation of TNFR1 or enhanced responsiveness to TNF in TRAPS. The enhanced production of IL-6 in TRAPS is not simply due to increased binding of TNF to the TNFR.
15:00 Metabolic disorders in the isoprenoid pathway- BT Poll Thé, Utrecht, the Netherlands
Description of other metabolic disorders in the isoprenoid pathway: mevalonic aciduria, caused by a deficiency in mevalonate kinase; X-linked dominant chondrodysplasia punctata/Conradi-Hünemann syndrome (CDPX2), which is caused by a deficiency of hydroxysterol isomerase; Smith-Lemli-Opitz syndrome (SLO), which is caused by a deficiency of 7-dihydrocholesterol reductase; and desmosterolosis, caused by a deficiency of hydroxysterol reductase. The last three syndromes are all caused by deficiencies of enzyme below squalene in the isoprenoid pathway; these syndromes show no disorder of acute phase response or periodic fever. This would indicate that the cholesterol pathway is not central in the pathophysiology of HIDS.
16:00 Cytokines and IgD - I Levan-Petit, Poitiers, France
The specific cytokines that are implicated in Ig class switching to IgD are not known. To find out more about this, we developed a capture ELISA for IgD. It appeared that IL-4 and IL-10 enhance IgD production in tonsil cells. IgD production by normal peripheral blood monocytes is classified in 3 groups: one group shows spontaneous high production of IgD, not influenced by cytokines, another exhibits low production of IgD which is not influenced by cytokines, and the third group shows low production of IgD which can be stimulated by cytokines. IgD production is inhibited by IFNg and IL-2 in peripheral blood monocytes. It’s not yet certain wheter IL-4 and/or IL-10 act as a switch factor or regulate alternative splicing. It can be concluded that IgD synthesis is a Th2 dependent phenomenon.
16:30 Pathophysiology of HIDS - W Kuis, Utrecht, the Netherlands
Of the 20 HIDS patients known in Utrecht, 17 showed diminished mevalonate kinase activity. The other three patients might have another defect in the isoprenoid pathway. No correlation could be found between mevalonate kinase activity levels and severity, frequency of attacks or genotype. This is demonstrated by two children who have the same mutation and the same residual mevalonate kinase activity, but a very different clinical picture. It is unclear yet how the metabolic defect leads to febrile attacks: it may result in an excess of toxic intermediary metabolites, or there may be a shortage of product. It would be interesting to know whether other febrile disorders are caused by similar metabolic mechanisms.
Saturday 11 December 1999
Therapy—chair: J.P.H. Drenth, D. Kastner
10:00 Thalidomide - RJ Powell, Nottingham, UK
The properties of Thalidomide (a -N-phthalimidiglutethimide) are sedation and immunomodulation. It has a number of side-effects, including teratogenesis (which might be anti-TNFa related), axonal neuropathy, sedation, appetite increase and weight gain. The use of thalidomide is subject to strict regulations and has to be monitored. It is used, among others, in erythema nodosum leprosum, M. Behçet, AIDS and graft-versus-host-disease (GVHD). A randomised, double blind, placebo controlled trial examining the effect of thalidomide in HIDS is in progress. Thalidomide has several immunomodulatory effects: selective inhibition of TNFa production by monocytes, T cell co-stimulatory properties, bi-directional effects on IL-12, anti-angiogenesis, modulation of adhesion molecules and free radical oxidative damage to DNA.
10:30 sTNFr - Etanercept (Enbrel®) for FHF/TRAPS - D Kastner, Bethesda, USA
Etanercept (Enbrel®) is a recombinant p75 TNFR:Fc fusion protein. Its mode of action could be blocking of signaling through membrane TNFR1 by binding TNFa. We have so far tried it with reasonable follow-up in 7 TRAPS patients, in a dose of 25 mg s.c. twice weekly (or 0.4 mg/kg in children). The results are promising. This may be related to the varying degree of impaired shedding of TNFR1 in different mutations.
Nottingham experience with Etanercept for FHF/TRAPS – E Drewe, Nottingham, UK
One TRAPS patient, who is being treated now with Etanercept, seems to show a partial response. Another patient in the same family has been started on Etanercept in October, mainly to try to prevent progression of her nephrotic syndrome caused by amyloidosis.
11:00 Statins - JPH Drenth, Nijmegen, the Netherlands
Statins are competitive inhibitors of HMG-CoA reductase, by which they decrease levels of LDL cholesterol and triglycerides. Statins also show anti-inflammatory effects in vitro: they induce a decrease of IL-6, IL-8 and other inflammatory parameters. Side-effects are rare; these include elevation of transaminases (0.1-0.5%) and elevation of CK (rare). Interestingly, it was found that lovastatin induced severe attacks in classical mevalonic aciduria. Cholesterol concentrations in HIDS are slightly but significantly lower than in controls. A pilot study of 4 weeks, using atorvastatin in 3 HIDS patients, showed a decrease in frequency and severity of febrile attacks, and a decrease in LDL-cholesterol. A randomized, double blind, placebo controlled cross-over trial using simvastatin in HIDS is now being prepared. We will include 10 HIDS patients with known MVK gene mutation.
11:30 Colchicine - A Livneh, Tel Hashomer, Israel
Colchicine has been just for 25 years in patients with FMF. It is an alkaloid, metabolized in the liver. It has anti-inflammatory and anti-fibrotic effects. Side-effects include gastro-intestinal symptoms, leukopenia, trombocytopenia and neuromuscular disorders. Some drugs interact with colchicine. Treatment is usually started at 1 mg/day, and this dose can be increased if needed to a maximum of 2 mg/day. Above this dose, toxic effects can be seen. Colchicine is not effective for the treatment of acute attacks of FMF, but has to be used as a chronic treatment. 60% of patients show a good response (that is, no more attacks), 30% a partial response and about 10% show no response. This is caused by non-compliance or possibly in some cases by decreased absorption of colchicine. Colchicine can also be used to prevent amyloidosis, and is useful in the treatment of a patient who has already developed amyloidosis, as it may prolong the life of the kidney.
Future plans - JWM van der Meer, Nijmegen, the Netherlands
There are a lot of research questions still left open in HIDS. Is the MVK deficiency the only defect in HIDS? In some HIDS patients, no defect in the MVK gene has been found yet. How does MVK deficiency cause classical mevalonic aciduria in one patient and HIDS in the next? Are exogenous factors involved? What is the role of IgD? And is there a place for intervention? How can a continuous defect lead to a paroxysmal disease? It is clear that much ground still needs to be covered.
