Hyper-IgD And Periodic Fever Syndrome Research Articles

Clinical and genetic features of Spanish patients with Mevalonate kinase deficiency

Mevalonate kinase deficiency (MKD) is a recessively-inherited autoinflammatory condition caused by loss-of-functionMVK mutations. This gene encodes for the enzyme mevalonate kinase (MVK), which catalyzes a crucial step of the biosynthetic pathway of cholesterol and isoprenoids. The partial deficiency of enzymatic activity causes the Hyper-IgD and periodic fever syndrome (HIDS), whereas it complete deficiency provokes the Mevalonic Aciduria (MA).

Treatment of adult hyper-IgD syndrome with canakinumab

Hyper-IgD and periodic fever syndrome (HIDS) is a rare, autosomal-recessive autoinflammatory disease characterized by lifelong recurrent episodes of systemic inflammation. HIDS frequently presents in infancy with intermittent fevers lasting from 4 to 7 days, recurring every 4 to 6 weeks. Febrile episodes may be unprovoked or precipitated by factors including infections, vaccinations, or stress. Associated symptoms may include abdominal pain, diarrhea, rashes, arthralgias, aphthous ulcers, and lymphadenopathy. During acute attacks, patients may exhibit leukocytosis, elevations in acute-phase reactants, and elevated levels of proinflammatory cytokines such as IL-1, IL-6, and TNF-a. At baseline, affected individuals may have elevated IgD levels; however, increases in IgD levels are not universal, particularly in very young patients. If clinical suspicion is high, HIDS should be considered despite normal serum IgD levels. Patients with HIDS may exhibit increased rates of infection, particularly with S pneumoniae; this may be secondary to infrequent IgG hypogammaglobulinemia or host conditions that may be permissive for persistence of this organism. HIDS is part of a clinical spectrum caused by decreased activity of mevalonate kinase, an enzyme involved in isoprenoid biosynthesis. Four mutations in MVK, the gene encoding mevalonate kinase (V377I, I268T, H20P/N, and P167L), account for more than 70% of the cases associated with HIDS. Lack of isoprenoid end products due to abnormal metabolism increases IL-1b secretion from mevalonate kinaseedeficient PBMCs, making IL-1 signaling a promising therapeutic target. Previous studies have shown inconsistent benefits of treatments including colchicine, cyclosporine, and statins. Many patients respond well to oral steroids, but the frequency of exacerbations makes a steroid-sparing therapy desirable. Biologic therapies have been successful in the treatment of other periodic fever syndromes. The cryopyrin-associated periodic syndromes are a group of fever disorders including familial cold autoinflammatory syndrome (FCAS) and Muckle-Wells syndrome (MWS). These conditions are also mediated through excessive IL-1b production. Canakinumab, a fully human antie IL-1b mAb, has been shown to induce rapid remission of symptoms in patients with cryopyrin-associated periodic syndromes and is approved by the Food and Drug Administration for the treatment of FCAS and MWS. Biologics including etanercept, adalimumab, and anakinra have all been shown to decrease the frequency and severity of febrile episodes in patients with HIDS. Small numbers of patients with HIDS treated with canakinumab have also shown clinical improvement. Here, we describe the case of a patient with HIDS who had significant clinical improvement with initiation of canakinumab therapy.

Renal parenchymal calcification secondary to systemic AA amyloidosis.

A 28-year-old man presented with a history of hyper-IgD and periodic fever syndrome (HIDS), which had resulted in systemic AA amyloidosis. He had evidence of amyloid deposition in the kidney, liver and spleen. A living donor kidney transplant in 2005 failed after 6 years due to recurrent amyloid in the transplant kidney. A trial of tocilizumab, an anti-IL-6 monoclonal antibody, started in July 2012 with a marked reduction of symptoms and inflammatory markers. He received a second living donor kidney transplant in August 2012. The transplant function is good and biopsy has shown no evidence of recurrent amyloidosis. Amyloid fibrils have an affinity for calcium, and radiographically detectable calcified amyloid deposits may occur in both primary and secondary amyloidosis. Fig. 1. This plain abdominal radiograph was taken at a time of intercurrent sepsis and demonstrated florid calcification of the parenchyma of both native kidneys (arrows). Of note, neither transplanted kidney has yet calcified (open arrows).

PReS-FINAL-2330: Canakinumab treatment in patients with HIDS

Hyper-IgD and periodic-fever syndrome (HIDS) is a recessively inherited-autoinflammatory condition caused by mevalonate-kinase mutations. It is characterized by early-onset (<1 year of age), 4-6 days-long acute inflammatory episodes that typically recur every 4-6 weeks. The main features during episodes include fever, lymphadenopathies, rash, headache, abdominal pain, diarrhea, and a marked acute phase reaction[1,2]. Previous case reports suggested IL-blockade as a potential therapy. Canakinumab (CAN) is a fully-human, selective anti-IL-1β monoclonal-antibody (MoAb). Preliminary clinical and pharmacokinetics (PK) data of CAN-therapy in active HIDS patients is presented.

Hyper-IgD syndrome or mevalonate kinase deficiency

The hyper-IgD and periodic fever syndrome (HIDS) is one of the classical monogenetic hereditary autoinflammatory disorders, and together with the more severe mevalonic aciduria it is also known as 'mevalonate kinase deficiency' (MKD). In this study, we will give an overview of the primary research on mevalonate kinase deficiency published in the past 2 years. Besides an inventory of a number of recent case reports, literature review shows there are several interesting developments in the basic field of research. First, a group of articles was recently published on chemically instead of genetically induced MKD mouse and cell models, investigating the effects of several isoprenoid pathway intermediates. Second, another study confirms a role for small GTPases and their isoprenylation in the inflammatory response in mevalonate kinase deficiency. Lastly, there are now, finally, modest new indications about the role of IgD. Both pathophysiological studies and clinical observations in the last 2 years have supported the central role of IL-1 in HIDS. There are some intriguing results and hypotheses about the link between isoprenoid metabolism and the IL-1 pathway through geranylgeranylation that deserve to be further examined.

Effects of the Histone Deacetylase Inhibitor ITF2357 in Autoinflammatory Syndromes

We explored the effects of the oral histone deacetylase (HDAC) inhibitor ITF2357 in patients with autoinflammatory syndrome. In this prospective open-label pilot study, eight patients were enrolled; one patient with tumor necrosis factor receptor-associated periodic syndrome (TRAPS), three patients with hyper-IgD and periodic fever syndrome (HIDS) and four patients with Schnitzler syndrome were closely followed during 90 d of ITF2357 treatment. Three patients with Schnitzler syndrome and one TRAPS patient experienced a partial remission. In four patients, there was no effect. In HIDS patients, there was a tendency toward a higher attack frequency and increasing attack severity. In two patients (one TRAPS and one HIDS), we observed a decrease of acute-phase response without signs of clinical improvement. One patient with Schnitzler syndrome showed a partial response despite an ongoing acute-phase response. In conclusion, ITF2357 monotherapy was able to induce partial response only in patients with Schnitzler syndrome and no response in patients with HIDS.

Autoinflammatory diseases - a new entity of inflammation

The autoinflammatory diseases are characterized by seemingly unprovoked episodes of inflammation, without high-titer autoantibodies or antigen-specific T cells. The concept was proposed ten years ago with the identification of the genes underlying hereditary periodic fever syndromes. NLRP3 inflammasome activation and IL-1β secretion have recently emerged as a central mechanism in the pathogenesis of disease. Here we describe four genetically defined syndromes like cryopyrin-associated periodic syndromes (CAPS, cryopyrinopathies), mevalonate kinase deficiency (MKD) or hyper-IgD and periodic fever syndrome (HIDS), pyogenic aseptic arthritis, pyoderma gangrenosum, and acne syndrome (PAPA syndrome), and deficiency of interleukin-1-receptor antagonist (DIRA) along with the pitfall for understanding the pathphysiology.

Regulation by SREBP-2 defines a potential link between isoprenoid and adenosylcobalamin metabolism

Mevalonate kinase (MVK) catalyses an early step in cholesterol biosynthesis converting mevalonate to phosphomevalonate. Cob(I)alamin adenosyltransferase (MMAB) converts cob(I)alamin to adenosylcobalamin, functionally required for mitochondrial methylmalonyl-CoA mutase activity and succinyl-CoA formation. These two synthenic genes are found in a head-to-head formation on chromosome 12 in man and chromosome 5 in mouse. The 330 bp intergenic region showed several conserved NF-Y sites indicative of potential bidirectional regulatory SREBP synergism. Both MVK and MMAB appear to be regulated in a similar manner, to a large extent by SREBP-2, since their tissue expression pattern was similar and both genes were suppressed by an excess of cholesterol as well as SREBP-2 knockdown. Statin treatment in mice upregulated both Mvk and Mmab mRNA levels indicating that this treatment may be useful in inborn errors of cblB complementation associated with methylmalonic aciduria as well as hyper IgD and periodic fever syndrome (HIDS).

Anakinra is safe and effective in controlling hyperimmunoglobulinaemia D syndrome‐associated febrile crisis

Hyper-IgD and periodic fever syndrome (HIDS) is a hereditary autoinflammatory syndrome, characterized by recurrent inflammatory attacks. Treatment of HIDS is difficult. Recently, the IL-1ra analogue anakinra was reported to be successful in aborting the IgD inflammatory attacks in a vaccination model. We report a clinical case of spectacular reduction of febrile attacks in a severe HIDS patient.

Mutational spectrum and genotype–phenotype correlations in mevalonate kinase deficiency

Mevalonate kinase deficiency (MKD) is an autosomal recessive autoinflammatory disorder caused by mutations in the MVK gene resulting in deficient activity of mevalonate kinase (MK). Depending on the clinical severity, MKD may present as hyper-IgD and periodic fever syndrome (HIDS) or the more severe mevalonic aciduria (MA). We analyzed the MVK gene in 57 patients with MKD and found 39 different mutations including 15 novel mutations, expanding the total mutational spectrum of MKD to 63 mutations. To get more insight into the genotype-phenotype correlation in MKD, we studied the effect of selected missense mutations on MK protein stability and activity in various patient fibroblast cell lines. All MKD cell lines showed markedly decreased MK activities that correlated well with the clinical severity and, for most of the cell lines, with the amount of MK protein. When fibroblasts of MKD patients were cultured under conditions known to promote a more controlled protein folding, all cell lines of patients with the HIDS phenotype and few cell lines of patients with the MA phenotype showed an increase in the residual MK activity. This increase in enzyme activity correlates well with an increase in the MK protein levels in these cell lines, indicating that most of the mutations in MKD affect stability and/or folding of the MK protein rather than affecting the catalytic properties of the enzyme. The finding that the residual activity in MKD can be manipulated by environmental conditions may offer therapeutic options to alleviate or prevent the clinical symptoms associated with MKD.

Serum amyloid A serum concentrations and genotype do not explain low incidence of amyloidosis in Hyper-IgD syndrome

Background. Hyper-IgD and periodic fever syndrome (HIDS) is an autosomal recessively inherited disorder characterized by recurrent episodes of fever and inflammation. Unlike other chronic inflammatory conditions, amyloidosis is very rare in HIDS. For deposition of amyloid of the AA type, high concentrations of SAA are a prerequisite, together with certain SAA1 gene polymorphisms. The SAA1.1 genotype predisposes for amyloidosis, while SAA1.5 genotype exerts a protective effect.Aim of the study. To determine if SAA concentrations and SAA1 gene polymorphisms could explain the virtual absence of amyloidosis in HIDS patients.Methods. We measured SAA and CRP concentrations in serum of 20 HIDS patients during an attack and during the asymptomatic phase. Genotype of SAA1 gene was determined in 60 HIDS patients.Results. SAA serum concentrations during attacks were very high (median 205 mg/l; range 75–520 mg/l, normal < 3.1 mg/l). During attack-free periods 45% of patients still had elevated SAA concentrations. The distribution of the genotype of SAA1 gene in HIDS was similar to healthy controls (SAA1.1 0.41 vs. 0.50 p = 0.32).Conclusion. Patients with HIDS have high SAA during attacks and show sub-clinical inflammation when asymptomatic. The low incidence of amyloidosis cannot be explained by a predominance of non amyloidogenic SAA related genotypes.

MVK mutations and associated clinical features in Italian patients affected with autoinflammatory disorders and recurrent fever

Autosomal recessive autoinflammatory disorder caused by mutations of the mevalonate kinase gene (MVK), leading to mild, incomplete MK enzyme deficiency (MKD), has been known so far as Hyper-IgD and periodic fever syndrome (HIDS) and regarded as mostly occurring in Northern Europe. Here we report the results of the molecular characterization of the first Italian series of patients affected with autoinflammatory disorders and periodic fever. A total of 13 different mutations, scattered throughout the MVK coding region, were identified in either homozygous or compound heterozygous state in 15 patients. The mutation leading to the V377I amino-acid change, already described also in other series, resulted the most common with a frequency of 50% of all MKD alleles. Among the other mutations, eight had never been described before, including an interstitial deletion of 19 nucleotides in exon 2. In addition to these nucleotide changes, private and polymorphic MVK variants have been detected in the patients under analysis and checked also in a set of control individuals. Clinical features are reported for each of the 15 MKD patients, and life-threatening infections and systemic amyloidosis presented as unexpected MKD-related complications. Our study demonstrates that MKD is a common cause of recurrent fever also in the Italian population, where it is associated with both a wide spectrum of previously unreported MVK mutations and peculiar phenotypic features.

Science enlightens etiology of periodic fever syndromes

It recently has been recognized that the hyperimmunoglobulinemia D (hyper-IgD) and periodic fever syndrome (HIDS) is caused by mutations of the MVK gene that encodes mevalonate kinase, which is involved with the isoprenoid biosynthesis pathway. It is speculated that a deficiency of isoprenoid activity contributes to the production of inflammatory cytokines and the clinical manifestations of HIDS. Increased serum immunoglobulin D concentrations were once considered to be the hallmark of HIDS; thus, leading to its appellation, hyper-IgD turns out not to be present in all affected children in the first few years of life, or in the first decade of life, as in the case reported by Saulsbury in this issue of The Journal. In a letter also in this issue, Cazeneuve et al report their investigation of six children in France with the PFAPA (Periodic Fever, Aphthous stomatitis, Pharyngitis, cervical Adenitis) syndrome for an array of mutations of the MEFV gene, which are known to cause familial Mediterranean fever (FMF). They found no association. With molecular technology and discovery of etiology of one periodic fever syndrome, (HIDS) is on its way to becoming a disease (burning for a name change), and another, PFAPA, stays a syndrome and not a variation of FMF disease. Power to the genes. Page 127

Carrier frequency of the V377I (1129G>A) MVK mutation, associated with Hyper-IgD and periodic fever syndrome, in the Netherlands.

Hyper-IgD and periodic fever syndrome (HIDS) and mevalonic aciduria (MA) are two autosomal recessive disorders that both are caused by a deficient activity of the enzyme mevalonate kinase (MK) due to mutations in the encoding gene (MVK). The most frequently occurring MVK mutation, V377I (1129G>A), has been identified exclusively in HIDS patients. Other common mutations have been associated with both HIDS and MA. To estimate the incidence of MK deficiency in the Netherlands, we determined the carrier frequency of the V377I mutation in genomic DNA extracted from anonymised newborn screening cards by PCR-RFLP. We found 14 carriers among 2138 analysed samples (1 : 153). Based on the V377I allele frequency of 42% in patients diagnosed with MK deficiency, the carrier frequency of any MVK mutation in the Dutch population can be calculated as 1 : 65. This predicts a disease incidence between 1 in 5196 and 1 in 53 656, which is far more than actually observed. Although under-diagnosis of patients with MK deficiency remains possible, this discrepancy probably is due to a reduced penetrance of V377I homozygosity. Analysis of the distribution of the V377I allele within patients carrying MVK mutations revealed that this was not according to the Hardy-Weinberg equilibrium principle, most probably due to an under-representation of V377I homozygotes in HIDS. Homozygotes for V377I might exhibit a much milder phenotype of MK deficiency or no disease-phenotype at all.

Regulation of Isoprenoid/Cholesterol Biosynthesis in Cells from Mevalonate Kinase-deficient Patients

Mevalonic aciduria (MA) and hyper-IgD and periodic fever syndrome (HIDS) are two inherited disorders both caused by depressed mevalonate kinase (MK) activity. MK is the first enzyme to follow the highly regulated 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase (HMGR), which catalyzes the rate-limiting step in the isoprenoid/cholesterol biosynthesis pathway. In fibroblasts of MA patients, but not of HIDS patients, HMGR activity is elevated under normal growth conditions. This activity is down-regulated when cells are supplemented with the isoprenoid precursors geraniol, farnesol, and geranylgeraniol, and a mixture of 25-hydroxycholesterol and cholesterol. This indicates that the regulation of the pathway in these cells is not disturbed. The elevated HMGR activity is probably due to a shortage of non-sterol isoprenoid end products, as indicated by normal HMGR mRNA levels in MA fibroblasts. Furthermore, the HMGR activity in MA cells was more sensitive to geranylgeraniol suppression and less sensitive to sterol suppression than the HMGR activity in low density lipoprotein receptor-deficient cells. HMGR activity in MA cells was down-regulated also by addition of its product mevalonate to the culture medium. Thus, it appears that the elevation of mevalonate levels, which are high in MA patients and moderate in HIDS patients, allows the cells to compensate for the depressed MK activity. Indeed, the isoprenylation of Ras and RhoA protein appeared normal in HIDS and MA fibroblasts under normal conditions but showed increased sensitivity toward inhibition of HMGR by simvastatin. Our results indicate that MK-deficient cells maintain the flux through the isoprenoid/cholesterol biosynthesis pathway by elevating intracellular mevalonate levels.

Temperature dependence of mutant mevalonate kinase activity as a pathogenic factor in hyper-IgD and periodic fever syndrome.

Hyper-IgD and periodic fever syndrome (HIDS) and mevalonic aciduria are autosomal recessive disorders characterized by recurrent episodes of fever and generalized inflammation. Both syndromes are caused by specific mutations in the gene encoding mevalonate kinase (MK), resulting in a depressed enzymatic activity mainly due to reduced protein levels. We studied the effect of temperature on the activity of wild-type and several mutant MKs in fibroblasts. All fibroblast cell lines from HIDS patients and harbouring the common V377I MVK allele displayed substantially higher MK activities at 30 degrees C as compared to 37 degrees C. As shown by temperature inactivation experiments this resulted in a protein nearly as stable as in control cell lines, indicating that primarily the maturation of the protein is affected. Accordingly, when HIDS cell lines were cultured at 39 degrees C, MK activity decreased further. This triggered a compensatory increase in 3-hydroxy-3-methylglutaryl-CoA reductase activity, indicating that MK becomes progressively rate-limiting. A similar phenomenon occurs in vivo. MK activity in peripheral blood mononuclear cells drops 2-8-fold when HIDS patients experience febrile attacks. Our results suggest that minor elevations in temperature can set off a chain of events with MK becoming progressively rate-limiting, leading to a temporary deficiency of isoprenoid end-products, which induces inflammation and fever.

Molecular analysis of the mevalonate kinase gene in a cohort of patients with the hyper-igd and periodic fever syndrome: its application as a diagnostic tool.

The hyper-IgD and periodic fever syndrome (HIDS) is characterized by recurrent attacks of fever, abdominal distress, and arthralgia and is caused by mevalonate kinase mutations. To ascertain the role of mevalonate kinase and the usefulness of molecular diagnosis in HIDS. Cross-sectional study. The international Nijmegen HIDS registry. 54 patients from 41 families who met the clinical criteria for HIDS. Clinical symptoms and signs, immunoglobulin concentration, leukocyte count, erythrocyte sedimentation rate, mutation analysis, and mevalonate kinase enzyme activity assay. There were two groups of patients: 41 patients with mevalonate kinase mutations (classic-type HIDS) and 13 patients without mutations (variant-type HIDS). Patients with classic-type HIDS had a lower mevalonate kinase enzyme activity, a higher IgD level, and more additional symptoms with attacks. The IgD level did not correlate with disease severity, mevalonate kinase enzyme activity, or genotype. Genetic heterogeneity exists among patients with a clinical diagnosis of HIDS.

Unstimulated peripheral blood mononuclear cells from patients with the hyper-IgD syndrome produce cytokines capable of potent induction of C-reactive protein and serum amyloid A in Hep3B cells.

The hyper-IgD and periodic fever syndrome (HIDS) and familial Mediterranean fever (FMF) are both characterized by attacks of periodic fever accompanied by acute phase responses that are substantially higher in HIDS than in FMF. To determine whether this difference could be due to differences in production of acute phase protein-inducing mediators, we studied PBMC from HIDS and FMF patients in the inactive phase of disease. Unstimulated PBMC from patients with inactive HIDS released significantly more IL-1 beta, IL-6, and TNF-alpha than did PBMC from patients with FMF, but unstimulated PBMC from the latter group released significantly more IL-1 beta and IL-6 compared with controls. Conditioned medium (CM) derived from PBMC of patients with inactive HIDS induced significantly greater CRP production and significantly higher mRNAs for CRP and SAA in Hep3B cells than did CM derived from the PBMC of patients with inactive FMF. Stimulation of PBMC with LPS led to further increases in cytokine production and in acute phase protein-inducing ability in both patient groups and in controls. These findings suggest that the greater acute phase response seen in HIDS compared with FMF reflects greater production of acute phase protein-inducing cytokines in the former patients and indicates that PBMC from inactive HIDS patients are already activated in vivo. Finally, the finding of both quantitative and qualitative differences in cytokine production by unstimulated PBMC from HIDS and FMF patients supports the likelihood of different pathogeneses of these diseases.

Immunoglobulin D enhances the release of tumor necrosis factor-alpha, and interleukin-1 beta as well as interleukin-1 receptor antagonist from human mononuclear cells.

Immunoglobulin D (IgD) is normally present in only low concentrations in serum. In the hyper-IgD and periodic fever syndrome (HIDS), however, serum levels exceed 140 mg/l. This syndrome is further characterized by recurrent inflammatory febrile attacks together with an acute phase response and appearance of cytokines in the circulation. The role of IgD in the pathogenesis of HIDS and its relation to the increased cytokine concentrations is unclear. Therefore, we tested whether IgD, IgG and alpha 1-acid glycoprotein (AGP) isolated from human serum influence the synthesis of interleukin-1 beta (IL-1 beta), tumour necrosis factor-alpha (TNF-alpha), and IL-1ra, as measured by specific radioimmunoassays, in human peripheral blood mononuclear cells (PBMC). Incubation of PBMC with IgD and AGP for 24 hr led to increased release of IL-1 beta, TNF-alpha, and IL-lra. The magnitude of stimulation of IgD exceeded that of AGP; the effect by IgD was dose-dependent and showed a 30-fold (TNF-alpha) to almost 150-fold (IL-1 beta) increase at the highest concentration (50 mg/l), while AGP (750 micrograms/ml) only increased the cytokine secretion fourfold (TNF-alpha) to almost 30-fold (IL-1 beta). The effect of IgD on IL-1ra was less dramatic but a fivefold increase was observed at 50 mg/l compared with a 2.5-fold increase with AGP. IgD potentiated the effect of lipopolysaccharide (LPS) on secretion of both IL-1 beta and TNF-alpha, although the effect was most apparent for TNF-alpha. Apart from inducing IL-1ra synthesis, IgG did not influence cytokine release in human PBMC. These data indicate that IgD is a potent inducer of TNF-alpha, IL-1 beta and IL-1ra and thus may contribute to the pathogenesis of HIDS.