Eleven years after the hyper-immunoglobulinaemia D syndrome was recognised, the International Hyper-IgD study group convened its first workshop, held in Nijmegen, Netherlands, last week. The hallmark of this disorder is the incapacitating recurrent febrile attacks necessitating bedrest. Each attack consists of severe abdominal pain, arthritis, red and occasionally painfull macular papular skin lesions, and swollen lymphnodes. Commonly, the patients have their first febrile attack before their first birthday. The distinguishing feature from other periodic fever syndromes is the polyclonal increase in serum IgD which can be associated with an increase of serum IgA.
Introducing the meeting, Prof J W M van der Meer (Nijmegen), who originally described the condition (Lancet 1984; i:1087-90-- PubMed ID 6144826), emphasised the importance of thinking of the hyper-IgD syndrome in patients with periodic fever, so that needless investigations can be avoided. For convenience, he suggested the use of an appropriate acronym and the group agreed on HIDS (hyper-IgD syndrome).
Next came a presentation, on behalf of other physicians, of the clinical features of the 60 known patients (59 from Europe and 1 from Japan) (J P H Drenth, Nijmegen). Subsequently, Dr A M Prieur (Paris) contrasted particular clinical aspects of HIDS with those seen in other diseases. The joint manifestations, for example, differed from those seen in juvenile chronic arthritis (Still's disease) and CINCA (chronic infantile syndrome with neurologic, cutaneous, and articular manifestations) in that in HIDS there is a flare-up during febrile attacks but no residual joint damage, even on long follow-up. She also highlighted the differing fever patterns, especially the contrast between the intermittent fever of Still's disease and the continuous pattern with gradual defervescence over 5 days seen in HIDS. The diverse inflammatory skin lesions of HIDS, demonstrated by Dr J Toonstra (Utrecht, Netherlands), ranged histologically from neutrophilic skin infiltration through to leucocytoclastic vasculitis. The presence of IgD deposits has not been consistently identified in biopsy specimens.
The highlight was the session on the pathogenetic mechanisms of the inflammation, which included data on the cytokine profiles found during the episodes of fever. In summary, plasma concentrations of interferon (IFN)-g and interleukin-6 seem to be consistently raised, and possibly also tumour-necrosis factor-a. Doubt was expressed whether any of these molecules are responsible for the fever. However, the striking acute-phase response during febrile attacks is clearly compatible with the cytokine profile.
Details on the fucosylation of a-acid glycoprotein during the attacks were described by Dr E C Havenaar (Amsterdam) and indicate a possible role of such molecules in the immunoregulation of this condition. Fucosylation is increased irrespective of the clinical state of the disease, which suggests an element of persistent inflammation.
Neopterin is released by activated macrophages in response to IFN and is excreted unchanged in the urine. Attacks of HIDS seem to be mirrored by a sharp increase in urinary excretion of neopterin (R J Powell, Nottingham).
Although HIDS differs from familial Mediterranean fever (FMF) in being accompanied by a high serum IgD, lymphadenopathy, and absence of amyloidosis and overt serositis, there are similarities between the two disorders -- ie, recurrent febrile episodes, abdominal pain, arthritis, and a definite acute-phase response. In reviewing current thinking on the pathogenesis of FMF, Prof Y Matzner Jerusalem, Israel) described his data suggesting the absence of a complement 5a inhibitor, and he discussed how findings could be related to the clinical features of the disorder. The possibility of a lack of an anti-inflammatory substance in HIDS was considered.
The familial clustering of patients with HIDS suggests an autosomal recessive mode of inheritance. However, the genetic location of the putative HIDS gene remains unknown. Candidate genes such as those related to FMF (MEF gene) are clearly not implicated. A racial tendency could be the reason why most cases of HIDS seem to be European in origin. However, it is conceivable that the under-identification of cases in the rest of the world could be due to the inability of hospital laboratories to measure IgD reliably. Although there are no good therapeutic agents for the syndrome, the pharmacological modulation of cytokines may well prove very satisfactory, so the identification of new cases becomes ever more important.
Workshop participants agreed to submit a collaborative project to the European Commission's BIOMED II programme, to further investigate the clinical, genetic, immunopathological, and therapeutic aspects of the condition. Ideas generated by the lively discussions contributed to the overall direction of the project. It was agreed that the project would include educational material for patients. In addition, steps will be taken to set up a European patient organisation on HIDS.
Joost P H Drenth, Richard J Powell
