Are You Confident of the Diagnosis?
The hyperimmunoglobulinemia D and periodic fever syndrome (HIDS) is a rare hereditary autoinflammatory syndrome. Autoinflammatory syndromes are characterized by lifelong recurrent and seemingly unprovoked inflammatory attacks. HIDS was first descibed in 1984 in the Netherlands with six patients with recurrent attacks of fever of unknown cause with high serum IgD levels. Patients with recurrent fevers without apparent infection should be evaluated with regard to autoinflammatory diseases.
Characteristic findings on physical examination
HIDS patients typically present within the first year of life (very rarely after the age of 5 years) with febrile attacks that last 3 to 7 days. These episodes recur every few weeks and are accompanied by cervical lymphadenopathy, joint pain and abdominal discomfort. Other common features include nausea, vomiting, skin lesions and headaches (Figure 1). Less frequently patients may have hepatosplenomegaly. Emotional and physical stress are reported as precipitating factors for an attack. Frequently the initial attack may coincide with childhood vaccination.
Examination during an attack reveals a sick-looking febrile patient (temperature often >40 degrees C). Lymphadenopathy is present in 90% of cases, most frequently affecting the cervical region. There may be signs of an acute abdomen. Arthralgia and arthritis have been seen in up to 83% of patients, mainly restricted to large peripheral joints, although both metacarpophalangeal and proximal interphalangeal may be involved. There is no specific cutaneous manifestation of HIDS, but about two thirds of patients will have skin findings during an acute attack. Most frequently patients have an exanthem characterized by widespread erythematous macules and papules.
Other morphologies have been described including urticarial lesions and annular erythema. Rarely petechiae or pustules are seen. Erythema nodosum has also been reported in HIDS. Typically the rashes are not itchy. Half of patients may also have oral aphthous ulcers with or without genital ulceration.
Expected results of diagnostic studies
Laboratory investigations during an acute attack show an exaggerated acute phase response with elevated ESR, CRP and leukocytosis. This may persist at lower levels between attacks or normalize. Although the initial description of this disease was elevated IgD, it is now known that 22% of patients diagnosed with HIDS have normal levels of IgD when measured during an attack. Most patients, however, will have elevated IgD and also two thirds of patients may have elevated serum IgA. Skin biopsy in patients has shown no consistent features and even may differ within the same patient who has had multiple biopsies.
The most frequent histopathologic finding is a non-specific perivascular lymphocytic infiltrate with some neutrophils. But vasculitis, Sweet’s-like changes, spongiosis and epidermotropism have all been reported. Urinary mevalonate may be mildly elevated during an attack, but it is not a sensitive test to rule out HIDS if the level is within reference range.
The gold standard for diagnosis is genetic testing for mutations in the Mevalonate Kinase (MVK) gene.
Differential diagnosis includes familial Mediterranean fever (FMF), which also presents with fever and abdominal pain although lymphadenopathy is less of a cardinal feature of FMF. FMF is seen frequently in populations from the Mediterranean. Oral and genital ulceration frequently seen in HIDS has led to the misdiagnosis of Behçet’s syndrome but Behçet’s rarely presents in infants, has a predilection for populations from the Silk Road and has other features such as uveitis.
Who is at Risk for Developing this Disease?
The international HIDS database (www.hids.net) reports that patients mostly have originated from Europe or have European ancestry. The country with the highest prevalence is the Netherlands, suggesting a founder effect there. A potential significant confounder is that developed nations have far greater access to healthcare and therefore confirmed diagnoses.
What is the Cause of the Disease?
HIDS is an autosomal recessive disease caused by mutations in the Mevalonate kinase (MVK) gene. Linkage analysis identified this gene, which is also mutated in another condition: mevalonic Aciduria. Mevalonic aciduria has a much severer phenotype with developmental delay, dysmorphic features, ataxia, cerebellar atrophy and psychomotor retardation in addition to acute inflammatory attacks. These two conditions are collectively known as mevalonate kinase deficiency. MVK gene mutations result in decreased activity of the enzyme mevalonate kinase (MK).
Although MK is important for the biosynthesis of all isopreninoids including cholesterol, it appears one pathway involving geranylgeranyl pyrophosphate is responsible for the inflammatory phenotype. The reduced synthesis of geranylgeranyl pyrophosphate leads to increased production of the pro-inflammatory cytokine interleukin-1 beta.
Systemic Implications and Complications
Long-term complications of HIDS are less frequently seen than in other autoinflammatory syndromes. Abdominal adhesions have been reported in patients even without a prior history of abdominal surgery, which suggests that they have been affected by sterile peritonitis. Type AA amyloidosis has been reported in 3% of patients with HIDS. All patients with amyloidosis had a long history (>20 years) of attacks. It may be prudent to monitor renal function (BUN and creatinine) and regular urinalysis checking for proteinuria, annually. Joint contractures have also been reported. HIDS does not appear to affect mortality adversely.
Many antiinflammatory agents have been tried including prednisone, colchicine, statins, antibiotics, biologics, thalidomide and cyclosporine. Prednisone appears to be beneficial in reducing severity of attack when given at onset of an attack, with greater than half experiencing a good response or some response. Colchicine does not appear to be effective in HIDS, although it is very helpful for FMF. Statins have been tried in HIDS as they interfere with the isopreninoid pathway that is affected in HIDS. Statins are HMG-CoA reductase inhibitors, which is the precursor enzyme that converts HMG-CoA in to mevalonate.
HIDS patients have elevated levels of mevalonate due to their MK deficiency. A small trial with six patients who received simvastatin (80mg/day) reported a reduction in number of febrile days, suggesting some benefit. However, inflammatory crises have been reported after treating patients with mevalonic aciduria (severer phenotype) with statins; 80% patients who have tried a biologic agent, either anakinra (interleukin 1 receptor antagonist) or etanercept (TNF alpha blocker) have reported improvement. Some patients who fail to respond to anakinra may respond to etanercept and vice versa.
Optimal Therapeutic Approach for this Disease
Refer to rheumatology for patient management. The skin findings are rarely troubelsome. Initial management with prednisone (1mg/kg) daily during an attack would be reasonable. For mildly affected patients, simvastatin may be considered (80mg once daily) although there have been reports of this agent worsening inflammation in the more severely affected patients with the mevalonic aciduria phenotype. If the patient is unresponsive to corticosteroids or requiring long-term maintenance with corticosteroids, biological agents may be considered. As the prognosis is not as severe as in autoinflammatory syndromes, with unlikely development of long-term sequelae, this should be considered prior to initiation of immunosuppressant agents.
Occult infection must be ruled out prior to commencement of biological therapy. Patients should be evaluated for latent/active tuberculosis (TB), hepatitis B, hepatitis C and HIV.
Anakinra (Il-1 receptor antagonist) subcutaneous administration daily (licensed for adults with rheumatoid arthritis). Please note that the use of anakinra and etanercept in HIDS is off label. Adult dosing: 100mg subcutaneously once daily. Pediatric dosing: 1 to 2mg/kg subcutaneously once daily.
Side effects include injection site reactions (relatively frequently); these normally settle down after a few weeks of administration of anakinra. Neutropenia has been seen and increased risk of serious infections. Regular CBC monitoring is required (every 3 months).
Etanercept (TNF blocker) subcutaneous administration weekly. Adult dosing: 50mg subcutaneously weekly; pediatric dosing: 0.4 to 0.8mg/kg subcutaneously weekly
It is unclear whether patients should just receive therapy during an acute attack to reduce severity and shorten the attack or to be placed on long-term treatment. There are no randomized controlled trials guiding management for HIDS. It may be reasonable to commence intermittent therapy and review patients’ response, including markers of inflammation such as CRP, between attacks.
Follow-up should probably be undertaken by rheumatology as joint issues are the main associated morbidity. The dermatologic manifestations are rarely troublesome. Routine follow-up every 6 months for patients to report symptomatology and monitor acute phase reactants such as CRP. It is probably prudent to also check urine for proteinuria although amyloidosis is extremely rare in these patients. The key take-home message for patients and families is that although this is a genetic disorder without cure, many patients will experience amelioration of their symptoms with therapeutic intervention. Patients live a normal life span.
Unusual Clinical Scenarios to Consider in Patient Management
There is a single case report of a patient with HIDS who was treated with etanercept and anakinra sequentially with apparent increased severity of inflammatory attacks.
What is the Evidence?
van der Meer, JW, Vossen, JM, Radl, J, van Nieuwkoop, JA, Meyer, CJ, Lobatto, S. “Hyperimmunoglobulinaemia D and periodic fever: a new syndrome”. Lancet. vol. 1. 1984. pp. 1087-90. (Original case report of HIDS in six patients of Dutch ancestry.)
van der Hilst, JC, Bodar, EJ, Barron, KS, Frenkel, J, Drenth, JP, van der Meer, JW. “Long term follow-up, clinical features, and quality of life in a series of 103 patients with hyperimmunoglobulinemia D syndrome”. Medicine (Baltimore). vol. 87. 2008. pp. 301-10. (Large case series of HIDS patients.)
Drenth, JP. “Cutaneous manifestations and histologic findings in the hyperimmunoglobulinemia D syndrome. International Hyper IgD study Group”. Arch Dermatol. vol. 130. 1994. pp. 59-65. (Reviewed 35 patients with HIDS with skin manifestations.)
Shendi, HM, Walsh, D, Edgar, JD. “Etanercept and anakinra can prolong febrile episodes in patients with hyperimmunoglobulin D and periodic fever syndrome”. Rheumatol Int. December 18, 2009. (Single case of HIDS with apparent worsening of symptoms with etanercept and anakinra.)
Simon, A, Drewe, E, van der Meer, JW, Powell, RJ, Kelley, RI, Stalenhoef, AF. “Simvastatin treatment for inflammatory attacks of the hyperimmunoglobulinemia and periodic fever syndrome”. Clin Pharmacol Ther. vol. 75. 2004. pp. 476-83. (Small open study reporting reduction in disease severity when patients treated with simvastatin.)
Topaloğlu, R, Ayaz, NA, Waterham, HR, Yüce, A, Gumruk, F, Sanal, O. “Hyperimmunoglobulinemia D and periodic fever syndrome; treatment with etanercept and follow-up”. Clin Rheumatol. vol. 27. 2008. pp. 1317-20. (Case report of infant with HIDS responding to etanercept.)
Cailliez, M. “Anakinra is safe and effective in controlling hyperimmunoglobulinaemia D syndrome-associated febrile crisis”. J Inherit Metab Dis. vol. 29. 2006. pp. 763(Case report of HIDS patient responding to anakinra.)
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