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Hyperimmunoglobulin D syndrome: Management

Yoram C Padeh, MD
Arye Rubinstein, MD
Section Editor
Jordan S Orange, MD, PhD
Deputy Editor
Elizabeth TePas, MD, MS


Hyperimmunoglobulin D syndrome (HIDS, MIM #260920) is a rare genetic disorder characterized by recurrent febrile episodes typically associated with lymphadenopathy, abdominal pain, and an elevated serum polyclonal immunoglobulin D (IgD) level. Recurrent fever that is not due to infection is a clinical feature of several disorders that are collectively referred to as autoinflammatory diseases. HIDS is one of the major periodic fever syndromes, which is a subset of autoinflammatory diseases. An overview of periodic and recurrent fevers and other autoinflammatory diseases is presented separately. (See "Periodic fever syndromes and other autoinflammatory diseases: An overview".)

The management of HIDS is reviewed here. The pathophysiology, clinical features, and diagnosis of HIDS are reviewed in detail separately. (See "Hyperimmunoglobulin D syndrome: Pathophysiology" and "Hyperimmunoglobulin D syndrome: Clinical manifestations and diagnosis".)


In general, patients with HIDS have a normal lifespan and rarely suffer any serious physical complications of the disease, with the one uncommon exception of AA amyloidosis [1,2]. However, the attacks may have a significant negative impact on quality of life (QoL), particularly if the episodes are more frequent and severe [3]. Social functioning, general health perception, vitality, autonomy, and social development were the QoL areas most impacted in one study. The periodic fever attacks are usually lifelong, although the frequency of attacks appears to decrease with age, and there are a few case reports of patients going into remission after therapy. (See "Pathogenesis of AA amyloidosis" and "Causes and diagnosis of AA amyloidosis and relation to rheumatic diseases" and "Treatment of AA (secondary) amyloidosis".)


The goal of treatment is to alleviate the immediate symptoms for the purpose of improving quality of life (QoL) and avoiding unnecessary therapies. Amyloidosis, the one serious potential complication, is quite rare. The drugs used to control symptoms also ameliorate inflammation and may mitigate some of the long-term effects of inflammation, such as the development of amyloidosis. Curative treatments that are sufficiently low risk are lacking. Interventions that prevent the febrile episodes are available but are associated with a higher risk of adverse events and are therefore reserved for patients who develop amyloidosis. (See "Hyperimmunoglobulin D syndrome: Clinical manifestations and diagnosis".)

Alleviate symptoms — Symptomatic treatment of the fever and associated symptoms is one of the main focuses of management since the disease primarily affects QoL and rarely leads to severe physical complications. (See 'Symptomatic treatment' below.)

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Literature review current through: Nov 2017. | This topic last updated: Jun 07, 2017.
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  1. Neven B, Valayannopoulos V, Quartier P, et al. Allogeneic bone marrow transplantation in mevalonic aciduria. N Engl J Med 2007; 356:2700.
  2. Kallianidis AF, Ray A, Goudkade D, de Fijter JW. Amyloid A amyloidosis secondary to hyper IgD syndrome and response to IL-1 blockage therapy. Neth J Med 2016; 74:43.
  3. van der Hilst JC, Bodar EJ, Barron KS, et al. Long-term follow-up, clinical features, and quality of life in a series of 103 patients with hyperimmunoglobulinemia D syndrome. Medicine (Baltimore) 2008; 87:301.
  4. Drenth JP, Haagsma CJ, van der Meer JW. Hyperimmunoglobulinemia D and periodic fever syndrome. The clinical spectrum in a series of 50 patients. International Hyper-IgD Study Group. Medicine (Baltimore) 1994; 73:133.
  5. Picco P, Gattorno M, Di Rocco M, Buoncompagni A. Non-steroidal anti-inflammatory drugs in the treatment of hyper-IgD syndrome. Ann Rheum Dis 2001; 60:904.
  6. de Dios García-Díaz J, Alvarez-Blanco MJ. Glucocorticoids but not NSAID abort attacks in hyper-IgD and periodic fever syndrome. J Rheumatol 2001; 28:925.
  7. Yoshimura K, Wakiguchi H. Hyperimmunoglobulinemia D syndrome successfully treated with a corticosteroid. Pediatr Int 2002; 44:326.
  8. Drenth JP, van Deuren M, van der Ven-Jongekrijg J, et al. Cytokine activation during attacks of the hyperimmunoglobulinemia D and periodic fever syndrome. Blood 1995; 85:3586.
  9. Normand S, Massonnet B, Delwail A, et al. Specific increase in caspase-1 activity and secretion of IL-1 family cytokines: a putative link between mevalonate kinase deficiency and inflammation. Eur Cytokine Netw 2009; 20:101.
  10. Bodar EJ, Kuijk LM, Drenth JP, et al. On-demand anakinra treatment is effective in mevalonate kinase deficiency. Ann Rheum Dis 2011; 70:2155.
  11. Rubinstein A, Albert Einstein College of Medicine and Montefiore Hospital Medical Center, 2017, personal communication.
  12. Stoffels M, Jongekrijg J, Remijn T, et al. TLR2/TLR4-dependent exaggerated cytokine production in hyperimmunoglobulinaemia D and periodic fever syndrome. Rheumatology (Oxford) 2015; 54:363.
  13. Arkwright PD, McDermott MF, Houten SM, et al. Hyper IgD syndrome (HIDS) associated with in vitro evidence of defective monocyte TNFRSF1A shedding and partial response to TNF receptor blockade with etanercept. Clin Exp Immunol 2002; 130:484.
  14. Takada K, Aksentijevich I, Mahadevan V, et al. Favorable preliminary experience with etanercept in two patients with the hyperimmunoglobulinemia D and periodic fever syndrome. Arthritis Rheum 2003; 48:2645.
  15. Bodar EJ, van der Hilst JC, Drenth JP, et al. Effect of etanercept and anakinra on inflammatory attacks in the hyper-IgD syndrome: introducing a vaccination provocation model. Neth J Med 2005; 63:260.
  16. Shendi HM, Walsh D, Edgar JD. Etanercept and anakinra can prolong febrile episodes in patients with hyperimmunoglobulin D and periodic fever syndrome. Rheumatol Int 2012; 32:249.
  17. Topaloğlu R, Ayaz NA, Waterham HR, et al. Hyperimmunoglobulinemia D and periodic fever syndrome; treatment with etanercept and follow-up. Clin Rheumatol 2008; 27:1317.
  18. Demirkaya E, Caglar MK, Waterham HR, et al. A patient with hyper-IgD syndrome responding to anti-TNF treatment. Clin Rheumatol 2007; 26:1757.
  19. Rigante D, Ansuini V, Bertoni B, et al. Treatment with anakinra in the hyperimmunoglobulinemia D/periodic fever syndrome. Rheumatol Int 2006; 27:97.
  20. Cailliez M, Garaix F, Rousset-Rouvière C, et al. Anakinra is safe and effective in controlling hyperimmunoglobulinaemia D syndrome-associated febrile crisis. J Inherit Metab Dis 2006; 29:763.
  21. Goldsmith D, Barron K, Ombrello A, et al. Anakinra for the treatment of hyper-IgD with periodic fever syndrome in chidren [abstract]. Arthritis Rheum 2011; 63 Suppl 10:2028.
  22. Ter Haar N, Lachmann H, Özen S, et al. Treatment of autoinflammatory diseases: results from the Eurofever Registry and a literature review. Ann Rheum Dis 2013; 72:678.
  23. Galeotti C, Meinzer U, Quartier P, et al. Efficacy of interleukin-1-targeting drugs in mevalonate kinase deficiency. Rheumatology (Oxford) 2012; 51:1855.
  24. Kostjukovits S, Kalliokoski L, Antila K, Korppi M. Treatment of hyperimmunoglobulinemia D syndrome with biologics in children: review of the literature and Finnish experience. Eur J Pediatr 2015; 174:707.
  25. Dinarello CA, van der Meer JW. Treating inflammation by blocking interleukin-1 in humans. Semin Immunol 2013; 25:469.
  26. Curtis CD, Fox CC. Treatment of adult hyper-IgD syndrome with canakinumab. J Allergy Clin Immunol Pract 2015; 3:817.
  27. Tsitsami E, Papadopoulou C, Speletas M. A case of hyperimmunoglobulinemia d syndrome successfully treated with canakinumab. Case Rep Rheumatol 2013; 2013:795027.
  28. Musters A, Tak PP, Baeten DL, Tas SW. Anti-interleukin 6 receptor therapy for hyper-IgD syndrome. BMJ Case Rep 2015; 2015.
  29. Shendi HM, Devlin LA, Edgar JD. Interleukin 6 blockade for hyperimmunoglobulin D and periodic fever syndrome. J Clin Rheumatol 2014; 20:103.
  30. Ostuni P, Vertolli U, Marson P. Atypical hypergammaglobulinaemia D syndrome with amyloidosis: an overlap with familial Mediterranean fever? Clin Rheumatol 1996; 15:610.
  31. Hoffmann GF, Charpentier C, Mayatepek E, et al. Clinical and biochemical phenotype in 11 patients with mevalonic aciduria. Pediatrics 1993; 91:915.
  32. Simon A, Drewe E, van der Meer JW, et al. Simvastatin treatment for inflammatory attacks of the hyperimmunoglobulinemia D and periodic fever syndrome. Clin Pharmacol Ther 2004; 75:476.
  33. Drenth JP, Vonk AG, Simon A, et al. Limited efficacy of thalidomide in the treatment of febrile attacks of the hyper-IgD and periodic fever syndrome: a randomized, double-blind, placebo-controlled trial. J Pharmacol Exp Ther 2001; 298:1221.