Favorable preliminary experience with etanercept in two patients with the hyperimmunoglobulinemia D and periodic fever syndrome

Arthritis Rheum. 2003 Sep;48(9):2645-51. doi: 10.1002/art.11218.


Objective: The hyperimmunoglobulinemia D and periodic fever syndrome (HIDS; MIM 260920) is caused by recessive mutations in the mevalonate kinase gene (MVK), which encodes an enzyme involved in cholesterol and nonsterol isoprenoid biosynthesis. HIDS is characterized by persistently elevated polyclonal IgD and recurrent febrile episodes. Although abnormalities in tumor necrosis factor alpha (TNF alpha) are not the primary cause of HIDS, plasma TNF alpha levels are elevated in HIDS patients during attacks and thus may be a therapeutic target. This study assessed the effects of etanercept, a soluble p75 TNF alpha receptor-Fc fusion protein, in 2 patients with HIDS.

Methods: We performed biochemical and molecular genetic analyses on 2 girls with periodic episodes of fever, skin rash, abdominal pain, and arthralgia, of whom 1 had elevated levels of serum IgD. After the diagnosis of HIDS was made, treatment with etanercept was initiated in both patients. Clinical response was recorded in a standardized diary, and serum levels of cytokines and their decoy receptors were serially measured in 1 of the 2 patients.

Results: Urinary mevalonate levels were elevated in both girls. Patient 1 was heterozygous for a known MVK missense mutation (V377I) and a novel mutation that led to skipping of exon 3. Patient 2 was found to have V377I and a new missense mutation, S329R. Neither patient had mutations in TNFRSF1A or MEFV, the genes for the TNF receptor-associated periodic syndrome and familial Mediterranean fever, respectively. Etanercept reduced the frequency and severity of symptoms in both patients, whereas the levels of serum IgD and urine mevalonate remained unchanged.

Conclusion: Our favorable experience with etanercept for the treatment of HIDS suggests that further investigation of this therapy is warranted.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, CD / genetics
  • Child
  • Cytokines / blood
  • Cytoskeletal Proteins
  • Etanercept
  • Familial Mediterranean Fever / drug therapy*
  • Familial Mediterranean Fever / genetics
  • Familial Mediterranean Fever / immunology
  • Female
  • Humans
  • Hypergammaglobulinemia / drug therapy*
  • Hypergammaglobulinemia / genetics
  • Hypergammaglobulinemia / immunology
  • Immunoglobulin D*
  • Immunoglobulin G / administration & dosage*
  • Immunosuppressive Agents / administration & dosage*
  • Periodicity*
  • Proteins / genetics
  • Pyrin
  • Receptors, Tumor Necrosis Factor / administration & dosage*
  • Receptors, Tumor Necrosis Factor / genetics
  • Receptors, Tumor Necrosis Factor, Type I


  • Antigens, CD
  • Cytokines
  • Cytoskeletal Proteins
  • Immunoglobulin D
  • Immunoglobulin G
  • Immunosuppressive Agents
  • MEFV protein, human
  • Proteins
  • Pyrin
  • Receptors, Tumor Necrosis Factor
  • Receptors, Tumor Necrosis Factor, Type I
  • Etanercept