OVERVIEW: What every practitioner needs to know

Are you sure your patient has a Hyper IGD? What are the typical findings for this disease?

Hyperimmunoglobulinemia D with periodic fever (HIDS) is an inherited periodic fever syndrome (PFS) characterized by unprovoked systemic inflammation in the absence of infectious symptoms or evidence for autoimmunity.

The most common symptoms include attacks beginning in the first year of life with a median age of initial onset of 6 months. Attacks are characterized by unremitting fever ≥38.5°C lasting for 3-7 days and recurring every 4-8 weeks. Bouts of severe abdominal pain with febrile attacks are also a cardinal feature and are due to serositis. This may lead to unnecessary surgeries such as appendectomy. Prominent cervical or generalized lymphadenopathy (in >90%) and splenomegaly (in 50%) distinguish HIDS from most PFS.

The next most common symptoms are non-destructive recurrent arthritis or arthralgias in 80% patients. In addition to the abdominal pain, GI symptoms of nausea, vomiting, diarrhea are also common during attacks. These patients also commonly present with chronic rashes such as a non-specific erythematous maculopapular rash, urticaria, erythematous subcutaneous nodules, petechiae in an acral to truncal distribution. Seventy-five percent of patients have chronically elevated serum IgD >100 IU/ml while typically 70% patients have elevated IgA (>260 mg/dL) while 20-25% of patients (usually those under the age of 5) have normal serum IgD and IgA levels.

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Some prodromal symptoms that are typical include chills, nasal congestion, pharyngitis, fatigue, headache, behavioral changes and back pain. A small percent of patients uncommonly present with painful aphthous ulcers in the mouth or on genitalia. A subset of patients have neurological problems similar to mevalonic aciduria.

During inflammatory attacks, a patient may present with leukocytosis with neutrophilia, elevated ESR and CRP, increased serum amyloid A protein (SAA), and elevated ferritin. Between attacks, acute phase reactants normalize and symptoms other than rash and arthralgias resolve.

Patients diagnosed with HIDS have a normal lifespan with few serious complications. Three percent will develop 2° amyloidosis.

The diagnosis of HIDS is unlikely in a patient if the age at onset of fever is greater than 5 years and fever persists for more than 14 days without joint symptoms. Diagnosis of HIDS is often delayed unless there is a family history. The median time from onset of symptoms to diagnosis is 10 years. The diagnosis may be delayed when there is a prodrome of upper respiratory tract symptoms or the symptoms of serositis suggest more common illnesses.

What other disease/conditions share some of these symptoms?

There are a host of diseases that share the same symptoms as HIDS and include the following: cyclic neutropenia, HIV/AIDS, tuberculosis, CMV, brucellosis, rat-bite fever, relapsing fever or other chronic viral, bacterial or parasitic infections, systemic lupus erythematosus, relapsing polychondritis, ANCA-mediated vasculitis including Wegener’s granulomatosis and microscopic polyangiitis, Takayasu’s arteritis, other systemic autoinflammatory diseases, HLA B27-associated juvenile spondyloarthropathies, sarcoidosis, malignancies including leukemia and lymphoma, autoimmune lymphoproliferative syndrome (ALPS), acute intermittent porphyria, relapsing pancreatitis, and certain surgical emergencies including appendicitis, intussusception, and ovarian torsion.

Due to autosomal recessive mutations in the mevalonic acid kinase (MVK) gene, a patient may present with total or near total absence of MVK activity causing mevalonic aciduria. MVK mutations resulting in HIDS are less deleterious and allow residual MVK function. Genotyping can be used to confirm the diagnosis if the serum IgD is not elevated. Unlike familial Mediterranean fever, colchicine does not improve symptoms or prevent amyloid nephropathy.

Systemic autoinflammatory syndromes that mimic HIDS

Systemic autoinflammatory syndromes that mimic HIDS include the following: Periodic fever with aphthous stomatitis, pharyngitis and adenitis (PFAPA syndrome), TNF receptor associated periodic fever syndrome (TRAPS), familial Mediterranean fever (FMF), Muckle-Wells syndrome (MWS), Behcet’s disease, Crohn’s disease, Macrophage activation syndrome, Hereditary or acquired angioedema, Gout, and Autoimmune bone diseases such as Chronic Recurrent Multicoal Osteomyelitis (CRMO) and Synovitis, Acne, Pustulosis, Hyperostosis, Osteitis (SAPHO).

What caused this disease to develop at this time?

Triggers may include emotional stress, minor trauma, surgery, illness or vaccinations. In many cases, no specific trigger is identified before onset of HIDS.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

To screen initially for HIDs, the following laboratory studies are helpful: a CBC with differential obtained during fever episodes and when the patient is symptom-free; an ESR with CRP during fever and when symptom-free; a complete metabolic panel; uric acid, LDH; ferritin, fibrinogen, quantitative serum immunoglobulins (IgG, IgA, IgM); urinalysis; blood, urine, throat cultures; and a PPD. Marked leukocytosis with left shift, and ESR and CRP greater than 80 suggest infection. A positive PPD suggests tuberculosis. An elevated uric acid and LDH suggests leukemia.

Additional tests can be performed as clinically indicated and often include: a throat culture; IgG and IgM antibody titers for CMV, EBV, and Brucella; PCR for CMV and EBV DNA; ANA panel; ANCAs; ACE (angiotensin converting enzyme); C3, C4, C1 inhibitor activity; HLA typing (specifically for HLA B27 and B51), analysis of synovial fluid for cell count, crystals and culture; a 24 hour urine collection for protein and creatine clearance; and lymph node and/or bone marrow biopsy for histology and culture.

Once initial tests suggest HIDS, the following studies are helpful in confirming diagnosis: serum IgD, urinary mevalonic acid/creatinine ratio, genotyping for HIDS, TRAPS, FMF, MWS, and renal or rectal biopsy and staining for amyloid deposition.

One may suspect diagnosis of HIDS if there is both an elevated serum IgD and IgA in association with periodic fevers, adenopathy, rash, abdominal pain, or arthritis.

Would imaging studies be helpful? If so, which ones?

Several imaging studies are helpful in confirming diagnosis of HIDS or a related disease. Conducting a chest x-ray can assist in diagnosing infection, inflammatory lung disease or serositis (pleuritis, pericarditis). Abdominal x-ray, ultrasound and/or computerized tomography (CT) is helpful in evaluating abdominal pain and ruling out peritonitis or surgical emergency. To evaluate for lymphadenopthy and splenomegaly, consider a chest, abdomen, and/or pelvis CT. An echocardiogram can rule out pericarditis and a gallium scan can evaluate for adenopathy.

Confirming the diagnosis

Pertinent history that can assist in suspecting HIDS include peak fever temperature, the pattern and duration of fever (hectic, quotidian, recurrent, relapsing/periodic, continuous, intermittent, remittent), the antecedent or prodromal symptoms prior to fever, and any associated symptoms (infectious, rash, arthritis, diarrhea, etc). If there are symptoms associated with the fever, their pattern of appearance, duration, and predictability can be suggestive of a certain illness course.

One should note the duration of fever-free intervals and the overall health and persistence of chronic symptoms when afebrile. This too will help with confirming a diagnosis. A famly history is helpful when there have been individuals with similar unexplained febrile illnesses and responses to treatment, distinct parent ethnicity, and individuals whith abnormal types and numbers of infections with poor responses to treatment.

Suspect the diagnosis of HIDS if a patient presents with recurrent fevers in typical pattern of 3-7 days every 4-8 weeks, the first attack of symptoms occur after a childhood vaccination, or three or more of the following are present: cervical lymphadenopathy, abdominal pain, vomiting or diarrhea, arthritis or arthralgias of large joints, rash, aphthous ulcers, elevated serum IgD and IgA, and urine melavonic acid to creatinine ratio in an untimed urine sample is less than 20 mmol/mol (up to 80 mg/g) creatinine (should not be used to confirm diagnosis).

These symptoms are even more suggestive when the age of the patient at presentation is under 5 years and patient history reveals siblings with genetically confirmed HIDS. One must be skeptical of the diagnosis of HIDS if the age of fever onset is greater than 5 years of age, the fever persists for more than 14 days, the patient is devoid of joint symptoms, and serum IgD and IgA are normal. Normal serum IgD and IgA do not rule out diagnosis if clinical symptoms are typical of HIDS. In that circumstance, genetic testing should be considered.

If you are able to confirm that the patient has Hyper IGD, what treatment should be initiated?

Once HIDS is confirmed, initial treatment includes the use of NSAIDS for fever and/or pain. One can start with naproxen 10 mg/kg (max 500 mg) b.i.d., celecoxib 50-200 mg q.day or b.i.d., meloxicam 0.125 mg/kg (max 15 mg) daily, orindomethacin 1-2 mg/kg b.i.d.

For more severe or NSAID-resistant symptoms, consider methylprednisolone 30 mg/kg (max 1 gm) IV daily times 1-3 days, and/or oral Prednisone 0.5-2 mg/kg/day. Steroids can be tapered and discontinued with symptomatic improvement.

For more long-term treatment, NSAIDS such as naproxen 10 mg/kg (max 500 mg) b.i.d., celecoxib 50-200 mg q.day or b.i.d., meloxicam 0.125 mg/kg (max 15 mg) daily, or indomethacin 1-2 mg/kg b.i.d. are used.

For acute flares in disease activity, prednisone 0.25-2 mg/kg/day, anakinra 1-2 mg/kg (max 100 mg) SQ daily at onset of symptoms, etanercept 0.4 mg/kg (max 25 mg) SQ b.i.w. or 0.8 mg/kg (max 75 mg) SQ q.wk.

If standard treatment fails, there are alternate treatment options (see Table I) However, several are controversial and others have proven no benefit to the patient. The more controversial options include infliximab 3-7.5 mg/kg IV Q.4-8 wk and simvastin 10-20 mg (max 80 mg) daily. Options with low rates of benefits include colchicine 0.3-1.2 mg daily, azathioprine 1-2 mg/kg (max 150-200 mg) daily, and cyclosporine 1-3 mg/kg/day with goal trough level: 100-200 ng/ml.

Table I.
Treatment Advantages Disadvantages
Prednisone or Solu-Medrol at 1st sign of an attack Immediate response to decrease attack severity, but does not prevent flares Adverse effects; often of no benefit
Anakinra: given either continuously or at onset of attacks Immediate response; may abort attack Adverse effects; if no response, try etanercept
Etanercept: given either continuously or at onset of attacks Fairly rapid response; few side effects if given to abort attacks Adverse effects; if no response, try anakinra
Simvastin Inhibits HMG-CoA reductase upstream of MVK in isoprenoid pathway; may decrease fever duration; few side effects Limited efficacy; may worsen symptoms

What are the adverse effects associated with each treatment option?

See Table II. Adverse effects of therapies used for Hyper IgD Syndrome

Table II.
NSAIDS Gastritis, gastric ulcer, gastroesophageal reflux, rash, edema, liver/renal toxicity uncommon in children
Corticosteroids Infection, weight gain, muscle atrophy, adrenocortical insufficiency, osteopenia, growth delay, avascular necrosis, emotional lability, rash, edema, hypertension, diabetes
Colchicine Nausea, vomiting, diarrhea, abdominal pain, anorexia, peripheral neuropathy, muscle weakness, rhabdomyolysis, renal/liver toxicity, rash
Etanercept Infection, injection site reaction, CNS/demyelinating disorder, ANA positivity, malignancy (very low risk)
Infliximab Infection (risk > etanercept), allergic reaction, anaphylaxis, nausea, diarrhea, abdominal pain, fatigue, elevated LFTs, serum sickness, ANA positivity, CNS/demyelinating disease, increased heart failure, cytopenias, future malignancy (risk > etanercept)
Anakinra Infection, severe injection site reaction/pain, future malignancy
Azathioprine Infection, leukopenia, pancytopenia with low thiopurine S-methyl transferase (TPMT) activity, liver toxicity, nausea, vomiting, secondary malignancy
Simvastatin Constipation, dyspepsia, rhabdomyolysis, hepatitis, acute renal failure
Cyclosporine Infection, hypertension, renal toxicity, renal failure, hirsutism, GI upset, malignancy, CNS toxicity, gingival hyperplasia

What are the possible outcomes of hyper IGD?

The patient and family should be prepared for several possible outcomes of HIDS. First, acute HIDS attacks will often begin in the first year of life and certainly before 5 years of age. A person with HIDS can have a normal lifespan with few serious complications other 2° amyloidosis (in <3% patients). Significant complications are uncommon and may or may not be related to residual MVK activity. Table III can assist the clinician and family in determining the best treatment options for each patient after weighing the risks and benefits to each option.

Table III.
Drug Indication Risks Benefits
NSAIDS Arthritis; pain, fever Adverse reactions Reduce fever, pain, arthritis
Corticosteroids Fever, arthritis, serositis, urticaria, splenomegaly, lymphadenopathy Adverse reactions Relieve fever, rash; improve adenopathy, arthritis; lessen serositis
Colchicine Arthritis, oral stomatitis Adverse reactions Reduces fever, oral aphthae.
Etanercept Arthritis, aphthous stomatitis, fever Adverse reactions; may trigger flares Controls fever, arthritis, aphthous stomatitis; improve inflammatory markers
Infliximab Chronic arthritis, fever, chronic uveitis Adverse reactions Controls fever, arthritis, uveitis; improves inflammatory markers
Anakinra Fever, rash, arthritis, elevated ESR/CRP Adverse reactions; may trigger flares; no longlasting disease control after stopped Remits fever, rash, arthritis, laboratory abnomalities
Azathioprine HIDS resistant to standard therapy Adverse reactions May reduce HIDS symptoms in a few patients
Cyclosporine HIDS resistant to standard therapy Adverse reactions May reduce HIDS symptoms and episodes in a few patients
Simvastatin HIDS resistant to standard therapy Adverse reactions; may tigger flares of HIDS May reduce HIDS episodes in a few patients

What causes Hyper IGD and how frequent is it?

HIDS has a very rare incidence rate with less than 200 individuals affected worldwide. It is caused by homozygous or compound heterozygous mutations throughout the MVK
gene encoding mevalonate kinase. The V3771 mutation is present in 80% of all affected patients. The mutation frequency rate is 1:350 in the Netherlands, secondary to a founder effect. The mutation effects males and females equally but primarily in those of caucasian ethnicity. Twenty-five percent of affected patients with typical HIDS symptoms and elevated serum IgD lack MVK mutations.

How do these pathogens/genes/exposures cause the disease?

Mevalonate kinase (MVK) is necessary for cholesterol synthesis. MVK catalyzes conversion of mevalonic acid to 5-phospho-mevalonic acid in the isoprenoid pathway. Severe loss-of-function mutations resulting in absent MVK activity will cause mevalonic aciduria. Less severe mutations (>60 identified) in MVK resulting in 1-10% residual MVK activity cause HIDS.

Etiology of elevated serum IgD and IgA, fevers, and illness from decreased MVK activity are not fully understood, but are thought to involve modulation of the innate immune response. Shortage of isoprenoid end products may lead to increased production of the proinflammatory cytokine, IL-1beta.

Other clinical manifestations that might help with diagnosis and management

Development of 2° amyloidosis is rare but can be devastating. Amyloid deposition usually occurs in the kidneys and often presents as proteinuria without renal insufficiency. Amyloidosis is diagnosed by biopsy of kidney or rectum. Unfortunately, colchicine does not prevent 2° amyloidosis in HIDS, as it does in FMF.

What complications might you expect from the disease or treatment of the disease?

Most complications self-limited, but some do affect health and quality of life. Most worrisome disease complications are bowel adhesions, unnecessary surgery, 2° amyloidosis. Treatment complications may be more or as common as from disease, including worsening inflammation, organ toxicity, infection and future malignancy.

Are additional laboratory studies available; even some that are not widely available?

Urine mevalonic acid level is one laboratory study also available for use.

How can Hyper IGD be prevented?

There is no known means of preventing HIDS. Prenatal diagnosis is required to identify the disease-causing mutation(s). Genetic counseling is important if HIDS is suspect.

What is the evidence?

The following articles provide general overviews of the Periodic Fever Syndromes:

Simon, A, van der Meer. “Pathogenesis of familial periodic fever syndromes or hereditary autoinflammatory syndromes”. Am J Physiol Regul Integr Comp Physiol. vol. 292. 2006. pp. R86

Bodar, EJ, Drenth, JPH, van der Meer, JWM, Simon, A. “Dysregulation of innate immunity: hereditary periodic fever syndromes”. Brit J Hematol. vol. 144. 2008. pp. 279

Glaser, RL, Goldbach-Mansky, R. “The Spectrum of Monogenic Autoinflammatory Syndromes: Understanding Disease Mechanisms and Use of Targeted Therapies”. Curr Allergy Asthma Rep. vol. 8. 2008. pp. 288

Goldbach-Mansky, Kastner, DL. “Autoinflammation: The prominent role of IL-1 in monogenic autoinflammatory diseases and implications for common illnesses”. J Allergy Clin Immunol. vol. 124. 2009. pp. 1141

Masters, SL, Simon, A, Aksentijevich, Kastner, DL. “Horror Autoinflammaticus: The Molecular Physiology of Autoinflammatory Disease”. Ann Rev Immunol. vol. 27. 2009. pp. 621

Kastner, DL, Aksentijevich, A, Goldbach-Mansky, R. “Autoinflammatory Disease Reloaded: A Clinical Perspective”. Cell. vol. 140. 2010. pp. 784

Henderson, C, Goldbach-Mansky, R. “Monogenic autoinflammatory diseases: new insights into clinical aspects and pathogenesis”. Curr Opin Rheumatol. vol. 22. 2010. pp. 567

Ombrello, MJ, Kastner, DL. “Expanding clinical spectrum and broadening therapeutic horizons”. Nat Rev Rheumatol. vol. 7. 2011. pp. 82

van der, Hilst, JCH, Simon, A, Drenth, JPH. “Hereditary periodic fever and reactive amyloidosis”. Clin Exp Med. vol. 5. 2005. pp. 87

Bilginer, Y, Akpolat, T, Ozen, S. “Renal amyloidosis in children”. Pediatr Nephrol March. 2011.

Doherty, TA, Brydges, SD, Hoffman, HM. “Autoinflammation: translating mechanism to therapy”. J Leukocyte Biol February. 2011.

van der Hilst, JC, Bodar, EJ, Barron, KS, Frenkel, J, Drenth, JP, van der Meer, JW, Simon, A. “Long-term follow-up, clinical features, and quality of life in a series of 103 patients with hyperimmunoglobulinemia D syndrome”. Medicine. vol. 87. 2008. pp. 301

van der Hilst, Frenkel, J. “Hyperimmunoglobulin D syndrome in childhood”. Curr Rheumato Rep. vol. 12. 2010. pp. 101

Korppi, M, van Gijn, ME, Antila, K. “Hyperimmunoglobulinemia D and periodic fever syndrome in children. Review on therapy with biologic drugs and case report”. Acta Pediatrica. vol. 100. 2011. pp. 21

Haas, D, Hoffmann, GF. “Mevalonate knase deficiency and autoinflammatory disorders”. N Engl J Med. vol. 357. 2007. pp. 1871

Ongoing controversies regarding etiology, diagnosis, treatment

Long term risks/benefits of treatment with biologics, given uncertain future risks, particularly for malignancies, opportunistic infections, autoimmune diseases, organ toxicity.

Consensus for treatment of HIDS since conventional immunosuppression rarely of benefit, most patients do well over time, and may not need chronic biologic therapy.