Hyper IgD

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.

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.