Hyper-Igd Syndrome

About Hyper IgD Syndrome (HIDS), one of the Mevalonate Kinase Deficiency (MKD) illnesses.

Hyper-IgD syndrome (HIDS),  or HIDS disease, is caused by an inherited autosomal recessive gene mutation of the mevalonate kinase gene (MVK). Most patients have two mutations on the MVK gene, one from each parent to cause HIDS disease symptoms. However, there are some patients with only one identified mutation on the MVK gene, and some cases where no MVK mutations were found that have been identified as having clinical HIDS.

A clinical diagnosis can, and should be made after a full evaluation of symptoms, labs, and genetic testing.  Almost all autoinflammatory diseases that are associated with genetic mutations also have cases that are “mutation negative” that have full symptoms and characteristics of the disease.  New genetic testing methods have led to finding genetic mutations in previously “mutation negative” patients with clinical diagnosis of CAPS, and it is very likely that with more research, new genetic findings will be discovered for other autoinflammatory diseases.

This mutation causes a malfunction in the innate immune system’s inflammatory processes and a variety of symptoms. Like other recurrent fever syndromes, HIDS disease symptoms are caused by the patient’s genetic mutations and are not contagious at any time.

HIDS DC6D90DD33 1 300x239 Hyper Igd Syndrome

HIDS rash image from Le Clube Rheumatismes et Inflammation

Hyper-IgD Syndrome Symptoms

Symptoms are usually present before the age of one. However, because these symptoms, such as a high fever, are typical in early childhood, many doctors and parents may not recognize the symptoms as being abnormal until the child is older. A few cases of adult or later-onset HIDS have been reported.

Symptoms do vary greatly among individuals and even from flare to flare in the same person. The symptoms can also be progressive, as many parents report that their child develops more symptoms and symptoms may become more severe or pronounced with each flare over time. In some adults, the symptoms may become less frequent and less severe. But this does not happen in all cases.

Severity of symptoms, and signs of chronic inflammation, can vary greatly between each case of MVK, but these are generally lifelong diseases for most patients. Most patients with the HIDS form of MVK have significant symptoms during flares of their disease and can have some chronic inflammatory issues, but few have significant, permanent damage to their organs or tissues.

The most severe form of MVK is called mevalonate aciduria (MA), which involves a high level of chronic inflammation from birth leading to permanent and debilitating symptoms.  More information about MA features and symptoms is on our comparative chart.

Common Hyper-IgD Syndrome Symptoms

High fever, often reaching 104.0 F or higher, that lasts less than 14 days is the main symptom. Fever flares occur usually every 1 to 12 weeks in childhood. The fever usually lasts 3 to 7 days, but a range of 2 to 12 days has been reported. Some patients report regular, almost predictable fevers, while in others the frequency of fevers is erratic and unpredictable. Some patients also report having feverless flares between fever flares. Feverless flares may have all or some of the symptoms of a fever flare, but may be milder and the fever does not develop.

With each flare, there are usually several other common symptoms that can include:

  • Abdominal pain which can look like appendicitis to the observer
  • Diarrhea
  • Vomiting
  • Mouth ulcers
  • Sore throat
  • Joint pain, swelling, and redness
  • Muscle pain
  • Rash
  • Swelling of cervical lymph nodes
  • Headache
  • Enlarged spleen (Splenomegaly)
  • Cutaneous vasculitis
  • Cold chills
  • Fatigue

Less Common Symptoms

  • Conjunctivitis
  • Enlarged liver (Hepatomegaly)
  • Serositis

Rare Symptoms and Complications

  • Amyloidosis has been seen in less than 10% of HIDS cases.
  • Henoch-Schonlein purpura (HSP)

Flare Triggers

Vaccines, travel, illness, injury, birthday parties, big celebrations, excursions, school pressures, and any other stress, good or bad, to the immune system can cause a flare. In teens and adult women, menstruation is often a trigger for flares. Some patients with HIDS have more frequent and severe flares in the winter and fewer and less severe flares in the summer. Sometimes the flare may seem random and the trigger can’t be identified.

Abnormal Lab Tests

Several tests are needed to help lead to a HIDS diagnosis and monitor a patient with Hyper-IgD disease.

IgD

The high IgD levels common to HIDS gave the disease its name of hyperimmunoglobulinemia D with periodic fever syndrome. However the test results, whether normal or high, are not conclusive.

Having a high IgD test result and recurrent fevers does rule HIDS in as a possible diagnosis, however is not diagnostic to HIDS. Other periodic fever syndromes can sometimes have elevated IgD, including FMF, TRAPS, and PFAPA. Also, around 20% of cases with confirmed genetic HIDS do not have high IgD or develop it later in life. Rarely do children under the age of 3 years have high IgD. Therefore having a normal IgD test result does not rule out HIDS as a possible diagnosis.

IgD levels do not correlate with disease severity.

IgA

80% of patients  may also have a high IgA test result, often in correlation with elevated IgD.

ESR and CRP

The inflammatory tests ESR and CRP are often high during a flare and normal when not in a flare.

White Blood Counts

Neutrophils, and/or monocytes, and/or the overall WBC are also often high during a flare. This often leads to unnecessary treatment with antibiotics or a misdiagnosis as a recurrent virus or other infection.

In some, IgD, ESR, CRP, and/or WBCs may be high when not in a flare as well.

Mevalonic Acid Urine Test

MVK deficiency causes high levels of mevalonic acid in the urine during a flare. However, this is a difficult test to perform and not always a reliable diagnostic test. Patients with genetic confirmed HIDS have been known to have normal mevalonic acid tests. Having a normal test does not rule out HIDS disease as a possible diagnosis. This test is often reserved for research purposes.

Diagnosing Hyper-IgD Syndrome

All of the tests above are helpful in determining if a person has a periodic fever syndrome that could be HIDS, but  each of these tests alone do not diagnose HIDS specifically.

The only way to positively confirm a genetic HIDS diagnosis is through genetic testing.

It’s ideal to have a full panel of genetics testing for similar hereditary autoinflammatory diseases if  HIDS disease is suspected. This not just to test for HIDS, but to also rule out other periodic fever syndromes, such as FMF, CAPS, and TRAPS, which have many symptoms and abnormal lab results that can overlap with HIDS. There are a number of  laboratories to obtain the test for HIDS, or for other autoinflammatory diseases in the world, but very few in the U.S. test for HIDS mutations. Most doctors in the U.S. use the GeneDX Periodic Fever Syndromes 7 gene panel.

There are also cases of patients having multiple fever syndromes, such as HIDS and FMF, confirmed by genetics. If only the HIDS genetic test is performed when HIDS is suspected, these other conditions will be missed in some patients. It is also more cost effective to run the entire panel, as doing multiple individual fever syndrome tests can be more expensive. Also, the wait time for genetic testing is often over 2-3 months, so testing each disease individually would delay diagnosis and treatment for the patient.

If no mutations are found after genetic testing, then a clinical diagnosis of HIDS can be made based on symptoms, laboratory tests, and negative genetics for similar conditions, such as FMF, CAPS, and TRAPS. In clinical HIDS, the recommended treatments are generally the same as for genetic cases of HIDS.

When is Genetic Testing for Hyper-IgD Syndrome Warranted?

Van der Hilst et al suggest HIDS genetic testing if the patient has:

  • Recurrent fever episodes lasting 3 to 7 days persisting more than 6 months

AND 1 or more of the following:

  • Sibling with genetically confirmed HIDS
  • Elevated serum IgD (>100 IU/L)
  • First attack after childhood vaccination

OR 3 or more of the following symptoms during fever attacks:

  • Cervical lymphadenopathy
  • Abdominal pain
  • Vomiting or diarrhea
  • Arthralgia or arthritis of large peripheral joints
  • Aphthous ulcers
  • Skin lesions

Inheritance

HIDS is considered a recessive disorder. This means that you need to inherit one mutation from each parent to have the symptoms of HIDS. However, some patients with only one known HIDS mutation show symptoms of disease, even when their parent does not. It’s not completely understood why these patients have symptoms with only one mutation. However studies have shown that symptomatic patients with a single mutation on the MVK gene, can have the same symptoms and severity of disease as those with two HIDS mutations.

There is also a recognized variant HIDS form of this disease in which patients have the symptoms of HIDS but no mutation is found.

Researchers continue to look for genes and mutations involved in HIDS.

HIDS is most common in those with a Dutch or French ancestry, but has been reported in a range of ethnic groups.

Most Common Hyper-IgD Syndrome Treatment Options are Experimental and “Off Label”

HIDS does not have a single treatment that works well for every patient and there are no FDA-approved medications for HIDS as of 2014. We only have research studies to refer to in our discussion about the use of “off-label” treatments that were used in controlled clinical trials.  “Off-label” means that the drug  does not currently have FDA approval for use as a treatment for HIDS. The medications used in these trials are only approved officially for other uses or diseases.  Most autoinflammatory diseases do not have FDA-approved medications, so prescribed medications to treat these diseases are written “off-label.” Experimental use of medications, based on clinical research studies, is very common for rare diseases.

There are also no known treatments that effectively prevent all HIDS flares in most patients. This is partly because researchers still do not understand the entire biological process of the disease making it difficult to develop a targeted medication.

All medications prescribed for HIDS at this time are experimental, and patients need to work with their doctor in what “off-label” medications to try for their disease. We are merely presenting a discussion of what has been prescribed during clinical research, and are not suggesting, or recommending the use of one medication over another for use with HIDS.

Common Hyper-IgD Syndrome Treatment Options Include

Most patients are first prescribed treatment with ibuprofen and acetaminophen (over the counter non-steroidal anti-inflammatory drugs-aka NSAIDS) to control the flares. However, in many patients, these medications become less effective over time or were never effective. After NSAIDS, the most commonly prescribed medication for HIDS is a high dose of oral prednisone, at a dose of 1mg/kg/day reports the authors of The Autoinflammatory Diseases, to be given at the first sign of a flare. Prednisone has been found to help patients more effectively if administered at the first onset of symptoms.

Kineret (anakinra) is FDA approved for other diseases, but has been prescribed by clinicians and researchers for some patients with HIDS as an “off label” experimental treatment.

In some cases, Kineret has been prescribed “off-label” for daily use to help increase the time between flares or for “on demand use.” For patients with less frequent flares, doctors may often prescribe off-label Kineret on demand for use during flares only. Some doctors prescribe Kineret off-label for daily injections for patients with more frequent HIDS flares or who are more symptomatic in an attempt to reduce the frequency of flares and symptom severity.

Patients using Kineret on demand are prescribed an injection to give on each day of a HIDS flare, or for a set number of days starting with the onset of flare symptoms. In various studies, the first Kineret injection was usually given at the first sign of a flare for the best results. In some cases for severe flares, doctors may prescribe Kineret and prednisone combined to treat flares on-demand.

In the study entitled  Anakinra for the Treatment of Hyper-IgD with Periodic Fever Syndrome in Children, researchers report for HIDS patients, “Dosage (of Kineret) most often was initiated at 1mg/kg with further increases when needed up to 3–5mg/kg/day.” This lead to, “The majority (8 [72%] ) of 11 children with HIDS demonstrated a beneficial response to anakinra therapy…”

Success of these medications varies greatly from patient to patient. What works well in some may not work well, or at all in others. Also, prednisone in some patients has been found to cause flares to occur more frequently, or at closer intervals of time.

Other Treatments

Several other medications have been tried experimentally, and again “off-label,” with HIDS patients with varied success. These include Enbrel, statin drugs, daily NSAIDS, and colchicine. Studies have shown that a few patients have found relief for HIDS symptoms with Enbrel and daily NSAIDS. HIDS.net reports that Simvastatin use in some adults with HIDS helped to “diminish the number of days of illness (although it did not stop all fever attacks).” However, comprehensive studies have not been done with Simvastatin in children with HIDS, and statin drugs are not generally recommended by researchers as a treatment for children with HIDS. Colchicine has not proven effective in helping to control HIDS fevers and flares report the authors of Hyperimmunoglobulinemia D (hyperIgD) and periodic fever, but some patients have found that colchicine has helped to relieve joint and muscle pain.

Other medications are being studied in Europe for use in hyper-IgD syndrome. These include canakinumab (Ilaris) and tocilizumab (Actemra). Of these, canakinumab has the most research for use as a HIDS treatment as of 2014. According to Juan Ignacio Arostegui, MD, PhD in a 2013 study, “CAN (canakinumab) in active HIDS markedly reduced the rate of acute flares, and a sustained good/excellent disease control was observed.” In this study, most patients were given a dose of 4mg/kg every 6 weeks. With this the median flares went from 5 in 6 months to 0 in 6 six months.

As of 2014, there are a two case reports of tocilizumab (Actemra), which is an interleukin-6 inhibitor, being used to treat HIDS. In one study, it was considered a successful treatment in a 13-year-old girl after several other treatments had failed. In another study from the National Amyloidosis Center in London, U.K., it was reported that, “All patients reported improvement in symptoms.” This study included one HIDS patient.

Long Term Prognosis of HIDS

It was once thought, and is still often stated, that HIDS is something children will outgrow. However, since the discovery of the HIDS gene and mutations, and the identification of more adult cases, it is now known that most adults do suffer from some degree of HIDS symptoms, ranging from mild to more severe. What studies have shown is that some, but not all, HIDS patients may suffer from fewer and/or less severe flares as adults than they did as children.

The following statements come from a study that included 103 HIDS patients published in the journal Medicine in 2008 by the International HIDS Study Group:

HIDS is a severe disease that starts early in life with lifelong recurrent attacks of fever accompanied by a variety of symptoms, including lymphadenopathy, abdominal pain, arthralgia, vomiting and diarrhea, skin lesions, and aphthous ulcers.

There was a significant decrease in frequency of attacks with increasing age, although no patients had a remission.

After the age of 20 years, 17.8% of patients continued to have attacks more than 12 times per year, while 50% of patients still had more than 6 attacks per year. Thirty-three of 45 patients above the age of 20 years had fewer attacks after the age of 20 years than in the first decade of life.

HIDS is a lifelong chronic condition that can be managed with successful treatment.  For some adults, managing their disease is easier than it was when they were a child. It’s not known why some adults improve, but in some cases it may be due to improved understanding and treatment of their condition.

Rarity of HIDS

HIDS is one of the rarer autoinflammatory conditions. As of 2014, estimates show there are about 300 total confirmed HIDS cases in the world. Most are found in The Netherlands. Less than 50 HIDS patients have been identified by researchers in the U.S. Likely this is an under-diagnosed autoinflammatory disease, in part because the symptoms can very closely resemble PFAPA, another recurrent fever syndrome.

References

  1. GeneDx: Periodic Fever Syndromes Panel (7 Genes)
  2. American College of Rheumatology: The Clinical Significance of a Single MVK Mutation in HIDS
  3. Clinical Rheumatology: Different clinical presentation of the hyperimmunoglobulin D syndrome (HIDS) (four cases from Turkey)
  4. Rheumatology International: Incidence and clinical features of hyperimmunoglobulinemia D and periodic fever syndrome (HIDS) and spectrum of mevalonate kinase (MVK) mutations in German children
  5. Mediators of Inflammation: Biological Treatments: New Weapons in the Management of Monogenic Autoinflammatory Disorders
  6. van der Hilst JCH, 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. 2008;87(6):301–310.
  7. Case Reports in Rheumatology: A case of hyperimmunoglobulinemia d syndrome successfully treated with canakinumab
  8. Italian Journal of Pediatrics: Autoinflammatory syndromes: diagnosis and management
  9. DermNet NZ: Hyperimmunoglobulinaemia D with periodic fever syndrome
  10. Firestein: Kelley’s Textbook of Rheumatology, 8th ed.: Hyper-immunoglobulin D Syndrome
  11. HIDS.net: Treating the Disease
  12. HIDS.net: Life with a fever every ten days
  13. Hereditary Autoinflammatory Syndromes with Emphasis on Hyper-IgD and Periodic Fever Syndrome; Dr. Anna Simon
  14. ISSAID 2013: Single MVK Mutation and Recurrent Fevers
  15. Pediatric Rheumatology: Tocilizumab in autoinflammation and AA amyloidosis
  16. NIH: Hyper-Immunoglobulin A in the Hyperimmunoglobulinemia D Syndrome
  17. NIH: Mevalonate kinase deficiencies: from mevalonic aciduria to hyperimmunoglobulinemia D syndrome.
  18. Johns Hopkins Arthritis Center: The Expanding Spectrum of Systemic Autoinflammatory Diseases: Misadventures in the Genomics of Inflammation by Dan Kastner, MD, PhD, Clinical Director, NIAMS, Chief, Genetics and Genomics Laboratory, NIAMS/NIH/DHHS
  19. Rheumatology: Efficacy of interleukin-1-targeting drugs in mevalonate kinase deficiency
  20. Rheumatology: Canakinumab Treatment In Active Hyper-IgD With Periodic Fever Syndrome
  21. Blackwell Publishing: Anakinra for the Treatment of Hyper-IgD with Periodic Fever Syndrome in Children
  22. Orpha.net: Hyperimmunoglobulinemia D (hyperIgD) and periodic
  23. PRINTO: Mevalonate Kinase Deficiency (MKD) (or Hyper IgD Syndrome)
  24. HIDS.net: HIDS