Periodic Fever, Aphthous Stomatitis, Pharyngitis, & Cervical Adenitis Syndrome (PFAPA Syndrome) Research and Information

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Updated 6/11/21

Below are links to research and information about periodic fever, aphthous stomatitis, pharyngitis, & cervical adenitis syndrome (PFAPA syndrome). These are not all the studies available however. For more search Pubmed.gov.

Eurofever Classification Criteria – This diagnostic questionnaire by the EUROFEVER project is really helpful for doctors considering symptoms when trying to diagnose some of the hereditary periodic fever (autoinflammatory) syndromes, like CAPS, TRAPS, HIDS and FMF. CAPS, TRAPS, HIDS, and FMF all have symptoms similar to PFAPA.

Autoinflammatory Diseases Online Database – This compares the most notable and classic symptoms and lab results for the known periodic fever syndromes including PFAPA.

Undifferentiated recurrent fevers in pediatrics are clinically distinct from PFAPA syndrome but retain an IL-1 signature

In this 2021 study published in Clinical Immunology, Dr. Broderick et al of Rady Children’s Hospital in San Diego defines SURFS as a subset of patients with a specific set of symptoms and treatment responses that can be similar to PFAPA, but these patients do not have PFAPA as they do not fit the PFAPA diagnostic criteria. According to the study,

“Many pediatric patients are often grouped with patients with periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome despite failing to meet diagnostic criteria. Here, we categorize these patients as syndrome of undifferentiated recurrent fever (SURF), and identify the unique features which distinguish them from the PFAPA syndrome. SURF patients were more likely to report gastrointestinal symptoms of nausea, vomiting and abdominal pain, and experienced inconsistent responses to on-demand steroid therapy compared to PFAPA patients.”

Study shows mutations in inflammation-related genes are associated with PFAPA syndrome

NIH study shows the Il12A gene has the strongest association with both PFAPA and Behcet’s disease. “Due to genomic similarities between PFAPA syndrome, Behçet’s and canker sores, the researchers proposed naming them Behçet’s spectrum disorders. On the severity scale, canker sores would be on the mild end, Behçet’s disease on the severe end, and PFAPA syndrome between the two.”

*Currently (as of 2021) none of the fever syndrome genetic panels here include the Il12A gene, however if testing with Fulgent Genetics the doctor can request this gene as an add-on to the PID/autoinflammatory panel. If you get this testing, do know that the results may not be helpful yet. The NIH article mentions SNPs, not mutations. This NIH study is ongoing and in the future may identify specific disease causing mutations that are more helpful for diagnosis.

The First International Conference on Periodic Fever, Aphthous, Stomatatis, Pharyngitis, Adenitis Syndrome –

“PFAPA is the only other truly periodic fever syndrome in children…patients with classic PFAPA are not difficult to recognize…Parents volunteer that each episode is identical, from the clingy, glassy-eyed, whiny prodrome to the abrupt onset of high fever and the sudden cessation of fever 3 or 4 days later. There is a distinct absence of other symptoms such as cough, vomiting, and diarrhea..Aphthous stomatitis, pharyngitis, and/or (cervical) lymphadenitis, if present, support the diagnosis, and the absence of all 3 symptoms calls the diagnosis into question. Acute phase reactants are elevated during episodes and normal between episodes; if a corticosteroid is given—even a single dose of 1 mg/kg of prednisone—the episode resolves dramatically in a few hours. The child usually does not have a rash, joint complaints, or other symptoms that would suggest an alternative diagnosis, and although there is no family history of heritable periodic fever syndromes, the parents themselves may have had recurrent fevers or had their tonsils removed as young children. Episodes occur without provocation and are so predictable that the family can plan activities around them. Between episodes, the child is perfectly well.

Hyperimmunoglobulinemia syndrome (HIDS) is the great mimicker of PFAPA. Pharyngitis, aphthous ulcers, and lymphadenopa-they are reported to occur during attacks and can be prominent features. Hyperimmunoglobulinemia syndrome is a spectrum of diseases that can range from milder symptoms to severe. The milder end of the spectrum is characterized by recurrent episodes of unexplained fever, which can be periodic, for example, monthly attacks. Some individuals present with an abrupt onset of fever accompanied by fatigue, chills, abdominal pain, lymphadenopathy, and tonsillitis. However, patients with hyperimmunoglobulinemia syndrome often have arthritis or arthralgia, rash, nausea, diarrhea, vomiting, or hepatosplenomegaly, which are not seen in PFAPA.

To avoid a variety of misdiagnoses, we suggest that the presence of any of the following should exclude the diagnosis of PFAPA: neutropenia; cough, coryza; severe abdominal pain; significant diarrhea; rash, arthritis, or neurologic abnormalities; elevated acute phase reactants between attacks; and intermittent flares rather than a true periodic disorder.”

The PFAPA Work Group of CARRA (Childhood Arthritis and Rheumatology Research Alliance) expert consensus on the treatment path for PFAPA – Acute and preventive treatments for PFAPA are included.

Immune Dysregulation in the Tonsillar Microenvironment of Periodic Fever, Aphthous Stomatitis, Pharyngitis, Adenitis (PFAPA) Syndrome – A study from the Recurrent Fever Disorders Clinic at Rady Children’s hospital in San Deigo, CA.

“In our tertiary care center cohort, 62 patients with PFAPA syndrome had complete resolution of symptoms after surgery (95.3%).

…(Tonsil) evaluation demonstrates an inflammatory cell population, distinct from patients with infectious pharyngitis… with increased percentage of IL-1β positive cells compared to control tonsil-derived cells…Gene expression analysis demonstrates a fivefold upregulation in IL1RN and TNF expression in whole tonsil compared to control tonsils, with persistent activation of the NF-κB signaling pathway, and differential microbial signatures, even in the afebrile period. Our data indicates that PFAPA patient tonsils have localized, persistent inflammation, in the absence of clinical symptoms, which may explain the success of tonsillectomy as an effective surgical treatment option.”

UpToDate – Periodic fever with aphthous stomatitis, pharyngitis and adenitis (PFAPA syndrome) – UptoDate is a peer reviewed, evidence-based medical reference site for medical professionals. The PFAPA page includes the diagnostic criteria, differential diagnosis, and treatments for PFAPA. Notes are also made on what would exclude the diagnosis of PFAPA; these include symptoms between flares, abnormal labs, such as elevated CRP, between flares, and neutropenia. The authors note that, “The following symptoms as a part of most attacks should trigger consideration of other diagnoses: cough, coryza, severe abdominal pain, significant diarrhea, rash, arthritis, or neuromuscular symptoms.”

Diagnostic criteria of PFAPA per UpToDate:

  • At least 3 episodes of fevers lasting no more than 5 days that occur at regular intervals. It’s noted that, “For individual patients, intervals between attacks are nearly identical within a range of three to six weeks, and the symptoms with each episode are identical.”
  • Pharyngitis with swollen cervical lymph nodes and/or with mouth ulcers.
  • Normal growth and no symptoms between flares.
  • Resolution of symptoms with a single dose of prednisone. (Do note that PFAPA is not the only fever syndrome that responds to prednisone.)

Further per UpToDate: “Clinical features that exclude PFAPA include: the presence of neutropenia before or during an episode, the presence of atypical symptoms (ie, cough, coryza, severe abdominal pain, diarrhea, rash, arthritis, or neurologic deficits) in association with most episodes, an elevated ESR or CRP between attacks, impaired growth,”

To Make the PFAPA Syndrome More Familiar Questions & Answers by Dr. Beata Wolska-Kusnierz, MD-PhD – This PDF gives a good detailed overview of PFAPA. Some highlights:

    • Between the recurrent episodes, children don’t complain about any ailments and do not manifest any worrying symptoms during the medical examination.
    • The lack of remission after tonsillectomy will indicate the direction of extended diagnostics, e.g. toward genetic autoinflammatory illnesses.
    • There are absolutely no contraindications against immunization. Vaccines have no impact on PFAPA.
    • Usually no skin changes are observed with patients suffering from PFAPA…If urticaria or other skin changes occur together with the recurrent high fever episodes, autoinflammatory illnesses other than PFAPA should be considered in the diagnostic process. (Click here for the comparison chart of periodic fever syndromes.)
    • Diet does not affect the course of PFAPA.

Review of autoinflammatory diseases, with a special focus on periodic fever aphthous stomatitis, pharyngitis and cervical adenitis syndrome– An overview of PFAPA and similar syndromes such as FMF, HIDS, TRAPS, and CAPS.

“PFAPA also needs to be distinguished from monogenic periodic fever syndromes, such as FMF, MKD and TRAPS, and the diagnosis of PFAPA should be challenged in children who fulfill the criteria but show additional signs and symptoms suggestive of hereditary periodic fever syndromes. These include skin rashes, arthritis, severe abdominal pain, diarrhoea, chest pain and splenomegaly, fever episodes longer than seven days, a history of hearing loss or symptoms secondary to cold exposure (21,34,35).”

In regards to rash which is mentioned but not defined or described in any detail in many PFAPA studies, the authors of this study state, “In our hands the diagnosis is questioned in patients with skin rash.”

PFAPA Syndrome – A simple definition of PFAPA – of interest is this statement: “Neutropenia or other symptoms (eg, diarrhea, rash, cough) are not present; their presence suggests a different disorder.” Statement reviewed by Dr. Stephen E. Goldfinger.

Colchicine trial in PFAPA Syndrome and MEFV-negative patients – 27 of 36 PFAPA patients had a good response to colchicine in that flare frequency and/or severity of flares were reduced. Dosing was similar to what is used for FMF patients.

The Pathogenesis of Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Cervical Adenitis Syndrome: A Review of Current Research – A 2015 review of what is known about what causes PFAPA.

“Recent findings suggest that there is a familial tendency to PFAPA but the level of evidence does not warrant definite conclusions. The absence of a clear monogenic trait indicates a heterogenous, polygenic, or complex inheritance of PFAPA syndrome. As two mutations with a possible functional effect on the inflammasomes (MEFV E148Q and NLRP3 Q703K) have been found in several PFAPA cohorts, the role of inflammasome-related genes in PFAPA pathogenesis cannot be excluded. Immunological mechanisms of PFAPA involve an abnormal, IL-1β dependent innate immune response to an environmental trigger, which leads to Th1-driven inflammation expressed by recruitment of T-cells to the periphery.”

Physicians employ flexible diagnostic criteria for PFAPA in children – Rheumatologists were surveyed on their adherence to the PFAPA diagnostic criteria when diagnosing PFAPA. It was found that a high percentage of physicians were not applying all aspects of the diagnostic criteria. According to the study authors,

“We found that physicians did not adhere to their original criteria, and that physicians almost used it as a field test: if it seems like PFAPA, then they diagnose it as PFAPA.”

Vitamin D levels and effects of vitamin D replacement in children with periodic fever, aphthoous stomatitis, pharyngitis, and vervical adenitis (PFAPA) syndrome – “vitamin D supplementation seems to significantly reduce the typical PFAPA episodes and their duration, supporting the role of vitamin D as an immune-regulatory factor in this syndrome.”

Follow-up of Children with PFAPA Syndrome – 50 of 59 PFAPA patients had resolution of fever flares an average of 6.3 years after symptoms started. Three patients received another diagnosis including Behcet’s and FMF. Authors note, “Before PFAPA is diagnosed, other potential causes of periodic fever (e.g., infection, malignancy, cyclic neutropenia) should be ruled out.”

Periodic fever, aphthous stomatitis, pharyngitis, cervical adenitis syndrome is linked to dysregulated monocyte IL-1β production. Our data strongly suggest that IL-1β monocyte production is dysregulated in patients with PFAPA syndrome. Approximately 20% of them were found to have NLRP3 variants…”

Before PFAPA is diagnosed, other potential causes of periodic fever (e.g., infection, malignancy, cyclic neutropenia) should be ruled out. – See more at: http://www.jwatch.org/id201112210000007/2011/12/21/follow-children-with-pfapa-syndrome#sthash.e2qKVhHH.dpuf
Before PFAPA is diagnosed, other potential causes of periodic fever (e.g., infection, malignancy, cyclic neutropenia) should be ruled out. – See more at: http://www.jwatch.org/id201112210000007/2011/12/21/follow-children-with-pfapa-syndrome#sthash.e2qKVhHH.dpuf
Before PFAPA is diagnosed, other potential causes of periodic fever (e.g., infection, malignancy, cyclic neutropenia) should be ruled out. – See more at: http://www.jwatch.org/id201112210000007/2011/12/21/follow-children-with-pfapa-syndrome#sthash.e2qKVhHH.dpuf
Before PFAPA is diagnosed, other potential causes of periodic fever (e.g., infection, malignancy, cyclic neutropenia) should be ruled out. – See more at: http://www.jwatch.org/id201112210000007/2011/12/21/follow-children-with-pfapa-syndrome#sthash.e2qKVhHH.dpuf

The mean platelet volume levels in children with PFAPA syndrome. The mean platelet volume for PFAPA patients was found to be lower, both during fever flares and between flares, than health controls. In the PFAPA patients, the platelet values were lower during flares than between flares.

PFAPA syndrome: clinical characteristics and treatment outcomes in a large single-centre cohort.

Urban Legends Series: Recurrent Aphthous Stomatitis

“A relevant number of patients with monogenic periodic fevers also meet the diagnostic criteria for PFAPA syndrome (Gattorno et al., 2008). In a preliminary experience, 83% of patients with MKD, 57% of patients with TRAPS, and 8% of patients with FMF satisfied the criteria for PFAPA syndrome, which shows that the criteria have limited utility in differentiating PFAPA syndrome from monogenic periodic fevers. Importantly, oral aphthosis was found to be independently associated with a positive genetic test result indirectly suggesting the possible lack of specificity of this clinical feature for PFAPA diagnosis (Gattorno et al., 2008).

Moreover, a recent large multicenter multinational study employing genetic tests to distinguish PFAPA from other inherited periodic fevers clearly confirmed that PFAPA syndrome criteria are not able to distinguish genetically positive patients (i.e. patients likely without PFAPA but with a PFAPA-like phenotype) from genetically negative patients (the likely PFAPA affected). In this case-control study of 210 children that met the clinical criteria for PFAPA syndrome, 38% were genetically positive for either MKD, FMF, TRAPS or displayed low penetrance or incomplete mutations, and 62% had negative genetic testing profiles (Gattorno et al., 2009).”

PFAPA vs. HIDS – Without genetic testing it can be very difficult in some patients to differentiate between HIDS and PFAPA. This comprehensive chart compares the typical presentation of PFAPA to the typical presentation of HIDS.

Tonsillectomy efficacy is comparable to the standard medical treatment in PFAPA syndrome

NIH researchers identify cause and new treatment for common recurrent fever in children – Kineret is a viable treatment for PFAPA – “The anakinra treatment has the potential to restore these children to a mostly symptom-free childhood,” said Dr. Kastner.”

PFAPA syndrome is not a sporadic disease-Report about the number of patients with a positive family history for periodic fever symptoms.

Urban Legends Series: Recurrent Aphthous Stomatitis – This discusses the difficulty of differentiating HIDS, TRAPS, and FMF from PFAPA without genetic testing due to overlapping symptoms. “In this case-control study of 210 children that met the clinical criteria for PFAPA syndrome, 38% were genetically positive for either MKD, FMF, TRAPS or displayed low penetrance or incomplete mutations, and 62% had negative genetic testing profiles (Gattorno et al., 2009)…. Cardinal features of the PFAPA syndrome, such as oral aphthosis and enlargement of cervical lymph nodes, were observed with similar frequencies in genetically negative patients and in subjects positive for MKD and FMF.”

Periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) is a disorder of innate immunity and Th1 activation responsive to Il-1 blockade – a comprehensive study of the PFAPA biological process by the NIH. Discusses possible biomarkers that can be used as a test to help confirm PFAPA.

Tonsillectomy in children with periodic fever with aphthous stomatitis, pharyngitis, and adenitis syndrome

A clinical review of 105 patients with PFAPA (a periodic fever syndrome) – This is the diagnostic criteria used:

“Subjects met our case definition of PFAPA (i) if they had at least six episodes of documented fever (T>38.9C), (ii) if each febrile episode lasted no more than 10 days, (iii) if the fevers recurred at regular intervals of 2–8 weeks, (iv) if they were well between febrile episodes, (v) if they did not have arthritis or a distinctive rash or documented neutropenia and (vi) if they did not have a clinical explanation for the fever other than PFAPA. In addition to fever, patients needed to have at least one of the three major clinical findings associated with PFAPA – aphthous stomatitis, pharyngitis or cervical adenitis.”

PFAPA: a single phenotype with genetic heterogeneity – evidence that PFAPA may be  genetic.

Tonsillectomy for periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis syndrome (PFAPA).

PFAPA syndrome in children: A meta-analysis on surgical versus medical treatment

Vitamin D linked to PFAPA syndrome.

Long-term surgical outcomes of adenotonsillectomy for PFAPA syndrome. – This is a follow up of 102 PFAPA patients who underwent adenotonsillectomy. “Of 102 patients, 99 had complete resolution of symptoms immediately after surgery,” report the study authors. One child who did not respond to surgery was later found to have HIDS.

List of TNF Receptor-Associated Periodic Syndrome (TRAPS) Research and Information

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Below are links to helpful research and information TNF receptor-associated periodic syndrome (TRAPS) symptoms and treatment. These are not all the studies available. For more search Pubmed.gov.

On-demand treatment with anakinra: a treatment option for selected TRAPS patients. – On-demand use of Kineret refers to using this medication only during flares to shorted the flare and relieve symptoms. This is a case study of two TRAPS patients in which on-demand anakinra treatment was successful.

The phenotype of TNF receptor-associated autoinflammatory syndrome (TRAPS) at presentation: a series of 158 cases from the Eurofever/EUROTRAPS international registry. As of 2013 this is the largest TRAPS study.

The most recent advances in pathophysiology and management of tumour necrosis factor receptor-associated periodic syndrome (TRAPS): personal experience and literature review. “Thanks to a better understanding of its pathogenesis, the disease is now managed with anti-interleukin (IL)-1 antagonists, rather than corticosteroids or tumour necrosis factor (TNF) inhibitors.”

Different presentations in patients with tumor necrosis factor receptor-associated periodic syndrome mutations: report of two cases. “We report two children, one with a severe mutation in the TNFRSF1A gene causing the typical phenotype. The second patient had a homozygous R92Q-type mutation and displayed a periodic fever with aphthous stomatitis, pharyngitis and adenitis (PFAPA) syndrome-like phenotype.”

Tumor necrosis factor receptor-associated periodic syndrome – NIH Reference Page on TRAPS

Tumour necrosis factor receptor-associated periodic syndrome – A good and thorough synopsis of TRAPS that’s fairly easy to read and understand by the New Zealand Dermatological Society

Hereditary Periodic Fever Syndromes – Written by Dr. Kastner, this covers FMF, TRAPS, HIDS, NOMID. Explains differences between TRAPS and the other similar syndromes.

Rash Pattern and Duration Distinguish Hereditary Periodic Fever Syndromes – By Dr. Kastner. Explains the differences in rashes of TRAPS, HIDS, FMF, and CAPS. The TRAPS rash is migratory.

Autoinflammatory syndromes: Fever is not always a sign of infection – From Doctors Zeft and Spalding at the Cleveland Clinic. Good diagrams of the biological pathways of TRAPS, Blau, CAPS, FMF, HIDS, and PAPA. Differences between TRAPS and FMF or HIDS are discussed.

Dramatic Improvement Following Interleukin 1ß Blockade in Tumor Necrosis Factor Receptor-1-Associated Syndrome (TRAPS) Resistant to Anti-TNF-α Therapy – Anakinra case study

Typical and severe tumor necrosis factor receptor-associated periodic syndrome in the absence of mutations in the TNFRSF1A gene: a case series.

Tumor Necrosis Factor Receptor-Associated Periodic Syndrome or Familial Hibernian Fever: Presentation in a Four-Day-Old Infant

Tumor Necrosis Factor Receptor-associated Periodic Syndrome Mimicking Systemic Juvenile Idiopathic Arthritis

Autoinflammatory syndromes: diagnosis and management – a good synopsis of FMF, HIDS, TRAPS, CAPS, Blau Syndrome, PAPA Syndrome, PFAPA, and Majeed’s Syndrome. Gives information on differences in the diseases and best treatments as of 2010.

The autoinflammatory diseases – Published in 2012, this also covers FMF, MVK Deficiency (HIDS), TRAPS, CAPS,  NLRP 12 mutations, Blau Syndrome, PAPA Syndrome, Majeed’s, DIRA, and PFAPA.

The Expanding Spectrum of Systemic Autoinflammatory Diseases: Misadventures in the Genomics of Inflammation – More information on the different fever disorders. From a lecture given by Dr. Kastner, has lots of details on individual cases.

Novartis data show ACZ885 delivered rapid and strong symptom relief while reducing frequency of attacks in two periodic fever syndromes – Ilaris phase 2 study results for TRAPS and FMF

Tumor necrosis factor receptor 1-associated periodic syndrome without fever: cytokine profile before and during etanercept treatment.

Multiple sclerosis and the TNFRSF1A R92Q mutation: clinical characteristics of 21 cases.

“Periodic fever” without fever: two cases of non‐febrile TRAPS with mutations in the TNFRSF1A gene presenting with episodes of inflammation or monosymptomatic amyloidosis – “TRAPS associated mutations can induce considerable inflammation that is not necessarily accompanied by fever.”

Falling into TRAPS – receptor misfolding in the TNF receptor 1-associated periodic fever syndrome– Info on the biological pathway of TRAPS with diagrams and the different mutations.

Tumor necrosis factor receptor associated periodic fever syndrome with photographic evidence of various skin disease and unusual phenotypes: case report and literature review.

Tumor necrosis factor receptor-associated periodic fever syndrome in a 58-year-old man: caution not to discount TRAPS as a diagnosis in older patients.

Clinical Immunology Review Series: An approach to the patient with a periodic fever syndrome – Covers FMF, TRAPS, HIDS, CAPS, DIRA, PAPA, BLAU, PFAPA, and Schnitzeler’s

Idiopathic recurrent pericarditis refractory to colchicine treatment can reveal tumor necrosis factor receptor-associated periodic syndrome.

Role of tumour necrosis factor (TNF)-α and TNFRSF1A R92Q mutation in the pathogenesis of TNF receptor-associated periodic syndrome and multiple sclerosis – information on the R92Q and it’s association with MS and information on why this and the P46L mutation sometimes causes disease.

Long-Term Clinical Profile of Children With the Low-Penetrance R92Q Mutation of the TNFRSF1A Gene – “Although some cases may progress to a more chronic disease course, the majority of children with an R92Q mutation of the TNFRSFA1 gene show a milder disease course than that in children with TNFRSFA1 structural mutations and have a high rate of spontaneous resolution and amelioration of the recurrent fever episodes.

Hyper-IgD Syndrome (HIDS) Research and Information

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Below are links to helpful research and information relating to Hyper-IgD syndrome (HIDS). These are not all the studies available. For more search at Pubmed.gov. You can also read more about HIDS here.

The Phenotype and Genotype of Mevalonate Kinase Deficiency – Published in 2016, this is one of the largest studies of HIDS and MA patients.

Some findings from this study:

  • Flare triggers included vaccination, stress, and infections.
  • Many patients had symptoms between flares.
  • Almost all patients had GI involvement. Most experienced abdominal pain, diarrhea, and vomiting. Some had these symptoms when not in a fever episode. 18 patients had severe GI symptoms including aseptic peritonitis, GI bleeding, perianal ulcers, intestinal occlusion, gut perforation, and GI ulcers.
  • One patient had macrophage activation syndrome (MAS) that started as a typical flare. This patient was only being treated with NSAIDS at the time of the flare that turned into MAS.
  • Of 15 patients who tried statins for treatment, it failed in 11 and made the disease worse in 3.
  • Colchicine was not effective in most.
  • NSAIDS had some benefit for most, but was not highly effective.
  • Corticosteroids were highly effective in most for terminating flares.
  • Interleukin-1 biologics (anakinra and canakinumab) were effective in most, but not as effective as what is seen in CAPS patients.
  • Some patients did not benefit from any biologic medications, but in some cases that may have been due to insufficient dose.
  • 27 patients tried etanercept. 2 had a complete response. 14 had some response. In 11 patients etanercept failed as a treatment.

 

Hyper-IgD syndrome/mevalonate kinase deficiency: what is new? – Published in 2015, this is an updated overview of HIDS and MA (mevalonate aciduria). The biological pathway is discussed. Current best treatments are Il-1 inhibitors (anakinra and canakinumab), although not all patients have a complete response to these treatments.

Rheumatology: Hyperimmunoglobulinemia D with Periodic F ever Syndrome – Chapter on HIDS in the medical book Rheumatology.

Mevalonate Kinase Deficiency (MKD) (or Hyper-IgD Syndrome) – This is from the Paediatric Rhematology International Trials Organisation (PRINTO). It’s a good simple explanation for HIDS – great for passing out to family, friends, teachers to help explain this condition.

NORD: Mevalonate Kinase Deficiency – This has excellent easy to understand details on HIDS and MA symptoms, risks, and complications, and latest research, and treatment options.

A81: spectrum of mevalonate kinase deficiency: is colitis more common than we think? “The persistence of ESR elevation outside of febrile episodes seen in patients with HIDS/MKD may indicate the presence of chronic subclinical inflammation. Hematochezia was commonly seen, and could indicate the presence of colitis.”

Efficacy of interleukin-1-targeting drugs in mevalonate kinase deficiency – This study followed 11 HIDS patients who anakinra (Kineret) or canakinumab (Ilaris). Kineret was used on demand (with flares only) in one patient. Two patients used anakinra 3 times a week. Dosing of anakinra ranged from 1 to 5 mg/kg/day. Dosing of canakinumab ranged from 2 to 7 mg/kg every 4 to 8 weeks depending on the patient. “… our observations show that all patients with MKD had an improvement of disease activity under IL-1-targeting drugs with regard to the reduction of a clinical score during attacks, the reduction of the duration and frequency of attacks, and the decreased biological inflammation. However, complete clinical and biological remission was obtained in only one of nine patients on anakinra and three of six on canakinumab.”

Mevalonate kinase deficiency: current perspectives (July 2016) – Highlights from this study:

  • “…there is some hint that MAS may be a relatively common complication of MKD.”
  • MKD symptom presentation and severity is highly variable.
  • Sometimes flares have a cyclic fever pattern of every 4 to 6 weeks (very similar to PFAPA pattern), sometimes flares are triggered.
  • “(V377I) …high carrier rate would imply a much higher disease incidence than what is typically reported and suggests that many individuals who are homozygous for the V377I variant have a mild phenotype that is not recognized as MKD…HIDS and MA phenotypes are clearly defined entities, but MKD encompasses patients with overlapping features and even those with a minimal or clinically silent course.”
  • Statins can trigger flares in some, particularly patients with MA. Statins as a treatment “has been largely abandoned.”
  • “…the elevated risk for pneumococcal infections and progression to life-threatening sepsis has been documented in some larger cohorts. It has been speculated that increased plasma mevalonic acid is advantageous for the bacterium’s survival in blood and tissues.”
  • Single mutation HIDS and the wide and variable range of disease severity and symptoms may be due to “the role of additional genes as modifiers…,” an area of current active research.

Inherited Metabolic Disease in Adults: A Clinical Guide – This medical textbook includes a chapter on mevalonate kinase deficiency (MKD). This textbook can be purchased here.

Different Presentations of mevalonate kinase deficiency: a case series – This gives details on 4 patients with HIDS and the symptoms they experienced.

Single MK mutation and recurrent fevers – This study compared symptoms and severity of patients with 2 mutations for HIDS with patients with 1 mutation for HIDS. “Aside for the presence of rash and high IgA and IgD levels in those children with 2 MVK mutations, there are no significant clinical differences between these groups.”

Treatment of hyperimmunoglobulinemia D syndrome with biologics in children: review of the literature and Finnish experience. – “The accumulating evidence on the efficacy and safety of biological drugs in pediatric HIDS suggests that the anti-interleukin-1 agent anakinra is the drug of choice for HIDS in children… Based on the 90 % response rate, anakinra seems to be the drug of choice for HIDS in children.”

Canakinumab treatment in patients with HIDS – “The median number of flares/patient reduced from 5(3-12) during the HP to 0(0-2)…”

Long-term follow-up in a national cohort of MKD patients: search for clinical predictors of a spontaneous improvement “The homozygous state for V377I and female sex are associated to a spontaneous improvement of disease course in MKD patients.”

Periodic Fever in MVK Deficiency: A Patient Initially Diagnosed with Incomplete Kawasaki Disease

Observational Study of a French and Belgian Multicenter Cohort of 23 Patients Diagnosed in Adulthood With Mevalonate Kinase Deficiency – “Twenty-three patients were analyzed. The mean age at diagnosis was 40 years, with a mean age at onset of symptoms of 3 years. All symptomatic patients had fever. Febrile attacks were mostly associated with arthralgia (90.9%); lymphadenopathy, abdominal pain, and skin lesions (86.4%); pharyngitis (63.6%); cough (59.1%); diarrhea, and hepatosplenomegaly (50.0%). Seven patients had psychiatric symptoms (31.8%). One patient developed recurrent seizures. Three patients experienced renal involvement (13.6%). Two patients had angiomyolipoma (9.1%). All but one tested patients had elevated serum immunoglobulin (Ig) D level. Twenty-one patients had genetic diagnosis; most of them were compound heterozygote (76.2%). p.Val377Ile was the most prevalent mutation. Structural articular damages and systemic AA amyloidosis were the 2 most serious complications. More than 65% of patients displayed decrease in severity and frequency of attacks with increasing age, but only 35% achieved remission.”

Tocilizumab in autoinflammation and AA amyloidosis – mentions use of tocilizumab (Actemra) in patients with amyloidosis, including one with HIDS.

Different clinical presentation of the hyperimmunoglobulin D syndrome (HIDS) (four cases from Turkey). Cases of “later-onset HIDS”.

A woman with recurrent “infections” since birth – a new mevalonate kinase mutation. A case of an adult misdiagnosed her entire life. She was diagnosed at age 32.

A Case of Hyperimmunoglobulinemia D Syndrome Successfully Treated with Canakinumab – “Treatment with canakinumab in a final single dose of 4 mg/kg every 4 weeks resulted in the disappearance of febrile attacks and a considerable improvement of patients’ quality of life during a 12-month follow-up period.”

Amyloidosis in a child with hyperimmunoglobulinemia d syndrome.

Hereditary autoinflammatory syndromes- with emphasis on hyper-IgD and periodic fever syndrome.

This one is long – 200 pages! It’s written by Dr. Simon, one of the lead HIDS researchers in The Netherlands and the world. It was written in 2008, so some information may be outdated. However, still lots of good info not easily found elsewhere. MWS, NOMID, FCAS, FMF and TRAPS are also discussed.

The Clinical Significance of a Single MVK Mutation in HIDS – Not all cases of HIDS have 2 mutations. This shows how those with only one MVK mutation can have the same symptoms as those with 2 mutations.

Mevalonate Kinase Deficiency: A Survey of 50 Patients– In depth survey study in France. Includes details on symptoms, prognosis, and treatments. “MKD is not only an autoinflammatory syndrome but also a multisystemic inflammatory disorder, a possible immunodeficiency disorder, and a condition that predisposes patients to the development of renal angiomyolipoma.” Renal angiomyolipoma is a benign kidney tumor.

NIH MVK information

Recurrent arthritis as a unique manifestation of hyperimmunoglobulinaemia D

Anakinra for the Treatment of Hyper-IgD with Periodic Fever Syndrome in Children

Autoinflammatory syndromes: diagnosis and management – a good synopsis of FMF, HIDS, TRAPS, CAPS, Blau Syndrome, PAPA Syndrome, PFAPA, and Majeed’s Syndrome. Gives information on differences in the diseases and best treatments as of 2010.

Long-Term Follow-Up, Clinical Features, and Quality of Life in a Series of 103 Patients With Hyperimmunoglobulinemia D Syndrome – Published in 2008, as of 2014, this was still the largest study of HIDS patients that followed patients into adulthood. Shows statistics for lifelong prognosis and treatments that worked in these patients.

AA amyloidosis complicating hyperimmunoglobulinemia D with periodic fever syndrome: A report of two cases

Hereditary periodic fever with systemic amyloidosis: is hyper-IgD syndrome really a benign disease?

First report of macrophage activation syndrome in hyperimmunoglobulinemia D with periodic fever syndrome

The autoinflammatory diseases – Published in 2012, this also covers FMF, MVK Deficiency (HIDS), TRAPS, CAPS,  NLRP 12 mutations, Blau Syndrome, PAPA Syndrome, Majeed’s, DIRA, and PFAPA.

Retinitis pigmentosa in mevalonate kinase deficiency. – Eye damage that can occur with HIDS

Nummular keratopathy in a patient with Hyper-IgD Syndrome – Another eye condition associated with HIDS.

Hyperimmunoglobulinaemia D with periodic fever syndrome – A good synopsis of HIDS that’s easier to read and understand.

The Expanding Spectrum of Systemic Autoinflammatory Diseases: Misadventures in the Genomics of Inflammation – More information on the different fever disorders. From a lecture given by Dr. Kastner, has lots of details on individual cases.

Recurrent Pericarditis in a Child with Hyper IgD Syndrome Responding to Etanercept – Case of inflammation affecting the heart in HIDS.

Effect of etanercept and anakinra on inflammatory attacks in the hyper-IgD syndrome: introducing a vaccination provocation model – this study is in adults with HIDS.

Neonatal Hepatitis as First Manifestation of Hyperimmunoglobulinemia D Syndrome – Case of severe liver involvement in HIDS. “We present a case of severe HIDS in a young girl, whose symptoms started in the neonatal period with hepatomegaly, hepatitis, thrombocytopenia, and conjugated hyperbilirubinemia. From the age of five months, the child had recurrent febrile episodes, stomatitis, adenitis, and persistent hepatomegaly.”

MVK mutations and associated clinical features in Italian patients affected with autoinflammatory disorders and recurrent fever This includes symptom details for 15 patients with HIDS (MVK).

Diagnostic value of urinary mevalonic acid excretion in mevalonate kinase deficiency (MKD) – Study shows that some with HIDS mutations can have negative mevalonic acid excretion and some with no HIDS mutations found can have positive mevalonic acid urine tests.

Hyper Immunoglobulinemia D syndrome in a Saudi girl: A Case Report – This is a case report of 8-year-old girl from Saudia Arabia with HIDS. She was not diagnosed until after her death. “After the age of eight years she had her last febrile attack was complicated by severe status epilepticous and multi-organ failure which leads to her death [5]…The diagnosis of hyper IgD syndrome for the first time in Saudi Kingdom should raise the awareness of the importance of genetic study in any patient with periodic fever. More of research is needed for treatment of HIDS to avoid severe morbidity and mortality related to this disease.”
Natural history of mevalonate kinase deficiency: a literature review – This is a good overview of HIDS and MA that includes symptoms, complications, and life long prognosis.