Definition

Auto-inflammatory diseases is suspected in children and adolescents with recurrent episodes of fever without infection being detected (Periodic Fever Syndromes). Except for fever, there are often various symptoms or a combination of the following: neck pain, abdominal area, joints and muscles, headaches, rashes and swollen lymph nodes. Sores in the mouth and mucous membranes, as well as fatigue are also common.

Blood tests show high inflammation tests such as CRP and Lowering Reaction (SR) in connection with fever.

Fever syndromes have common features with autoimmune connective tissue disorders og vasculitides Fordi immune system attacks his own tissue with rheumatic inflammation (inflammation) as a result.

Genetic cause

A major difference is that auto-inflammatory fever diseases are most often caused by one mutation (lasting change) in a single gene (Genetic material). One exception to this PFAPA (and Still's disease og systemic JIA) where multiple genes are involved. They are also separated primary immune immunodeficiency may be raised which causes frequent childhood infections. Auto-inflammatory diseases usually begin among young children.

Occurrence

All periodic fever syndromes / autoinflammatory diseases are defined as  rare diseases.

Immune system and disease mechanisms

An important part of the immune system develops as we grow and grow older and is called acquired immune system. This section can "remember" foreign proteins and other substances (antigen) that we have been in contact with and can fight them if necessary. Important actors are the white blood cells (especially the lymphocytes) that can destroy harmful substances.

We also have a native immune system (innate). This also works through white blood cells, but most in the form of granulocytes og monocytes.

• The cause of the auto-inflammatory fever diseases is that congenital (innate) The immune system lacks braking mechanisms and thus overreacts
• The reactions occur even if the body has never been in contact with foreign antigen (bacteria, viruses, etc.). It is known that many have genetic mutations (hereditary changes) in molecules that regulate this innate immune response, but much information about the disease mechanisms is still unknown.

Symptoms

Auto-inflammatory febrile diseases are characterized by debut in childhood, although Familiar Mediterranean Fever (FMF) og TRAPS can debut later.

Typically, the symptoms begin abruptly:

• Episodes with severe rheumatic inflammation
  • High fever which comes and goes
  • Rash
  • Swollen joints / Arthritis
  • Joint pain in children can be similar to joint swelling / arthritis ha many reasons, please see here (in Danish)
  • High blood inflammation tests (CRP, ESR) during fever attacks
• The diseases (especially familial Mediterranean fever, FMF) may lead to AA-amyloidosis in many important organs (usually kidneys) if not treated. PFAPA is less harmful and disappears or becomes much better in adulthood

There are many autoinflammatory diseases. They may occur in adolescents and adults (see Familiar Mediterranean Fever (FMF) og TRAPS), but most commonly among young children:

• Common age <5 years at onset
• Not very hereditary
• They can be divided into various diseases

Different fever history may make it easier to diagnose the individual diseases:

• Familiar Mediterranean Fever (FMF)  has the shortest fever duration (2-3 days)
• TRAPS  longest lasting fever attack (15 days in severe form, 5-9 days mild form)
• HIDS Hyper Ig-D associated syndrome (Mevalonate kinase disease) very regular fever, however suddenly rising temperature
• PFAPA have regular fever attacks with a few days duration and become less annoying (lower fever, minor symptoms) later in adolescence

• Blood tests
  • Decrease response (SR) and CRP increase in fever, mild leukocytosis (increased white blood cell count)
• No infection

Symptoms and diagnoses

• Arthritis (Arthritis) PAPA, Blau syndrome
• Artritt + Interstitial pulmonary disease, often lung hemorrhage: COPA
• Behcet's disease-like (mucous ulcer): A20 protein haplo insufficiency (Reference Zhou Q, 2015)
• MAS (macrophage activation syndrome): Monogenic (hereditary) cases, NLRC4 inflammatory mutation mediated
• Panniculitis (fat tissue with necrosis): CANDLE
• pustular Psoriasis: Dira, DITRA
• Urticaria vasculitis: FCAS, Muckle-Wells, CINCA
• Vasculitis and pulmonary disease: SAVI

Diagnosis

• Disease history
• Symptoms
• Genetic testing (not possible for all types)
  • Current tests are performed here (Genetikportalen.no)

Complication

AA-Amyloidosis (especially at FMF)

Debut at (small) children

• Blau syndrome (Juvenil sarcoidosis?)

• Cryopyrin Associated Periodic Syndromes (CAPS) / Cryopyrin associated with periodic fever syndromes

  • Three diseases with similar clinical features are the interleukin-1-associated autoinflammatory diseases:

  • Familial cold autoinflammatory syndrome (FCAS):

    • Develops during the first year of life
    • Symptoms:
      • Cold from air conditioning or cold climates regularly leads to systemic inflammatory reaction with fever
      • Cold Urtikaria (approx. 7 hours after cold exposure)
      • Conjunctival redness (on the eye)
      • Substantial joint pain
      • Leukocytosis up to 30.000 (after approx. 10 hours)
      • Episodes progress gradually after 24 hours

  • Muckle-Wells syndrome (MWS):

    • Symptoms:
      • Intermittent (varying) fever episodes
      • Headache
      • Urticaria (English: Hives)
      • Arthralgia or Arthritis
      • Progressive sensory hearing loss

  • Neonatal Onset Multisystem Inflammatory Disease (NOMID) = Chronic Infantile Neurological Cutaneous Articular Syndrome (CINCA).

    • Symptoms
      • Urticaria («hives»)
      • Fever
      • Reduced growth
      • Striking facial features
      • Chronic severe course with meningitis
      • Development of brain and eye damage

• Dira

  • Sterile (not bacteria or other infection) multifocal osteomyelitis with shin bone og pustulosis. "Deficiency of the interleukin 1 receptor antagonist" (DIRA)

• Cyclic neutropenia (in children)

  • Adult (adult) form occurs

• HIDS (Hyper IgD syndrome) (Mevalonatkinase deficiency disease)

  • Vomiting. Splenomegaly (large spleen). Lymph nodes are swollen on the throat, stomatitis (mouth ulcers) or pharyngitis / tonsilitis (sore throat) and affected general condition. Abdominal pain.

• PFAPA

  • Starts in children under the age of 5. Sore throat, sometimes with sores.

Fever syndromes that may not be start among (young) adults (but most often among children)

• Familiar Mediterranean Fever (FMF) E85.0.

  • Starts among children and young adults

• TRAPS (Tumor-necrosis factor receptor-associated periodic syndrome)

  • Debut among children and a rare debut of (young) adults

• Adult onset Cyclic neutropenia

  • An autoimmune disease that is related to cytotoxic (cell-harmful) lymphocytes, associated with clonal proliferation of CD56 + large granular lymphocytes. Treatment is immunosuppression. Reminds of cyclic neutropenia in children who, however, debute in the first year of life. Associated with LGL syndrome 

Some believe that Behcet's syndrome belongs to the autoinflammatory diseases, although the disease is most often classified among Systemic vasculitis.

More info on the various auto-inflammatory diseases (Periodic Fever Syndromes) on each diagnosis:

• Blau syndrome
• CANDLE
• CAPS
• COPA
• CRMO
• DaDa2 (former juvenil PAN)
• Dira
• DITRA
• FCAS
• Familiar Mediterranean Fever (FMF)
• HIDS (Hyper IgD Syndrome)
• MKM (Mevalonatkinase deficiency) (see HIDS)
• Muckle-Wells (MWS)
• NLRC4 inflammatory mutation
• NOMID
• PAPA
• PFAPA
• SAVI (STING-associated Vasculopathy Beginning in Childhood)
• Cyclic neutropenia syndrome
• TRAPS

Literature

• Lidar M, 2017
• Ter Haar NM, 2019
• Grans Compendium in Rheumatology

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• You can search for rare diseases via Orphanet  (which also has one Norwegian information page)
• Periodic Fever Syndromes on Wikipedia here (in Danish)
• More about auto-inflammatory diseases are also found NOMID Alliance (in English)

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• Bindevevssykdommer.no
• Vaskulitt.no
• revmakompendium.no