Autoinflammatory Disease


Autoinflammatory diseases, commonly called systemic autoinflammatory diseases, are a group of disorders mediated by dysfunction of the innate immune system, wherein the innate immune response is activated without an apparent trigger, leading to hyperinflammation.1 This is different from autoimmune diseases, which are caused by dysfunction with the adaptive immune response, though there can be a significant overlap of symptoms between the two, and some diseases showcase the properties of both autoinflammatory and autoimmune disorders.2

Autoinflammatory disorders share a core of phenotypic manifestations, including recurrent attacks of fever, lymphadenopathy, cutaneous signs, vasculopathy, chest or abdominal pain, and musculoskeletal symptoms.3 Most cases are genetically inherited and stem from a single gene mutation.4 These are known as monogenic autoinflammatory diseases and account for the most common variations of the disease, such as familial Mediterranean fever (FMF).5

Autoinflammatory diseases are often diagnosed in childhood, but there is a growing number of adult-onset patients.3  Diagnosis is often made based on clinical presentation and genetics testing, and the time from onset to diagnosis can take up to 7.3 years.4

Autoinflammatory Disease History

Autoinflammatory diseases are a relatively new branch of medicine. The first specific genetic variation, MEFV, that causes familial Mediterranean fever (FMF), was identified in 1997.6 Symptoms of FMF, however, have been previously described as far back as 1949, and the disease was known then as Siegal-Cattan-Mamou syndrome. A complete description that first utilized the term “periodic disease” was also given in 1949 by Hobart Reiman.

At the end of the 1990s, two other diseases with recurrent or periodic fevers had been identified (hyper-IgD and tumor necrosis factor receptor-associated periodic syndrome),6 and in 1999, Michael McDermott and Daniel Kastner introduced the term “autoinflammation” to label this expanding family of disorders characterized by seemingly unprovoked localized or systemic inflammation in the absence of primary features of autoimmunity (autoreactive lymphocytes and high titer antibodies).3 Since then, an increasing number of autoinflammatory diseases have been discovered, and more than 30 new genes associated with autoinflammatory diseases affecting different parts of the innate immune system have been identified 4

Initially, it was believed that there was a clear distinction between autoinflammatory diseases and autoimmune diseases, but recent research has led to the development of the concept of an immunological disease continuum, which was proposed to integrate the complex interplay between the innate and the adaptive immune system. On one end of the spectrum lies monogenic systemic autoinflammatory diseases, and on the other end, monogenic autoimmune diseases.3

Autoinflammatory Disease Epidemiology

Overall, autoinflammatory diseases are a rare group of disorders.3 As of now, there has been no research into the epidemiology of autoinflammatory diseases as a whole, but there are prevalence and incidence numbers for specific diseases that fall under the umbrella of autoinflammatory disease.

Familial Mediterranean fever (FMF) primarily affects populations originating in the Mediterranean region, most notably people of Armenian, Arab, Turkish, or Jewish ancestry. The prevalence of FMF is roughly one in 200 to 1000 people within these populations, but it is less common in other populations.7

Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) is considered the second most common inherited recurrent fever syndrome, and has an estimated prevalence of one per million individuals.8 It has been diagnosed in more than 1000 people worldwide.8

Cryopyrin-associated periodic syndromes (CAPS) are a group of conditions with overlapping signs and symptoms and the same genetic cause, all of which are considered autoinflammatory diseases. The estimated prevalence of CAPS is 2 to 5 per million individuals; however, it is thought to be underdiagnosed due to its similarity with other common conditions.9

Yao syndrome (formerly called NOD2-associated autoinflammatory disease) is usually diagnosed in adulthood and has an estimated prevalence of 1 in 10,000 to 1 in 100,000 people worldwide. Some studies suggest that it is one of the most common systemic autoinflammatory diseases in adults.10

Etiology and Risk Factors

The etiology of autoinflammatory diseases is a mutation of a specific gene, with different gene mutations leading to different clinical manifestations and diseases. Risk factors vary, but most autoinflammatory diseases are hereditary.6 Occasionally, environmental stimuli can cause dysregulation and overproduction of cytokines with over-response of innate and adaptive mechanisms due to transcriptional and post-transcriptional mechanisms not being able to mitigate cytokine synthesis and release.3 That said, these environmental triggers remain unexplained for most autoinflammatory diseases.

Some of the different autoinflammatory diseases are outlined below:

Familial Mediterranean Fever (FMF)

Familial Mediterranean fever (FMF) is an autoinflammatory genetic disorder characterized by recurrent episodes of painful inflammation in the abdomen, chest, or joints, often accompanied by fever and sometimes a rash or headache.7 In approximately 90% of patients, FMF episodes start before 20 years of age, and about 75% of patients experience the first episode before the age of 10 years.11 FMF episodes generally occur once per month, last 12 to 72 hours, and vary in severity. In women of reproductive age, FMF episodes often correspond with menstruation or ovulation. During periods between attacks, which can range from days to years, individuals usually have no signs or symptoms related to the disease. Lack of treatment to help prevent attacks and complications can lead to kidney failure due to a buildup of protein deposits within the body’s organs and tissues.7 FMF is caused by mutations in the MEFV gene. These mutations reduce the activity of the pyrin protein, disrupting the control of the inflammation process and causing an inappropriate or prolonged inflammatory response that ends with the traditional symptoms of FMF.7 FMF is traditionally inherited in an autosomal recessive pattern, but there have been rare cases in which it was inherited in an autosomal dominant pattern, although these could be instances of pseudodominance.7

Tumor Necrosis Factor Receptor-Associated Periodic Syndrome (TRAPS)

TRAPS is an inherited autoinflammatory condition characterized by recurrent episodes of fever that typically last more than 1 week and are associated with chills and severe muscle pain in the torso and the arms.12 Individuals may also experience a spreading skin rash and inflammation in various areas of the body.8 Most patients present in the first decade of life,12 but the fever episodes characteristic of TRAPS can begin at any age. These fevers typically last about 3 weeks, but the range can vary from a few days to a few months.

The frequency of TRAPS episodes varies greatly among individuals and can happen anywhere from every 6 weeks to every few years. Attacks are usually spontaneous, but occasionally they can be brought on by triggers such as infection, stress, minor injury, exercise, or hormonal changes.8 It is estimated that 15% to 20% of patients with TRAPS will develop amyloidosis, an abnormal build-up of amyloid protein in the kidneys that can lead to kidney failure.8

TRAPS is caused by mutations in the TNFRSF1A gene, a gene that provides instructions for making a protein called tumor necrosis factor receptor 1 (TNFR1). These mutations disrupt signaling pathways within the cell and lead to excess inflammation. TRAPS is typically inherited in an autosomal dominant pattern, although not everyone who inherits the gene develops features of the disease. Some cases are caused by new mutations in the gene and occur in people with no familial history of TRAPS.8

Cryopyrin-Associated Periodic Syndromes (CAPS)

CAPS is a group of three conditions that have overlapping signs and symptoms and the same genetic cause, all of which are considered autoinflammatory diseases.9 CAPS is characterized by periodic episodes of skin rash, fever, and joint pain, and the signs and symptoms of the disease affect multiple body systems. Attacks typically present in infancy or early childhood and persist throughout life.9 CAPS affects both males and females of all ethnicities.13

Episodes of CAPS last anywhere from a few hours to a few days and may arise spontaneously or be triggered by exposure to cold temperatures, fatigue, and other stressors.9 If left untreated, CAPS can lead to deafness or amyloidosis.13 CAPS are caused by mutations in the NLRP3 gene, a gene that provides instructions for making a protein called cryopyrin.

It is believed that these NLRP3 gene mutations result in overactive cryopyrin protein, which leads to inappropriate inflammatory responses that cause the episodes of fever and damage to the body’s cells and tissues seen in CAPS.9 CAPS are usually inherited in an autosomal dominant pattern, though some cases are caused by new mutations in the gene and occur in people with no familial history of the disease.

Yao Syndrome

Yao syndrome (formerly called NOD2-associated autoinflammatory disease) is a complex autoinflammatory disease characterized by episodes of fever and abnormal inflammation affecting many parts of the body, in particular, the skin, joints, and gastrointestinal system.10 Yao syndrome is usually diagnosed in adulthood and, for unknown reasons, seems to affect women more than men. The episodes associated with the disease occur weeks to months apart and can last for several days at a time.

Yao syndrome is a chronic disease, and episodes can recur for many years. The causes of Yao syndrome are complex, with the condition likely developing from a combination of genetic and environmental factors, many of which are unknown.10 Certain mutations in the NOD2 gene increase the risk of Yao syndrome, and studies suggest that most people with the disease have at least one variation in the NOD2 gene, although it is unclear what effect these mutations have on the amount or function of the NOD2 protein or how they contribute to abnormal inflammation. It is suspected that environmental factors, such as infections, may trigger the disease in individuals with genetic variants that increase their risk.10

Due to the complexity of the disease and lack of a single genetic cause, Yao syndrome does not have a straightforward pattern of inheritance. A small percentage of affected individuals have a family history of the disease. Many people who have one or more NOD2 gene mutations never develop Yao syndrome.10

Autoinflammation with Infantile Enterocolitis (AIFEC)

AIFEC, known to some as NLRC4 autoinflammatory disease, is a newly identified and extremely rare autoinflammatory disorder characterized by recurrent flares of autoinflammation in early infancy, followed by recurrent febrile episodes with splenomegaly and sometimes hematologic disturbances, arthralgias, or myalgias.14 AIFEC typically presents in infancy with enterocolitis, and recurring episodes of symptoms affect patients throughout adulthood. Symptoms occur in flares, alternating with periods that are symptom-free. The affected population of this disease is small, with only seven individuals being identified since the first diagnosis in 2014.15

The exact cause of AIFEC episodes is not known, but they may be linked to environmental factors such as emotional stress, physical stress, or stresses on the immune system, like viral or bacterial infections. The type of autoinflammation seen in AIEFC is macrophage activation syndrome (MAS), in which macrophages are overactive. MAS causes fevers, enlarged spleen, and blood disturbances and, if left untreated, can progress to organ damage and death.

AIFEC is caused by a mutation in the NLCR4 gene resulting in activation of the NLRC4 protein, leading to uncontrolled activation of the immune system that results in typical AIFEC symptoms.15 AIFEC is inherited in an autosomal dominant pattern and has been observed in some patients due to somatic mutations. NLRC4 gene mutations are also associated with familial cold autoinflammatory syndrome (FCAS4), in which exposure to cold temperatures triggers symptoms such as fevers, joint and muscle pain, skin rashes, conjunctivitis, and limb swelling.15

Autoinflammatory Keratinization Diseases (AiKDs)

AiKDs are a group of autoinflammation disorders characterized by recurring bouts of hyperkeratosis in the skin and hyperkeratotic lesions with inflammation.16 The primary inflammation sites are the epidermis and upper dermis.17 The umbrella term of AiKDs was first proposed in 2017 and includes diseases such as pustular psoriasis and related disorders, pityriasis rubra pilaris, and familial keratosis lichenoides chronica.16

Each disease within the AiKDs group has unique characteristic manifestations and causations, though all possess primary genetic causal features associated with autoinflammation of the skin. Genetic mutations lead to the different disease manifestations of AiKDs. Some of the genes associated with these diseases are IL36RN, CARD14, NLRP1, γ-secretase genes, and mevalonate pathway-related genes.16 Most patients with AiKDs have recurrent and persistent cutaneous lesions.

Autoinflammatory Disease Prognosis

The prognosis for autoinflammatory disease depends mainly on the frequency of the attacks and the development of complications, but it is generally good. Often, attacks improve with treatment and decrease in frequency with age.18 Different variations of autoinflammatory diseases have different severity and frequency of attacks, and so the prognosis varies between diseases.

If left untreated, many autoinflammatory diseases carry the risk of serious complications, such as amyloidosis,13 which can lead to kidney failure. Due to this, combined with the overall rarity of autoinflammatory diseases, it is important for clinicians to be educated and maintain a high degree of suspicion to diagnose and treat potential cases of autoinflammatory disease properly.

Autoinflammatory Disease Diagnosis & Presentation

The presentation of autoinflammatory disease depends on the specific disease the patient is experiencing. Most share a core of phenotypic manifestations, including recurrent attacks of fever, lymphadenopathy, cutaneous signs, vasculopathy, chest or abdominal pain, and musculoskeletal symptoms.3 FMF is the most common type of autoinflammatory disease.4 FMF presents most commonly, and sometimes only, with recurring bouts of fever, with temperatures reaching up to 104 degrees F.

Abdominal pain attacks often accompany the fever, and upon physical examination, guarding, abdominal distension, rebound tenderness,  and decreased bowel sounds are typically noted due to inflammation of the peritoneum. These attacks generally resolve spontaneously within 2 to 3 days.18 Other symptoms of FMF can include chest pain that is usually unilateral and worsens with deep inspiration or coughing, joint pain and stiffness that typically affects large joints of the lower extremities, erysipelas-like lesions of the lower extremities, unilateral scrotal swelling, and myalgia of the upper and lower extremities.18

Autoinflammatory diseases are diagnosed based on clinical manifestations, suspicion, and, depending on the type, genetic testing.4 Genetic analysis and identification of a pathogenic mutation are pivotal for diagnosing monogenic systemic autoinflammatory diseases.3 However, for at least 40% to 60% of patients with phenotypes typical for systemic autoinflammatory diseases, a distinct diagnosis cannot be made.4 The diagnosis of autoinflammatory disease is often associated with significant delay, especially in adults, reiterating the importance for clinicians to maintain a high index of suspicion.3

Physical Examination Findings

The physical examination findings will vary widely from case to case, as it is highly dependent on the specific disease the patient has. Generally, patients with autoinflammatory diseases present with recurrent attacks of fever, lymphadenopathy, cutaneous signs, vasculopathy, chest or abdominal pain, and musculoskeletal symptoms.3 That said, there is a wide variety of clinical manifestations that can be exhibited. It is helpful for the clinician to be familiar with different types of autoinflammatory diseases and their corresponding symptoms.

Autoinflammatory syndromes associated with fever include19:

  • FMF
  • Mevalonate kinase deficiency (MKD), formerly known as hyperimmunoglobulin D syndrome
  • Cryopyrin-associated periodic fever syndromes, which includes familial cold autoinflammatory syndrome, Muckle-Wells syndrome, and neonatal-onset multisystem inflammatory disorder

Autoinflammatory disorders that do not present with fever include19:

  • Deficiency of the IL-1RA (DIRA) that causes osteomyelitis with periostitis and pustulosis
  • Pyogenic sterile arthritis, pyoderma gangrenosum, and acne syndrome
  • Blau syndrome (juvenile systemic granulomatosis)
  • Deficiency of adenosine deaminase 2 that can present with stroke
  • Deficiency of the IL-36 receptor antagonist that causes generalized pustular psoriasis

Diagnostic Workup

The clinical approach to autoinflammatory diseases is based on physical examination and taking a thorough history, especially family history. Even in monogenic autoinflammatory diseases, a comprehensive clinical approach is required to interpret genetic testing properly.3 The diagnostic workup should begin with a physical examination accompanied by the patient’s description of symptoms.

Patients who have a history of recurring inflammatory episodes over the course of months or years in the absence of another cause should be evaluated for an autoinflammatory disease after first excluding unusual infections or malignancy.19 After the physical examination and an accounting of the symptomatic history, a thorough family history should be obtained. If the patient has a family history of a similar syndrome, or they genetically hail from specific geographic locations (e.g., the Mediterranean for FMF), it is likely that they have a heritable disorder such as monogenic autoinflammatory diseases, although recessive or de novo mutations may lack such a history.19

Next, the clinician should attempt to identify a clinical pattern consistent with one of the major autoinflammatory diseases. These are reviewed in detail in a chart created and maintained by the Autoinflammatory Alliance, formerly known as the NOMID Alliance.19 Clinical diagnostic criteria are available for some defined monogenic autoinflammatory diseases.

The Tel Hashomer criteria are the most widely used criteria for diagnosing FMF in adult patients, while the Yalcinkaya-Ozen criteria enable a diagnosis of FMF in children. In 2019, Gattorno et al. published another classification criteria combining genetic and clinical findings to classify FMF, TRAPS, NLRP3- AID, and MKD patients.4 Generally, in regard to multifactorial autoinflammatory diseases, clinical criteria are not available or applicable.4

Genetic testing is used to help confirm a diagnosis in autoinflammatory diseases that are caused by genetic mutations, such as in monogenic systemic autoinflammatory diseases.3 Depending on the case, various approaches can be used, including genetic panels testing multiple disorders, targeted sequencing, or whole-exome/whole-genome sequencing.19 Diseases with multifactorial inheritance or multiple causal factors, including environmental factors, have a cumulative effect on the disease, eliminating the ability of genetic testing to make a diagnosis.4 The diagnosis of these cases relies on clinical manifestations and a high degree of suspicion by the clinician.

Proper diagnosis of the specific autoinflammatory disease is vital due to the potential implications for therapy, monitoring for the development of complications, and the need for genetic counseling.  Even so, many patients defy diagnostic classification despite advances in diagnostic testing. The clinician should reconsider the complete differential diagnosis for autoinflammatory diseases in these cases. If it still seems likely that the patient has an autoinflammatory disease, empiric therapeutic trials with treatments used in other autoinflammatory diseases may be warranted. If possible, these patients should be referred to a treatment center with appropriate expertise in guiding empiric therapeutic trials.19

Differential Diagnosis

The differential diagnosis for autoinflammatory diseases is extensive. Listed below are some common differential diagnoses:

  • Relapsing fever — An arthropod-borne infectious disease caused by spirochetes of the Borrelia genus that is characterized by recurrent episodes of fever. Due to its etiology, it is not an autoinflammatory disease.19
  • Cyclic neutropenia — Aside from PFAPA syndrome (discussed below), autoinflammatory diseases present with fever that is episodic and not truly periodic. If a patient has a predictable recurrent fever pattern, the clinician should suspect cyclic neutropenia, which can be of childhood- or adult-onset.19
  • Systemic lupus erythematosus18
  • Rheumatoid arthritis18
  • Fever of unknown origin20
  • Insufficiently treated infection — Recurrent fever can be caused by inappropriate antibiotic use or not using the antibiotics for a sufficient amount of time.21
  • A single persisting infection that leads to recurrent fevers — Borrelia recurrentis, Spirillum minor, and B. duttoni are three infections that can cause recurrent fevers.21
  • Immunodeficiencies — A patient who is immunocompromised may develop recurrent fevers due to continual infections.21
  • Malignancy — Malignancies, especially lymphomas and leukemias, can cause recurrent fevers and inflammation.21
  • Premalignant states — This includes neuroblastoma, acute lymphoblastic leukemia, and Hodgkin lymphoma [Pel-Ebstein fever]19
  • Factitious fever21
  • Drug fever21
  • Benign hyperthermia21
  • Rheumatic fever22
  • Acute abdomen18
  • Angioedema23 
  • Urticaria24
  • Acute intermittent porphyria23
  • Neoplastic fever25
  • Immune-mediated diseases,25 such as Crohn’s disease and psoriasis26
  • Uveitis27
  • Organ-specific inflammatory syndromes28
  • Multi-system inflammatory syndrome — An inflammatory condition associated with COVID-1929


Treatment options for autoinflammatory diseases are determined by the specific disease the patient has. Regardless, the main focus of treatment is to block the primary inflammatory pathway involved in the disease.19

Traditional Drugs

  • Colchicine — Colchicine has been the standard therapy for FMF for many years and should be adjusted to the body weight, with a mean optimal dose of 0.03 ± 0.02 mg/kg per day. The drug has not demonstrated effectiveness in MKD or CAPS but has shown to be partially effective in TRAPS and PFAPA syndrome.30
  • Non-steroidal anti-inflammatory drugs (NSAIDs) — NSAIDs have been used in monogenic autoinflammatory diseases as symptomatic treatment, alone or in addition to the baseline therapy, but will not influence the underlying cause of the disease. They appear to offer some help in 70% to 80% of all cases.30
  • Glucocorticoids — Glucocorticoids have been used to help treat many different autoinflammatory diseases. They have shown positive effects in patients with FMF when colchicine alone becomes insufficient to control the disease. Short-term usage of glucocorticoids has shown to be useful in patients with TRAPS, MKD, and CAPS. In PFAPA syndrome, glucocorticoids are the treatment of choice as prompt administration can rapidly and completely discontinue attacks in most patients.30

Biologic Agents

  • Interleukin 1 Blockers — Interleukin 1 blockers have become the most specific and useful treatment for inflammasome-mediated autoinflammatory diseases, such as FMF, TRAPS, MKD, and CAPS. They can be used as first-line therapy or when previous conventional anti-inflammatory or immunosuppressive agents are not useful.20 The three commercially available Interleukin 1 blockers are:30
    • Anakinra
    • Canakinumab
    • Rilonacept
  • TNF Blockers — TNF blockers, mainly etanercept, infliximab, and adalimumab, have been used in different monogenic autoinflammatory inflammasomopathies but generally have poorer efficacy than IL-1 blockers.30
  • Anti–IL-6 Agents — Tocilizumab is an anti-IL-6 agent that has been used in patients unresponsive to other biologic agents. It has shown success in FMF, TRAPS, and MKD, although the number of cases is minuscule.30
  • JAK Inhibitors — JAK inhibitors have shown to produce positive effects in several monogenic autoinflammatory diseases mediated by type I interferon. These specific diseases include STING-associated vasculopathy with onset in infancy, Aicardi–Goutières syndrome, chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature/proteasome-associated autoinflammatory syndrome, and familial chilblain lupus.30

Monitoring and Complications

Lifelong monitoring will be required, as there is no absolute cure for autoinflammatory diseases. Treatment is aimed at suppressing systemic inflammation and avoiding potential complications.4 If left untreated, many autoinflammatory diseases carry the risk of serious complications, such as amyloidosis,13 which can lead to kidney failure. It may take continued observation to make a proper diagnosis.

Once that diagnosis is achieved, the patient should be closely monitored to optimize treatment based on the clinical and biological response and disease evolution over time. Periodic surveillance for the development of AA amyloidosis and organ failure should be standard clinical practice.5 Patients should be encouraged to keep a journal of attack frequency and symptoms to be reviewed by their healthcare providers.7

Side effects of medication should be monitored, as they can be serious.  

  • Colchicine includes diarrhea and vomiting. These effects tend to be dose-dependent and occur more frequently at higher doses. Other uncommon side effects include nephrotoxicity, neuropathy, myelosuppression, hepatotoxicity, myopathy, and hypersensitivity reaction.7
  • Glucocorticoids administered in high doses for prolonged periods can have adverse effects such as osteoporosis and fractures, suppression of the hypothalamic-pituitary-adrenal axis, Cushingoid features, diabetes and hyperglycemia, myopathy, glaucoma and cataracts, psychiatric disturbances, immunosuppression, cardiovascular disease, gastrointestinal and dermatologic adverse effects.31
  • NSAIDs may have side effects that affect the gastric mucosa, cardiovascular system, renal system, hepatic system, and hematologic system.32
  • Interleukin 1 blockers can have adverse effects such as infections and local skin reactions at the injection site.33
  • TNF blockers are generally well-tolerated, with minor adverse effects that do not warrant drug discontinuation. These adverse effects can include headaches, rashes, anemia, injection site reaction with the subcutaneous route, and infusion reaction with the intravenous route of administration, transaminitis, sinusitis, cough, upper respiratory tract infections, diarrhea, nausea, pharyngitis, and abdominal pain. Some severe adverse effects have occurred, with the most common being serious infections.34
  • Tocilizumab’s main potential side effect is elevated liver enzyme levels that appear to be dose-dependent. Neutropenia or thrombocytopenia are uncommon effects, and severe infection and bowel perforation have been reported as well.35
  • JAK inhibitors have been associated with an increased risk for infectious events, embolism, and thrombosis.36



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Author Bio:

Jonathan Poole is a freelance writer and copy-editor with a BSc in Exercise Science living in West Lafayette, IN. When not writing, he owns and operates a fitness training company, Unstoppable Athletes. More information regarding his training business can be found here: