Autoinflammatory disorders are disorders characterized by rash, arthritis, fever, and systemic inflammation. These disorders are caused by mutations in genes important in innate immune system sensors. This review highlights the workup of an individual with recurrent episodes of inflammation, features of these disorders, the genetic defects that cause these disorders, and the specific treatments available.
Key points
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Autoinflammatory disorders result in persistent or recurrent episodes of inflammation due to mutations in innate immune system sensors.
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Autoinflammatory disorders should be considered only after a workup for autoimmune disorders, malignancy, or immune deficiency.
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Once an autoinflammatory disorder is diagnosed, targeted therapies are often available.
Background and pathophysiology of autoinflammatory disorders
Inflammation, the classic quadrad of “rubor (redness), tumor (swelling), calor (heat), and dolor (pain)”, is a fundamental concept of immunology and a common observation in clinical medicine. One could add “fever” as a fifth marker of inflammation, although it is not unusual to have inflammation without fever.
Inflammation is central to the function of the innate immune system that has evolved to recognize pathogens of all types, including fungi, bacteria, virus, protozoa, and helminths. This system is highly diverse, with multiple related and unrelated protein family members, likely due to the evolution driven by diverse pathogens. These protein families are often referred to pathogen recognition receptors (PRR) and they have evolved to recognize conserved microbial products, known as pathogen-associated molecular patterns (PAMPs). PAMPs are equally diverse, and include molecules unique to microbes, such as lipopolysaccharide (LPS), lipoteichoic acid (LTA), flagellin, and viral nucleic acids, among others. Because humans do not make these molecules, they are natural targets for recognition by the immune system.
This recognition of pathogens is the first line of defense of the immune system, and recognition by PRRs leads to rapid induction of inflammation. Inflammation by these different pathways is scripted, and thus consistent each time that pathogen is recognized. The response to subsequent challenges is no faster or of greater magnitude than the initial response; that is, the innate immune system does not “learn,” but is essential to activate the adaptive immune system (ie, T and B lymphocytes) that does learn, and through the acquisition of memory is much more effective at clearing pathogens than the innate immune system.
Not all inflammation is alike, however, and different PRRs are activated by different PAMPs, resulting in differing responses. For example, antiviral PRRs activate the production of interferons that induce inflammation but also induce changes in stromal cells to help slow viral replication until the adaptive immune system can be activated. PRRs specific for LPS or other bacterial products lead to nuclear factor (NF)-κB activation and the generation of number inflammatory proteins. These pathways promote immune cell recruitment, production of stromal cell factors that aid in slowing microbial infiltration, and activate systemic pathways that help protect the host, such as the acute phase response.
Autoinflammatory syndromes are defined as disorders characterized by persistent or recurrent bouts of inflammation without features of autoimmunity (ie, autoantibodies or autoreactive T cells). These disorders are also referred to as periodic fever syndromes, although this nomenclature is falling out of favor as we learn more about these disorders. Many of these disorders exhibit inflammation without fever, and the inflammation can be persistent rather than episodic. Autoinflammatory disorders typical involve activating mutations in PRRs, or loss of regulatory proteins that regulate signaling of PRRs. Because the innate immune system does not exhibit memory and thus each inflammatory episode is of similar magnitude to past episodes, these bouts of inflammation can persist or recur for years before pathology occurs. In contrast, autoimmune disorders do exhibit memory, and thus autoimmune responses can ramp up quickly leading to serious illness in a relatively short period of time ( Fig. 1 ).
When to Consider Autoinflammatory Disorders
When considering the diagnosis of an autoinflammatory syndrome in a child with recurrent fevers or inflammation, it is important to realize that fevers are a part of childhood and are overwhelmingly caused by innocuous infections. Autoinflammatory disorders should not be the first consideration of a child with recurrent fevers, as these are rare disorders. The initial workup of a child with recurrent infections should focus on ruling out more serious conditions, such as autoimmune disease, malignancy, or immune deficiency. A conservative workup of a child with recurrent fevers may include the following:
- 1.
Physical examination for signs of autoimmunity or malignancy
- 2.
Infectious workup to determine the organism(s)
- 3.
Imaging or other investigations as indicated (eg, masses on examination, endoscopy to rule out inflammatory bowel disease, bone scan to rule out osteomyelitis)
- 4.
Limited laboratory evaluation
- a.
Complete blood count
- b.
Immunoglobulin levels
- c.
Vaccine titers (diphtheria, tetanus, pneumococcus)
- d.
Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) (when afebrile)
- e.
Uric acid and lactate dehydrogenase (LDH)
- a.
Malignancies and autoimmune diseases do not wax and wane, so these would be unlikely with a history of recurrent fevers followed by periods of general well-being. Signs of a characteristic rash, arthritis, or weight loss can be seen juvenile idiopathic arthritis or inflammatory bowel disease. These disorders may have intermittent fevers, but other symptoms typically persist. Inflammatory markers (ie, ESR and CRP) are generally not helpful during febrile episodes, but assessment of these markers between episodes and when fever free may help to rule out autoimmune diseases or malignancy. Persistent inflammation needs to be further evaluated, and this may include endoscopy for inflammatory bowel disease, imaging to rule out vasculitis or masses/malignancies, or a bone scan to look for osteomyelitis. Generally, however, children with recurrent fevers are healthy between these episodes, are growing and developing normally, and have a normal laboratory examination. In these cases, observation is recommended until fevers resolve. If they do not resolve over time, or if symptoms more classically associated with an autoinflammatory disorder appear, genetic testing can be pursued. Because autoinflammatory disorders typically take a long time to cause tissue damage, such as amyloidosis, it is general appropriate to watch and wait to see if the fevers resolve, as long as the patient is generally doing well between episodes.
Autoinflammatory Disorder Overview
Autoinflammatory disorders display stereotypical features that occur during the episodes. These symptoms will occur with each episode. These are varied, and some patients will not present will all of the symptoms of a specific autoinflammatory disorder. Furthermore, young children may present only with fever and it may take some time for other symptoms to occur. Some common symptoms associated with autoinflammatory disorders include the following:
- 1.
Characteristic rash (ie, livedo, erysipelas, granulomas, pustulosis)
- 2.
Serositis (ie, abdominal pain, pericarditis, pleuritis)
- 3.
Arthritis (can be episodic or persistent)
- 4.
Mouth sores/aphthosis
- 5.
Laboratory evidence of inflammation
There are several ways to classify autoinflammatory disorders. They can be organized according to symptoms, although there is considerable overlap of symptoms between these disorders, or by pathophysiology. In this review, we highlight the clinical features of autoinflammatory disorders based on predominant symptoms.
Background and pathophysiology of autoinflammatory disorders
Inflammation, the classic quadrad of “rubor (redness), tumor (swelling), calor (heat), and dolor (pain)”, is a fundamental concept of immunology and a common observation in clinical medicine. One could add “fever” as a fifth marker of inflammation, although it is not unusual to have inflammation without fever.
Inflammation is central to the function of the innate immune system that has evolved to recognize pathogens of all types, including fungi, bacteria, virus, protozoa, and helminths. This system is highly diverse, with multiple related and unrelated protein family members, likely due to the evolution driven by diverse pathogens. These protein families are often referred to pathogen recognition receptors (PRR) and they have evolved to recognize conserved microbial products, known as pathogen-associated molecular patterns (PAMPs). PAMPs are equally diverse, and include molecules unique to microbes, such as lipopolysaccharide (LPS), lipoteichoic acid (LTA), flagellin, and viral nucleic acids, among others. Because humans do not make these molecules, they are natural targets for recognition by the immune system.
This recognition of pathogens is the first line of defense of the immune system, and recognition by PRRs leads to rapid induction of inflammation. Inflammation by these different pathways is scripted, and thus consistent each time that pathogen is recognized. The response to subsequent challenges is no faster or of greater magnitude than the initial response; that is, the innate immune system does not “learn,” but is essential to activate the adaptive immune system (ie, T and B lymphocytes) that does learn, and through the acquisition of memory is much more effective at clearing pathogens than the innate immune system.
Not all inflammation is alike, however, and different PRRs are activated by different PAMPs, resulting in differing responses. For example, antiviral PRRs activate the production of interferons that induce inflammation but also induce changes in stromal cells to help slow viral replication until the adaptive immune system can be activated. PRRs specific for LPS or other bacterial products lead to nuclear factor (NF)-κB activation and the generation of number inflammatory proteins. These pathways promote immune cell recruitment, production of stromal cell factors that aid in slowing microbial infiltration, and activate systemic pathways that help protect the host, such as the acute phase response.
Autoinflammatory syndromes are defined as disorders characterized by persistent or recurrent bouts of inflammation without features of autoimmunity (ie, autoantibodies or autoreactive T cells). These disorders are also referred to as periodic fever syndromes, although this nomenclature is falling out of favor as we learn more about these disorders. Many of these disorders exhibit inflammation without fever, and the inflammation can be persistent rather than episodic. Autoinflammatory disorders typical involve activating mutations in PRRs, or loss of regulatory proteins that regulate signaling of PRRs. Because the innate immune system does not exhibit memory and thus each inflammatory episode is of similar magnitude to past episodes, these bouts of inflammation can persist or recur for years before pathology occurs. In contrast, autoimmune disorders do exhibit memory, and thus autoimmune responses can ramp up quickly leading to serious illness in a relatively short period of time ( Fig. 1 ).
When to Consider Autoinflammatory Disorders
When considering the diagnosis of an autoinflammatory syndrome in a child with recurrent fevers or inflammation, it is important to realize that fevers are a part of childhood and are overwhelmingly caused by innocuous infections. Autoinflammatory disorders should not be the first consideration of a child with recurrent fevers, as these are rare disorders. The initial workup of a child with recurrent infections should focus on ruling out more serious conditions, such as autoimmune disease, malignancy, or immune deficiency. A conservative workup of a child with recurrent fevers may include the following:
- 1.
Physical examination for signs of autoimmunity or malignancy
- 2.
Infectious workup to determine the organism(s)
- 3.
Imaging or other investigations as indicated (eg, masses on examination, endoscopy to rule out inflammatory bowel disease, bone scan to rule out osteomyelitis)
- 4.
Limited laboratory evaluation
- a.
Complete blood count
- b.
Immunoglobulin levels
- c.
Vaccine titers (diphtheria, tetanus, pneumococcus)
- d.
Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) (when afebrile)
- e.
Uric acid and lactate dehydrogenase (LDH)
- a.
Malignancies and autoimmune diseases do not wax and wane, so these would be unlikely with a history of recurrent fevers followed by periods of general well-being. Signs of a characteristic rash, arthritis, or weight loss can be seen juvenile idiopathic arthritis or inflammatory bowel disease. These disorders may have intermittent fevers, but other symptoms typically persist. Inflammatory markers (ie, ESR and CRP) are generally not helpful during febrile episodes, but assessment of these markers between episodes and when fever free may help to rule out autoimmune diseases or malignancy. Persistent inflammation needs to be further evaluated, and this may include endoscopy for inflammatory bowel disease, imaging to rule out vasculitis or masses/malignancies, or a bone scan to look for osteomyelitis. Generally, however, children with recurrent fevers are healthy between these episodes, are growing and developing normally, and have a normal laboratory examination. In these cases, observation is recommended until fevers resolve. If they do not resolve over time, or if symptoms more classically associated with an autoinflammatory disorder appear, genetic testing can be pursued. Because autoinflammatory disorders typically take a long time to cause tissue damage, such as amyloidosis, it is general appropriate to watch and wait to see if the fevers resolve, as long as the patient is generally doing well between episodes.
Autoinflammatory Disorder Overview
Autoinflammatory disorders display stereotypical features that occur during the episodes. These symptoms will occur with each episode. These are varied, and some patients will not present will all of the symptoms of a specific autoinflammatory disorder. Furthermore, young children may present only with fever and it may take some time for other symptoms to occur. Some common symptoms associated with autoinflammatory disorders include the following:
- 1.
Characteristic rash (ie, livedo, erysipelas, granulomas, pustulosis)
- 2.
Serositis (ie, abdominal pain, pericarditis, pleuritis)
- 3.
Arthritis (can be episodic or persistent)
- 4.
Mouth sores/aphthosis
- 5.
Laboratory evidence of inflammation
There are several ways to classify autoinflammatory disorders. They can be organized according to symptoms, although there is considerable overlap of symptoms between these disorders, or by pathophysiology. In this review, we highlight the clinical features of autoinflammatory disorders based on predominant symptoms.
Genetic disorders with prominent arthritis
Although many of the autoinflammatory disorders have joint symptoms, several present with prominent arthritis.
Familial Mediterranean Fever
Familial Mediterranean fever (FMF) is the most common autoinflammatory syndrome, and is an autosomal recessive disorder due to mutations in the MEFV gene that encodes the protein pyrin. FMF is characterized by short episodes of fever (ie, 1–3 days), serositis/peritonitis, erysipelas-like rash, and arthritis, although fever can be the only symptom early in life. The arthritis is typically monoarticular and predominantly neutrophilic. FMF is treated with daily colchicine, leading to symptomatic relief in 95% of patients with nearly 75% achieving near complete remission, significantly reducing the risk of amyloidosis. Amyloidosis prevalence varies considerably among patients, due to ethnicity or more importantly the type of mutation. Recently, interleukin (IL)-1 antagonists have been used successfully in patients unresponsive to colchicine.
To date, more than 200 variants in the MEFV gene have been reported; however, 4 mutations (M680I, M694V, M694I, and V726A) account for most disease-associated alleles in various FMF populations. Pyrin regulates inflammation via interaction with the inflammasome (see later in this article), and thus patients with pyrin mutations exhibit increased processing and secretion of IL-1β and IL-18.
Blau Syndrome
Blau syndrome is an autosomal dominantly inherited disease originally described in 11 family members exhibiting granulomatous inflammation in the skin, joints, and uveal tract. Blau syndrome is closely related to sarcoidosis and should be considered in patients with early-onset sarcoidosis, although NOD2 mutations are not found in sarcoidosis, and pulmonary involvement in Blau is unusual. Joint involvement includes boggy synovitis and tenosynovitis, cystic swelling of large joints, campylodactyly, and interphalangeal contractures. Skin involvement is described as erythematous maculopapular, lichenoid papules, and biopsy shows noncaseating granulomas. Less frequent involvement includes granulomatous liver disease, cranial neuropathies, large vessel vasculitis, and interstitial lung disease.
Gain-of-function mutations in NOD2/CARD15 cause Blau syndrome and result in spontaneous activation of the NOD2 protein, activation of NF-κB, and production of proinflammatory cytokines. Laboratory studies in Blau syndrome are typically normal, although elevated inflammatory markers (ie, ESR), elevated angiotensin-converting enzyme levels can be seen, and hypergammaglobulinemia can occur. Corticosteroids have been used to treat patients with Blau syndrome, although limited reports have shown effectiveness of the tumor necrosis factor (TNF)-α blockers infliximab and etanercept, and IL-1 receptor antagonist (anakinra). Ironically, loss-of-function mutations in NOD2 result in Crohn disease, another granulomatous disorder. Mutations in NOD2 that cause Crohn disease result in decrease responsiveness to bacterial peptides and decreased NF-κB activation, although how this results in granulomatous disease is not well understood.
Pyogenic Arthritis, Pyoderma Gangrenosum, and Acne
Pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome is a rare autosomal dominant disorder presenting in early childhood with recurrent, sterile, monoarticular erosive arthritis. By puberty, cystic acne occurs together with ulcerative skin lesions similar to pyoderma gangrenosum. Treatment with intra-articular or systemic steroids have shown benefit in resolving arthritis. Treatment with IL-1 receptor antagonist (anakinra) or TNF-α inhibitors (infliximab and etanercept) has been beneficial.
Mutations in PSTPIP1 were shown to cause PAPA. PSTPIP1 interacts with pyrin, and PSTPIP1 mutations in PAPA cause a gain-of-function effect by increasing the strength of this interaction, resulting in IL-1β activation.
Genetic disorders with prominent rash
Although rash is common in autoinflammatory syndromes, the following present with prominent cutaneous inflammation that if recognized can lead to rapid diagnosis.
Cryopyrin-Associated Periodic Syndrome
Cryopyrin-associated periodic syndrome (CAPS) consists of 3 related disorders due to mutations in NLRP3/CIAS1 : neonatal-onset multisystem inflammatory disorder (NOMID), Muckle-Wells syndrome (MWS), and familial cold autoinflammatory syndrome (FCAS). FCAS is the mildest form of this disorder that only occurs after generalized cold exposure, whereas patients with MWS and NOMID display daily symptoms. The rash is often mistaken for urticaria due to its evanescent nature, but it lacks angioedema, signs of mast cell proliferation or degranulation, and is characterized by neutrophil infiltrates. Unlike cold urticaria, localized cold challenge (ie, ice cube test) will not precipitate an attack in FCAS, because full-body cold exposure is necessary. NOMID is the most severe variant of CAPS, with patients exhibiting rash at or shortly after birth, aseptic meningitis, cerebral atrophy, uveitis, and hearing loss and mental retardation. The chronic arthropathy in NOMID is severe and deforming due to recurrent bouts of inflammation leading to epiphyseal and patellar overgrowth. Approximately 20% of patients with NOMID die before adulthood. MWS presents similar to NOMID but with less severe features. Unlike NOMID and MWS, FCAS does not typically exhibit chronic meningitis and sensorineural hearing loss, arthropathy, or amyloidosis. Laboratory evaluation of MWS and NOMID demonstrate persistent leukocytosis, neutrophilia, anemia, thrombocytosis, and elevated ESR and CRP levels. Similar abnormalities are seen in patients with FCAS during an attack.
FCAS, NOMID, and MWS are caused by autosomal dominantly inherited mutations in the CIAS1/NLRP3 gene that encodes for the cryopyrin protein. A lack of a family history is not unusual, because de novo mutations occur, particularly in the most severe cases, and somatic mutations also can occur. Mutations in NLRP3 that cause CAPS occur in an autoinhibitory domain of the cryopyrin protein, leading to spontaneous inflammasome assembly, activation of caspase-1, and cleavage of pro–IL-1β to biologically active IL-1β.
A variety of immunosuppressive treatments have been used in CAPS, including corticosteroids and colchicine, but IL-1 inhibitors are now the treatment of choice. Anakinra (ie, recombinant IL-1 receptor antagonist), rilonacept (ie, IL-1 Trap), and canakinumab (IL-1β monoclonal antibody) have been shown to lead to rapid and sustained improvements in inflammatory markers and symptoms. IL-1 inhibitors have been shown to improve long-term morbidity, such as hearing loss, joint deformity, and amyloidosis. Patients with FCAS are encouraged to avoid cold exposure.
Deficiency of Interleukin-1 Receptor Antagonist
Because IL-1 receptor antagonist (anakinra) is the effective treatment of several autoinflammatory disorders, it was not surprising that patients with deficiency of IL-1 receptor antagonist (ie, DIRA) developed an autoinflammatory disorder. DIRA is an autosomal recessive disorder presenting with symptoms shortly after birth with erythroderma, pustular rash, osteopenia with lytic bone lesions, and systemic inflammation. Respiratory distress, aphthous ulcers, hepatomegaly, and failure to thrive also occurred, and laboratory abnormalities include elevated ESR and CRP, leukocytosis, anemia, and thrombocytosis. Numerous anti-inflammatory medications have been tried in patients with DIRA with limited efficacy. Corticosteroid showed some benefit, but did not prevent the complications of the disease, and 3 of the original 10 infants died despite treatment. Anakinra treatment results in a rapid and sustained response, with correction of laboratory abnormalities, resolution of rash, and healing of bone lesions. IL-1RA binds the IL-1 receptor and competes for binding with IL-1 preventing receptor activation. Monocytes from patients with DIRA stimulated with IL-1β exhibited elevated production of inflammatory cytokines caused by the lack of inhibition of IL-1 receptor antagonist.
Guadalupe-Type Fever Syndrome
A group of patients from Guadalupe exhibited symptoms similar to FCAS with fever, rash, arthralgias, and myalgias after generalized cold exposure but without a genetic mutation in CIAS1/NLRP3 . Using a candidate gene approach, mutations in the NLRP12 gene were discovered. Headache, abdominal pain, lymphadenopathy, and aphthous ulcers also can been seen, whereas sensorineural hearing loss and other central nervous system (CNS) manifestations occurred variably. Laboratory studies reflect an acute phase response with elevated ESR and CRP during the attacks that normalized between attacks. Limiting cold exposure appears effective to prevent attacks, and low-dose steroids, antihistamines, or nonsteroidal anti-inflammatory drugs (NSAIDs) were reported to be somewhat effective. Anakinra was effective in 1 patient, although the response waned over time.
Deficiency of Interleukin-36 Receptor Antagonist
A syndrome of generalized pustular psoriasis was described in 19 individuals from 9 Tunisian families inherited in an autosomal recessive manner due to mutations in the IL-36 receptor antagonist. The age of onset varied greatly, but all individuals exhibited episodes characterized by fevers and erythematous skin eruption with pustules. A variety of other symptoms were described, including geographic tongue, nail dystrophy, arthritis, and cholangitis. Episodes were triggered by viral or bacterial infections, menstruation, and pregnancy. White blood cell count, ESR, and CRP are elevated during the attacks. Most patients with this disorder were treated with Acitretin, an oral retinoid, which was beneficial; withdrawal of the medication was associated with recurrence of symptoms. Some patients were also treated with oral and topical steroids, cyclosporine, methotrexate, and TNF antagonists with variable results. IL-36 receptor antagonist is evolutionarily similar to IL-1 receptor antagonist, and the skin manifestations of either disease can appear similar. However, IL-36 receptor antagonist deficiency has no bone or CNS involvement.
Chronic Atypical Neutrophilic Dermatosis with Lipodystrophy and Elevated Temperature
Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) is an autosomal recessive disease resulting from mutations in the proteasome subunit beta type-8 (PSMB8). Patients exhibit early onset of recurrent fevers, purpuric skin plaques with dermal neutrophilic infiltrates, periorbital edema, hepatomegaly, lymphadenopathy, anemia, elevation in acute phase reactants, failure to thrive, and increased level of interferon (IFN)-γ–induced protein (IP-10). Conjunctivitis, myositis, aseptic meningitis, interstitial lung disease, Coombs-positive hemolytic anemia, and hypothyroidism can be seen. PSMB8 is a proteasome subunit involved in protein degradation, and failure to degrade proteins leads to cellular stress, apoptosis, and activation of IFN signaling pathways. Multiple treatment modalities have been attempted, including NSAIDs, colchicine, dapsone, cyclosporine, glucocorticoids, methotrexate, infliximab, etanercept, and anakinra, all of which have minimal success. IL-6 blocking agents normalize inflammatory markers and anemia, but the lipodystrophy appears resistant to therapy. Recent therapeutic developments of specific Janus kinase (JAK) inhibitors (tofacitinib, ruxolitinib, and baricitinib) offer promise in the treatment of this disease and others associated with dysregulated interferon responses (ie, interferonopathies). JAKs are protein tyrosine kinases involved in signaling of many immune cytokines, and JAK1 and JAK2 are important in IFN signaling.
Stimulator of Interferon Genes–Associated Vasculopathy with Onset in Infancy
Patients with stimulator of IFN genes (STING)-associated vasculopathy with onset in infancy (SAVI) present early in life with systemic inflammation, interstitial lung disease, and violaceous scaly skin lesions. These lesions worsen over time, can become necrotic, and are caused by leukocytoclastic vasculitis and microthrombotic angiopathy. Affected patients showed that SAVI occurs secondary to a de novo gain-of-function mutation in the TMEM173 gene that encodes for STING. STING mediates the production of IFN-β, which then signals through the JAK/STAT pathway resulting in production of IFN-responsive genes. Treatment of SAVI is limited, but the development of JAK inhibitors has shown some promise in blocking the transcription of IFN-β and the activation of IFN-response genes.
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