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 Table of Contents  
Year : 2020  |  Volume : 15  |  Issue : 3  |  Page : 207-216

Autoinflammatory diseases: Emerging phenotypes

1 Advanced Pediatrics Centre, Postgraduate Institute of Medical Education and Research, Chandigarh, India
2 Department of Paediatrics and Chief, Allergy Immunology Unit, Advanced Pediatrics Centre, Postgraduate Institute of Medical Education and Research, Chandigarh, India
3 Department of Paediatrics, Paediatric Allergy and Immunology Unit, Advanced Paediatrics Centre, Postgraduate Institute of Medical Education and Research, Chandigarh, India

Date of Web Publication3-Sep-2020

Correspondence Address:
Dr. Amit Rawat
Department of Paediatrics, Paediatric Allergy and Immunology Unit, Advanced Paediatrics Centre, Postgraduate Institute of Medical Education and Research, Chandigarh
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/injr.injr_31_20

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Autoinflammatory diseases (AIDs) are a heterogeneous group of genetically inherited disorders involving genes regulating innate immune response. The genetic basis of several AIDs has been characterized and many new syndromes have been identified in the past few years. This review focuses on some of the common AIDs encountered in clinical practice.

Keywords: Blau syndrome, coatomer-associated protein alpha, deficiency of adenosine deaminase 2, infammasomopathies, interferonopathies, periodic fevers, STING-associated vasculopathy with onset in infancy

How to cite this article:
Anjani G, Singh S, Rawat A. Autoinflammatory diseases: Emerging phenotypes. Indian J Rheumatol 2020;15:207-16

How to cite this URL:
Anjani G, Singh S, Rawat A. Autoinflammatory diseases: Emerging phenotypes. Indian J Rheumatol [serial online] 2020 [cited 2021 Jun 18];15:207-16. Available from:

  Introduction Top

Autoinflammatory diseases (AIDs) are a set of clinically distinct disorders with a heterogeneous clinical spectrum that may include repeated episodes of recurrent/persistent fever, mucocutaneous lesions, serositis, uveitis, and osteoarticular involvement. These conditions are characterized by the activation of innate immune cells (especially neutrophils and macrophages), resulting in self-directed inflammation and target tissue damage.[1] These episodes of systemic inflammation are often unprovoked. Unlike autoimmune diseases, AIDs generally do not have antigen-specific T-cells and B-cells or high-titer autoantibodies.

  Search Strategy Top

We searched PubMed engine on November 1, 2019 using the search terms “AID” and “autoinflammatory syndromes.” Of a total of 4751 articles, 43 articles which described various AIDs were selected with the consensus of the authors and reviewed. Based on these articles, the manuscript was prepared including an opinion of authors wherever deemed necessary.

  History Top

The first AID identified was familial  Mediterranean fever More Details (FMF) and its genetic defect was elucidated in 1997.[2] The term “AID” was first proposed by McDermott et al. in 1999 with the discovery of geneTNFRSF1A causing the tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS).[3] Since that time, several new AIDs have been identified [Table 1].
Table 1: AIDs and their clinical correlates

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Over the past two decades, there have been several major advances in our understanding of these conditions. While most of the AIDs are monogenic (e.g., FMF, cryopyrin-associated periodic syndrome [CAPS], TRAPS), some disorders (e.g., Behcet's disease, systemic juvenile idiopathic arthritis) are probably polygenic.

Most AIDs have well-defined immune defects and represent a continuum between primary immunodeficiency disorders and rheumatological disorders. Further, several monogenic forms of AIDs have a clinical presentation that can mimic some common rheumatological disorders [Table 2]. It is, therefore, important for all rheumatologists to be familiar with these conditions.
Table 2: Monogenic autoinflammatory diseases that can mimic the clinical presentation of common rheumatological disorders

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While the clinical phenotype of several AIDs (e.g., Periodic Fever, Aphthous Stomatitis, Pharyngitis, Adenitis (PFAPA), Blau syndrome, TRAPS) is well recognized, genetic diagnosis is often necessary to confirm the diagnosis because of heterogeneity in clinical presentations – a distinct hallmark of AIDs.

  Pathophysiology Top

The final common abnormality in the pathogenesis of AIDs is enhanced production and release of proinflammatory cytokines. Common mechanisms[43] [Figure 1] involved in the pathogenesis of AIDs include the following:
Figure 1: Common mechanismsinvolved in the pathogenesis of autoinflammatory diseases. NLRP3: Nucleotide oligomerization domain, leucine-rich repeat and pyrin domain containing protein 3, NLRC4: Nucleotide oligomerization domain, leucine-rich repeat caspase activating and recruitment domain domain containing 4, IL-1: Interleukin 1, TNF: Tumour necrosis factor, NF-κB: Nuclear factor kappa light chain enhancer of activated B cells

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Type 1 interferonopathies (e.g., Aicardi-Goutières syndrome, STING-associated vasculopathy with onset in infancy, chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature)

These group of AIDs are characterized by an increased release of inflammatory mediators secondary to enhanced expression of Type I interferons (IFNs α, β).

Defects affecting the inflammasome (e.g., familial Mediterranean fever, cryopyrin-associated periodic syndrome, hyper IgD syndrome)

In this group of AIDs, there is involvement of the interleukin (IL)-1 pathway. Pro-IL-1 β is cleavedby activated caspase-1through intracellular complexes called inflammasomes. IL-1 β is released by the inflammasomes and this drives the autocatalytic activation of caspase-1.

Noninflammasome-related conditions

  1. TRAPS (e.g., TRAPS)
  2. AID related to IL-1 superfamily receptor antagonists (e.g., deficiency of the interleukin one receptor antagonist)
  3. AID related to ubiquitination defects (e.g., otulipenia)
  4. Nuclear factor-kappa B activation-mediated disorder (e.g., Blau syndrome)
  5. Proteasome-related disorders (e.g., pyogenic arthritis, pyoderma gangrenosum and Acne, proteasome-associated autoinflammatory syndrome)

  Clinical Pointers to an Underlying Autoinflammatory Disease Top

Although the spectrum of clinical manifestations of AIDs is very heterogeneous, there are several clinical pointers to these conditions:

  1. Unexplained, persistent, or recurrent fever-fever patterns in patients with AIDs vary from typically episodic or “periodic” (e.g., FMF) to continuous (e.g., CAPS). Duration of fever often provides valuable clues to the type of disorder
  2. Recurrent systemic manifestations-musculoskeletal (e.g., arthritis) or cutaneous (e.g., rash)
  3. Early onset of symptoms-before the age of 20 years
  4. Significant family history of similar diseases
  5. Persistently elevated laboratory parameters of inflammation during acute attacks.

Before starting laboratory workup for a possible AID, it is essential to rule out other common pediatric disorders (infective, autoimmune, and infiltrative) that can have a similar clinical presentation.

The clinical phenotype of these disorders often provides valuable clues to underlying AID [Table 3] and [Table 4].
Table 3: Classification of autoinflammatory diseases according to their predominant clinical manifestations

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Table 4: Clinical phenotypes of commonly encountered autoinflammatory diseases

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  Autoinflammatory Diseases Presenting as Predominant Fever Top

Familial Mediterranean fever

Clinical phenotype

Recurrent attacks of febrile illness ranging from 0.5 to 3 days.

Salient features

Cardinal signs and symptoms include peritonitis, arthritis, and pleurisy. Untreated children go on to develop amyloidosis.[4]


The mainstay of treatment is colchicine, which is helpful in preventing acute attacks as well as complications (e.g., secondary amyloidosis). In resistant cases, anti-IL1 treatment has been found to be useful.

Hyper IgD syndrome

Clinical phenotype

Characterized by recurrent attacks of febrile illness and a multisystem involvement including gastrointestinal symptoms (e.g., diarrhea, abdominal pain), rash, aphthous ulcers, and arthralgia. These symptoms last 3–6 days.[4]

Salient features

Skin manifestations may include macular, urticarial, or nodular rashes.


Acute episodes respond dramatically to corticosteroids. Anti-TNF and anti-IL1 therapies have been tried in severe disease.

Tumor necrosis factor-receptor-associated periodic syndrome

Clinical phenotype

Prolonged attacks of febrile illness with cutaneous, serosal, muscular, synovial oro-cular involvement. These attacks usually last 1–4 weeks and may recur 2–6 times each year.[4]

Salient features

Muscle cramps that migrate in a centrifugal pattern are typical of this disorder. Migrating erythematous rash occurring on extremities is the most common skin manifestation. Ocular inflammation can occur in the form of conjunctivitis or periorbital edema.


Acute episodes respond dramatically to corticosteroids. Anti-TNF and anti-IL1 therapies are useful in severe disease.

  Autoinflammatory Diseases Presenting as Fever and Rash (Urticarial) Top

Cryopyrin-associated periodic syndromes

The term CAPS encompasses three diseases: familial cold autoinflammatory syndrome (FCAS); Muckle–Wells syndrome (MWS); neonatal-onset multisystem inflammatory disease (NOMID) that is also known as chronic infantile neurologic cutaneous articular syndrome. All three are associated with variants in NLRP3.[4]

  1. FCAS: It is the mildest variant characterized by cold triggered attacks of fever, urticaria, joint symptoms, and conjunctivitis. The duration of symptoms is usually <2 days
  2. MWS: It has a variable spectrum and may present with fever, rash, arthritis, episcleritis, conjunctivitis, and hearing loss
  3. NOMID: It is the most severe form of CAPS and is characterized by persistent fever, rash, bony overgrowth of the knees, uveitis, optic disc edema, and a variety of the central nervous system manifestations (e.g., headaches, chronic meningitis, and hearing loss).


These conditions show a dramatic response to anti-IL1therapy.

  Autoinflammatory Diseases Presenting as Predominant Rash Top

STING-associated vasculopathy with onset in infancy

Clinical phenotype

Clinical features include neonatal onset of severe skin vasculopathy, peripheral gangrene, and interstitial lung disease.[29]

Salient features

An acral rash involving the digits, nose, and earlobes is characteristic. This often results in digital ischemia and autoamputation.


Although a variety of immunosuppressive therapies have been tried, none have been found to be effective.

H syndrome

Clinical phenotype

It is characterized by hyperpigmentation, hypertrichosis, heart anomalies, hallux valgus, hepatosplenomegaly, hypogonadism, hearing loss, hyperglycemia, and short stature.[10]

Salient features

Pathognomonic feature is cutaneous hyperpigmentation that typically affects the medial aspect of the thighs.


A variety of immunosuppressive therapies have been tried but none have been found to be effective. A few reports suggest that IL-6 blockade with tocilizumab may be beneficial in some cases.[11]

Deficiency of the interleukin thirty-six receptor antagonist

Clinical phenotype

It is characterized by childhood onset of recurrent episodes of high fever and generalized pustular psoriasis.[15]

Salient features

It should be considered in a differential diagnosis of children with generalized pustular psoriasis.


Biologics (anti-TNF, anti-IL1) have been tried. Ustekinumab (a monoclonal antibody against the p40 subunit of both IL-12 and IL-23)[44] has been found effective in refractory cases.

Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature syndrome

Clinical phenotype

Early-onset recurrent fever, skin involvement (nodular/bullae), myositis, and gradually progressive joint contractures are characteristic.[45]

Salient features

Panniculitis-induced lipodystrophy predominantly in the upper part of the body leading to characteristic thin facies is seen.


Oral steroids are effective in treating the inflammation. IFN-targeted drugs are currently being studied.

PLCG2-associated Antibody-deficiency and Immune Dysregulation

Clinical phenotype

Cold induced urticaria with associated recurrent sinopulmonary infections (due to underlying hypogammaglobinemia) is characteristic.[20]

Salient feature

Cutaneous granulomatous lesions develop in severe cases.


Replacement monthly intravenous immunoglobulin (IVIg) therapy with cold avoidance, high-dose corticosteroids, and antihistamines has been found effective.

Autoinflammatory PLCG2-associated Antibody deficiency and Immune Dys-regulation

Clinical phenotype

Rash in form of blisters/bullous lesions, enterocolitis, ocular symptoms (e.g., corneal blisters, cataracts, uveitis), musculoskeletal involvement (e.g., arthralgia), and interstitial lung disease is characteristic.[21]

Salient features

Patients have recurrent bacterial and viral sinopulmonary infections due to hypogammaglobinemia.


Replacement monthly IVIg along with corticosteroids and anakinra have been tried.

A20 haploinsufficiency

Clinical phenotype

Patients mostly present with recurrent oral, genital, or gastrointestinal ulcers. Other symptoms include recurrent fever, arthralgias, myalgia, arthritis, abdominal pain, rash (acne, cutaneous abscess, pustular rash), and recurrent infections. Ocular manifestations include retinal vasculitis, treatment refractory anterior uveitis, and macular fibrosis. Autoimmune features (e.g., thyroiditis, lupus) may also be prominent.[34],[35]

Salient features

Recurrent oro-genital ulcers are a hallmark of this condition. Some patients may have HLAB51positivity. Differential diagnoses include Behcet's disease and inflammatory bowel disease. Inheritance is autosomal dominant.


Colchicine is effective for patients with mild symptoms. For severe disease steroids and biological agents (anti-TNF, anti-IL1, and anti-IL6) can be effective.

  Autoinflammatory Diseases Presenting With Predominant Musculoskeletal System Involvement Top

Chronic/recurrent arthritis

Coatomer-associated protein alpha syndrome

Clinical phenotype

Is characterized by early onset of symptoms (<5 years), pulmonary manifestations (e.g., cough, diffuse alveolar hemorrhage, interstitial lung disease), and musculoskeletal involvement (usually polyarthritis with the involvement of interphalangeal joints of the hands and knees commonly). Glomerular disease (e.g., altered renal function tests, and proteinuria) is seen in the second decade.[31]

Salient feature

Inheritance is autosomal dominant. Most patients (80%) have a positive ANA titer.


Arthritis is treated with steroids and disease modifying agents (e.g., methotrexate or azathioprine). For pulmonary hemorrhages, either cyclophosphamide or rituximab can be used. Other immune-modulatory therapies include hydroxychloroquine and IVIg.

Blau syndrome

Clinical phenotype

Triad of uveitis (pan uveitis or chronic intermediate uveitis), skin rash, and musculoskeletal involvement (symmetrical polyarthritis, camptodactyly, and tenosynovitis) is characteristic.[5],[6]

Salient features

The presence of boggy swellings of the joints with uveitis is often pathognomonic.


Steroids, disease-modifying agents, methotrexate, adalimumab, and anakinra have been used with variable results.

Pyogenic arthritis, pyoderma gangrenosum, and acne syndrome

Clinical phenotype

Recurrent pyogenic arthritis, cutaneous lesions in form of severe acne, and pyoderma gangrenosum is typical. Other symptoms include aseptic abscesses, pustules, oral ulcers, psoriasis like lesions or suppurative hidradenitis.[7]

Salient features

The [resence of pyoderma gangrenosum with arthritis is a useful pointer to diagnosis.


Steroids, cyclosporine, anti-TNF have been tried in this condition.

  Inflammatory Osteolytic Lesions Top

Majeed syndrome

Clinical phenotype

Recurrent episodes of febrile illness, persistent multifocal sterile osteomyelitis, skin involvement (pustulosis, neutrophilic dermatosis), growth failure, and congenital dyserythropoietic anemia are presenting features.[8]

Salient features

Unlike chronic recurrent multifocal osteomyelitis, Majeed syndrome usually starts in early childhood.


Therapeutic modalities include non-steroidal anti-inflammatory drugs, corticosteroids, bisphosphonates, and biological drugs (anti-TNF and anti-IL1 therapies).

Deficiency of the interleukin one receptor antagonist

Clinical phenotype

Begins in early infancy and is characterized by skin involvement (e.g., pustular psoriasis-like lesions) and bone (e.g., multifocal sterileosteomyelitis with periostitis involving clavicles, long bones, vertebral bodies, ribs, and hips) involvement.[13]

Salient features

Fever is usually not prominent but the inflammatory markers in serum are high.


Rapid clinical response occurs with anti-IL1 therapy, anakinra.

  Autoinflammatory Diseases Presenting With Organ Involvement Top

Deficiency of adenosine deaminase 2

Clinical phenotype

Cardinal features include neurological manifestations (e.g., stroke due to vasculitis), cutaneous involvement (e.g., livedoid rash) and immunodeficiency due to hypogammaglobinemia. Hematological features include pure red cell aplasia, immune thrombocytopenia and hemolytic anemia.[24],[25],[26]

Salient features

The striking neurological feature is stroke. Recurrent infections are noted in 20% of cases. Hypogammaglobulinemia (usually low IgM) is present in 25%. Deficiency of adenosine deaminase 2 has a very variable clinical presentation. It is now considered in the differential diagnosis of children with a variety of clinical conditions including early-onset fevers, rashes, and strokes.


Anti-TNF therapy needs to be administered during acute attacks. Patients with symptomatic hypogammaglobulinemia require monthly replacement IVIg therapy.

Aicardi-Goutières syndrome

Clinical phenotypes

Patients with Aicardi-Goutières syndrome (AGS)[1],[2],[3],[4],[29],[43] develop neurological manifestations in form of white matter disease, subacute encephalomyelitis, basal ganglion calcification, developmental delay, and microcephaly. Patients with AGS7 present with developmental delay, spasticity, rash, and arthritis. Patients may have variable rash (e.g., chilblains).[41],[42]

Salient features

Neurological manifestations start in early infancy. As a result, most patients of AGS are followed up in neurology clinics.


Treatment is mostly supportive.

  Conclusion Top

AIDs have a wide spectrum of clinical manifestations. It is, therefore, important to identify the broad clinical diagnosis based on clinical features which will further help in narrowing the diagnosis and genetic diagnosis. Hence, it is essential for pediatricians and rheumatologists to be aware of AIDs to make an appropriate diagnosis and the management of patients with AIDs.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

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  [Figure 1]

  [Table 1], [Table 2], [Table 3], [Table 4]


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