Elsevier

Clinical Immunology

Volume 147, Issue 3, June 2013, Pages 155-174
Clinical Immunology

Review
Monogenic autoinflammatory diseases: Concept and clinical manifestations

https://doi.org/10.1016/j.clim.2013.03.016Get rights and content

Highlights

  • The spectrum of monogenic autoinflammatory diseases has grown over the years.

  • We grouped the autoinflammatory diseases (AIDs) according to clinical manifestations.

  • AID clinical findings should be recognized by primary care physicians.

  • Early referral and treatment is mandatory to improve morbidity and mortality.

Abstract

The objective of this review is to describe the clinical manifestations of the growing spectrum of monogenic autoinflammatory diseases including recently described syndromes. The autoinflammatory diseases can be grouped based on clinical findings: 1. the three classic hereditary “periodic fever syndromes”, familial Mediterranean Fever (FMF); TNF receptor associated periodic syndrome (TRAPS); and mevalonate kinase deficiency/hyperimmunoglobulinemia D and periodic fever syndrome (HIDS); 2. the cryopyrin associated periodic syndromes (CAPS), comprising familial cold autoinflammatory syndrome (FCAS), Muckle–Wells syndrome (MWS) and neonatal-onset multisystem inflammatory disease (NOMID) or CINCA, and; 3. pediatric granulomatous arthritis (PGA); 4. disorders presenting with skin pustules, including deficiency of interleukin 1 receptor antagonist (DIRA); Majeed syndrome; pyogenic arthritis, pyoderma gangrenosum and acne (PAPA) syndrome; deficiency of interleukin 36 receptor antagonist (DITRA); CARD14 mediated psoriasis (CAMPS), and early-onset inflammatory bowel diseases (EO-IBD); 5. inflammatory disorders caused by mutations in proteasome components, the proteasome associated autoinflammatory syndromes (PRAAS) and 6. very rare conditions presenting with autoinflammation and immunodeficiency.

Introduction

The history of “autoinflammatory diseases” dates back to the identification of the genetic causes of the two most prevalent monogenic autoinflammatory diseases worldwide. Mutations in MEFV as the cause of familial Mediterranean fever (FMF) and mutations in TNFRSF1A as the cause of TNF receptor associated periodic syndrome (TRAPS) were identified in 1997 and 1999 respectively [1], [2], [3]. These discoveries have marked the beginning of an exciting journey that led not only to the molecular understanding of previously clinically defined entities, but also to the characterization of novel diseases that were not previously clinically described.

The discovery that gain of function mutations in NLRP3, a component of an IL-1β processing complex, the NLRP3 inflammasome, can cause the spectrum of clinical disorders now called cryopyrinopathies, including familial cold autoinflammatory syndrome (FCAS), Muckle–Wells syndrome (MWS) and neonatal-onset multisystem inflammatory disease (NOMID) also called chronic infantile neurological and articular syndrome (CINCA) led to the hypothesis that the proinflammatory cytokine IL-1β may play an important role in the pathogenesis of these disorders [4]. Early proof of concept studies with the IL-1 blocking agent anakinra (Kineret®) surprisingly showed impressive clinical responses in the patients treated. These studies not only validated the role of IL-1 blockade in these disorders, but also led to the FDA approval of now three IL-1 blocking agents for the treatment of these disorders, the long acting IL-1 blocking agents, rilonacept (Arcalyst®) and canakinumab (Ilaris®) approved in 2008 and 2009, respectively, and the short acting IL-1 inhibitor anakinra (Kineret®) in 2012.

The wider use of IL-1 blocking therapies in other autoinflammatory phenotypes with similarities to the cryopyrinopathies has led to the identification of disorders that respond and those that do not respond to IL-1 blocking therapies and has fueled research in exploring other inflammatory pathways that can lead to autoinflammatory phenotypes [4].

The concept of autoinflammatory diseases was initially proposed to distinguish the then known autoimmune diseases, including systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), disorders that were thought to be caused by adaptive immune dysregulation, from the two hereditary fever syndromes, FMF and TRAPS, that lack features of adaptive immune dysregulation, such as specific autoantibodies and auto-reactive lymphocytes, and were thus suggested to be caused by innate immune defects [5]. This concept has been tremendously successful in promoting the recognition of innate immune pathway dysregulation in the pathogenesis of the expanding spectrum of noninfectious fever syndromes [5]. However, features of innate and adaptive immune dysregulation are present together in a number of disorders, most prevalent in the proteasome-associated disorders that often also present with specific autoantibodies. Moreover, the discovery that SLE, a “classic autoimmune” disease, has immune regulatory defects in the innate immune system, illustrates the overlapping immunological features of some autoinflammatory diseases with the classical autoimmune diseases and vice versa [4], [6].

Any classification of autoinflammatory diseases should be regarded as preliminary, and the complex consequences of the genetic defect associated with the respective diseases are not fully recognized and understood. In a number of diseases, the immune dysregulation is not limited to one cytokine pathway and may vary in different cells.

In this review, we grouped the monogenic autoinflammatory diseases based on easily identifiable clinical criteria that can be elicited from a patient's history and physical exam, taking into account fever patterns, characteristic skin lesions and associated clinical findings (Table 1).

Section snippets

The classic “periodic fever syndromes” presenting with recurrent episodic fevers, non-specific maculopapular rashes and abdominal pain

Among the three disorders, FMF and MVK deficiency/HIDS present with recurrent fever attacks of short duration (< 7 days), while TRAPS presents with fever attacks of longer than 7-day duration that can last up to weeks.

Syndromes presenting with neutrophilic urticaria (the cryopyrinopathies)

The cryopyrinopathies or cryopyrin associated periodic syndromes (CAPS) comprise a clinical continuum of three previously defined diseases: familial cold autoinflammatory syndrome (FCAS), Muckle–Wells syndrome (MWS) and neonatal-onset multisystem inflammatory disease (NOMID) also called chronic infantile, neurological, cutaneous and articular (CINCA) syndrome [86], [87], [88]. Although clinical similarities between these disorders exist, the discovery that these diseases are caused by mutations

Epidemiology and genetics

Pediatric granulomatous arthritis (PGA) (OMIM#186580) is caused by autosomal dominant gain of function mutations in the NACHT domain (exon 4) of NOD2/CARD15 [13], [115]. PGA can be inherited in an autosomal dominant pattern and familial cases have traditionally been called Blau syndrome. However, mutations can occur sporadically and, in these instances, the disease has historically been called early-onset sarcoidosis [116], [117]. The identification of the same mutations led to the recognition

Syndromes presenting with pustular skin rashes and episodic or continuous fever

This group of disorders presents the most pathogenetically heterogeneous group. Although all patients present with pustular skin lesions, the underlying pathogenic mechanism and the other clinical organ manifestations differ between the entities. Treatment is also different among the diseases. While the DIRA and Majeed syndromes present with sterile osteomyelitis that is IL-1 mediated, PAPA syndrome presents with pyogenic arthritis and pustular lesions that rapidly develop into pyoderma

Epidemiology and genetics

In 2010, four patients with early-onset recurrent fever, violaceous cutaneous rash, periorbital edema and erythema, lipodystrophy and increased acute phase reactants were reported and the syndrome was proposed to be called chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) [149]. In 2011, several studies showed that a number of disorders referred to as joint contractures, muscle atrophy, microcytic anemia and panniculitis-induced lipodystrophy (JMP)

Syndromes presenting with autoinflammation and with immunodeficiency

The description of additional monogenic diseases has led to the identification of conditions that present with autoinflammatory phenotypes but also with features of immunodeficiencies. The “mixed phenotype” is determined by the impact the mutation can have in different immune cells. Immunodeficiencies have also been suggested to be present in patients with HIDS and EO-IBD. Two recently described conditions caused by autosomal dominant mutations in PLCG2, PLCγ2-associated antibody deficiency and

Conclusion

The past 15 years were marked by the discovery of monogenic causes for a number of immune dysregulatory disorders, many presenting with fever, systemic and organ specific inflammation. Not only new insights into the genetics and the pathogenesis of these syndromes were gained, but a number of new clinical phenotypes have been described, thus growing the spectrum and heterogeneity of this group of autoinflammatory diseases/phenotypes. The discovery of novel diseases led to the recognition that

Conflict of interest statement

The authors declare that there are no conflicts of interest.

Acknowledgments

Both authors's research is supported by the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health.

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