Elsevier

Clinics in Dermatology

Volume 33, Issue 5, September–October 2015, Pages 520-526
Clinics in Dermatology

Cutaneous manifestations of systemic autoinflammatory disorders

https://doi.org/10.1016/j.clindermatol.2015.05.002Get rights and content

Abstract

Rare systemic autoinflammatory diseases (sAIDs) are driven by cytokine-mediated uncontrolled inflammation that results from activation of innate immune pathways. sAIDs present with recurrent fever episodes, fatigue, musculoskeletal symptoms, gastrointestinal, neurologic, and skin manifestations. They include hereditary monogenic and acquired multifactorial disorders, show a significant morbidity and usually persist for life. Due to the limited awareness of sAIDs, they are often associated with a considerable delay in diagnosis. Within the last decade, the use of cytokine-neutralizing therapies has been shown to improve the clinical symptoms of many patients with different sAIDs. Because skin involvement, such as urticarial, pustular, or ulcerative eruptions, is common in a variety of autoinflammatory disorders, dermatologists should be aware of the most important diseases and their skin phenotypes. This review gives an overview on prototype sAIDs with focus on cutaneous manifestations, clinical clues, and diagnostic approaches. Effective treatment options, such as anti–interleukin-1–targeted therapies, are discussed.

Introduction

Systemic autoinflammatory diseases (sAIDs) are heterogenous chronic disorders, characterized by an abnormal inflammatory phenotype that is mediated via innate immune pathways. As opposed to autoimmune diseases, antigen-specific T cells and autoantibodies are lacking in sAIDs. The term autoinflammatory disease was introduced in 1999 by Mc Dermott et al, following the discovery of the underlying mutation in the tumor necrosis factor receptor-associated periodic syndrome (TRAPS), a rare hereditary inflammatory disease.1 Within the last decade, many new sAIDs have been described; however, disease awareness is still limited, resulting in a diagnostic delay of many years or even decades.2 Delay in diagnosis goes along with considerable quality-of-life impairment and may cause irreversible long-term complications (eg, amyloidosis) and death.3 Typical clinical features of sAIDs include recurrent fever episodes, fatigue, and musculoskeletal, gastrointestinal, neurologic, and skin manifestations. The inflammation in many sAIDs is mediated via an overactive inflammasome and subsequent cytokine release. Both single mutations in inflammasome-related genes and other tissue-specific factors, such as microbes, oxidative stress, and crystals, may account for the uncontrolled inflammasome activation in autoinflammatory disorders.4

Section snippets

Spectrum of autoinflammatory diseases

sAIDs can be divided into hereditary monogenic disorders and multifactorial acquired disorders. Among them are the well-known hereditary periodic fever syndromes (HPFs), characterized by chronic recurrent fever attacks as one of the leading clinical manifestations. HPFs include TRAPS, cryopyrin-associated periodic syndrome (CAPS), mevalonate kinase deficiency (MKD), and familial Mediterranean fever (FMF) (Table 1). Except for FMF, which has a higher prevalence in Eastern Mediterranean

Skin manifestations in autoinflammatory diseases

Cutaneous manifestations are common and may even represent the leading clinical findings in autoinflammatory diseases. Cutaneous findings include urticarial or maculopapular eruptions, pustules, ulcerative lesions (aphthae and pyoderma gangrenosum), and granulomatous and erysipelas-like lesions (Table 2). None of these are specific for any disorder, and the extent of skin involvement varies among patients and diseases.

Cryopyrin-associated periodic Schnitzler's syndrome (CAPS)

CAPS is a very rare hereditary autosomal-dominant disorder with an estimated population frequency of 1 to 3 per million.14 A positive family history can be found in nearly half of patients. Most cases have been reported in Western European countries and North America, but the disease is known in other parts of the world as well.2

Disease pathogenesis in CAPS, a direct inflammasomopathy, is mediated via a gain of function mutation in the gene encoding for nucleotide binding–like receptor protein

Deficiency of the IL-1 receptor antagonist (DIRA)

DIRA is a neonatal-onset autoinflammatory disease that has been reported in very few patients, generally from Europe, the Middle East, North America, and Central America. The disease is caused by homozygous mutations in the IL-1RN gene, which encodes the IL-1 receptor antagonist, a competitor of IL-1β at the IL-1 receptor.26 The mutated IL-1 receptor antagonist cannot bind to the receptor, resulting in loss of its IL-1β inhibitory function.

Clinically, newborns present with localized or

Pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome

PAPA syndrome is another ultra-rare autosomal-dominant disease with about 40 published case reports. The underlying mutation in PSTPIP1 (proline-serine-threonine phosphatase interacting protein 1) enhances inflammasome activation via pyrin that results in caspase-1-driven IL-1β accumulation.28 Patients develop painful sterile pyogenic arthritis, beginning in early childhood. Cutaneous findings include severe nodulocystic acne and painful pyoderma gangrenosum lesions, usually developing during

Diagnostic approach

A diagnosis of autoinflammatory disease is usually made after exclusion of various other inflammatory conditions. Based on the leading clinical findings the differential diagnoses of sAIDs may include autoimmune diseases, infections, and other inflammatory disorders. In patients with recurrent urticarial eruptions, histamine-mediated urticaria would be the most common condition; however, in the presence of systemic symptoms, such as arthralgia and fatigue, urticarial autoinflammatory syndromes

Treatment options

Since the early 1970s, colchicine has been successfully used in the treatment of FMF patients.37 The treatment of other sAIDs has been limited to poorly effective nonsteroidal antiphlogistics and immunosuppressives.

Based on a better understanding of innate immune responses, new treatment options have emerged. For the majority of sAIDs, cytokine-blocking agents have had good efficacy. Clinical trials with IL-1–neutralizing drugs in CAPS have revealed a highly significant improvement of clinical

Conclusions

SAIDs are severe and disabling inflammatory conditions that start in early childhood (eg, CAPS and FMF) or adulthood (eg, AOSD and SchS) and persist for life. If not treated properly, these diseases lead to irreversible long-term complications, including amyloidosis (FMF, CAPS, SchS), hearing loss, and destructive arthropathy (CAPS), as well as malignant lymphoma (SchS).[20], [25], [56] Autoinflammatory disorders are associated with a high burden for patients and society. Although the treatment

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