Cutaneous manifestations of systemic autoinflammatory disorders
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
References (56)
- et al.
Germline mutations in the extracellular domains of the 55 kDa TNF receptor, TNFR1, define a family of dominantly inherited autoinflammatory syndromes
Cell
(1999) - et al.
PSMB8 encoding the beta5 i proteasome subunit is mutated in joint contractures, muscle atrophy, microcytic anemia, and panniculitis-induced lipodystrophy syndrome
Am J Hum Genet
(2010) - et al.
Prevention of cold-associated acute inflammation in familial cold autoinflammatory syndrome by interleukin-1 receptor antagonist
Lancet
(2004) - et al.
Familial cold autoinflammatory syndrome: Phenotype and genotype of an autosomal dominant periodic fever
J Allergy Clin Immunol
(2001) - et al.
Genetic predisposition (NLRP3 V198 M mutation) for IL-1-mediated inflammation in a patient with Schnitzler syndrome
J Allergy Clin Immunol
(2010) - et al.
Schnitzler syndrome: Beyond the case reports: Review and follow-up of 94 patients with an emphasis on prognosis and treatment
Semin Arthritis Rheum
(2007) - et al.
A novel mutation in the interleukin-1 receptor antagonist associated with intrauterine disease onset
Clin Immunol
(2012) - et al.
Monogenic autoinflammatory diseases: Concept and clinical manifestations
Clin Immunol
(2013) - et al.
Effects of interleukin-1 blockade with anakinra on aerobic exercise capacity in patients with heart failure and preserved ejection fraction (from the D-HART pilot study)
Am J Cardiol
(2014) - et al.
Complete remission in 3 of 3 anti-IL-6-treated patients with Schnitzler syndrome
J Allergy Clin Immunol
(2012)
An international registry on autoinflammatory diseases: The Eurofever experience
Ann Rheum Dis
Natural history and outcome in systemic AA amyloidosis
N Engl J Med
The NLR network and the immunological disease continuum of adaptive and innate immune-mediated inflammation against self
Semin Immunopathol
Adult Still's disease: A multicenter survey of Japanese patients
J Rheumatol
Adult onset Still's disease and viral infections
Ann Rheum Dis
Association between HLA-DR B1 and clinical features of adult onset Still's disease in Korea
Clin Exp Rheumatol
Crystals of monosodium urate monohydrate enhance lipopolysaccharide-induced release of interleukin 1 beta by mononuclear cells through a caspase 1-mediated process
Ann Rheum Dis
Activation of the NLRP3 inflammasome by islet amyloid polypeptide provides a mechanism for enhanced IL-1 beta in type 2 diabetes
Nat Immunol
The NLRP3 inflammasome in Alzheimer's disease
Mol Neurobiol
Interleukin-1 beta-driven inflammation promotes the development and invasiveness of chemical carcinogen-induced tumors
Cancer Res
Cold urticaria, immunodeficiency, and autoimmunity related to PLCG2 deletions
N Engl J Med
Mutations in the autoinflammatory cryopyrin-associated periodic syndrome gene: Epidemiological study and lessons from 8 years of genetic analysis in France
Ann Rheum Dis
Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle-Wells syndrome
Nat Genet
How not to miss autoinflammatory diseases masquerading as urticaria
Allergy
De novo CIAS1 mutations, cytokine activation, and evidence for genetic heterogeneity in patients with neonatal-onset multisystem inflammatory disease (NOMID): A new member of the expanding family of pyrin-associated autoinflammatory diseases
Arthritis Rheum
Efficacy and safety of anakinra therapy in pediatric and adult patients with the autoinflammatory Muckle-Wells syndrome
Arthritis Rheum
Schnitzler's syndrome: Diagnosis, treatment, and follow-up
Allergy
Dysfunctional inflammasome in Schnitzler's syndrome
Rheumatology
Cited by (6)
State of care for patients with systemic autoinflammatory diseases – Results of a tertiary care survey
2019, World Allergy Organization JournalCitation Excerpt :Patients with SAIDs presenting at the skin (e.g. urticarial, pustular or ulcerative lesions) often show neutrophil-rich dermal infiltrates upon skin biopsy. Although these findings are non-specific, they may guide the differential diagnosis and exclude other diseases with similar cutaneous phenotype.15,16 Dermatologists performed this procedure most frequently (59.3%), followed by rheumatologists (13.9%) and pediatricians (1.2%).
The skin as a target organ in multisystemic diseases II
2015, Clinics in DermatologyCitation Excerpt :In considering systemic disease concepts, the authors stress the role of self-antigens on the surface of basal keratinocytes that are believed to be the targets of the systemic T-cell response. Bölükbasi and Krause review the cutaneous involvement in different autoinflammatory syndromes.3 These syndromes present with recurrent fever episodes, fatigue, musculoskeletal findings, and gastrointestinal, neurologic, and skin manifestations.
Dermatologic and dermatopathologic features of monogenic autoinflammatory diseases
2019, Frontiers in Immunology