Autoinflammatory Syndromes: Relevance to Inflammatory Skin Diseases and Personalized Medicine


Disease

Mode of inheritance

Predominant ethnic group

Age at onset

Typical duration of flare

Typical frequency of flares

Typical/distinctive clinical features

Treatment

FMF

AR; rarely AD

Eastern Mediterranean

Childhood to early adulthood

1–3 days

Variable

Colchicine responsiveness

Colchicine

Pseudo-appendicular pain

Anakinra

Erysipelas-like erythema

TRAPS

AD

Northern European; numerous other ethnic groups

Childhood/early adulthood; rarely late onset

>7 days; may be prolonged over many weeks

Variable

Longer duration of attack; migratory myalgia with erythema; periorbital edema

Steroids on demand

Etanercept

MVK deficiency/HIDS

AR

Northern European

Infancy

3–7 days

1–2 monthly

Palpable lymph nodes; diarrhea; triggered by vaccinations

Steroids on demand

Anti-TNF

Anti-IL-1

FCAS

AD

Northern European

Childhood

24 h

Depends on exposure to cold

Triggered by exposure to cold

Cold avoidance

Neutrophilic urticarial dermatosis

Anti-IL-1

Conjunctivitis

Thirst and transpiration

Spectacular response to anakinra

MWS

AD

Northern European

Neonatal/infancy

Continuous; worse in the evening

Often daily

Neutrophilic urticarial dermatosis

Anti-IL-1

Hearing loss

Spectacular response to anakinra

CINCA

Sporadic

Northern European

Neonatal/infancy

Continuous

Continuous

Neutrophilic urticarial dermatosis

Anti-IL-1

Dysmorphia

Aseptic meningitis

Deforming arthropathy

Spectacular response to anakinra

PAPA

AD

Northern European

Childhood

Intermittent

Variable

Pathergy

Anti-TNF

Notion of familial pyoderma gangrenosum

Anti-IL-1

Migratory arthritis in early childhood

DIRA

AR

Newfoundland; Brazil; Lebanon; Puerto Rican, Dutch

Neonatal/infancy

Continuous

Continuous

Pustules

Anti-IL-1

Osteolytic bone lesions

Spectacular response to anakinra

CANDLE

AR

Japan

Infancy

Continuous

Continuous

Exacerbated in winter

No efficient treatment known

Plaques with atypical myeloid infiltrate

Pernio-like lesions

Lipoatrophy

Basal ganglia calcification

Blau syndrome

AD

Not known

Childhood

Continuous

Continuous

Granulomatous dermatitis

Steroids

Uveitis

Anti-TNF


FMF familial Mediterranean fever, TRAPS TNF-receptor-associated periodic syndrome, MVK mevalonate kinase, HIDS hyper-IgD syndrome, FCAS familial cold autoinflammatory syndrome, MWS Muckle-Wells syndrome, CINCA chronic infantile neurological and articular, PAPA pyogenic sterile arthritis, pyoderma gangrenosum, and acne, DIRA deficiency of interleukin-1 receptor antagonist, CANDLE chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature



An AIS should be suspected in every patient with otherwise unexplained recurrent flares of inflammation with or without fever. Age of onset, type of involvement, and duration of the attacks will help establishing a correct diagnosis (Table 7.1). In this author’s experience, a significant number of patients have however all the characteristics of a typical AIS, but they do not fit into established nosology, as the whole spectrum of these disorders is so far not delineated and new entities are regularly reported and mutations in new genes described.

We shall only briefly describe the cutaneous findings of some of these disorders, especially those that are clearly IL-1 mediated [4]. This will allow us to draw conclusions that we can apply to the much commoner complex polygenic disorders.


7.2.1 Clearly IL-1-Mediated AIS: IL-1 Is the Only or Main Pathogenic Factor



7.2.1.1 Excessive IL-1 Production: Cryopyrinopathies or Cold-Induced Autoinflammatory Syndromes (CAPS)


They include three, partially overlapping autosomal dominant entities related to mutations in the same NLRP3/CIAS1 gene: familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and chronic infantile neurological and articular (CINCA)/neonatal onset multi-inflammatory disorder (NOMID) [3, 4]. Within the CAPS spectrum, FCAS is the least severe entity, while CINCA is the most severe.

A closely related syndrome to the milder FCAS/MWS variants was described in patients with a NLRP12 mutation [6].

The three disorders usually start in the newborn or during early infancy with fever, fatigue, a flu-like syndrome, and rash. The flares are triggered by exposure to cold in FCAS – after an interval of 1–2 h – and are accompanied by thirst, transpiration, joint pain, and conjunctivitis. Cold-stimulation tests (ice cube, immersion) can be negative, as ventilated cold is the usual trigger. Cold dependency of flares is less marked in MWS, but this disorder is more severe and patients develop sensorineural hearing loss and they are at risk of AA amyloidosis.

Continuous flares with neutrophilic aseptic meningitis, dysmorphism, mental retardation, sensorineural deafness, and deforming arthropathy characterize CINCA, a very severe disorder. Diagnosis is based on typical clinical and biological findings; evidencing an autosomal dominant mutation in NLRP3/CIAS1 gene is helpful, but the mutation will not be present in all patients.


Skin Findings and Histopathology

Neutrophilic urticarial dermatosis (NUD; see also below) is the classic cutaneous manifestations in those children [7, 8]. An urticarial rash with a neutrophilic intravascular, perivascular, perieccrine, and interstitial infiltrate on histopathologic evaluation is typical. In this author’s experience, leukocytoclasia is frequent in patients with NUD in the context of Schnitzler’s syndrome (see below) but much less so in children with CAPS.


7.2.1.2 Deficient IL-1 Inhibition: Deficiency of Interleukin-1 Receptor Antagonist (DIRA)


DIRA is suspected in every newborn with a pustular dermatitis, multifocal osteomyelitis, and periostitis with marked elevation of acute phase reactants though fever is only low grade or absent. Pustules are aseptic. Chronic lung disease, respiratory distress syndrome, and central nervous system vasculitis were rarely described. Fatal evolution is reported [9, 10]. Diagnosis relies on clinical and radiological findings (widened rips and clavicles, osteolytic lesions of long bones) and is supported by evidencing an autosomal recessive loss-of-function mutation in IL-1Rn gene [9].


Skin Findings

Grouped pustules on an erythematous base in the newborn or within the first 3 weeks and evolution toward yellowish crusts [9, 11]. The lesions can be localized or widespread, including face and scalp involvement. Bullae with hypopyon can be present. Evolution toward ichthyosiform lesions with diffuse desquamating scaly and sometimes slightly red skin can occur [12]. Oral mucosa and nail can be affected, with pitting and onychomadesis.


Histopathology

Epidermal spongiosis and acanthosis and most notably a neutrophilic infiltrate of the epidermis, with intracorneal, subcorneal, and intraepidermal microabscesses, as well as a neutrophilic infiltrate in the dermis and the perifollicular and perieccrine areas [9, 11]. Neutrophilic syringotropism could be a distinctive feature [12], and this latter finding is also found in CINCA syndrome [8].


7.2.2 AIS in Which IL-1 Plays an Important Role, but Other Factors Are Involved



7.2.2.1 Familial Mediterranean Fever (FMF)


The disease usually starts before the age of thirty with recurrent flares of fever; abdominal pain, sometimes mimicking an acute abdomen; pleurisy; and large joint arthritis that last between 1 and 3 days. The major risk is the development of inflammatory AA amyloidosis, and this risk can be largely prevented with continuous treatment with colchicine. Diagnosis is supported by evidencing a pathogenic autosomal recessive MEFV gene mutation (rare dominant variant exist); diagnosis is based on the Livneh criteria [13].


Typical Skin Findings

The most typical cutaneous finding is the so-called erysipelas-like erythema [14, 15]. It consists of a red edematous, warm, swollen erythema, more often than a circumscribed plaque. The erythema is usually localized on the lower limbs below the knee, typically in the perimalleolar area or the dorsum of the foot.


Histopathology

A sparse neutrophilic infiltrate in the upper dermis is the hallmark of the erysipelas-like erythema [14, 15]. Leukocytoclasia can be present but no significant vasculitis. Histiocytes and eosinophils can also be present.


7.2.2.2 Pyogenic Sterile Arthritis, Pyoderma Gangrenosum, and Acne (PAPA) Syndrome


Early-onset childhood flares of recurrent painful sterile arthritis, sterile abscesses, and pathergy are typical. By puberty, joint symptoms tend to subside, while skin symptoms increase. Diagnosis is established on grounds of clinical history and finding an autosomal dominant mutation in PSTPIP1 [16].


Skin Findings

Pathergy and aseptic abscesses, as well as ulcerations related to pyoderma gangrenosum, can occur from childhood on. Gingival pustules can also occur from childhood on [16]. By puberty, severe nodulocystic acne develops. PAPA should be considered in every patient with a familial history of pathergy and/or pyoderma gangrenosum.

Hidradenitis suppurativa can also develop and has been reported in a patient with a novel PSTPIP1 mutation; authors then called this expanded entity PAPASH [17]. A related entity referred to as “PASH syndrome” has been described [18]. These patients lack the sterile arthritis, but they have nodulocystic acne and pyoderma gangrenosum; in addition, they develop hidradenitis suppurativa. The underlying genetic abnormality is so far unknown.


Histopathology

There are no specific histopathological findings reported so far.



7.3 Pathophysiology


CAPS are related to mostly missense mutations in the NLRP3/CIAS1 gene encoding a death domain protein known as NLRP3 (or cryopyrin). This protein is expressed in the epithelial cells of the skin and the mucosa, the granulocytes, the dendritic cells, and the T and B cells. A variety of danger signals, including “pathogen-associated molecular pattern” (PAMP), induce association of NLRP3 with other members of the death domain superfamily to form a cytosolic protein complex named the “inflammasome.” This results in activation of caspase 1 which cleaves biologic inactive pro-IL 1β into biologic active IL-1β [3, 4]. It also upregulates NF-κB expression and thereby increases IL-1 gene expression. IL-1 is a major proinflammatory cytokine and the key mediator of the manifestations of CAPS. This assumption is supported by the observation that IL-1 blockade induces rapid and complete response in patients with CAPS.

DIRA is related to a deficiency of the naturally occurring antagonist of the IL-1 receptor (IL-1Rn) [9, 11]. The result is an excess in IL-1-mediated inflammation, by lack of inhibition of (initially) normally produced IL-1.

The pathophysiology of FMF is less clear. FMF is usually an autosomal recessive disorder related to mutations in the MEFV gene, though rare dominant mutations exist [19]. MEFV encodes pyrin, which plays probably an important role in the modulation of caspase 1 and thus the production of IL-1.

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May 5, 2016 | Posted by in Dermatology | Comments Off on Autoinflammatory Syndromes: Relevance to Inflammatory Skin Diseases and Personalized Medicine

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