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Abstract
The emerging group of autoinflammatory diseases (AIDs) is caused by a dysregulation of the innate immune system while lacking the typical footprint of adaptive immunity. A prominent subgroup of AIDs are inflammasomopathies, which are characterised by periodic flares of cutaneous signs as well as systemic organ involvement and fever. The range of possible skin lesions is vast, ranging from urticarial, erysipelas-like and pustular rashes to erythematous patches, violaceous plaques and eventual necrosis and ulceration. This review provides a structured overview of the pathogenesis and the clinical picture with a focus on dermatological aspects of inflammasomopathies. Current treatment options for these conditions are also discussed.
- cryopyrin-associated periodic syndromes
- familial Mediterranean fever
- inflammation
- cytokines
- immune system diseases
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- cryopyrin-associated periodic syndromes
- familial Mediterranean fever
- inflammation
- cytokines
- immune system diseases
Introduction
The skin is not only our outermost protection layer against pathogens and environmental factors; it also mirrors the health status of internal organs. Therefore, examination of the skin helps physicians in the assessment of patients with systemic diseases. Autoinflammatory syndromes are defined by a hyperactive innate immune system and commonly reveal cutaneous lesions early in the disease course. While certain signs and symptoms may direct experienced physicians towards the correct diagnosis, the large pattern variability and overlap with other conditions present a significant challenge. It is important for dermatologists and physicians of other specialties dealing with autoinflammatory syndromes to be aware of the possible skin manifestations. This comprehensive review discusses the range of cutaneous signs visible in inflammasomopathies with reference to the causative molecular mechanisms.
Cutaneous signs observed in AIDs
Autoinflammatory diseases (AIDs) were initially introduced in 1990.1 These conditions show signs of harmful inflammatory processes although lacking the typical footprint of the adaptive immune system seen in autoimmune diseases. Manifold genetic aberrations have been described as underlying factors leading to overshooting innate immune responses that potentially damage cells in many tissues. Frequently, signs of this hyperactivated immune system appear on the skin accompanied by systemic symptoms such as fever or fatigue. Careful clinical evaluation of the morphology, pattern, localisation, onset, duration and the possible triggers of the cutaneous lesions may steer physicians to a specific diagnosis of autoinflammation. A wide range of lesions has been described in autoinflammatory syndromes; an effort of classifying cutaneous signs of monogenic AID resulted into nine distinct categories, including non-specific maculopapular rashes, neutrophilic urticaria, pustular skin rashes and panniculitis, as well as different vasculopathies, disorders with hyperkeratotic and pigmented skin lesions, and lastly also bullous and aphthous lesions (online supplemental table 1).2 The various differences in the histopathological evaluation are summarised in online supplemental table 2.
Supplemental material
Supplemental material
Inflammasomopathies
The inflammasome is considered a central player in the regulation of immune responses.3 As one of the main defenses against intracellular danger signals, distinct types of inflammasomes with various activators and mediators have been identified (figure 1). The main building blocks of the different forms of inflammasomes are largely similar. Sensors, often pattern recognition receptors, initially detect potential pathogenic signals. They connect with or without an adaptor, for example apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), to the effector molecule, mainly caspase-1. The activated effector molecule then splices procytokines, such as interleukin-1β (IL-1β) and IL-18, into their active forms.4 5 Furthermore, a lytic programmed cell death called pyroptosis can be triggered by the inflammasome.5–7
Inflammasomopathies. The inflammasome is a defensive mechanism of many innate immune cells (macrophages, monocytes, neutrophils, basophils and dendritic cells are shown in the upper left panel). The differences in the inflammasome’s building blocks and the main product (interleukin) of each AID are listed in the midsection of the figure. NRLP3 forms the canonical inflammasomes by interacting with the adapter molecule ASC and the effector molecule pro-caspase-1. Exemplary mechanism of NLRP3 is shown in the upper right panel. The priming signal (signal 1) can be delivered by various receptors, such as members of the toll-like receptors (mostly known via TLR4), the TNF receptor family and the IL-1 receptor family. Priming of the NLRP3 through other means (eg, via post-translational modulation) is not shown. Signal 1 induces the cellular upregulation of NLRP3, de novo protein synthesis, as well as the transcription of procytokines (especially pro-IL-1β) by NF-κB-mediated signalling pathways. Signal 2 includes various stimuli-like PAMPs or DAMPs but can also include ROS, mitochondrial dysfunction, ATP or ion influx, sensed by NLRP3. This activates the assembly of the proteins needed for an active inflammasome. Nek-7 bridges the gap between the NLRP3s and mediates the oligomerisation process. After ASCs connects to the card domain of the procaspases, it auto-proteolyzes into the p10 and p20 subunits. The active caspase-1 then cleaves procytokines of the IL-1 family (mainly pro-IL-1β, pro-IL-18) in their active form and GSDM in GSDM [C] and GSDM [N]. GSDM [N] oligomerises and forms pores in the membrane. IL-1β and IL-18, as well as GSDM [C] can be excreted through GSDM dependent and independent pores. Pores made by the GSDM [N] can lead to a cell death called pyroptosis. Gasdermin D can also be activated by the non-canonical pathway through caspase-4 or caspase-5, leading to pyroptosis. The non-canonical activation cascade is not shown. PSTPIP1, WDR and MVK-associated autoinflammatory disease indirectly influence the pyrin inflammasome, leading to an activation of the pyrin inflammasome. AIDs, autoinflammatory diseases; ASC, apoptosis-associated speck-like protein containing a caspase recruitment domain; DAMPs, damage-associated molecular patterns; GSDM, gasdermin D; GSDM [C], C-terminal fragment; GSDM [N], N-terminal fragment; IL, interleukin; PAMPs, pathogen-associated molecular patterns; ROS, reactive oxygen species.
IL-1β is central to the innate immune system as it induces further expression of proinflammatory cytokines, drives the fever response, prostaglandin synthesis, tissue infiltration and activation of various immune cells as well as Th17 differentiation.8 9 IL-18 induces the expression of interferon-gamma, thus influencing the adaptive immune system without inducing fever.10 When caspase-1 cleaves gasdermin D, a molecule involved in pyroptosis, rapid rupture of the plasma membrane commences, releasing the intracellular contents of the cell, which in turn stimulate neighbouring cells.11 These actions secure clearance of pathogens, making the inflammasome a critical regulator of the inflammatory reaction against potentially pathogenic endogenous and exogenous stressors such as microbes, viruses, fungi or parasites. It is obvious that alteration of this delicate process, for example through the chronic activation of the inflammasome, can result in an inflammatory state with distinct clinical signs and symptoms, culminating in organ damage.
The NLRP3 inflammasome-associated autoinflammatory disease
NLRP3 (NOD-containing, LRR-containing and pyrin domain-containing protein 3 or Nod-like receptor protein 3) acts as the sensor of the prototypic inflammasome complex, the NLRP3 inflammasome.3 Gain of function mutations of NLRP3 drive the group of AIDs termed cryopyrin-associated periodic syndrome (CAPS).12 13 CAPS is a rare, autosomal dominant genetic disorder with a prevalence of 2.8 cases per 1 million people.14 It refers to three clinical entities with a continuous severity spectrum and considerable overlap: familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS) and neonatal-onset-multisystem inflammatory disease (NOMID; also known as chronic infantile neurological cutaneous articular syndrome, CINCA) (figure 2-1).15 Another AID involving the NLRP3 inflammasome is Majeed syndrome with an estimated prevalence of <1–2 cases per 1 million. It is caused by a loss of function mutation in the gene coding for lipin-2, a protein involved in the regulation of fat metabolism inside cells and a known regulator of the NLRP3 inflammasome.16 17
Cutaneous signs of NLRP3-associated inflammasomopathies CAPS (1). Three clinical entities with a continuous clinical severity spectrum and considerable overlap: FCAS (mild), MWS (intermediate), NOMID/CINCA (severe). Cold-induced, non to mildly-pruritic urticaria-like rash consisting of flat wheals in symmetrical distribution, involving the trunk and/or extremities, in children sometimes also the face (B, back view; F, front view). Majeed syndrome (2). Pallor due to anaemia and Sweet-like skin lesions (dull red, raised, painful, itchy plaques with 0.5–4 cm in diameter, central depression and yellow crusts due to serosanguineous discharge, commonly studded with vesicles and pustules) on the face, trunk and extremities, palms and soles usually spared (B, back view; F, front view). Pustules and pustular psoriasis (B). CINCA, chronic infantile neurological cutaneous articular syndrome; FCAS, familial cold autoinflammatory syndrome; MWS, Muckle-Wells syndrome; NOMID, neonatal-onset-multisystem inflammatory disease.
Familial cold autoinflammatory syndrome (FCAS)
FCAS, the mildest form of CAPS, has its onset in infancy, rarely in childhood or adolescence.14 It is characterised by recurrent episodes of urticarial rashes, fever and arthralgia triggered by cold exposure.18 An urticarial rash 1–2 hours after cold exposure is one of the first signs of a flare-up, commonly followed by low-grade fever and arthralgia 4–6 hours later. Leucocytosis appears in laboratory evaluation after about 10 hours. Additional findings include conjunctivitis, malaise, fatigue, myalgia, headache, high levels of C reactive protein (CRP) and serum amyloid A (SAA), as well as an increase in erythrocyte sedimentation rate (ESR). Attacks are usually self-limited and resolve within 12–24 hours.19
Cutaneous signs
FCAS is characterised by a cold-induced, non to mildly-pruritic urticaria-like rash consisting of flat wheals (figure 2-1). In adults, the lesions tend to be symmetrically distributed involving the trunk and/or extremities but usually sparing the head. In children, the rash is commonly more widespread, sometimes even involving the face. Contrarily to classical cold urticaria, direct contact with a cold object does not trigger a flare-up, hence the ice cube test is negative.2 20
Muckle-Wells syndrome (MWS)
MWS is characterised by a triad of urticaria, deafness, and rarely also amyloidosis.21 It is more severe than FCAS but milder than NOMID/CINCA. The age of onset is typically in infancy.12 22 Flares are triggered by cold and hot temperatures, stress, physical exercise or occur without an identifiable trigger and typically resolve spontaneously.19 23 They usually occur weekly and last 12–36 hours causing an urticaria-like rash, fever, malaise, headache, arthralgia or conjunctivitis. In a subset of patients, more serious long-term complications such as progressive sensorineural hearing loss and AA amyloidosis may develop.22 Laboratory findings include leucocytosis, and elevated levels of inflammatory markers and SAA.
Neonatal-onset-multisystem inflammatory disease (NOMID)/chronic infantile neurological cutaneous articular syndrome (CINCA)
NOMID, also known as CINCA, is the most severe form of CAPS. It usually presents shortly after birth with an urticarial rash and a chronic state of inflammation. It shows frequent flare-ups occurring randomly or triggered by cold temperatures.13 25 Clinical features include a maculopapular rash and/or urticarial lesions, fever, malaise, lymphadenopathy, splenomegaly, headache, aseptic meningitis, cognitive deficits, sensorineural hearing loss, papilledema, conjunctivitis, uveitis, AA amyloidosis, impaired growth and arthropathy. Affected individuals exhibit characteristic facial features, such as frontal bossing, saddle nose deformity and exophthalmos. If left untreated, NOMID is fatal in 30% of cases.26–29 Laboratory findings include leucocytosis, eosinophilia, anaemia, coagulopathy, an increase in ESR, and elevated CRP and SAA levels.19 30 31
Cutaneous signs
Patients usually present with a permanent, non-pruritic maculopapular and/or urticarial rash shortly after birth which intensifies during flare-ups (figure 2-1). The distribution of the rash underlies temporal changes occurring throughout the day.20 25 32 33
Treatment
IL-1β plays a pivotal role in the pathogenesis CAPS, thus agents interfering with this cytokine are commonly used in clinical practice. Canakinumab, an anti-IL-1β monoclonal antibody showed rapid and sustained treatment response in a randomised controlled trial including patients with CAPS.34 35 Other trials confirmed the efficacy of canakinumab in patients with CAPS.36–38 Anakinra,30 39 an IL-1 receptor antagonist and rilonacept,40 41 an IL-1 trap, also yielded high efficacy in clinical trials.
Majeed syndrome
Lipin-2 is an enzyme which gained interest as a potential target for lipodystrophies or hypertriglyceridaemia as it plays a role in the development of adipose tissue and metabolism of triglycerides.42 43 Lipin-2, coded by LPIN2 on chromosome 18, is abundant in the liver, in granulocytes and macrophages, the central nervous system and the gastrointestinal tract and catalyses the conversion between phosphatidic acid (PA) and 1,2,-diacylglycerol (DAG).44 PA and DAG are two lipids highly relevant for the generation of glycerophospholipids needed in the biogenesis of the cell membrane.45–47 In the immune system, lipin-2 is known to control proinflammatory signalling initiated by high levels of saturated fatty acids and additionally influences the NLRP3 inflammasome through restricting the signalling cascade initiated by TLR4 (figure 1 (signal1)) and the ATP receptor P2×7R (figure 1 (signal2)).48 Majeed syndrome is a monogenic, autosomal recessive disease caused by the loss of function of lipin-2 which leads to a chronic autoinflammatory state.16 17 49
Onset of Majeed syndrome is in infancy with recurrent episodes of fever, Sweet-like skin lesions, chronic recurrent multifocal osteomyelitis (CRMO) and dyserythropoitic, hypochrome, microcytic anaemia. Hepatosplenomegaly is another possible finding.50 Disease flares usually last for 2–4 days and occur 1–4 times per month.51 52 The trigger for attacks is unknown. CRMO bone inflammation can lead to severe arthralgia, joint swelling, joint deformities and slow growth. Due to the anaemia, patients suffer from fatigue, weakness, shortness of breath and a pale skin. Apart from anaemia, laboratory studies show high ESR and sometimes leucocytosis. Cultures of blood, bone and pustular lesions are negative for bacteria of fungi.50 51
Cutaneous signs
Besides pallor due to anaemia, some patients present with dull red, raised, painful, itchy plaques with 0.5–4 cm in diameter, central depression and yellow crusts due to serosanguineous discharge resembling Sweet-like skin lesions (figure 2-2). The surface of these lesions is commonly studded with vesicles and pustules. Lesions develop on face, trunk and extremities. The palms and soles are usually spared.50 Lesions resembling pustules and pustular psoriasis have also been observed.16
Treatment
The treatment of Majeed syndrome—given its low prevalence—remains empiric. Anakinra and canakinumab led to a marked clinical and laboratory improvement in a case report of two patients who failed to respond to the TNF-α inhibitor etancercept and corticosteroids.53 Other case reports support the finding of a good response to anti-IL-1 treatment as opposed to TNF-α inhibition.49
The NLRC4 inflammasome-associated autoinflammatory disease
NLRC4-associated autoinflammatory disease (NLRC4-AD) encompasses a spectrum of autoinflammatory entities with the milder form, FCAS4 at one end and the life-threatening form, autoinflammation with infantile enterocolitis (AIFEC) on the other (figure 3). These monogenic entities are caused by a mutation in the NLRC4 gene with an autosomal-dominant inheritance pattern.54–56
Cutaneous signs of NLRC4-associated inflammasomopathies. NLRC4-MAS/AIFEC. Wide range of possible lesions: evanescent, urticaria-like rashes with dermographism (A), urticaria-like rashes evolving into ecchymosis (B) and petechiae (C), and maculopapular skin rashes resolving and being replaced by a reticulo-liveoid rash (D). Lesions occur on face, trunk, arms and legs. Other possible lesions include perianal (E) and facial abscesses (not shown) and itchy nodules (not shown) (B, back view; F, front view). FCAS4 not shown. AIFEC, autoinflammation with infantile enterocolitis; FCAS, familial cold autoinflammatory syndrome; NLRC4-MAS, NLRC4-associated macrophage activation syndrome.
Familial cold autoinflammatory syndrome 4 (FCAS4)
FCAS4 is a rare disease with symptoms similar to the FCAS (CAPS). Only two families have been reported.56 57 In most cases, FCAS4 first presents during infancy with recurrent episodes of fever, skin rashes, conjunctivitis, arthralgia and myalgia. Common triggers for flare-ups include cold exposure, change in weather, infection and emotional stress.56 57 Flares occur between 2 and 60 times per year. The duration of flares has not been reported in medical literature yet. In laboratory studies, ESR and levels of CRP, IL-1β and IL-18 are increased.56 57
Cutaneous signs
Skin manifestations in FCAS4 are age-dependent and present in paediatric patients with a non-itching urticarial rash. Adults often show painful erythematous nodes on the lower extremity. Those nodes can occur isolated or in combination with non-itching urticarial patches on the face, trunk, arms and legs.56 57
Treatment
In a case series, anakinra exhibited varying degrees of treatment response ranging from lack of treatment effect to complete remission.57
NLRC4-associated macrophage activation syndrome (NLRC4-MAS)/autoinflammation with infantile enterocolitis (AIFEC)
NLRC4-MAS is a rare disease with less than 15 reported patients.54 55 58–62 The first signs and symptoms usually manifest in the neonatal period. Clinically, it presents as recurrent bouts of fever, enterocolitis with loose stools up to bloody diarrhoea and vomiting, a wide range of different cutaneous manifestations, hepatosplenomegaly and lymphadenopathy. Flares can last up to several weeks and were reported to recur up to 11 times in 6 months.59 62 Disease episodes can be triggered by upper respiratory tract infections, minor surgery, physical stressors and emotional stress.54 59 If left untreated, life-threatening multiorgan failure including renal failure, respiratory distress syndrome and disseminated intravascular coagulopathy can occur.54 55 Enterocolitis was reported to subside after the first year of life.54 Serum IL-18 remains highly elevated independent of treatment and even during interictal periods. Other laboratory findings include pancytopaenia (anaemia, thrombocytopaenia, leucopaenia), elevated levels of transaminases, hyperferritinaemia, hypertriglyceridaemia, hypofibrinaemia and elevated levels of CRP, IL-1β and IL-2R as a sign of MAS.54 55 61 Leucocytosis was described as well.60 Despite inflammation, ESR is only initially increased and paradoxically decreases despite systemic inflammation due to hypofibrinemia in MAS.25 60
Cutaneous Signs
Skin manifestations cover a wide range of lesions (figure 3). Reported lesions include evanescent, urticaria-like rashes with dermographism, urticaria-like rashes evolving into petechiae and ecchymosis, as well as maculopapular skin rashes which may resolve and be replaced by a reticulo-liveoid rash. Common sites of involvement are the face, trunk, arms and legs.55 58 61 Other manifestations include perianal and facial abscesses, as well as erythematous, itchy nodules.59 60
Treatment
Treatment with recombinant human IL-18BP (rhIL-18BP) has been used successfully in case reports.62 Other less effective treatment options include corticosteroids, anakinra, infliximab (TNF-α inhibitor), ciclosporin, vedolizumab (anti-integrin α4β7 antibody), colchicine, and emapalumab (anti-IFNγ antibody).55 62 63
The pyrin inflammasome-associated autoinflammatory disease (PAAD)
Besides NLR-associated inflammasomes, other proteins are known to form inflammasome platforms. Among those proteins is pyrin, which is abundant in neutrophils and monocytes/macrophages.44 64 Pyrin acts as an indirect sensor for the inflammasome making use of a family of molecular switches, namely, RhoA-C GTPases. These GTPases cycle between ‘Off’’ (GDP-bound) and ‘On’ (GTP-bound) states, which changes their affinity for protein binding.65 Through this mechanism, they regulate multiple processes, such as cytoskeleton dynamics, cell cycle, phagocytosis and immune cell signalling, and are often targeted by invading bacteria (eg, Enterohemorrhagic Escherichia coli, Clostridium difficile, Yersinia species), parasites and viruses.66–69 Since the pyrin inflammasome is known to be influenced by various factors, there are multiple ways in which disturbances can lead to its overactivation, elevated production of IL-1β and IL-18, pyroptotic activity, and ultimately to clinically distinct autoinflammatory conditions.70
The most prominent disease in this AID family is familial Mediterranean fever (FMF) with thousands of known cases worldwide. FMF as well as the pyrin-associated autoinflammation with neutrophilic dermatosis (PAAND) are caused directly by the mutation of the MEFV gene, which encodes pyrin.71 72 Mutations influencing the pyrin inflammasome indirectly include PAPA (pyogenic arthritis, pyoderma gangrenosum, acne)73 and PAMI (proline–serine–threonine phosphatase-interacting protein 1 (PSTPIP1)-associated myeloid-related proteinaemia inflammatory syndrome),74 as well as PFIT (autoinflammatory periodic fever, immunodeficiency and thrombocytopaenia)75 and the mevalonate kinase deficiencies (MKDs) HIDS (hyperimmunoglobulinaemia D with periodic fever syndrome)76 and MA (mevalonic aciduria).77 Maculopapular rashes or inflammatory plaques, as well as acne, ulcers or pyoderma gangrenosum are cutaneous signs often associated with the dysregulation of the pyrin inflammasome (figures 4 and 5).
Cutaneous signs of FMF. Mostly well-defined erysipelas-like skin lesions (A, B) on the lower extremity (B, back view; F, front view). Rare skin manifestations: pruritic urticarial lesions (C), scattered pruritic papules (D), palmoplantar erythema and Raynaud-like lesions (E) and vasculitis (not shown). FMF, familial Mediterranean fever.
Cutanenaous signs of PSTPIP1-associated inflammatory diseases PAPA. Sterile abscesses (A, B), severe cystic acne (A, B) and deeply erythematous and violaceous papules (B) and ulcerated plaques (B, C) on the scalp, face, trunk and legs. A detailed case report of this patient was published by Geusau et al. 105 Biopsy reveals dilated follicular ostia studded with neutrophils. The surrounding dermis also shows an infiltrate mainly consisting of neutrophils (D). PAMI not shown. PAMI, PSTPIP1-associated myeloid-related proteinaemia inflammatory syndrome; PAPA, pyogenic arthritis, pyoderma gangrenosum, acne; PSTPIP1, proline–serine–threonine phosphatase-interacting protein 1.
Familial Mediterranean fever (FMF)
FMF is most prevalent in the Mediterranean area (eg, Turkey, Armenia) with 1–9 cases per 1000 people. Most patients show biallelic mutations on exon 10 in the region encoding for pyrin.78 79 FMF is usually diagnosed in adolescence with a mean age of 14 years showing recurrent attacks of fever, an erysipelas-like rash, abdominal pain (peritonitis), chest pain (pleuritis, pericarditis), joint pain (monarthritis), exertional myalgia and/or headache.80–82 AA amyloidosis, a long-term sequelae due to chronic inflammation, is a major cause of mortality.83 Several triggers like cold exposure, emotional stress, exhaustion, long-duration travel, exercise, infection, surgery, menstruation and intrauterine devices have been described.80 84 Flares usually last for 1–3 days and recur in intervals from days to several years.2 25 81 85 Laboratory findings during flares include leucocytosis with neutrophilia and an elevation of acute phase reactants (CRP, ESR, SAA, fibrinogen). The presence of proteinuria warrants further work-up to exclude renal amyloidosis.86 87
Cutaneous Signs
FMF skin lesions usually present as erysipelas-like, erythematous, tender, swollen and well-defined plaques on the lower extremity (figure 4).88 Rare skin manifestations include scattered pruritic papules, pruritic urticarial lesions, palmoplantar erythema and Raynaud-like lesions.2 89 90 Infrequently, vasculitis (IgA-related, polyarteritis nodosa, small and medium-sized vessel diseases) occurs as well.2 91
Treatment
Treatment goals for FMF are threefold: general symptom control, a decrease in flare frequency and the prevention of secondary AA amyloidosis. Colchicine is the first-line agent for flare control and amyloidosis prevention. In cases of colchicine resistance, other treatment options include IL-1 inhibition (canakinumab, anakinra), TNF-α inhibition (adalimumab, etanercept, infliximab), thalidomide, the IL-6 antagonist tocilizumab and the Janus kinase inhibitor tofacitinib.92–96 Treatment options for patients who develop arthralgia despite colchicine therapy include conventional synthetic disease-modifying antirheumatic drugs (methotrexate, sulfasalazine), TNF-α antagonists and intra-articular steroid injections. Non-steroidal anti-inflammatory drugs (NSAIDs) or, if refractory, prednisone or IL-1 antagonists can be used to treat FMF-related myalgias.92
Pyrin-associated autoinflammation with neutrophilic dermatosis (PAAND)
PAAND occurs in childhood with unknown prevalence.72 97 98 It is characterised by recurrent flares of fever, a wide range of possible skin lesions, arthralgia, myalgia and lymphadenopathy. Isolated cases with associated cardiomyopathy and hepatosplenomegaly have been described. In contrast to FMF, there is no clear association with amyloidosis or serositis.97 98 Flares take several weeks to resolve. Causal triggers and intervals remain to be determined. Laboratory abnormalities during flares include elevated levels of acute phase reactants and proinflammatory cytokines (IL-1β, IL-1Rα, IL-6, TNF-α), as well as leucocytosis with eosinophilia and anaemia.72 97 98
Cutaneous signs
PAAND encompasses a large variety of possible skin lesions with a predilection for the trunk, arms and face. Described lesions include severe acne, sterile skin abscesses, pyoderma gangrenosum, hidradenitis suppurativa, neutrophilic panniculitis, (pruritic) neutrophilic small-vessel vasculitis and oral ulcers.2 97 98
Treatment
There is no consistent treatment approach to PAAND. Some patients respond to anti-IL-1 treatment, others seem to benefit from anti-TNF-α therapy. Masters et al described successful treatment with the IL-1 receptor antagonist anakinra in one patient who failed to respond to corticosteroids and methotrexate. Colchicine led to partial remission in another patient.97 The TNF-α antagonist infliximab showed a long-lasting improvement of PAAND signs and symptom in a patient non-responsive to corticosteroids and anakinra. After a recurrence of disease symptoms, the patient was switched from infliximab to adalimumab.72 Hong et al reported partial disease control with corticosteroids, cyclophosphamide, mycophenolate mofetil, methotrexate, azathioprine and TNF-α antagonists in two patients.98
PSTPIP1-associated inflammatory diseases (PAID)
The mutation of PSTPIP1 leads to a variety of PAID (reviewed by Boursier et al 99), the most prominent are PAPA73 and PAMI.74 100 101
Pyogenic arthritis, pyoderma gangrenosum and acne syndrome (PAPA)
The prevalence of PAPA is unknown with disease onset in childhood. It is characterised by recurrent pauciarticular, aseptic, pyogenic, erosive, deforming arthritis triggered by minor trauma, aseptic abscesses, cystic acne and pyoderma gangrenosum. Painful joint involvement may be the first sign of disease. By puberty, joint symptoms tend to subside while skin lesions increase.102 Fever is rare.2 Haemolytic anaemia, cervical lymphadenopathy, bleeding diathesis, splenomegaly and recurrent infections have been reported as well.103 104 Laboratory studies show elevated levels of acute-phase reactants, IL-1β and leucocytosis with neutrophilia.103 105
Cutaneous signs
Skin lesions usually manifest or worsen during puberty and include sterile abscesses, severe cystic acne and deeply erythematous, violaceous papules as well as ulcerated plaques (figure 5). The skin pathergy test (hyper-reactivity in response to minor trauma) is commonly positive in PAPA. Skin lesions can be found on the scalp, face, trunk and legs.73 103–108
Treatment
IL-1 blocking agents, such as anakinra or canakinumab, yielded good treatment responses in case reports and case series.103 105 Other effective agents include TNF-α antagonists (adalimumab, infliximab), corticosteroids, methotrexate, tacrolimus, ciclosporin and the antibiotic dapsone.103 107 108
PSTPIP1-associated myeloid-related proteinaemia inflammatory syndrome (PAMI)
About 35 cases of PAMI have been reported so far with the mean age of onset of 13 months.74 106 109 It is characterised by a state of chronic inflammation including the skin, hepatosplenomegaly, failure to thrive and arthralgia or arthritis.74 Osteomyelitis of the talus, fibula and tibia have been reported in one case.106 Typical laboratory findings include hyperzincaemia and hypercalprotectinaemia with increased levels of MRP8 and MRP14 as well as pancytopaenia including anaemia, thrombocytopaenia and neutropaenia as a result of bone marrow dysfunction.74 100 One report described a mild increase in ESR and CRP.106
Cutaneous signs
Pyoderma gangrenosum, characterised by ulcers surrounded by a purple halo with undermined borders occur in 44% of all patients, typically on the lower extremities.74 100 106 Another common type of skin lesion is acne of the face and back.100 106 Pustular rashes and abscesses may manifest as well. A positive skin pathergy test has been reported in one patient.106
Treatment
Several agents have been used with varying degrees of success in PAMI. In the initial report by Holziger et al, anti-IL-1 treatment (anakinra, canakinumab), ciclosporin or corticosteroids were partially beneficial. Other treatments (etanercept, adalimumab, infliximab, tacrolimus, methotrexate, intravenous immunoglobulins, colchicine) were less effective.74 Klötgen et al showed that ciclosporin and a combination of corticosteroids and topical tacrolimus were efficacious, whereas treatment with infliximab, canakinumab or the IL-17A inhibitor secukinumab showed no additional benefit.106 If disease control cannot be achieved, allogenic haematopoietic stem cell transplantation might be considered.110
Autoinflammatory periodic fever, immunodeficiency, and thrombocytopaenia (PFIT)
PFIT is caused by a missense mutation in the WDR1 gene which promotes F-actin depolymerization and regulates cytoskeletal dynamics.75 Its prevalence is unknown and disease onset is between the neonatal period and early infancy.
It is characterised by fever attacks with unknown triggers, lasting for 3–7 days, recurring every 6–12 weeks. Additional clinical features include oral inflammation and ulcers leading to scarring and microstomia as well as perianal ulcerations. Furthermore, a predisposition for recurrent infections, such as pneumonia and septic arthritis, has been described. Laboratory studies show an elevation in acute phase reactants (CRP, SAA, ferritin), elevated levels of IL-18, leucocytosis with neutrophilia, and thrombocytopaenia during flares.75
Cutaneous signs
PFIT presents with severe recurrent oral inflammation and ulcers leading to scarring and microstomia. Recurrent perianal ulcerations can occur as well.75
Treatment
In the initial report by Standing et al, corticosteroids, colchicine and anakinra were associated with a partial response in two patients. In another patient, allogeneic hematopoietic stem cell transplantation was beneficial. As a key pathogenic mediator in PFIT, IL-18 was suggested as a possible treatment target.75
Mevalonate kinase deficiencies (MKD)
MKD describes a reduction of the mevalonate kinase (MK) activity caused by autosomal recessive mutations in the MVK gene111–113 and encompasses two genetically similar conditions with distinct clinical manifestations.114 As the name suggests, the disease severity depends on the remaining activity of MK, with the milder phenotype hyperimmunoglobulinaemia D with periodic fever syndrome (HIDS) and the more severe condition mevalonic aciduria (MA).114 115
Hyperimmunoglobulinaemia D with periodic fever syndrome (HIDS)
In 2007, a total of 244 patients were recorded in the International HIDS Database.115 The exact prevalence is unknown. Disease onset is at a mean age of 6 months. According to published data, 78.1% of patients experience their first flare within the first year of life.115 HIDS is characterised by flares of fever, malaise, abdominal complaints including pain, diarrhoea, and vomiting, (cervical) lymphadenopathy, skin rash, arthralgia, arthritis and headache. Flares typically last 3–7 days and recur every 2–12 weeks with a decreasing frequency during the course of life.76 115 116 Skin and joint symptoms resolve slowly.117 Disease attacks can occur without any preceding event, however reported precipitating factors include vaccination, surgery, minor trauma and physical as well as emotional stress.76 115 117 Elevated polyclonal IgD antibodies, as a hallmark of the disease, are reported in 78% of patients, accompanied by elevated IgA levels in 64% of patients.115 Other findings during a flare-up include leucocytosis, a rise of ESR, CRP and SAA levels, as well as MA.113 115
Cutaneous signs
Approximately 70%–80% of patients develop cutaneous manifestations during disease flares.115 118 The most common skin lesions are erythematous macules and papules, followed by urticarial lesions, erythematous nodules, annular erythema, palpable purpura, erythematous pustules and petechiae involving the extremities, trunk and neck.118 Roughly every second patient develops oral or bipolar ulcers.115 Cutaneous manifestations are usually asymptomatic or are only rarely accompanied by pain or itching.76 118
Treatment
The approach to treatment in patients with HIDS consists of two main components: symptomatic and preventive care. Symptomatic therapy includes NSAIDs,119 120 if refractory, glucocorticoids120 121 or anakinra.120 122 Since canakinumab has a slower onset of action compared with anakinra, it is preferably used as a preventive treatment of patients with HIDS.123 Other preventive treatment options include etanercept120 and tocilizumab.124 Statins are currently not recommended, despite blocking epigenetic and transcriptional changes in HIDS monocytes. In a preliminary analysis of six patients with HIDS, Simon et al showed no significant reduction in febrile days in patients taking simvastatin compared with placebo.114
Mevalonic aciduria (MA)
The exact prevalence of MA is unknown as only approximately 30 cases have been reported so far.125 The first signs and symptoms of MA are present at birth. Patients experience recurrent flares of fever, lymphadenopathy, morbilliform skin rashes, subcutaneous oedema, diarrhoea, vomiting and arthralgias. Flares usually last 4–5 days and may occur up to 25 times a year.126 No causative trigger has been identified so far. In addition, patients exhibit characteristic facial features (dolichocephaly with a delayed closure of the skull sutures and open fontanelles, a triangular face with down-slanting palpebral fissures and large, posteriorly rotated, low set ears), as well as ocular involvement (cataracts, blue sclera and retinitis pigmentosa), psychomotor retardation, seizures, failure to thrive and hepatosplenomegaly.126–128 Apart from persistent MA, laboratory findings include elevated inflammatory markers (CRP and ESR), anaemia as well as increased serum IgD, IgA, IgE, creatine kinase and transaminases.77 125–127
Cutaneous signs
Available data on cutaneous manifestations are scarce. Hoffmann et al reported a morbilliform rash without specifying the site of involvement.126
Treatment
MA treatment remains challenging. In a small case series, treatment with anakinra induced partial remission in one of two patients.122 Canakinumab can be used as an alternative to anakinra.129 130 A trial of the statin lovastatin had to be discontinued due to worsening of clinical symptoms and rhabdomyolysis.126 Stem cell transplantation might be considered as a treatment option; however, relapses can occur.131 132
The NLRP1-associated autoinflammatory disease (NLRP1-AD)
Keratinocytes make up most of the epidermis. They are important defenders of the body against trauma, exposure to ultraviolet radiation as well as one of the first cellular defenses in the fight against pathogens. The NLRP1 inflammasome is the main inflammasome in keratinocytes and mutations lead to an over-reactive immune response to these stressors. This leads to AID affecting the skin as well as a heightened risk of cancer.133 Epithelial skin cancers, such as squamous cell carcinoma commonly develop after many years of sun exposure and tumor-promoting inflammation represents one of the hallmarks of cancer. Autoinflammatory syndromes with prominent skin involvement should be monitored carefully for skin cancer development. MSPC (multiple self-healing palmoplantar carcinoma), NAIAD (NLRP1-associated autoinflammation with arthritis) and FKLC (familial keratosis lichenoides chronica) broadly represent these NLRP1-AD (figure 6).
Cutaneous signs of NLRP1-associated inflammasomopathies: FKLC (1). Perifollicular, hyperkeratotic papules arranged in a linear or reticular pattern on the arms, legs and trunk (1A). Palmoplantar keratoderma (1B). Other manifestations (not shown): seborrheic-like dermatitis or rosacea on the face, mucosal involvement, nail changes, ocular involvement, alopecia (B, back view; F, front view). MSPC (2). Numerous, hyperkeratotic, ulcerative nodules on the palms and soles resembling keratoacanthomas, usually 8–15 nodes with a size between 5 and 50 mm in diameter (2A, 2B). Dystrophic nails with thickening of the nail plate and mottling edges (2C). Conjunctival lesions such as squamous dyskeratotic lobules (2D) (B, back view; F, front view). Hyperkeratosis pilaris not shown. NAIAD not shown. FKLC, familial keratosis lichenoides chronica; MSPC, multiple self-healing palmoplantar carcinoma; NAIAD, NLRP1- associated autoinflammation with arthritis.
NLRP1-associated disease (NAIAD)
NAIAD is a rare autoinflammatory keratinisation disease of unknown prevalence caused by autosomal dominant or recessive mutations in the NLRP1 gene.134–136 The first signs usually develop in childhood as recurrent episodes of unprovoked fever lasting 3–4 days, dyskeratosis, oligoarticular and polyarticular arthritis, vitamin A deficiency and intermittent elevated CRP levels. Other findings include chronic infection, antinuclear antibodies and high transitional B cell levels.134
Cutaneous signs
NAIAD is characterised by skin dyskeratosis with phrynoderma (follicular hyperkeratosis), (filiform) hyperkeratosis, and papules with pseudo-comedones on the trunk, arms, hands, legs and feet. Ungual dyskeratosis has been described as well.134
Treatment
NAIAD skin manifestations have been successfully treated with the retinoid acitretin. For arthritis, etanercept and anakinra improved clinical symptoms, whereas methotrexate was not helpful. Supplementation of vitamin A led to either no disease modification or worsening of the disease.134
Familial keratosis lichenoides chronica (FKLC)
FKLC is a rare semidominant disease with only about 80 reported cases.137 It shows scaly papules on the trunk and extremities appearing at a mean age of 35.6 years, ranging from 6 months to 78 years. About a quarter of all FKLC are paediatric cases.137 Skin lesions occur without any preceding event such as sun exposure or trauma. FKLC was reported to be associated with glomerulonephritis, haematological malignancies, hypothyroidism and hepatitis. Laboratory studies are usually unremarkable. Alterations in laboratory values—if occurring—are related to the associated diseases.137
Cutaneous signs
FKLC is characterised by perifollicular, hyperkeratotic papules arranged in a linear or reticular pattern (figure 6-1).137–139 The papules are mostly asymptomatic, a mild pruritus was reported to occur only in a third. The papules are usually symmetrically distributed and located on the arms, legs and trunk (88.7%, 84.5% and 59.2%, respectively).137 Another common finding (69% of cases) is seborrhoeic-like dermatitis or rosacea on the face. Seborrhoeic-like dermatitis presents as infiltrated papules or plaques with hyperkeratotic scales typically on the convex areas of the face and usually sparing body folds. Other cutaneous manifestations include palmoplantar keratoderma (28.2%), mucosal involvement (28.2%), nail changes (26.7%; yellow discolouration, thickening, ridging), ocular involvement (19.3%) and alopecia (7%).137
Treatment
Phototherapy, sunlight exposure and systemic retinoids were associated with a clinical improvement. Treatment with topical corticosteroids, salicylic acid or vitamin D derivatives was not or only to a limited extent helpful.137
Multiple self-healing palmoplantar carcinoma (MSPC)
MSPC is a rare monogenic AID caused by an autosomal dominant mutation in the NLRP1 gene with less than 30 reported cases as of 2021.140 141 Mean onset of MSPC is 8.8 years ranging from 1 to 25 years of age.140 142 It manifests as self-healing ulcerative nodules on the palms and soles as well as ocular and nail lesions. These lesions usually occur at sites of friction. There are no reports on laboratory values in patients with MSPC .140
Cutaneous signs
MSPC is characterised by numerous hyperkeratotic, ulcerative nodules on the palms and soles resembling keratoacanthomas (figure 6-2). Patients usually display 8–15 nodes with a size between 5 and 50 mm in diameter, which grow rapidly, evolve over weeks to years and regress spontaneously after 6 months, leaving atrophic scars.140 In addition, 80% of patients with MSPC develop conjunctival lesions such as squamous dyskeratotic lobules in their second decade of life.140–142 Less common manifestations include dystrophic nails with thickening of the nail plate and mottling edges, and hyperkeratosis pilaris.142
Treatment
Cutaneous lesions usually regress spontaneously after 6 months. Surgical removal of atrophic scars is an additional treatment option. The use of retinoids leads to a stop of lesion formation, but regression as well.140 143
The emerging field of inflammasome-associated diseases
The growing interest of the clinical and scientific community as well as sequencing efforts have steadily expanded the field of inflammasome-associated diseases. For some of these conditions, a definitive link to genetic alterations in the inflammasome has not been established but is suspected. While beyond the scope of this review to list all of these diseases, an example is the NLRP12-associated AID FCAS2 with over 60 reported cases worldwide and a similar clinical presentation as the mildest form of CAPS.144–146 NLRP12 is a known inhibitor of the inflammasome mainly influencing the canonical and non-canonical NFκB-pathway, as well as neutrophil recruitment and migration during infection.147–151 To what extent FCAS2 is driven by the inflammasome is uncertain and treatment with anakinra (anti-IL-1R), while showing initial clinical improvement, was followed by a relapse in one patient.152
The effector cytokines of the inflammasome, namely IL-1β and IL-18, can also be induced by non-canonical activation of caspases-4 or caspases-5. The functional consequences of canonical and non-canonical inflammasome activation remain largely the same, as crosstalk between these systems regularly triggers the activation of the canonical NLRP3 inflammasome (reviewed by Downs et al).153 Göös et al recently described a mutation in a transcription factor resulting in the constitutive activation of the caspase-5 mediated non-canonical inflammasome.154 The disease is termed CAIN (C/EBPε-associated autoinflammation and immune impairment of neutrophils) and shows high fever and purulent paronychia, eventually progressing into ascending lymphangitis, oral ulcerations, abscesses, pyoderma gangrenosum, impaired wound healing, and abdominal pain. Treatment data targeting IL-1β or IL-18 are still outstanding.154
Future genetic and functional assays and treatment regimens targeting the inflammasome or its effector proteins are needed to identify the actual impact the inflammasome dysregulation has on the respective emerging diseases.
Concluding remarks
AIDs, including the subgroup of inflammasomopathies, commonly involve the skin with the range of possible lesions being vast (online supplemental table 1). While NLRP3-associated and NLRC4-associated inflammasomopathies commonly manifest as urticarial rashes on the skin, patients suffering from pyrin-associated inflammasomopathies exhibit erysipelas-like rashes (FMF), acne, abscesses and pyoderma gangrenosum (PAAND, PAID), maculopapular rashes (MKD) or oral and perianal ulcers (PFIT). Hyperkeratosis is a frequent finding of NLRP1-associated inflammasomopathies (NAIAD, FKLC, MSPC).
A definite diagnosis of AID should be made by the interplay of clinical and cutaneous presentation, as well as histopathological, laboratory and genetic findings. It is important to be aware of the possible skin manifestations, as cutaneous lesions may direct clinicians towards the correct diagnosis, even though the pattern variability and overlap with other, non-autoinflammatory conditions represents a significant challenge.
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Footnotes
CB and DS are joint first authors.
Handling editor Mary K Crow
Contributors CB and DS contributed equally to this paper and are both corresponding authors. CB, DS and WW wrote the manuscript. MD proofread and edited the manuscript. DS prepared the figures. All authors read and approved the manuscript.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
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