Autoinflammatory syndromes: A review

INTRODUCTION

Autoinflammatory syndromes (AIS) are enigmatic and diagnostic challenges for clinicians [Table 1]. These are rare disorders often having a striking-onset and manifest inflammatory features without an infectious or autoimmune cause. Genetically driven dysregulated innate immune response with the activation of inflammasome and excess of cytokines leads to the development of these disorders.^[1-3] This differs from classical autoimmunity since, unlike autoimmune diseases, the primary pathogenesis of AIS does not involve antibodies or T-cell- mediated pathways or major histocompatibility complex-related processes.

Recurrent febrile episodes accompanied by cutaneous, mucosal, serosal, and osteoarticular manifestations, hepatosplenomegaly, lymphadenopathy, elevated acute-phase reactants, neutrophilia, and long-term risk of secondary amyloidosis characterize AIS. Cutaneous manifestations in AIS often warrant dermatology evaluation; hence, dermatologists should be aware of these syndromes and their varying presentations to diagnose and evaluate the patients.

Many may present with skin lesions (urticaria, pustules, maculopapular rash, oral ulcers, generalized pustular psoriasis, pyoderma gangrenosum, and Sweet’s syndrome-like lesions). Infections, connective tissue diseases, and malignancies as the causes of recurrent fever need to be evaluated and ruled out before considering the possibility of AIS. Other clues to diagnosis are childhood onset, positive family history, and raised laboratory markers of systemic inflammation during the episodes.

TRAPS

TRAPS is also called familial Hibernian fever due to high frequency of incidence in people of Irish, Scottish, Austrian, or Northern European descent. It is characterized by febrile attacks that last for 1–3 weeks and occasionally up to 6 weeks. The clinical features include fever, arthralgia, myalgia, migratory rash, abdominal pain, pleuritis, conjunctivitis, periorbital edema, oral ulcers, and scrotal swelling. Skin manifestations include migratory macular erythematous rash or patches, ecchymoses, edematous dermal plaques, serpiginous or annular lesions, and periorbital edema.

The genetics underlying this was studied in large multiplex Irish families who had an AD syndrome characterized by recurrent fever, rash, and abdominal pain. Vast majority had childhood onset at around 3 years, but adult onset may occur. The disease develops due to mutation of the gene encoding P55 TNF receptor type 1. There are 46 missense mutations involving TNF receptor type 1 which are localized to distal chromosome 12 p. Etanercept is an effective treatment which reduces the frequency and severity of flares in TRAPS.^[11,12]

FMF

It is the most common autoinflammatory disease. It preferentially affects the Sephardic Jews, Armenians, Turks, Arabs, and Moroccans whose familial origin can be traced to the Mediterranean basin. However, it has been diagnosed in non-Mediterranean as well. It begins in childhood or adolescence, and up to 20% may have their first attack after the age of 20 years. Febrile episodes are accompanied by cutaneous, serosal, synovial, or tenosynovial inflammation. Fever is high grade and lasts for 1–3 days. Bouts are unpredictable in frequency and may be provoked by infection, stress, exercise, or surgery. Cutaneous features are rather unilateral than bilateral. Erysipelas-like erythema located on the extensor surface of arms and legs or dorsum of feet which is often painful is a characteristic feature. Recurrent inflammatory, sterile monoarticular inflammation, joint effusion, or tenosynovial swelling may also occur. Serositis manifests as peritonitis, pleuritis, pericarditis, or scrotal swelling. Aseptic meningitis is a rare manifestation. Leukocytosis and elevated ESR and CRP are the laboratory abnormalities noted. Amyloidosis may complicate FMF as serum amyloid A gets deposited in kidneys or other organs. It results from a recessive mutation of the MEFV (Mediterranean fever gene 16p13) located on short arm of chromosome 16. There are more than 80 missense mutations. MEFV is found in neutrophils and myeloid cells and encodes 86 KDa protein called pyrin. Defective pyrin function leads to uncontrolled inflammation with elevated levels of IFN gamma and pro-inflammatory cytokines like TNF alpha, and interleukins (IL) 1, 6, and 8. Colchicine controls the attacks and prevents amyloidosis. Refractory cases respond to IL-1 inhibitor anakinra. Combination of recurrent bouts of fever with synovial, serosal, or cutaneous inflammation and elevated acute-phase proteins should raise the suspicion of FMF.^[13]

HIDS

HIDS and mevalonic aciduria (MA) represent the two ends of a clinical spectrum caused by deficiency of mevalonate kinase (MVK), an enzyme involved in the cholesterol and isoprenoid biosynthetic pathway.^[14] Complete deficiency induces MA while partial deficiency manifests with recurrent fever and usually but not always with overproduction of immunoglobulin D (HIDS).^[15] The median age of onset of disease ranges from ^1st week of life to 10 years. Inheritance pattern is AR. In HIDS, the clinical picture is dominated by recurrent febrile attacks lasting for 3–7 days with headache, polyarthralgia, abdominal pain, diarrhea, and bilateral tender cervical adenopathy.^[16] Two-third of the patients with HIDS manifest an eruption with fever. Erythematous macules, maculopapular rashes, urticaria, purpura, erythema nodosum, and oral and genital aphthae are the observed features in the affected. Immunization, surgery, trauma, and stress are the classical triggering factors. Similar to HIDS, patients with MA present with febrile episodes and systemic inflammation, but other features include severe failure to thrive, developmental delay, hepatosplenomegaly, anemia, dysmorphic facies, and cerebellar ataxia. The diagnosis of HIDS is usually suspected clinically, but definitive diagnosis is made by genetic testing, while MVK gene analysis is the gold standard testing. IgD levels are more than 100 IU/dl. Fever and arthralgia may respond to NSAIDS, but colchicine is usually ineffective. Anakinra, an IL-1 receptor antagonist, has been effective in reducing the clinical and biochemical inflammation in MA. Canakinumab, a long-acting monoclonal antibody against IL- 1β, anti-TNF agents, and HMG-CoA reductase inhibitors are found useful in some cases.^[17]

CAPS

Cryopyrinopathies are rare autoinflammatory diseases that present with recurrent bouts of systemic inflammation involving chiefly skin and joint.^[18] It comprises a spectrum of diseases caused by a defect of NLRP3 (NOD-like receptor family, protein pyrin domain containing protein 3; or cryopyrin) functions and is inherited in an autosomal dominant fashion.^[19] Three closely related phenotypes that are included under cryopyrinopathies are FCAS, MWS, and chronic infantile neurological cutaneous articular syndrome (CINCA)/NOMID. Among these, FCAS is the mildest form and CINCA is the most severe. CAPS mainly occurs in pediatric age group.^[20]

Skin involvement is found in all three diseases, and most cases usually present with skin rash. Nonpruritic urticarial lesions appear on the trunk and limbs, but a few may report a burning sensation.^[21] Lesions are usually migratory in nature and last for <24 h.^[22] This urticarial rash differs from classical urticaria and shows dermal perivascular infiltrate composed of neutrophils instead of the typical lymphocytic and eosinophilic infiltrate observed in urticaria. Therefore, the term neutrophilic urticarial dermatosis is used for this manifestation.^[23]

FCAS

This entity is characterized by recurrent self-limiting episodes of low-grade fever, urticarial rash, arthralgia, and conjunctivitis which are precipitated by cold exposure. Patients may also present with nausea, drowsiness, extreme thirst, sweating, and headaches.^[24] Symptoms usually begin within 1–2 h of cold exposure and attacks lasts for <24 h.^[1] Most of the patients present before 6 months of age.^[25]

MWS

This syndrome is characterized by recurrent episodes of fever, rash, arthralgia, headache, and conjunctivitis. Sensorineural deafness occurs in about 70% and may appear in childhood or early adulthood.^[26] Secondary amyloidosis due to chronic inflammation is the most serious complication that may develop in about 25% of the affected.^[27]

CINCA/NOMID

A triad of arthropathy, urticaria, and CNS involvement is the hallmark of CINCA. CNS manifestations can occur in almost all patients and range from aseptic meningitis to increased intracranial pressure and cognitive impairment. Sensorineural deafness is found in 75% of patients and is detectable in the first decade of life.^[28] Bone and joint inflammation lead to severe and disabling arthropathy in one-third cases. Renal amyloidosis is rare in these patients. Compared to other cryopyrinopathies, CINCA is associated with an increased mortality rate when compared to other AIS.

PAPA

Mutation in PST P1P1 gene is recognized as the cause for this autosomal dominant disease. Hyperphosphorylated PSTP1P1 protein causes prolonged binding to pyrin, and this prevents inhibitory action of pyrin on NLRP 3 inflammasome. This, in turn, leads to the elevation of IL- 1b and inflammation ensues. Manifestation begins in early childhood with recurrent painful sterile, pauciarticular, and nonaxial arthritis precipitated by trauma. It may occasionally lead to significant joint destruction. By puberty, joint symptoms subside and skin lesions appear. Severe nodular acne, hidradenitis suppurativa, pyoderma gangrenosum and positive pathergy are the other features. PAPASH is characterized by pyogenic arthritis, pyoderma gangrenosum, acne and suppurative hidradenitis. PASH include pyoderma gangrenosum, acne and suppurative hidradenitis. Anakinra and anti-TNF alpha agents are used in treatment.^[29]

OTHER AUTOINFLAMMATORY DISORDERS

PFAPA - Periodic fever, aphthous stomatitis, pharyngitis, and adenopathy. It is the most common periodic fever syndrome during childhood. Marshall syndrome or PFAPA syndrome was first described by Marshall et al. in 1987.^[36] Characteristically, it begins during childhood, commonly between 2 and 5 years of age, and resolves before the end of first decade. There is a slight male predominance.^[37,38] Patients present with abrupt episodes of fever that last for 3–6 days and recur every 3–4 weeks and may associate with one or more of the following symptoms: aphthous stomatitis, exudative or nonexudative pharyngitis, tender cervical lymphadenopathy, and mild abdominal pain. Other less specific symptoms are fatigue, myalgias, and headache.

In children with PFAPA, periodic fever rather than stomatitis is the primary complaint.^[39]

An important differential diagnosis of PFAPA syndrome is cyclic neutropenia, also characterized by recurrent fever, oral aphthae, pharyngitis, and lymphadenopathy. In addition, cyclic neutropenia patients also manifest intermittent neutropenia (<500/mm³) during febrile episodes which put them at risk of infection. The gene neutrophil elastase is mutated in cyclic neutropenia.^[40]

CONCLUSION

AIS are a group of rare disorders of innate immunity characterized by repeated episodes of inflammation without an obvious cause. Many of these disorders have a childhood onset and present with recurrent fevers, skin lesions, joint pains, and other systemic features. Several of these have distinctive cutaneous manifestations, and dermatologists have an important role in diagnosing these conditions. Recently, molecular basis for many of these diseases has been identified, thus paving the way for novel targeted therapies. IL-1 blockers have been found to be more effective than the conventional immunosuppressants in their treatment.

There is not one clinical symptom, but rather a set of symptoms occurring repeatedly which suggests the diagnosis of AIS. Urticaria is a common presenting feature of AIS and has to be differentiated from ordinary urticaria. GPP, erysipelas-like lesion, and maculopapular rash may also be the presenting features.