Autoinflammatory conditions: when to suspect? How to treat?

The term ‘autoinflammatory disease’ encompasses an enlarging group of inflammatory disorders defined as Mendelian genetic diseases of the innate immune system. This group is growing considering the fact that diseases sharing strong similarities with this core group can be defined as autoinflammatory.

The core group consists now of six disorders also known as hereditary recurrent fever syndromes. Thez most common is familial Mediterranean fever, an autosomal recessive disease affecting mainly populations of Mediterranean ancestry. All these six diseases are characterised by inflammatory attacks both at the clinical and at the biological level. The diagnosis of each of these diseases relies first on clinical features and second on genetic testing, which is guided by the clinical results.

Deciphering the role of interleukin-1 in the regulation of the inflammatory response through the inflammasome represents a major advance in the knowledge of the mechanisms of these diseases with, as a main consequence, treatment with interleukin-1 inhibitors.

What are autoinflammatory conditions?

The term ‘autoinflammatory syndrome’ has been coined by Mc Dermott et al. in the article reporting the discovery of mutations in the gene TNFRSF1A (TNF receptor superfamily 1A) in a series of families with a dominant inherited periodic fever syndrome, this syndrome hassubsequently been named TNF receptor-associated periodic fever syndromes (TRAPS) . Autoinflammatory syndromes thus originally referred to a group of inflammatory diseases (therefore the word ‘inflammatory’) with a strong genetic basis defined by a Mendelian inheritance (therefore the word ‘auto’). This term contains also another idea, as it refers ‘in mirror’ to the consensual term of auto-immunity. It means implicitly that syndromes and diseases candidate to a status of autoinflammatory disorder have no auto-immune abnormalities such as specific auto-antibodies or auto-reactive T-lymphocytes.

In this primary group could be included four diseases: familial Mediterranean fever (FMF), by far the most frequent of these diseases; TRAPS, the group of mevalonate kinase deficiencies (MKD) including the severe type: mevalonic aciduria (MA) and the moderate one: hyper immunoglobulin D and periodic fever syndrome (HIDS); a fourth subgroup includes three syndromes that were independently described: the Muckle Wells syndrome (MWS), familial cold urticaria (FCU) also known as familial cold-associated syndrome (FCAS) and the chronic infantile neurological cutaneous and articular (CINCA) syndrome, also known as neonatal-onset multisystemic inflammatory disease (NOMID) syndrome . Two other syndromes fulfilling these early criteria have been since described: nucleotide-binding oligomerisation domain, Leucine rich Repeat and Pyrin domain (NLRP12)-associated syndrome and the deficiency of the interleukin (IL)-1–receptor antagonist (DIRA) . Curiously, the main characteristic of this first group, notably of the first three entities, is the intermittent appearance of the clinical symptoms, usually described as attacks of the disease that sharply contrasts with the genetic and therefore permanent nature of the underlying defect. Clinical symptoms consist, therefore, mainly in intermittent inflammatory attacks with general and local manifestations. General symptoms consist in a mild to very high fever associated with blood neutrophilia and a constant acute-phase response usually evaluated by serum amyloid A (SAA) or C-reactive protein (CRP). Local symptoms focus on essentially three areas: abdomen, skin and the musculo-skeletal system. This article will focus on this group of six diseases.

In a second step, some rare inflammatory diseases lacking the intermittent character of the symptoms but still with a Mendelian pattern of inheritance have been considered as autoinflammatory, such as the rare dominant pyogenic arthritis, pyoderma grangrenosum and acne (PAPA) syndrome, or even the very uncommon syndrome described by Majeed that associates a chronic multifocal recurrent osteomyelitis and anaemia .

The third step concerns the expansion of the concept of autoinflammation to inflammatory diseases without a strong genetic basis, that is, without a Mendelian inheritance. In fact, some sporadic diseases share strong clinical and biological features with genetic autoinflammatory diseases, notably juvenile idiopathic arthritis and adult-onset Still’s disease and even gout . Some authors have proposed a classification based mainly on the molecular mechanism of the disease. From this point of view, provided that their basis may imply innate immunity, a number of diseases would be called autoinflammatory, including type 1 diabetes or atherosclerosis. Although interesting with regard to the mechanisms of these diseases, this classification has less clinical relevance . More pertinent, the recognition that some so-far unclassified inflammatory diseases without features of adaptive immunity are in fact disorders of the innate immune system has led to a novel classification of all inflammatory disorders. In this scheme, inflammatory disorders are divided into two poles – auto-immune and autoinflammatory – with a continuum of diseases between them .

How common are periodic fever syndromes, when to suspect, how to differentiate?

Epidemiology

Autoinflammatory conditions are rare and their incidence depends on the gene distribution of the background population. FMF is an autosomal recessive disorder and is the most common autoinflammatory disease, which is found in persons originating from the eastern Mediterranean area, including Turks, Jews (primarily non-Ashkenazi), Armenians and Arabs. FMF can be found with lower incidence in other ethnic groups around the Mediterranean Sea and, uncommonly, out of it . The prevalence of FMF shows considerable geographical variation. In Turkey, the prevalence rates were reported as 0.0027–0.82% and about 1 in 25 in Arabs . The carrier frequency in the eastern Mediterranean area can be as high as one in five to one in three . Tumour necrosis factor (TNF) receptor-associated periodic syndrome is probably the most frequent autosomal dominant autoinflammatory disease. Some families and over 200 sporadic cases have been reported from Central America, Australia and Europe . Cryopyrin-associated periodic syndromes (with dominant inheritance) and MKD are also very rare, as around 200 cases of each syndrome have been reported .

Analytical presentation

It is often a challenge to investigate suspected periodic fever syndromes. Good clinical case history, family history, patient diary, ethnicity and physical examination are always valuable for accurate clinical approach ( Table 1 ). Many conditions such as occult or recurrent infections (e.g., malaria, brucellosis and some viral infections), atypical auto-immune diseases and malignant diseases can mimic autoinflammatory conditions. Overlaps in the clinical presentation of the different diseases may present difficulties during the interpretation of the symptoms. There are many patients with suspected autoinflammatory disease, who may not fit in with any of the known diseases. The understanding of these ‘undifferentiated’ disorders should be improved with further studies.

Table 1

The characteristics of periodic fever syndromes.

	FMF	TRAPS	NOMID/CINCA	MWS	FCAS	HIDS
Inheritence	Autosomal Recessive	Autosomal dominant/sporadic	Autosomal dominant de novo	Autosomal dominant	Autosomal dominant	Autosomal recessive
Gene	MEFV	TNFRSF1A	CIAS 1	CIAS 1	CIAS 1	MVK
Chromosome	16p13	12p13	1q44	1q44	1q44	12Q24
Protein	Pyrin (marenostrin)	TNF receptor 1 (p55)	Cryoprin	Cryoprin	Cryoprin	Mevalonate kinase
Attack duration	1–3 days	7–21 days	Continuous with worsening episodes	24–48 hours	<24 hours	3–7 days
Cutaneous involvement	Erysipeloid erythema HSP, PAN	Migratory macules, patches, papules, plaques	Urticaria like lesions	Urticaria like lesions	Cold induced urticaria like lesions	Maculo-papular rash
Fever	Present	Present	Present	Present	Present	Present
Abdominal involvement	Sterile peritonitis 85%	Severe pain very common	Hepatosplenomegaly	May ocur	None	Severe pain common
Amyloidosis	Present (uncommon)	Present (%10)	Possible in adulthood	25%	Uncommon	Extremely rare
Eye involvement	Uncommon	Conjunctivitis, periorbital edema common	Papilledema with possible loss of vision, uveitis	Conjunctivitis, episcleritis	Conjunctivitis	Uncommon
Joint involvement	Monoarthritis (mostly knees, ankles, hips)	Mainly arthralgies	Nonaxial arthropathy with radiologic findings	Arthralgia, arthritis, limb pain	Severe arthralgia (hand, knee, ankle)	Arthralgia, myalgia rare oligoarthritis
Distinctive features	Monoarthritis, peritonitis, erysipelas like lesions	Migratory myalgia, eruption, periorbital edema, rash	Aseptic meningitis and arthropathy	Sensorineural hearing loss	Cold induced urticaria like lesions	Cervical LAD, aphtous ulcers
Other findings	Pleuritis, pericarditis, scrotal pain	Pleuritis and headaches	Mental retardation, hepatosplenomegaly	Myalgias	Myalgias, headache, drowsiness	Splenomegaly during attack