Clinical and biochemical landmarks in systemic autoinflammatory diseases.

Systemic autoinflammatory diseases are a group of inherited disorders of the innate immune system characterized by seemingly unprovoked inflammation recurring at variable intervals and involving skin, serosal membranes, joints, and gastrointestinal apparatus, with reactive amyloidosis as a possible severe long-term complication. Recent advances in genetics and molecular biology have improved our understanding of the pathogenesis of these diseases, including familial Mediterranean fever, mevalonate kinase deficiency syndrome, tumor necrosis factor receptor-associated periodic syndrome, cryopyrin-associated periodic syndromes, and hereditary pyogenic and granulomatous disorders: the vast majority of these conditions are related to the activation of the interleukin-1 pathway, which results in (or from?) a common unifying pathogenetic mechanism. Their diagnostic identification derives from the combination of clinical data, evaluation of acute phase reactants, clinical efficacy in response to specific drugs, and recognition of specific mutations in the relevant genes, although genetic tests may be unconstructive in some cases. This review will discuss clinical and laboratory clues useful for a diagnostic approach to systemic autoinflammatory diseases

Putative Role of Serum Amyloid-A and Proinflammatory Cytokines as Biomarkers for Behcet's Disease

Behcet's disease (BD) is a multisystemic disorder of unknown etiology characterized by relapsing oral-genital ulcers, uveitis, and involvement of vascular, gastrointestinal, neurological, and musculoskeletal system. Although disease pathogenesis is still unclear, both innate and adaptive immunity have shown to play a pivotal role, and multiple proinflammatory cytokines seem to be involved in different pathogenic pathways that eventually lead to tissue damage.The aims of our study were to evaluate serum cytokines levels of IL-8, IL-18, IFN-α2a, IL-6, IFN-γ, CXCL10, CXCL11, CXCL9, and SAA levels in patients with BD, in comparison to healthy controls (HC), and to correlate their levels to disease activity.We included 78 serum samples obtained from 58 BD patients and analyzed a set of proinflammatory cytokines including IL-8, IL-18, IFN-α2a, IL-6, IFN-γ, CXCL10, CXCL11, and CXCL9 by multiplex bead analysis as well as SAA by enzyme-linked immunosorbent assay.Compared to HC, BD patients showed elevated cytokine levels of IL-8, IL-18, IFN-α2a, and IL-6, and low levels of CXCL11. BD patients with SAA serum levels >20 mg/L showed higher levels of proinflammatory markers than HC or group with SAA ≤20 mg/L. IL-18, IFN-α2a, and IL-6 were higher in BD group with SAA >20 mg/L than HC, while IL-8 and CXCL9 levels were higher than in patients with SAA ≤20 mg/L and HC.Active BD patients with SAA >20 mg/L exhibited elevated levels of inflammatory mediators, suggesting that may exist a relationship between SAA and proinflammatory cytokines in the intricate scenario of BD pathogenesis

Childhood versus adulthood-onset autoinflammatory disorders: myths and truths intertwined

Autoinflammatory disorders are characterized by spontaneous episodes of systemic inflammation deriving from inherited defects of the innate immune system. Childhood is usually the lifetime involved in most inherited autoinflammatory disorders, but a moderate number of patients may experience disease onset during adulthood. Herein we report our experience in the clinical and genetic approach to the diagnosis of autoinflammatory disorders in regard of the first 500 pediatric and adult patients evaluated during the period 2007-2012 in our Center, due to histories of periodically-recurring inflammatory attacks, giving emphasis to the differences observed according to patients'age and to the most relevant data differentiating child and adult-onset autoinflammatory disorders in the medical literature

First Report of Circulating MicroRNAs in Tumour Necrosis Factor Receptor-Associated Periodic Syndrome (TRAPS)

Tumor necrosis factor-receptor associated periodic syndrome (TRAPS) is a rare autosomal dominant autoinflammatory disorder characterized by recurrent episodes of long-lasting fever and inflammation in different regions of the body, such as the musculo-skeletal system, skin, gastrointestinal tract, serosal membranes and eye. Our aims were to evaluate circulating microRNAs (miRNAs) levels in patients with TRAPS, in comparison to controls without inflammatory diseases, and to correlate their levels with parameters of disease activity and/or disease severity. Expression levels of circulating miRNAs were measured by Agilent microarrays in 29 serum samples from 15 TRAPS patients carrying mutations known to be associated with high disease penetrance and from 8 controls without inflammatory diseases. Differentially expressed and clinically relevant miRNAs were detected using GeneSpring GX software. We identified a 6 miRNAs signature able to discriminate TRAPS from controls. Moreover, 4 miRNAs were differentially expressed between patients treated with the interleukin (IL)-1 receptor antagonist, anakinra, and untreated patients. Of these, miR-92a-3p and miR-150-3p expression was found to be significantly reduced in untreated patients, while their expression levels were similar to controls in samples obtained during anakinra treatment. MiR-92b levels were inversely correlated with the number of fever attacks/year during the 1st year from the index attack of TRAPS, while miR-377-5p levels were positively correlated with serum amyloid A (SAA) circulating levels. Our data suggest that serum miRNA levels show a baseline pattern in TRAPS, and may serve as potential markers of response to therapeutic intervention

Caution should be used in the recognition of adult-onset autoinflammatory disorders: facts or fiction?

Autoinflammatory disorders (AIDs) are a group of inherited diseases of innate immunity, characterized by seemingly unprovoked inflammation recurring with variable rhythmicity and involving skin, serosal membranes, synovial membranes, and gastrointestinal tube, with reactive amyloidosis as a potential severe long-term complication. Diagnosis of AIDs in adults requires a strict differentiation with a host of protean inflammatory and non-inflammatory conditions

The hereditary autoinflammatory disorders uncovered

There is a thriving interest in the field of hereditary autoinflammatory disorders (HAID), a gamut of heterogeneous conditions deriving from an aberrant orchestration of innate immunity, unified by the common feature of seemingly unprovoked inflammation, which might be systemic or occur in localized niches of the organism. Recurrent fever and episodic inflammation in the joints, serosal membranes, skin, gut, and other organs are the common denominator of HAID. Mutations in the inflammasome-related genes have been associated with different HAID, showing the intimate link existing between interleukin-1 (IL-1)-structured inflammasome and their pathogenesis. Differential diagnosis of HAID can be challenging, as there are no universally accepted diagnostic protocols, and near half of patients may remain without any genetic abnormality identified. The use of IL-1-antagonists has been associated with beneficial effects in a large number of HAID associated with excessive IL-1 signalling, such as cryopyrin-associated periodic syndromes, familial Mediterranean fever, and deficiency of IL-1 receptor antagonist. This review will discuss about the key-clues of HAID which might guide for an early recognition and drive decisions for treatment

The role of the F402L allele in the NLRP12-autoinflammatory disorder. Reply to: F402L variant in NLRP12 in subjects with undiagnosed periodic fevers and in healthy controls, De Pieri et al

The role of the F402L variant in the pathogenesis of NLRP12-autoinflammatory disorder is discussed in this case report

Long-term clinical course of patients carrying the Q703K mutation in the NLRP3 gene: a case series

BACKGROUND: Cryopyrin-associated periodic syndromes (CAPS) comprise a spectrum of apparently distinct, rare, autosomal dominant autoinflammatory disorders of increasing severity caused by NLRP3 gene mutations. The Q703K allele is a variant of unknown pathogenetic significance, and has been considered to be both a clinically unremarkable polymorphism and a low- penetrance mutation. OBJECTIVES: To analyse the long-term clinical course in a cohort of patients presenting with periodic fever attacks and carrying the Q703K mutation in the NLRP3 gene. METHODS: Seven Caucasian patients (mean age 37.3±8.5 years, 2 males and 5 females) were identified as carriers of the Q703K mutation among 71 patients with CAPS-like symptoms. RESULTS: The mean age at disease onset was 25.58±16.08 years and the mean disease duration was 12.28±8.36. The mean number of febrile episodes was 7.56±6.48 and the mean duration of fever attacks was 6.66±4.71 days. Six out of 7 patients had a low grade fever, while 1 patient had no fever episodes. All patients were characterised by symptoms consistent with recurrent inflammatory syndrome. Six patients out of 7 presented skin lesions, 4/7 arthralgia, 4/7 myalgia, 4/7 conjunctivitis, 3/7 headache. All patients also complained of severe fatigue. In 4/7 patients symptoms were triggered or worsened by generalised cold exposure. CONCLUSIONS: We suggest that patients carrying the low-penetrance Q703K mutation in the NLRP3 gene may present with FCAS-like symptoms. However, given the high frequency of healthy carriers, the role of additional, still unknown genetic and/or environmental modifiers is conceivable

Efficacy of anakinra in refractory Behçet's disease sacroiliitis

A report of Behçet's disease-associated sacroiliitis responsive to anakinra is described