Autoinflammatory disease reloaded: a clinical perspective.

Our understanding of the etiology of autoinflammatory disease is growing rapidly. Recent advances offer new opportunities for therapeutic intervention and suggest that the definition of what constitutes an autoinflammatory disease should be reassessed.

The relationship between defects in DNA repair genes and autoinflammatory diseases.

Tissue inflammation and damage with the abnormal and overactivation of innate immune system results with the development of a hereditary disease group of autoinflammatory diseases. Multiple numbers of DNA damage develop with the continuous exposure to endogenous and exogenous genotoxic effects, and these damages are repaired through the DNA damage response governed by the genes involved in the DNA repair mechanisms, and proteins of these genes. Studies showed that DNA damage might trigger the innate immune response through nuclear DNA accumulation in the cytoplasm, and through chronic DNA damage response which signals itself and/or by micronucleus. The aim of the present review is to identify the effect of mutation that occurred in DNA repair genes on development of DNA damage response and autoinflammatory diseases.

Performance of recently proposed periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome criteria in a region endemic for familial Mediterranean fever.

The periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome is an auto-inflammatory condition characterized by recurrent episodes of fever accompanied by aphthosis, cervical adenitis, and pharyngitis. Diagnosis of PFAPA could be challenging due to clinic overlap with familial Mediterranean fever (FMF). An international consensus has been established recently, to define a new set of classification criteria for PFAPA syndrome. We aimed to evaluate the performance of recently proposed PFAPA criteria, to assess their utility in FMF regions. Patients diagnosed with PFAPA syndrome, FMF, and juvenile idiopathic arthritis (JIA) were included. Two investigators blindly evaluated all of patients for the newly proposed PFAPA criteria. A total of 542 patients (322 with PFAPA syndrome, 118 FMF and 102 JIA) were evaluated. Mean age of patients was 6.6 ± 2.81, 12.75 ± 3.9, and 12.42 ± 4.8 years for PFAPA, FMF, and JIA, respectively. We found quite high sensitivity (89.7%) but insufficient specificity of newly proposed PFAPA criteria (69.5%). When applied to control patients separately, specificity was found to be 61% and 79.4% for FMF and JIA patients, respectively. Positive predictive value was 81%, while negative predictive value was 82%. Recently proposed PFAPA criteria have satisfactory sensitivity, but its specificity is still under expectation. There is a need for a distinctive criterion between PFAPA syndrome and FMF, in FMF endemic regions, e.g., cryptic tonsillitis rapidly responsive to single dose of glucocorticoids. Further studies with higher patients' number in different regions are needed.

Pattern and diagnostic evaluation of systemic autoinflammatory diseases other than familial Mediterranean fever among Arab children: a multicenter study from the Pediatric Rheumatology Arab Group (PRAG).

To define the spectrum and phenotypic characteristics of systemic autoinflammatory diseases (SAIDs) other than familial Mediterranean fever (FMF) in Arab children and to delineate diagnostic evaluation. Data retrospectively collected on patients with clinical and/or genetically proven SAIDs other than FMF at 10 tertiary Arab pediatric rheumatology clinics from 1990 to 2018. The collected data comprised the clinical findings and diagnostic evaluation including genetic testing, the provided treatment and the accrual damage related to SAIDs. A total of 144 patients (93 female) with a median age at onset of 2.5 (range 0.1-12) years were enrolled. The initial diagnosis was inaccurate in 49.3%. Consanguinity rate among parents was 74.6%. The median time-to-diagnosis for all SAIDs was 2.5 (range 0.1-10) years. There were 104 patients (72.2%) with a confirmed diagnosis and 40 patients with suspected SAIDs. Seventy-two had monogenic and 66 patients with multifactorial SAIDs while six patients had undifferentiated SAIDs. The most frequent monogenic SAIDs were LACC1 mediated monogenic disorders (n = 23) followed by CAPS (12), TRAPS (12), HIDS (12), and Majeed's syndrome (6). The most frequent multifactorial SAIDs was CRMO (34), followed by PFAPA (18), and early onset sarcoidosis (EOS) (14). Genetic analysis was performed in 69 patients; 50 patients had genetically confirmed disease. Corticosteroid used for 93 patients while biologic agents for 96 patients. Overall, growth failure was the most frequent accrual damage (36%), followed by cognitive impairment (13%). There were three deaths because of infection. This study shows a heterogenous spectrum of SAIDs with a high number of genetically confirmed monogenic diseases; notably, LACC1 associated diseases. Hopefully, this work will be the first step for a prospective registry for SAIDs in Arab countries.

[Pathophysiology of autoinflammatory dermatoses]. / Pathophysiologie der autoinflammatorischen Dermatosen.

Autoinflammation leads to inflammation that mostly occurs without any clinically obvious reason. It can be so severe that organ damage with relevant tissue damage occurs. Inflammasomes are the drivers of autoinflammation. Although IL­1 beta and the inflammasomes as its critical regulators are very important in autoinflammation, not all patients respond to inhibition of this signalling pathway. Several autoinflammatory diseases were associated with mutations in proteasome-immunoproteasome components. Autoinflammatory diseases caused by highly relevant genetic variants are mostly hereditary. Usually in childhood but not always. The coming years will show whether inflammatory dermatoses will be increasingly treated with suppression of the innate immune system in addition to inhibition of adaptive immunity.

The innate immune perspective of autoimmune and autoinflammatory conditions.

Innate immunity is one of two immune defence system arms. It is present at birth and does not require 'learning' through exposure to foreign organisms. It activates various mechanisms collectively to eliminate pathogens and hold an infection until the adaptive response are mounted. The innate immune system consists of four elements: the epithelial barrier, cells (e.g. macrophages, NK cells), plasma proteins (e.g. complement) and cytokines. These components act in concert to induce complex processes, as well as recruitment, activation and differentiation of adaptive responses. The innate response is more than just the 'first line of defence', as it essentially withholds the vast majority of any intruder, has a complex interplay with the adaptive arm and is crucial for survival of the host. Finally, yet importantly, a myriad of diseases has been linked with innate immune dysregulation. In this mini-review we will shed some light on these conditions, particularly regarding autoinflammatory ones.

What's new in autoinflammation?

The pathogenesis of autoinflammatory diseases has shed light on the concept of inflammation in general and on our understanding of the role of the innate immune system. The autoinflammatory diseases have a large spectrum with varying features of inflammation. The most common autoinflammatory diseases are those associated with periodic fevers. The delay in diagnosis of these four common diseases (familial Mediterranean fever, cryopyrin-associated periodic fever syndrome, mevalonate kinase deficiency, and TNF receptor-associated periodic fever syndrome) results in secondary amyloidosis of the kidney. The new work towards classification criteria for these diseases is presented. Recently a group of autoinflammatory diseases that are associated with vasculitis have also been identified. These are stimulators of interferon genes (STING)-associated vasculopathy of infancy (SAVI), which is a monogenic defect associated with excessive activity in interferon alpha and deficiency of adenosine deaminase 2, which is characterized by a polyarteritis nodosa-like picture. These monogenic diseases are now in our differential diagnosis of vasculitides. Secondary amyloidosis is a complication of autoinflammatory diseases. Understanding the inflammatory mechanisms in these diseases has led to the use of targeted biologics for this complication. It is hoped that enlightening the mechanisms underlying these monogenic autoinflammatory diseases will also teach us about the pathways in common diseases.

Hints for Genetic and Clinical Differentiation of Adult-Onset Monogenic Autoinflammatory Diseases.

Monogenic autoinflammatory diseases (mAIDs) are inherited errors of innate immunity characterized by systemic inflammation recurring with variable frequency and involving the skin, serosal membranes, synovial membranes, joints, the gastrointestinal tube, and/or the central nervous system, with reactive amyloidosis as a potential severe long-term consequence. Although individually uncommon, all mAIDs set up an emerging chapter of internal medicine: recent findings have modified our knowledge regarding mAID pathophysiology and clarified that protean inflammatory symptoms can be variably associated with periodic fevers, depicting multiple specific conditions which usually start in childhood, such as familial Mediterranean fever, tumor necrosis factor receptor-associated periodic syndrome, cryopyrin-associated periodic syndrome, and mevalonate kinase deficiency. There are no evidence-based studies to establish which potential genotype analysis is the most appropriate in adult patients with clinical phenotypes suggestive of mAIDs. This review discusses genetic and clinical hints for an ideal diagnostic approach to mAIDs in adult patients, as their early identification is essential to prompt effective treatment and improve quality of life, and also highlights the most recent developments in the diagnostic work-up for the most frequent hereditary periodic febrile syndromes worldwide.

New autoinflammatory diseases.

PURPOSE OF REVIEW: Advances in sequencing techniques and systematic cohort-analysis of patients with autoinflammatory phenotypes have enabled a burst in the recognition of new autoinflammatory diseases and contributed to the description of the mechanisms involved in autoinflammation. This review focuses on new genetic and mechanistic discoveries that have broadened the definition of autoinflammatory diseases in the context of the established landscape, providing new therapeutic opportunities and avenues for further discoveries. RECENT FINDINGS: Mechanistic insights of inflammatory diseases open opportunities for new targeted therapies. Advances in high-throughput screening of small-molecule inhibitors accelerate the discovery of new and more specific therapeutic options. Recent evidence establishes IL-18 as a driver of macrophage activation, emerging as a new biomarker and therapeutic target. Finally, the identification of escape of nonsense-mediated decay as the genetic mechanism resulting in a monogenic immune-dysregulatory disease, unveils a possibility for future discoveries. SUMMARY: Recent mechanistic findings in autoinflammatory diseases as well as the identification of specific biomarkers and discovery of new diseases, continue to pave the way for ever more specific targeted approaches. These therapies are not only applicable to monogenic autoinflammatory syndromes but also for other diseases in which the same pathways are dysregulated.

Musculoskeletal manifestations in hereditary periodic fever syndromes.

Monogenic autoinflammatory diseases (AIDs) are a group of inflammatory disorders induced by deregulation of the innate immune system and characterised by inflammatory bouts with fever as well as a large spectrum of other possible manifestations involving most organs and tissues. In this context, musculoskeletal manifestations represent a frequent finding in the clinical picture of patients with AIDs and may range from less severe affections including myalgia and arthralgia to severe arthritis, muscle fasciitis, bone erosions, and joint deformities. Therefore, as diagnostic suspicions originates from a careful and detailed clinical evaluation, physicians dealing with mono- genic AIDs should bear in mind their possible muscle and joint manifestations, some of which are typical and very useful for diagnostic purposes. Indeed, their prompt recognition may reduce the diagnostic delay thus allowing an early and appropriate therapeutic management. For these reasons, the present review is aimed at providing a wide overview on the different patterns of joint and muscle affections in the four main monogenic AIDs.

The eye involvement in monogenic autoinflammatory diseases: literature review and update.

Monogenic autoinflammatory diseases (AIDs) are rare entities characterised by improper activation of the innate immune system. This in turn determines recurrent episodes of systemic inflammation characterised by fever, which is variously combined with a wide range of inflammatory manifestations involving the skin, joints, serous membranes, gastrointestinal tract, and central nervous system. As shown by research efforts conducted during the last decade, the eye is not exempt from the systemic inflammatory process and may be involved in almost all of the most frequent AIDs, with several distinct peculiarities. Ocular affections may severely impact patients' quality of life due to orbital pain, impairment of visual acuity, and/ or long-term, sight-threatening complications. Consequently, in the context of a multidisciplinary team, ophthalmologists should be aware of ocular manifestations related to these disorders as they may have a dominant diagnostic weight in patients with a challenging presentation as well as a salient role in therapeutic choice in sight-threatening situations. This review describes a variety of aspects of ophthalmologic involvement in AIDs, looking at both well-recognised eye manifestations as well as rarely reported ocular presentations, with a particular focus on the recent literature.

Neurological manifestations in autoinflammatory diseases.

Autoinflammatory diseases (AIDs) are a distinct group of diseases characterised by a dysregulation of the innate immune response leading to systemic inflammation. The clinical spectrum of these conditions is extremely variable and possibly every system and tissue can be involved, including the central nervous system (CNS). Indeed, neurological manifestations may dominate the clinical picture from disease onset in some rare conditions. However, the involvement of the CNS in AIDs is not a disease in itself, but represents a rare complication which is consequent to a systemic or local immune response, mainly involving cells of the innate immunity. This review will describe neurological manifestations associated with AIDs, including: chronic aseptic meningitis and brain atrophy, sensori-neural hearing loss, early-onset haemorrhagic and ischaemic strokes, mental retardation, cerebellitis, and ataxia, and severe encephalopathy with brain calcifications.

Autoinflammatory Disease-Associated Vasculitis/Vasculopathy.

PURPOSE OF REVIEW: Autoinflammatory diseases (AIDs) constitute several disorders that share similar characteristics, clinical features, disease course, and prognosis. They are characterized by the presence of recurrent episodes of unprovoked inflammation due to dysregulated innate immune system in the absence of autoantibodies or infections. AIDs include periodic fever syndromes and other less commonly growing list of syndromes. In this review, vasculitis associated with different AIDs will be highlighted. RECENT FINDINGS: Vasculitis is inflammation and necrosis of the blood vessels causing impaired blood flow, ischemia, and infarction of the dependent tissues. It is a very rare manifestation of AIDs and when it occurs, the skin is the most affected tissue than any other organs such as kidneys, lungs, or CNS. Although vasculitis and AIDs share similar manifestations such as fever, skin rashes, and neuropathy, vasculitis is not a characteristic feature of AIDs and still not clear if it represents a main clinical feature or a manifestation of other disease process.

The challenge of autoinflammatory syndromes: with an emphasis on hyper-IgD syndrome.

Autoinflammatory syndromes are disorders with an exaggerated inflammatory response, mostly in the absence of an appropriate trigger. Prototypic autoinflammatory syndromes are FMF, hyper-IgD syndrome (also known as mevalonate kinase deficiency), TNF receptor-associated periodic syndrome and cryopyrin-associated periodic syndrome. The clinical phenotypes partly overlap (with fever and acute phase response), but also differ between the various syndromes (e.g. regarding fever pattern, episodic vs chronic inflammation and accompanying clinical signs). In recent years, the genetic basis of quite a number of these relatively rare and mostly hereditary disorders has been elucidated. These genetic defects lead to either enhanced production of inflammatory mediators or to a lack of inhibition of these components of the innate immune system. Among these dysregulated inflammatory mediators, the pro-inflammatory cytokine IL-1ß stands out. Hence, targeted treatment with blockers of IL-1 action, such as recombinant IL-1 receptor antagonist (IL-1Ra, anakinra) and mAb against IL-1ß has met with impressive clinical results. In this article, hyper-IgD syndrome is discussed in more detail, based on 30 years of experience with this syndrome.

A novel assessment tool for clinical care of patients with autoinflammatory disease: juvenile autoinflammatory disease multidimensional assessment report.

OBJECTIVES: To develop and test a new multidimensional questionnaire for assessment of children with auto-inflammatory disease (AID) such as FMF, PFAPA, HIDS, TRAPS in standard clinical care. METHODS: The juvenile auto-inflammatory disease multidimensional assessment report (JAIMAR) includes 16 parent or patient-centered measures and four dimensions that assess functional status, pain, therapeutic compliance and health-related quality of life (physical, social, school, emotional status) with disease outcome. It is proposed for use as both a proxy-report and a patient self-report, with the suggested age range of 8-18 years for use as a self-report. RESULTS: 250 children with FMF were included in the study. Total of 179 forms were filled up by parents and patients, and 71 forms were filled up by parents having children less than 8 years. Completing and scoring the JAIMAR can be done in 15 minutes. For the JAIMAR's dimensions, the Cronbach's alpha coefficient for internal consistency was between 0.507-0.998. There was a significant and a positive correlation between the test-retest scale scores (ICC=0.607-0.966). Concerning construct validity, all factors loadings were above 0.30. For the criterion validity, the correlation level between each dimension and the related scale ranged from medium (r=0.329, p<0.0001) to large (r=0.894, p<0.0001). The parents' proxy-reported and children's self-reported data were outstandingly concordant (r=0.770-0.989). CONCLUSIONS: The development of the JAIMAR introduces a new and multi-dimensional approach in paediatric rheumatology practice. It is a new tool for children with auto-inflammatory dis-ease and it may help enhance their quality of care.

[Autoinflammatory diseases]. / Enfermedades autoinflamatorias.

The monogenic autoinflammatory diseases are rare, genetic disorders resulting in constitutive innate immune defects leading to excessive response to danger signals, spontaneous activation of inflammatory mediators or loss of inhibitory regulators. During the past 15 years, a growing number of monogenic inflammatory diseases have been described and their respective responsible genes identified. The proteins encoded by these genes are involved in the regulatory pathways of inflammation and are mostly expressed in cells of the innate immune system. Although a group of patients exhibit episodic systemic inflammation (periodic fevers), these disorders are mediated by continuous overproduction and release of pro-inflammatory mediators, notably IL-1ß, and are best considered as autoinflammatory diseases rather than periodic fevers. The most common autoinflammatory diseases are familial Mediterranean fever (FMF), TNF receptor-associated periodic syndrome (TRAPS), mevalonate kinase deficiency/hyperimmunoglobulin D syndrome (MKD/HIDS) and the cryopyrin-associated periodic syndromes (CAPS). Clinical features often include fever, cutaneous rash, serosal involvement and acute phase reactants. Autoantibodies are usually absent but may accompany certain syndromes. Diagnosis remains clinical and is based on the different phenotypic features. Genetic diagnosis is of utmost importance, but must be performed judiciously and interpreted cautiously. Treatment with biologic agents that block proinflammatory cytokines, particularly IL-1, has proved to be dramatically effective in many patients. Still, in many cases of autoinflammation no genetic abnormalities are detected and treatment remains suboptimal, raising the question of novel pathogenic mutations in unexplored genes and pathways.

The phenotype of TNF receptor-associated autoinflammatory syndrome (TRAPS) at presentation: a series of 158 cases from the Eurofever/EUROTRAPS international registry.

OBJECTIVE: To evaluate the genetic findings, demographic features and clinical presentation of tumour necrosis factor receptor-associated autoinflammatory syndrome (TRAPS) in patients from the Eurofever/EUROTRAPS international registry. METHODS: A web-based registry collected retrospective data on patients with TNFRSF1A sequence variants and inflammatory symptoms. Participating hospitals included paediatric rheumatology centres and adult centres with a specific interest in autoinflammatory diseases. Cases were independently validated by experts in the disease. RESULTS: Complete information on 158 validated patients was available. The most common TNFRSF1A variant was R92Q (34% of cases), followed by T50M (10%). Cysteine residues were disrupted in 27% of cases, accounting for 39% of sequence variants. A family history was present in 19% of patients with R92Q and 64% of those with other variants. The median age at which symptoms began was 4.3 years but 9.1% of patients presented after 30 years of age. Attacks were recurrent in 88% and the commonest features associated with the pathogenic variants were fever (88%), limb pain (85%), abdominal pain (74%), rash (63%) and eye manifestations (45%). Disease associated with R92Q presented slightly later at a median of 5.7 years with significantly less rash or eye signs and more headaches. Children were more likely than adults to present with lymphadenopathy, periorbital oedema and abdominal pains. AA amyloidosis has developed in 16 (10%) patients at a median age of 43 years. CONCLUSIONS: In this, the largest reported case series to date, the genetic heterogeneity of TRAPS is accompanied by a variable phenotype at presentation. Patients had a median 70 symptomatic days a year, with fever, limb and abdominal pain and rash the commonest symptoms. Overall, there is little evidence of a significant effect of age or genotype on disease features at presentation.

Validation of the auto-inflammatory diseases activity index (AIDAI) for hereditary recurrent fever syndromes.

OBJECTIVES: To validate the Auto-Inflammatory Diseases Activity Index (AIDAI) in the four major hereditary recurrent fever syndromes (HRFs): familial Mediterranean fever (FMF), mevalonate kinase deficiency (MKD), tumour necrosis factor receptor-associated periodic syndrome (TRAPS) and cryopyrin-associated periodic syndromes (CAPS). METHODS: In 2010, an international collaboration established the content of a disease activity tool for HRFs. Patients completed a 1-month prospective diary with 12 yes/no items before a clinical appointment during which their physician assessed their disease activity by a questionnaire. Eight international experts in auto-inflammatory diseases evaluated the patient's disease activity by a blinded web evaluation and a nominal group technique consensus conference, with their consensus judgement considered the gold standard. Sensitivity/specificity/accuracy measures and the ability of the score to discriminate active from inactive patients via the best cut-off score were calculated by a receiver operating characteristic analysis. RESULTS: Consensus was achieved for 98/106 (92%) cases (39 FMF, 35 CAPS, 14 TRAPS and 10 MKD), with 26 patients declared as having inactive disease and 72 as having active disease. The median total AIDAI score was 14 (range=0-175). An AIDAI cut-off score ≥9 discriminated active from inactive patients, with sensitivity/specificity/accuracy of 89%/92%/90%, respectively, and an area under the curve of 98% (95% CI 96% to 100%). CONCLUSIONS: The AIDAI score is a valid and simple tool for assessing disease activity in FMF/MKD/TRAPS/CAPS. This tool is easy to use in clinical practice and has the potential to be used as the standard efficacy measure in future clinical trials.

AA amyloidosis complicating the hereditary periodic fever syndromes.

OBJECTIVE: AA amyloidosis is a life-threatening complication of the hereditary periodic fever syndromes (HPFS), which are otherwise often compatible with normal life expectancy. This study was undertaken to determine the characteristics, presentation, natural history, and response to treatment in 46 patients who had been referred for evaluation at the UK National Amyloidosis Centre. METHODS: Disease activity was monitored by serial measurement of serum amyloid A. Renal function was assessed by measurement of serum creatinine and albumin levels, the estimated glomerular filtration rate, and proteinuria from 24-hour urine collections. The amyloid load was measured by serum amyloid P scintigraphy. RESULTS: Twenty-four patients had familial Mediterranean fever, 12 patients had tumor necrosis factor receptor-associated periodic syndrome, 6 patients had cryopyrin-associated periodic syndromes, and 4 patients had mevalonate kinase deficiency. The median age at onset of HPFS was 5 years; median age at presentation with AA amyloidosis was 38 years. Diagnosis of an HPFS had not been considered prior to presentation with AA amyloidosis in 23 patients (50%). Eleven patients (24%) had end-stage renal failure (ESRF) at presentation; of these, 3 had received transplants prior to referral. A further 13 patients developed ESRF over the followup period, with 10 undergoing renal transplantation. The median time to progression to ESRF from onset of AA amyloidosis was 3.3 years (interquartile range [IQR] 2-8), with a median time to transplant of 4 years (IQR 3-6). Eleven patients (24%) died. The median survival in the entire cohort was 19 years from diagnosis of AA amyloidosis. Of the 37 patients who were treated successfully, or in whom at least partial suppression of the underlying HPFS was achieved, 17 (46%) showed amyloid regression, 14 (38%) showed a stable amyloid load, and 2 (5%) showed increased amyloid deposition over the followup period. CONCLUSION: AA amyloidosis remains a challenging and serious late complication of HPFS; however, outcomes are excellent when HPFS is diagnosed early enough to allow effective treatment, thus preventing or retarding further amyloid deposition and organ damage.