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Update on ocular manifestations of the main monogenic and polygenic autoinflammatory diseases.

Autoinflammatory diseases include disorders with a genetic cause and also complex syndromes associated to polygenic or multifactorial factors. Eye involvement is present in many of them, with different extent and severity. The present review covers ophthalmological lesions in the most prevalent monogenic autoinflammatory diseases, including FMF (familial Mediterranean fever), TRAPS (TNF receptor-associated periodic syndrome), CAPS (cryopyrin-associated periodic syndromes), Blau syndrome, DADA2 (deficiency of adenosine deaminase 2), DITRA (deficiency of the interleukin-36 receptor antagonist), other monogenic disorders, including several ubiquitinopathies, interferonopathies, and the recently described ROSAH (retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and headache) syndrome, and VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome. Among polygenic autoinflammatory diseases, ocular manifestations have been reviewed in Behçet's disease, PFAPA (periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis) syndrome, Still's disease and autoinflammatory bone diseases, which encompass CRMO (chronic recurrent multifocal osteomyelitis) and SAPHO (synovitis, acne, pustulosis, hyperostosis and osteitis) syndrome.

Preliminary data revealing efficacy of K12 (SSK12) in Periodic Fever, Aphthous stomatitis, Pharyngitis, and cervical Adenitis (PFAPA) syndrome: A multicenter study from the AIDA Network PFAPA syndrome registry.

To evaluate the potential role of K12 (SSK12) in controlling febrile flares in patients with Periodic Fever, Aphthous stomatitis, Pharyngitis, and cervical Adenitis (PFAPA) syndrome. Further aims were to assess the impact of SSK12 on (i) flare duration, (ii) variation in the degree of the highest body temperature during flares, (iii) steroid-sparing effect, and (iv) change of PFAPA accompanying symptoms before and after SSK12 introduction. The medical charts from 85 pediatric patients with PFAPA syndrome (49 males and 36 females) enrolled in the AIDA registry and treated with SSK12 for a median period of 6.00 ± 7.00 months in the period between September 2017 and May 2022 were examined. Children recruited had a median time of disease duration of 19.00 ± 28.00 months. The number of febrile flares significantly decreased comparing the 12 months before [median (IQR), 13.00 (6.00)] and after SSK12 initiation [median (IQR), 5.50 (8.00), < 0.001]. The duration of fever was significantly reduced from 4.00 (2.00) days to 2.00 (2.00) days [ < 0.001]. Similarly, the highest temperature in°C was found significantly lower in the last follow-up assessment [median (IQR), 39.00 (1.00)] compared to the period prior to SSK12 start [median (IQR), 40.00 (1.00), < 0.001]. Steroid load (mg/year) of betamethasone (or any equivalent steroid) significantly decreased between 12 months before treatment with SSK12 [median (IQR), 5.00 (8.00) mg/year] and the last follow-up visit [median (IQR), 2.00 (4.00) mg/year, < 0.001]. The number of patients experiencing symptoms including pharyngitis/tonsillitis ( < 0.001), oral aphthae ( < 0.001) and cervical lymphadenopathy ( < 0.001) significantly decreased following SSK12. SSK12 prophylaxis given for at least 6.00 months was found to reduce febrile flares of PFAPA syndrome: in particular, it halved the total number per year of fever flares, shortened the duration of the single febrile episode, lowered body temperature by 1°C in the febrile flare, provided a steroid-sparing effect, and significantly reduced the accompanying symptoms related to the syndrome.

Development and implementation of the AIDA International Registry for patients with Periodic Fever, Aphthous stomatitis, Pharyngitis, and cervical Adenitis syndrome.

Aim of this paper is to illustrate the methodology, design, and development of the AutoInflammatory Disease Alliance (AIDA) International Registry dedicated to patients with the Periodic Fever, Aphthous stomatitis, Pharyngitis, and cervical Adenitis (PFAPA) syndrome. This is a physician-driven, non-population- and electronic-based registry proposed to gather real-world demographics, clinical, laboratory, instrumental and socioeconomic data from PFAPA patients. Data recruitment is realized through the on-line Research Electronic Data Capture (REDCap) tool. This registry is thought to collect standardized information for clinical research leading to solid real-life evidence. The international scope and the flexibility of the registry will facilitate the realization of cutting-edge study projects through the constant updating of variables and the possible merging and transfer of data between current and future PFAPA registries. A total of 112 centers have already been involved from 23 countries and 4 continents starting from August 24th, 2021, to April 6th, 2022. In total 56/112 have already obtained the formal approval from their local Ethics Committees. The platform counts 321 users (113 principal investigators, 203 site investigators, two lead investigators, and three data managers). The registry collects retrospective and prospective data using 3,856 fields organized into 25 instruments, including PFAPA patient's demographics, medical histories, symptoms, triggers/risk factors, therapies, and impact on the healthcare systems. The development of the AIDA International Registry for PFAPA patients will enable the on-line collection of standardized data prompting real-life studies through the connection of worldwide groups of physicians and researchers. This project can be found on https://clinicaltrials.gov NCT05200715.

Evolving Frontiers in the Treatment of Periodic Fever, Aphthous Stomatitis, Pharyngitis, Cervical Adenitis (PFAPA) Syndrome.

Fevers recurring at a nearly predictable rate every 3-8 weeks are the signature symptom of periodic fever, aphthous stomatitis, pharyngitis, cervical adenitis (PFAPA) syndrome, an acquired autoinflammatory disorder which recurs in association with at least one sign among aphthous stomatitis, pharyngitis, and/or cervical lymph node enlargement without clinical signs related to upper respiratory airways or other localized infections. The disease usually has a rather benign course, although it might relapse during adulthood after a spontaneous or treatment-induced resolution in childhood. The number of treatment choices currently available for PFAPA syndrome has grown in recent years, but data from clinical trials dedicated to this disorder are limited to small cohorts of patients or single case reports. The response of PFAPA patients to a single dose of corticosteroids is usually striking, while little data exist for treatment with cimetidine and colchicine. Preliminary interesting results have been published with regard to vitamin D supplementation in PFAPA syndrome, while inhibition of interleukin-1 might represent an intriguing treatment for PFAPA patients who have not responded to standard therapies. Tonsillectomy has been proven curative in many studies related to PFAPA syndrome, although the evidence of its efficacy is not widely shared by different specialists, including pediatricians, rheumatologists and otorhynolaryngologists.

A comprehensive comparison between pediatric and adult patients with periodic fever, aphthous stomatitis, pharyngitis, and cervical adenopathy (PFAPA) syndrome.

Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenopathy (PFAPA) syndrome is a mysterious disorder characterized by periodically recurrent fevers, oropharyngeal inflammation, and adenitis, which mainly affects children, though in very recent times, it has been also recognized in adulthood. We enrolled 115 unrelated pediatric and adult patients with history of periodic fevers who fulfilled the current diagnostic criteria for PFAPA syndrome in three Italian referral centers and highlighted differences between children and adults. Eighty-five children and 30 adults were evaluated: the frequency of flares was significantly higher in pediatric cases, while febrile attack duration was significantly longer in adults. Clockwork periodicity of fever and recurrent pharyngitis were more frequently observed in childhood, but no differences were identified for aphthosis and cervical adenopathy. Conversely, joint symptoms, myalgia, headache, fatigue, ocular signs, and rashes were more common in adults. The simultaneous occurrence of two or three cardinal PFAPA signs did not show any statistical difference between the groups, while the occurrence of only one cardinal manifestation was more frequent in adults. Corticosteroids were effective in 98.82 % of children and 88.2 % of adults. Tonsillectomy was rarely performed, resulting effective in only two patients. Our data illustrate the clinical overlap between pediatric and adult cases of PFAPA syndrome. Adults are characterized by a wider repertoire of inflammatory signs, suggesting that onset in adulthood might leave the disease misdiagnosed. Clinicians, not only pediatricians, should take into account this clinical entity in every patient of whatever age suffering from recurrent fevers of unknown origin.

Canakinumab efficacy in refractory adult-onset PFAPA syndrome.

Diagnostic Criteria for Adult-Onset Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Cervical Adenitis (PFAPA) Syndrome.

To identify a set of variables that could discriminate patients with adult-onset periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome from subjects with fever of unknown origin (FUO). We enrolled 74 adults diagnosed with PFAPA syndrome according to the currently used pediatric diagnostic criteria and 62 additional patients with FUO. After having collected clinical and laboratory data from both groups, univariate and multivariate analyses were performed to identify the variables associated with PFAPA diagnosis. Odds ratio (OR) values, their statistical significance, and corresponding 95% confidence interval (CI) were evaluated for each diagnostic factor both at the univariate and multivariate analyses. Diagnostic accuracy was evaluated by the area under receiver operating characteristic (ROC) curve, while the leave-one-out cross-validation procedure was used to ensure that the model maintains the same diagnostic power when applied to new data. According to the multivariate analysis, the clinical variables that discriminated PFAPA patients were: fever episodes associated with cervical lymphadenitis (OR = 92;  < 0.0001), fever attacks associated with erythematous pharyngitis (OR = 231;  < 0.0001), increased inflammatory markers during fever attacks (OR = 588;  = 0.001), and the lack of clinical and laboratory signs of inflammation between flares (OR = 1202;  < 0.0001). These variables were considered for a diagnostic model which accounted for their OR values. The diagnostic accuracy of the proposed set of criteria corresponded to an area under ROC curve of 0.978 (95% CI 0.958-0.998), with a model sensitivity and specificity equal to 93.4% (95% CI 87.5-96.5%) and 91.7% (95% CI 82.8-96.7%), respectively. we have provided herein a set of clinical diagnostic criteria for adult-onset PFAPA syndrome. Our criteria represent an easy-to-use diagnostic tool aimed at identifying PFAPA patients among subjects with FUO with a high-predictive potential, as shown by its very high sensitivity and specificity.

PFAPA syndrome and Behçet's disease: a comparison of two medical entities based on the clinical interviews performed by three different specialists.

The pediatric syndrome characterized by periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) and adult Behçet's disease share some clinical manifestations and are both polygenic autoinflammatory disorders with interleukin-1β showing to play a pivotal role. However, the diagnosis is mostly clinical and we hypothesize that specific criteria may be addressed differently by different physicians. To determine the diagnostic variability, we compared the answers of 80 patients with a definite diagnosis of Behçet's disease (age 42.1 ± 13.7 years) obtained by separate telephone interviews conducted by a rheumatologist, a pediatrician, and an internist working largely in the field of autoinflammatory disorders. Questions were related to the age of symptom onset, the occurrence of recurrent fevers during childhood, and the association with oral aphthosis, cervical adenitis and/or pharyngitis, previous treatments, possible growth impairment, the time lapse between PFAPA-like symptoms and the onset of Behçet's disease, and the occurrence of Behçet-related manifestation during childhood. The rheumatologist identified 30 % of patients with Behçet's disease fulfilling PFAPA syndrome diagnostic criteria, compared to the pediatrician and the internist identifying 10 and 7.5 %, respectively. Most of the patients suffered from recurrent oral aphthosis in childhood also without fever (50, 39, and 48 % with each interviewer), yet no patient fulfilled the Behçet's disease diagnostic criteria. Our data suggest that physician awareness and expertise are central to the diagnosis of autoinflammatory disorders through an accurate collection of the medical history.

Demographic, clinical and therapeutic findings in a monocentric cohort of adult patients with suspected PFAPA syndrome.

Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenopathy (PFAPA) syndrome is a non-Mendelian autoinflammatory disorder until now considered to be specifically limited to paediatric age. Recently, an increasing number of reports seems to suggest that PFAPA syndrome, diagnosed by the Marshall criteria revised by Thomas et al., can also affect adults. The Marshall/Thomas criteria have been applied to 989 adult patients presenting for recurrent fever episodes: all patients enrolled were reviewed for demographic, clinical, and therapeutic data. Infectious, neoplastic, autoimmune and other autoinflammatory diseases were ruled out. We identified 30 adult patients (19 males, 11 females) with a suspected PFAPA syndrome: their mean age at disease onset was 33.75±14.01 years, mean age at diagnosis 39.1±14.39 years, and mean body temperature peak 39.5±0.7°C. In addition, the mean frequency of febrile episodes was 11.58±8.97 per year. More precisely, patients complained of pharyngitis (77%), cervical adenitis (73%), asthenia (63%), arthralgia (67%), oral aphthosis (50%), myalgia (54%), cephalalgia (43%), abdominal pain (27%), nausea/vomiting (17%), periorbital pain (17%), and arthritis (10%). Six out of 30 (20%) patients had suffered from PFAPA syndrome also during childhood, and the disease had reappeared in adulthood. We provide the largest monocentric cohort of patients diagnosed with a suspected PFAPA syndrome in adulthood confirming that this syndrome can occur also during adulthood; moreover, due to the medical history of our patients and based on our experience, PFAPA syndrome might relapse during adulthood after a temporary remission reached in the course of paediatric age.

Interleukin-1 as a common denominator from autoinflammatory to autoimmune disorders: premises, perils, and perspectives.

A complex web of dynamic relationships between innate and adaptive immunity is now evident for many autoinflammatory and autoimmune disorders, the first deriving from abnormal activation of innate immune system without any conventional danger triggers and the latter from self-/non-self-discrimination loss of tolerance, and systemic inflammation. Due to clinical and pathophysiologic similarities giving a crucial role to the multifunctional cytokine interleukin-1, the concept of autoinflammation has been expanded to include nonhereditary collagen-like diseases, idiopathic inflammatory diseases, and metabolic diseases. As more patients are reported to have clinical features of autoinflammation and autoimmunity, the boundary between these two pathologic ends is becoming blurred. An overview of monogenic autoinflammatory disorders, PFAPA syndrome, rheumatoid arthritis, type 2 diabetes mellitus, uveitis, pericarditis, Behçet's disease, gout, Sjögren's syndrome, interstitial lung diseases, and Still's disease is presented to highlight the fundamental points that interleukin-1 displays in the cryptic interplay between innate and adaptive immune systems.

A case of resistant adult-onset periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA) syndrome responsive to anakinra.

Diagnosis of PFAPA syndrome applied to a cohort of 17 adults with unexplained recurrent fevers.

The pathophysiology of PFAPA syndrome, mainly characterised by regularly recurring periodic fevers associated with aphthous stomatitis, pharyngitis and/or lymphadenitis, and mostly occurring in the paediatric setting, resembles an acquired autoinflammatory disease. The description of PFAPA syndrome in adult patients is largely increasing. To recognise PFAPA syndrome in a group of adult patients evaluated for recurrent fevers in our Rheumatology Unit. To apply current diagnostic criteria for PFAPA syndrome in a group of 359 adults with unexplained recurrent fevers monitored in our Unit between January 2007 and June 2011. We have found 17 out of 359 patients fulfilling the diagnosis of PFAPA syndrome: these patients (10 males, 7 females) were Caucasian with a mean age of 33.3±9.5 years, had recurrent febrile episodes begun at a mean age of 25.9±8.3 years and a mean number of episodes of 8.3±5.2 per year with a mean duration of 5.5±1.8 days. In particular, 7/17 patients had the 3 cardinal signs, the other 10 had a combination of 2 signs. Corticosteroids were given in 14/17 patients; tonsillectomy was performed in 9/17 patients: corticosteroid responsiveness and tonsillectomy efficacy were observed respectively in 11 and 2 patients. Our case highlights the importance of considering PFAPA syndrome in adults presenting with unexplained recurrent fevers and symptoms commonly encountered in general medical practice.