Unravelling the clinical heterogeneity of undefined recurrent fever over time in the European registries on Autoinflammation.

BACKGROUND: Systemic autoinflammatory disorders (SAIDs) represent a growing spectrum of diseases characterized by dysregulation of the innate immune system. The most common pediatric autoinflammatory fever syndrome, Periodic Fever, Aphthous Stomatitis, Pharyngitis, Adenitis (PFAPA), has well defined clinical diagnostic criteria, but there is a subset of patients who do not meet these criteria and are classified as undefined autoinflammatory diseases (uAID). This project, endorsed by PRES, supported by the EMERGE fellowship program, aimed to analyze the evolution of symptoms in recurrent fevers without molecular diagnosis in the context of undifferentiated AIDs, focusing on PFAPA and syndrome of undifferentiated recurrent fever (SURF), using data from European AID registries. METHODS: Data of patients with PFAPA, SURF and uSAID were collected from 3 registries including detailed epidemiological, demographic and clinical data, results of the genetic testing and additional laboratory investigations with retrospective application of the modified Marshall and PRINTO/Eurofever classification criteria on the cohort of PFAPA patients and preliminary SURF criteria on uSAID/SURF patients. RESULTS: Clinical presentation of PFAPA is variable and some patients did not fit the conventional PFAPA criteria and exhibit different symptoms. Some patients did not meet the criteria for either PFAPA or SURF, highlighting the heterogeneity within these groups. The study also explored potential overlaps between PFAPA and SURF/uAID, revealing that some patients exhibited symptoms characteristic of both conditions, emphasizing the need for more precise classification criteria. CONCLUSIONS: Patients with recurrent fevers without molecular diagnoses represent a clinically heterogeneous group. Improved classification criteria are needed for both PFAPA and SURF/uAID to accurately identify and manage these patients, ultimately improving clinical outcomes.

[The most frequent febrile syndromes and autoinflammatory diseases in adulthood]. / Die häufigsten Fiebersyndrome und autoinflammatorischen Erkrankungen im Erwachsenenalter.

Autoinflammatory diseases are characterized by inflammatory manifestations in various organ systems, whereby recurrent febrile episodes, musculoskeletal complaints, gastrointestinal and cutaneous symptoms frequently occur accompanied by serological signs of inflammation. Autoinflammatory diseases include rare monogenic entities and multifactorial or polygenic diseases, which can manifest as a variety of symptoms in the course of time. Examples of monogenic autoinflammatory diseases are familial Mediterranean fever (FMF), cryopyrin-associated periodic syndrome (CAPS), tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS) and the recently described VEXAS (vacuoles, E1 enzyme, X­linked, autoinflammatory and somatic) syndrome. For non-monogenically determined autoinflammatory diseases, the most important representatives in adulthood are adult-onset Still's disease (AOSD) and the Schnitzler syndrome, in which a polygenic susceptibility and epigenetic factors are more likely to play a role.

Deficiency of adenosine deaminase 2: a genetic autoinflammatory disorder mimicking childhood polyarteritis nodosa.

A girl in the early adolescent age group presented with multisystem manifestations in the form of periodic fever, recurrent abdominal pain, hypertension, seizure, skin lesions over the chest and gangrene over the left ring and middle fingertips. Her condition had remained undiagnosed for 11 years. On evaluation, she had features of polyarteritis nodosa (PAN) (multiple aneurysms, symmetric sensorimotor peripheral neuropathy, superficial ulcers, digital necrosis, myalgia, hypertension and proteinuria). As childhood PAN is a phenocopy of adenosine deaminase 2 with a different management strategy, whole-exome sequencing was performed, which revealed a pathogenic variant in ADA2 gene. The child was treated with TNF alpha inhibitors and showed improvement in the Paediatric Vasculitis Activity Score. The paper highlights the gratifying consequences of correct diagnosis with disease-specific therapy that ended the diagnostic odyssey, providing relief to the patient from debilitating symptoms and to the family from the financial burden of continued out-of-pocket health expenditure.

[THE 12TH CONGRESS OF THE INTERNATIONAL SOCIETY OF SYSTEMIC AUTOINFLAMMATORY DISEASES (ISSAID) HELD ON 15-18 MAY 2023, TORONTO, CANADA].

INTRODUCTION: THE 12TH CONGRESS OF THE INTERNATIONAL SOCIETY OF SYSTEMIC AUTOINFLAMMATORY DISEASES (ISSAID) HELD ON 15-18 MAY 2023, TORONTO, CANADA.

Identifying high-risk neurological phenotypes in adult-onset classic monogenic autoinflammatory diseases: when should neurologists consider testing?

BACKGROUND: Monogenic autoinflammatory disorders result in a diverse range of neurological symptoms in adults, often leading to diagnostic delays. Despite the significance of early detection for effective treatment, the neurological manifestations of these disorders remain inadequately recognized. METHODS: We conducted a systematic review searching Pubmed, Embase and Scopus for case reports and case series related to neurological manifestations in adult-onset monogenic autoinflammatory diseases. Selection criteria focused on the four most relevant adult-onset autoinflammatory diseases-deficiency of deaminase 2 (DADA2), tumor necrosis factor receptor associated periodic fever syndrome (TRAPS), cryopyrin associated periodic fever syndrome (CAPS), and familial mediterranean fever (FMF). We extracted clinical, laboratory and radiological features to propose the most common neurological phenotypes. RESULTS: From 276 records, 28 articles were included. The median patient age was 38, with neurological symptoms appearing after a median disease duration of 5 years. Headaches, cranial nerve dysfunction, seizures, and focal neurological deficits were prevalent. Predominant phenotypes included stroke for DADA2 patients, demyelinating lesions and meningitis for FMF, and meningitis for CAPS. TRAPS had insufficient data for adequate phenotype characterization. CONCLUSION: Neurologists should be proactive in diagnosing monogenic autoinflammatory diseases in young adults showcasing clinical and laboratory indications of inflammation, especially when symptoms align with recurrent or chronic meningitis, small vessel disease strokes, and demyelinating lesions.

Case report: Novel compound heterozygous IL1RN mutations as the likely cause of a lethal form of deficiency of interleukin-1 receptor antagonist.

Undiagnosed monogenic diseases represent a challenging group of human conditions highly suspicious to have a genetic origin, but without conclusive evidences about it. We identified two brothers born prematurely from a non-consanguineous healthy couple, with a neonatal-onset, chronic disease characterized by severe skin and bone inflammatory manifestations and a fatal outcome in infancy. We conducted DNA and mRNA analyses in the patients' healthy relatives to identify the genetic cause of the patients' disease. DNA analyses were performed by both Sanger and next-generation sequencing, which identified two novel heterozygous IL1RN variants: the intronic c.318 + 2T>G variant in the father and a ≈2,600-bp intragenic deletion in the mother. IL1RN mRNA production was markedly decreased in both progenitors when compared with healthy subjects. The mRNA sequencing performed in each parent identified two novel, truncated IL1RN transcripts. Additional experiments revealed a perfect intrafamilial phenotype-genotype segregation following an autosomal recessive inheritance pattern. The evidences shown here supported for the presence of two novel loss-of-function (LoF) IL1RN pathogenic variants in the analyzed family. Biallelic LoF variants at the IL1RN gene cause the deficiency of interleukin-1 receptor antagonist (DIRA), a monogenic autoinflammatory disease with marked similarities with the patients described here. Despite the non-availability of the patients' samples representing the main limitation of this study, the collected evidences strongly suggest that the patients described here suffered from a lethal form of DIRA likely due to a compound heterozygous genotype at IL1RN, thus providing a reliable genetic diagnosis based on the integration of old medical information with currently obtained genetic data.

The First Case of a Korean Patient with a Mutation-Confirmed Tumor Necrosis Factor Receptor-Associated Periodic Syndrome.

Tumor necrosis factor receptor-associated periodic syndrome (TRAPS, OMIM: #142680) is a rare autoinflammatory disease (AID) with recurrent febrile episodes. To our knowledge, we report herein the first case of a patient with TRAPS in South Korea whose symptoms included fever, arthralgia, abdominal pain, rash, myalgia, cough, and lymphadenopathy. A pathogenic de novo mutation, c.175T>C (p.Cys59Arg), in the tumor necrosis factor receptor superfamily member 1A (TNFRSF1A) gene, was confirmed by gene sequencing. The patient has been with tocilizumab (an interleukin-6 inhibitor); tocilizumab administration every other week has completely alleviated the patient's symptoms. Our report further expands the clinical spectrum of patients with TRAPS and reaffirms the use of tocilizumab as a viable alternative treatment option for those patients who are unsatisfactorily responsive to other commonly used biologics, such as canakinumab, anakinra, infliximab, and etanercept. Furthermore, our report may aid in increasing awareness about the existence of mutation-confirmed TRAPS in South Korea in addition to emphasizing the importance of actively pursuing genetic testing to correctly diagnose rare AID.

Ocular and orbital manifestations in VEXAS syndrome.

BACKGROUND: VEXAS (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) is a hematoinflammatory disease that typically affects adults. It results from a somatic mutation of the E1 ubiquitin conjugating enzyme encoded by the UBA1 gene. VEXAS is frequently accompanied by myelodysplastic syndrome (MDS). The purpose of this study is to describe the ocular and orbital manifestations of VEXAS patients in a case series in our medical centre. METHODS: A retrospective chart review was performed for all patients who were diagnosed with VEXAS syndrome in a tertiary medical centre over two years. RESULTS: Eight patients were identified with VEXAS. In six patients, the diagnosis was confirmed by genomic sequencing. Two patients were identified based on their phenotype. All patients were males. The mean age at diagnosis was 78.7 years. In two patients, the ocular manifestation was the presenting symptom for VEXAS. Seven patients (87.5%) had history of MDS. Systemic inflammation manifestations include: skin rash (n = 5), recurrent fevers (n = 2), relapsing polychondritis (n = 2), pleuritis and pleural effusion (n = 2), poly arteritis nodosa- PAN (n = 1) and thrombophlebitis (n = 1). Seven (87%) patients were presented with periorbital oedema. Three patients showed orbital inflammation. Dacryoadenitis was observed in two patients, and extraocular muscle (EOM) myositis was detected in two patients. Four patients demonstrated ocular inflammation such as: episcleritis, scleritis and anterior uveitis. CONCLUSION: ocular manifestations in VEXAS include orbital inflammation, dacryoadenitis, myositis, uveitis, scleritis, episcleritis and periorbital oedema. We recommend that in old male patients, with history of haematological disorder, presenting with ocular symptom, VEXAS investigation should be taken into consideration.

Orbital/ocular inflammatory involvement in VEXAS syndrome: Data from the international AIDA network VEXAS registry.

VEXAS syndrome is a recently described monogenic autoinflammatory disease capable of manifesting itself with a wide array of organs and tissues involvement. Orbital/ocular inflammatory manifestations are frequently described in VEXAS patients. The objective of this study is to further describe orbital/ocular conditions in VEXAS syndrome while investigating potential associations with other disease manifestations. In the present study, twenty-seven out of 59 (45.8 %) VEXAS patients showed an inflammatory orbital/ocular involvement during their clinical history. The most frequent orbital/ocular affections were represented by periorbital edema in 8 (13.6 %) cases, episcleritis in 5 (8.5 %) patients, scleritis in 5 (8.5 %) cases, uveitis in 4 (6.8 %) cases, conjunctivitis in 4 (6.8 %) cases, blepharitis in 3 (5.1 %) cases, orbital myositis in 2 (3.4 %) cases. A diagnosis of systemic immune-mediated disease was observed in 15 (55.6 %) cases, with relapsing polychondritis diagnosed in 12 patients. A significant association was observed between relapsing polychondritis and orbital/ocular involvement in VEXAS syndrome (Relative Risk: 2.37, 95 % C.I. 1.03-5.46, p = 0.048). Six deaths were observed in the whole cohort of patients after a median disease duration of 1.2 (IQR=5.35) years, 5 (83.3 %) of which showed orbital/ocular inflammatory involvement. In conclusion, this study confirms that orbital/ocular inflammatory involvement is a common finding in VEXAS patients, especially when relapsing polychondritis is diagnosed. This makes ophthalmologists a key figure in the diagnostic process of VEXAS syndrome. The high frequency of deaths observed in this study seems to suggest that patients with orbital/ocular involvement may require increased attention and more careful follow-up.

Practical Approach to Diagnosis and Management of IL-1-Mediated Autoinflammatory Diseases (CAPS, TRAPS, MKD, and DIRA).

Systemic autoinflammatory diseases (SAIDs) are a group of rare genetic and nongenetic immune dysregulatory disorders associated with high morbidity and mortality if left untreated. Therefore, early diagnosis and initiation of targeted treatment is vital in SAID patients to control the disease activity and prevent long-term immune-mediated damage. A specific group of genetically defined SAIDs is associated with increased inflammasome-mediated production of active interleukin (IL)-1. Even though progress in immunobiology and genetics has brought forth diagnostic tools and novel treatments that have been described in the literature extensively, many challenges remain in the clinical setting. Some challenges that health care providers may face on a day-to-day basis include the requirement of a multidisciplinary approach due to the complexity of these diseases, limited evidence-based treatment options, and barriers to access available therapies. Primarily, IL-1 inhibitors anakinra, canakinumab, and rilonacept are used to control the inflammation in these patients, with the goal of achieving sustainable remission. Recently published provisional points to consider from the European Alliance of Associations for Rheumatology (EULAR) and American College of Rheumatology (ACR) provide diagnosis, management, and monitoring recommendations for four IL-1-mediated autoinflammatory diseases: cryopyrin-associated periodic syndromes (CAPS), tumour necrosis factor receptor-associated periodic syndrome (TRAPS), mevalonate kinase deficiency (MKD), and deficiency of the IL-1 receptor antagonist (DIRA). The goal of this paper is to aid health care professionals by providing a practical approach to diagnosis and management of these four IL-1 mediated SAIDs on the basis of the recent EULAR/ACR recommendations.

The expanding clinical spectrum of autoinflammatory diseases with NOD2 variants: a case series and literature review.

Objective: To assess the impact conferred by NOD2 variants on the clinical spectrum of patients with systemic autoinflammatory diseases (SAIDs) in Greece. Methods: Consecutive patients (n=167) with confirmed SAIDs who underwent screening by next generation sequencing (NGS) targeting 26 SAID-associated genes, and carried at least one NOD2 gene variant, were retrospectively studied. The demographic, clinical and laboratory parameters were recorded. Results: In total, 24 rare NOD2 variants in 23/167 patients (14%) were detected. Notably, 18 patients had at least one co-existing variant in 13 genes other than NOD2. Nine patients had juvenile- and 14 adult-onset disease. All patients presented with symptoms potentially induced by the NOD2 variants. In particular, the candidate clinical diagnosis was Yao syndrome (YAOS) in 12 patients (7% of the whole SAID cohort). The clinical spectrum of patients with YAOS (mean episode duration 8 days) was fever (n=12/12), articular symptoms (n=8), gastrointestinal symptoms (n=7; abdominal pain/bloating in 7; diarrhea in 4; oral ulcers in 3), serositis (n=7), and rash (n=5), while the inflammatory markers were elevated in all but one patient. Most of these patients showed a poor response to nonsteroidal anti-inflammatory drugs (n=7/9), colchicine (n=6/8) and/or anti-TNF treatment (n=3/4), while a complete response was observed in 6/10 patients receiving steroids and 3/5 on anti-IL1 treatment. Another 8 patients were diagnosed with either FMF (n=6) or PFAPA syndrome (n=2) presenting with prominent diarrhea (n=7), oral ulcers (n=2), periorbital swelling and sicca-like symptoms (n=1), or maculopapular rash (n=1). One patient had a clinically undefined SAID, albeit characterized by oral ulcers and diarrhea. Finally, one patient presented with chronic relapsing urticaria with periorbital edema and inflammatory markers, and another one had a Crohn-like syndrome with good response to anti-IL-1 but refractory to anti-TNF treatment. Conclusion: NOD2 variants were detected in 1 out of 7 SAID patients and seem to have an impact on disease phenotype and treatment response. Further studies should validate combined molecular and clinical data to better understand these distinct nosological entities.

A diffuse, pustular eruption in a neonate: Recognizing SAMD9L-associated autoinflammatory disease (SAAD).

A 3-week-old baby with hydrops fetalis, acute respiratory failure, and shock of unknown etiology developed a diffuse, pustular rash with worsening inflammatory markers and respiratory status despite antimicrobials. Whole exome sequencing revealed a de novo, frameshift mutation in the SAM9DL gene, leading to the diagnosis of SAMD9L-associated autoinflammatory disease.

NLRP1-associated autoinflammatory disease with epithelial dyskeratosis.

Several gain-of-function variants in NLRP1 cause a distinctive autoinflammatory disease reported under different names featuring mainly skin and mucosal involvement and variable systemic signs. Here, we report a new case of NLRP1-associated autoinflammatory disease in a 6-year-old Peruvian girl, who presented with confluent hyperkeratotic plaques that drained purulent material with subsequent scarring. A c.3641C > G (p. Pro1214Arg) variant that has been previously been reported was found in NLRP1 and was not present in either parent. The term NLRP1-associated autoinflammatory disease with epithelial dyskeratosis (NADED) is proposed to encompass all reported cases, which have received different nomenclature so far.

[Lung involvement in autoinflammatory diseases]. / Atteinte pulmonaire dans les maladies auto-inflammatoires.

Genetic autoinflammatory diseases are now a recognized and rapidly expanding group. The lung involvement historically associated with autoinflammatory diseases is inflammatory seritis, primarily seen in familial Mediterranean fever and other interleukin-1 mediated diseases. Over the last ten years, pulmonary involvement has been the core presentation of two autoinflammatory diseases associated with constitutive type I interferon activation, i.e. SAVI and COPA syndrome. Most patients with these diseases usually develop early progression to pulmonary fibrosis, which is responsible for high rates of morbidity and mortality. Other rare autoinflammatory diseases are associated with alveolar proteinosis, particularly when related to MARS mutations. Additionally, in adults, VEXAS is frequently associated with pulmonary involvement, albeit without prognosis effect. A molecular approach to autoinflammatory diseases enables not only the definition of biomarkers for diagnosis, but also the identification of targeted treatments. Examples include JAK inhibitors in SAVI and COPA syndrome, even though this therapy does not prevent progression to pulmonary fibrosis. Another illustrative example is the efficacy of methionine supplementation in alveolar proteinosis linked to MARS mutations. Overall, in autoinflammatory diseases the lung is now emerging as a possible affected organ. Continuing discovery of new autoinflammatory diseases is likely to uncover further pathologies involving the lung. Such advances are expected to lead to the development of novel therapeutic perspectives.