Is gene panel sequencing more efficient than clinical-based gene sequencing to diagnose autoinflammatory diseases? A randomized study.

The aim of this study was to compare the effectiveness of the gene-panel next-generation sequencing (NGS) strategy versus the clinical-based gene Sanger sequencing for the genetic diagnosis of autoinflammatory diseases (AIDs). Secondary goals were to describe the gene and mutation distribution in AID patients and to evaluate the impact of the genetic report on the patient's medical care and treatment. Patients with AID symptoms were enrolled prospectively and randomized to two arms, NGS (n = 99) (32-55 genes) and Sanger sequencing (n = 197) (one to four genes). Genotypes were classified as 'consistent/confirmatory', 'uncertain significance' or 'non-contributory'. The proportion of patients with pathogenic genotypes concordant with the AID phenotype (consistent/confirmatory) was significantly higher with NGS than Sanger sequencing [10 of 99 (10·1%) versus eight of 197 (4·1%)]. MEFV, ADA2 and MVK were the most represented genes with a consistent/confirmed genotype, whereas MEFV, NLRP3, NOD2 and TNFRSF1A were found in the 'uncertain significance' genotypes. Six months after the genetic report was sent, 54 of 128 (42·2%) patients had received effective treatment for their symptoms; 13 of 128 (10·2%) had started treatment after the genetic study. For 59 of 128 (46%) patients, the results had an impact on their overall care, independent of sequencing group and diagnostic conclusion. Targeted NGS improved the diagnosis and global care of patients with AIDs.

Diagnostic utility of a targeted next-generation sequencing gene panel in the clinical suspicion of systemic autoinflammatory diseases: a multi-center study.

Systemic autoinflammatory diseases (sAIDs) are a heterogeneous group of disorders, having monogenic inherited forms with overlapping clinical manifestations. More than half of patients do not carry any pathogenic variant in formerly associated disease genes. Here, we report a cross-sectional study on targeted Next-Generation Sequencing (NGS) screening in patients with suspected sAIDs to determine the diagnostic utility of genetic screening. Fifteen autoinflammation/immune-related genes (ADA2-CARD14-IL10RA-LPIN2-MEFV-MVK-NLRC4-NLRP12-NLRP3-NOD2-PLCG2-PSTPIP1-SLC29A3-TMEM173-TNFRSF1A) were used to screen 196 subjects from adult/pediatric clinics, each with an initial clinical suspicion of one or more sAID diagnosis with the exclusion of typical familial Mediterranean fever (FMF) patients. Following the genetic screening, 140 patients (71.4%) were clinically followed-up and re-evaluated. Fifty rare variants in 41 patients (20.9%) were classified as pathogenic or likely pathogenic and 32 of those variants were located on the MEFV gene. We detected pathogenic or likely pathogenic variants compatible with the final diagnoses and inheritance patterns in 14/140 (10%) of patients for the following sAIDs: familial Mediterranean fever (n = 7), deficiency of adenosine deaminase 2 (n = 2), mevalonate kinase deficiency (n = 2), Muckle-Wells syndrome (n = 1), Majeed syndrome (n = 1), and STING-associated vasculopathy with onset in infancy (n = 1). Targeted NGS panels have impact on diagnosing rare monogenic sAIDs for a group of patients. We suggest that MEFV gene screening should be first-tier genetic testing especially in regions with high carrier rates. Clinical utility of multi-gene testing in sAIDs was as low as expected, but extensive genome-wide familial analyses in combination with exome screening would enlighten additional genetic factors causing disease.

Vasculitis and vasculitis-like manifestations in monogenic autoinflammatory syndromes.

Monogenic autoinflammatory syndromes are a rare group of disorders characterized by periodic episodes of systemic inflammation of endogenous origin. Sometimes, these diseases may present with features akin to vasculitis. We conducted a literature review on such vasculitic manifestations in described monogenic autoinflammatory syndromes utilizing the Online Mendelian Inheritance in Man (OMIM), Medline, and Scopus databases. Our search identified that Familial Mediterranean fever (FMF) can manifest with features of either small, medium, large, or variable-vessel vasculitis. Stimulator of interferon gene (STING)-associated vasculopathy of infancy (SAVI) is an interferonopathy that can mimic the presentation of medium-vessel or small-vessel vasculitis, whereas deficiency of adenosine deaminase 2 (DADA2) is another such mimic of medium-vessel vasculitis, associated in a significant number of patients with features of immunodeficiency. Occasional reports exist of vasculitic manifestations in tumor necrosis factor (TNF) receptor-associated periodic fever syndrome (TRAPS) and chronic infantile neurologic cutaneous and articular disorder (CINCA), whereas mevalonate kinase deficiency can also mimic the presentation of small- or medium-vessel vasculitis. Clinicians should be aware of the possibility of autoinflammatory disease presenting as vasculitis to diagnose and treat the same appropriately.

Perioperative care of the patient with a periodic fever syndrome.

Periodic fever syndromes are autoinflammatory disorders associated with recurrent fevers unrelated to infection. Little is known about the perioperative management of patients with these syndromes, and existing literature consists primarily of case reports and occasional case series. This narrative review discusses background information and diagnostic criteria for the three most common periodic fever syndromes: periodic fever, aphthous stomatitis, pharyngitis, adenitis (PFAPA), familial Mediterranean fever (FMF), and TNF receptor-associated periodic syndrome (TRAPS), and describes perioperative considerations for anesthesia providers when caring for the patient with a periodic fever syndrome. We include a systems-based framework in which to organize these considerations.

Analysis of clinical characteristics and factors affecting treatment responses in patients with pyoderma gangrenosum: a multicenter study of 239 patients☆.

BACKGROUND: Pyoderma Gangrenosum (PG) is a chronic disease characterized by recalcitrant skin ulcers. OBJECTIVE: We aimed to evaluate the demographic, clinical characteristics, treatments and factors affecting the treatment responses of patients with PG. METHODS: We performed a multicenter study of 12 tertiary care centers. We analyzed the data of the patients who were followed up with a diagnosis of PG between the years 2012‒2022 retrospectively. RESULTS: We included a total of 239 patients of whom 143 were female and 96 were male, with an average age of 54.2 ±â€¯17.4 years. The most common treatment was systemic steroids (n = 181, 75.7%). Among these patients, 50.8% (n = 92) used systemic steroids as the sole systemic agent, while 49.2% (n = 89) used at least one adjuvant immunosuppressive agent. The independent factors determined in regression analysis to influence response to systemic steroids positively were disease onset age ≥ 30-years, negative pathergy, absence of leukocytosis, negative wound culture, presence of a single lesion, and absence of upper extremity involvement. Biological agents were used in 18.4% (n = 44) of the patients in the present study. We also analyzed pathergy positive PG and early onset (onset age < 30) PG separately due to their distinct clinical features which were revealed during statistical analysis. STUDY LIMITATIONS: Retrospective nature of the present study. CONCLUSIONS: Analyses of the factors influencing treatment responses are addressed in this study. Also, we concluded that investigation for accompanying autoinflammatory diseases of pathergy positive PG and early onset PG is necessary and the patients in these two groups are more resistant to treatment, necessitating more complicated treatments.

Extensive thrombosis in a patient with familial Mediterranean fever, despite hyperimmunoglobulin D state in serum. [corrected].

Familial Mediterranean fever (FMF) is an autosomal recessive disease characterized by recurrent episodes of fever accompanied by peritonitis, pleuritis, arthritis, or erysipelas-like erythema. It is known to occur mainly among Mediterranean and Middle Eastern populations such as non-Ashkenazi Jews, Arabs, Turks, and Armenians. FMF is not familiar to clinicians beyond this area and diagnosing FMF can be challenging. We report a 22-yr old boy who presented with fever, arthalgia and abdominal pain. He had a history of recurrent episodes of fever associated with arthalgia which would subside spontaneously or by antipyretics. Autosomal recessive periodic fever syndromes were suspected. Immunoglobulin D (IgD) level in the serum was elevated and DNA analysis showed complex mutations (p.Glu148Gln, p.Pro369Ser, p.Arg408Gln) in the MEFV gene. 3D angio computed tomography showed total thrombosis of splenic vein with partial thrombosis of proximal superior mesenteric vein, main portal vein and intrahepatic both portal vein. This is a case of FMF associated with multiple venous thrombosis and elevated IgD level. When thrombosis is associated with elevated IgD, FMF should be suspected. This is the first adult case reported in Korea.

[Autoinflammatory diseases in children: The contribution of genetics]. / Maladies auto-inflammatoires de l'enfant : apport de la génétique.

AUTOINFLAMMATORY DISEASES IN CHILDREN: THE CONTRIBUTION OF GENETICS. Autoinflammatory diseases (AIDs) have benefited from modern genetic tools, in particular the widespread use of high-throughput sequencing, which has helped to improve our knowledge of the inheritance patterns of AIDs, whether hereditary or multifactorial. The case for genetic testing has become compelling. However, the new modes of inheritance revealed in recent years complicate genetic counselling and justify close collaboration between clinicians and biologists during multidisciplinary clinical meetings.

MALADIES AUTO-INFLAMMATOIRES DE L'ENFANT : APPORT DE LA GÉNÉTIQUE. Les maladies auto-inflammatoires (MAI) ont bénéficié des outils modernes de la génétique, notamment de la généralisation du séquençage en haut débit ayant participé à l'amélioration des connaissances concernant les modes de transmission des MAI, héréditaires ou multifactorielles. Les arguments en faveur d'une indication de test génétique sont devenus incontournables pour les MAI. Or les nouveaux modes de transmission héréditaires révélés ces dernières années rendent compliqué le conseil génétique et justifient l'étroite collaboration entre cliniciens et biologistes lors de réunions cliniques pluridisciplinaires.

[Hereditary systemic autoinflammatory diseases associated with cryopyrin]. / Pathologies auto-inflammatoires systémiques héréditaires associées à la cryopyrine.

HEREDITARY SYSTEMIC AUTOINFLAMMATORY DISEASES ASSOCIATED WITH CRYOPYRIN. CAPS (cryoprine-associated periodic syndromes) are a group of auto-inflammatory diseases of varying severity, most often beginning very early in life and characterized by febrile episodes, a pseudo-urticarial skin rash, joint manifestations and inconstantly neurosensory involvement. These symptoms may be intermittent and triggered by cold exposure but can also be chronic. Cryopyrinopathies are associated with heterozygous, gain-of-function mutations in NLRP3. These mutations are most often germline, but somatic mutations recapitulating the symptomatology are also possible. The NLRP3 gene codes for cryopyrin, an essential component of the inflammasome. The consequence of these mutations is the deregulated and excessive production of interleukin 1-ß (IL1-ß). Our understanding of the pathophysiology of these diseases has led to propose targeted anti-IL1 therapies, which are highly effective, significantly improving the natural history of the disease and the quality of life of patients.

PATHOLOGIES AUTO-INFLAMMATOIRES SYSTÉMIQUES HÉRÉDITAIRES ASSOCIÉES À LA CRYOPYRINE. Les CAPS (cryopyrin-associated periodic syndromes) constituent un groupe de maladies auto-inflammatoires de sévérité variable, débutant le plus souvent très précocement dans la vie et caractérisées par des épisodes fébriles, une éruption cutanée pseudourticarienne, des manifestations articulaires et potentiellement une atteinte neurosensorielle. Ces symptômes peuvent être intermittents et inconstamment déclenchés par le froid mais ils peuvent également prendre une forme chronique. Les cryopyrinopathies sont en lien avec des mutations hétérozygotes, gain de fonction de NLRP3. Ces mutations sont le plus souvent germinales mais des mutations somatiques récapitulant la symptomatologie sont possibles. Le gène NLRP3 code pour la cryopyrine, un constituant essentiel de l'inflammasome. La conséquence de ces mutations est la production dérégulée et excessive d'interleukine 1 bêta (IL-1ß). La compréhension physiopathologique de ces maladies a conduit à proposer des traitements ciblés par anti-IL-1, qui se sont révélés très efficaces, modifiant de façon importante l'histoire naturelle de la maladie et la qualité de vie des patients.

Systemic autoinflammatory disorders.

Inflammation is a physiologic defense mechanism against an out-side attack. Usually, it resolves after the removal of noxious causes, but systemic autoinflammatory disorders (SAIDs) have recurrent or repeated acute inflammation through uncontrolled gene function, which can present as gain-of-function or loss-of-function of a gene during inflammation. Most SAIDs are hereditary autoinflammatory diseases and develop by dysregulation of innate immunity through various pathways including inflammasomes, endoplasmic reticulum stress, nuclear factor-κB dysregulation, and interferon production. The clinical manifestations include periodic fever with various skin findings such as neutrophilic urticarial dermatosis, or vasculitic lesions. Some SAID cases stem from immunodeficiency or allergic reactions related to monogenic mutation. The diagnosis of SAIDs is based on clinical findings of systemic inflammation and genetic confirmation, and have to exclude infections or malignancies. Moreover, a genetic study is essential for clinical features to be suspect SAID with or without a family history. Treatment is based on understanding the immunopathology of SAID, and targeted therapy to control disease flares, reduce recurrent acute phases and prevent serious complications. Diagnosing and treating SAID requires understanding its comprehensive clinical features and pathogenesis related to genetic mutation.

[Marshall syndrome]. / Syndrome de Marshall.

MARSHALL SYNDROME. Marshall syndrome also known as PFAPA syndrome belongs to the group of autoinflammatory diseases. The acronym reflects the main clinical features of the disease: periodic fever, aphthous stomatitis, pharyngitis, and adenitis. It is the most common autoinflammatory disease, beginning between 1 and 5 years of age. There is little or no impact on growth, but the recurrence of febrile seizures can compromise the quality of life of patients. Clinical diagnosis meets positive and exclusion criteria. Putting it correctly allows a reassuring framework of care and avoids many unnecessary antibiotic treatments. Corticosteroid therapy is the reference treatment for the crisis. Tonsillectomy associated with adenoidectomy can be discussed but is not systematically recommended in this pathology, which is generally benign and most often heals spontaneously with age.

SYNDROME DE MARSHALL. Le syndrome de Marshall, aussi connu sous le nom de syndrome PFAPA, appartient au groupe des maladies auto-inflammatoires. L'acronyme reflète les principales caractéristiques cliniques de la maladie : fièvre périodique, aphtes, pharyngite, adénite. Il s'agit de la maladie auto-inflammatoire la plus fréquente, débutant entre 1 et 5 ans. Il n'y a pas ou peu de retentissement sur la croissance, mais la récurrence des accès fébriles peut obérer la qualité de vie des patients. Le diagnostic clinique répond à des critères positifs et d'exclusion. Bien poser celui-ci permet de poser un cadre de prise en charge rassurant pour l'entourage et d'éviter de nombreux traitements antibiotiques inutiles. La corticothérapie est le traitement de référence de la crise. L'amygdalectomie associée à l'adénoïdectomie peut être discutée mais n'est pas recommandée de façon systématique dans cette pathologie en général bénigne et guérissant le plus souvent spontanément avec l'âge.

[Mevalonate kinase deficiency]. / Déficit en mévalonate kinase.

MEVALONATE KINASE DEFICIENCY. Mevalonate kinase deficiency is a rare, autosomal recessive, auto- inflammatory disease, linked to mutations in the gene MVK, resulting in the activation of pyrin inflammasome and hypersecretion of interleukin-1ß (IL-1ß). The clinical spectrum realizes a continuum which extends from the mild phenotype of the partial MVK deficiency (hyperimmunoglobulinemia D) resulting in periodic fever syndrome to a letal form of mevalonate aciduria (MA, complete MVK deficiency). Symptoms occur before the age of one, often with a trigger. The partial MVK deficiency (HIDS) is characterized by recurrent episodes of fever with an intense inflammatory syndrome, accompanied with lymphadenopathy, aphthous stomatitis, digestive, articular and cutaneous symptoms. There is in more in mevalonate aciduria a psychomotor retardation, a failure to thrive, a cerebellar ataxia and a dysmorphic syndrome. The diagnosis is based on the mevalonic aciduria during febrile attack and the search for mutations in MVK. The most severe patients can be treated by anti-IL-1.

DÉFICIT EN MÉVALONATE KINASE. Le déficit en mévalonate kinase (MVK) est une maladie autoinflammatoire rare, de transmission autosomique récessive, liée à des mutations dans le gène MVK, aboutissant à une activation de l'inflammasome pyrine et à une hypersécrétion d'interleukine 1ß (IL-1ß). Le spectre clinique est large : de la forme modérée de syndrome avec déficit partiel en MVK (anciennement appelé syndrome hyper-IgD) à des formes létales d'acidurie mévalonique (AM ; déficit complet). Les symptômes surviennent avant l'âge de 1 an, souvent déclenchés par un trigger. Le déficit partiel en MVK comporte des accès de fièvre périodique avec un syndrome inflammatoire important, accompagnés d'adénopathies cervicales, d'une stomatite aphteuse, de signes digestifs, articulaires et cutanés. Il existe également dans l'AM un retard psychomoteur, un retard de croissance, une ataxie et un syndrome dysmorphique. Le diagnostic repose sur la mise en évidence de la mévalonaturie en période fébrile et sur la recherche de mutations dans le MVK. Les patients les plus sévères reçoivent des anti-IL-1.

R202Q prevalence in clinically diagnosed Familial Mediterranean Fever patients: 9 years of data analysis from 1570 patients living Central Black Sea region, Turkey.

INTRODUCTION: Familial Mediterranean fever (FMF) is an autosomal recessive disease characterized by recurrent self-limiting fever, peritonitis, arthritis, and erysipelas-like-erythema, common among ethnic groups such as Turkish, Armenian, Arab, and Jewish. The disease is caused by mutations in the MEFV gene encoding the Pyrin. This study examines the genotypes of FMF patients from Amasya, Turkey. METHOD: According to the Tel Hashomer criteria, one thousand five hundred seventy patients (871 female, 699 male, mean age 21.2 ± 15.5 years) living in Amasya Province and the surroundings were screened for sequence variants in the entire MEFV gene. Besides, mutation types and alleles were evaluated with clinical findings. RESULTS: MEFV mutations and polymorphisms were found in 1413 of the 1570 patients (90%). Among these patients, 5 (0.3%) were double homozygous, 152 (9.7%) were homozygous, 373 (23.8%) were double heterozygous, and 882 (56.2%) were heterozygous. The most frequent genotype was R202Q (960, 43.5%) followed by M694V (n = 412, 18.7%), E148Q (n = 321, 14.6%), and M680I (n = 200, 9.1%). The most common clinical symptoms were abdominal pain (96.4%) and fever (91.3%). CONCLUSIONS: The fact that the R202Q genotype, which is compatible with the known FMF clinic, is frequently seen shows that it should be included in routine molecular screenings of the patients. Functional studies of the R202Q variant pyrin protein should be performed to understand FMF better. Finally, it is unclear whether the R202Q genotype might be regarded as a mutation while being approved as a polymorphism in the inFevers database.

A possibly new autoinflammatory disease due to compound heterozygous phosphomevalonate kinase gene mutation.

BACKGROUND: Mevalonate kinase (MVK) plays a role in cholesterol and non-sterol isoprenoid biosynthesis and its deficiency-related diseases are caused by bi-allelic pathogenic mutations in the MVK gene, (MVK), which leads to rare hereditary autoinflammatory diseases. The disease may manifest different clinical phenotypes depending on the degree of the deficiency in the enzyme activity. The complete deficiency of the enzyme activity results in the severe metabolic disease called mevalonic aciduria, while a partial deficiency results in a broad spectrum of clinical presentations called hyper-immunoglobulin D syndrome (HIDS). Serum immunoglobulin (Ig) D and urine mevalonic acid levels may be increased during inflammatory attacks of HIDS. CASE PRESENTATION: Herein, for the first time in the literature, we present a 6-year-old male patient who suffered from recurrent episodes of fever, polyarthritis, skin rash, diarrhea, abdominal pain, and inflammatory bowel disease-like manifestations with elevated levels of serum IgD, and urine mevalonic acid. Eventually we detected compound heterozygous mutations in the phosphomevalonate kinase (PMVK) gene coding the second enzyme after mevalonate kinase in the mevalonate pathway. CONCLUSION: For patients presenting with HIDS-like findings, disease exacerbations and persistent chronic inflammation, and having high urinary mevalonic acid and serum IgD levels, raising suspicion in terms of MVK deficiency (MVKD), it is recommended to study all mevalonate pathway enzymes, even if there is no mutation in the MVK gene. It should be kept in mind that novel mutations might be seen such as PMVK gene.

Updates on ankylosing spondylitis: pathogenesis and therapeutic agents.

Ankylosing spondylitis (AS) is an autoinflammatory disease that manifests with the unique feature of enthesitis. Gut microbiota, HLA-B*27, and biomechanical stress mutually influence and interact resulting in setting off a flame of inflammation. In the HLA-B*27 positive group, dysbiosis in the gut environment disrupts the barrier to exogenous bacteria or viruses. Additionally, biomechanical stress induces inflammation through enthesial resident or gut-origin immune cells. On this basis, innate and adaptive immunity can propagate inflammation and lead to chronic disease. Finally, bone homeostasis is regulated by cytokines, by which the inflamed region is substituted into new bone. Agents that block cytokines are constantly being developed to provide diverse therapeutic options for preventing the progression of inflammation. In addition, some antibodies have been shown to distinguish disease selectively, which support the involvement of autoimmune immunity in AS. In this review, we critically analyze the complexity and uniqueness of the pathogenesis with updates on the findings of immunity and provide new information about biologics and biomarkers.

Case report: JAK inhibition as promising treatment option of fatal RVCLS due to TREX1 mutation (pVAL235Glyfs*6).

Introduction: Autosomal dominant mutations in the C-terminal part of TREX1 (pVAL235Glyfs*6) result in fatal retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCLS) without any treatment options. Here, we report on a treatment of a RVCLS patient with anti-retroviral drugs and the janus kinase (JAK) inhibitor ruxolitinib. Methods: We collected clinical data of an extended family with RVCLS (TREX1 pVAL235Glyfs*6). Within this family we identified a 45-year-old woman as index patient that we treated experimentally for 5 years and prospectively collected clinical, laboratory and imaging data. Results: We report clinical details from 29 family members with 17 of them showing RVCLS symptoms. Treatment of the index patient with ruxolitinib for >4 years was well-tolerated and clinically stabilized RVCLS activity. Moreover, we noticed normalization of initially elevated CXCL10 mRNA in peripheral blood monocular cells (PBMCs) and a reduction of antinuclear autoantibodies. Discussion: We provide evidence that JAK inhibition as RVCLS treatment appears safe and could slow clinical worsening in symptomatic adults. These results encourage further use of JAK inhibitors in affected individuals together with monitoring of CXCL10 transcripts in PBMCs as useful biomarker of disease activity.

Clinical and Laboratory Parameters of Autoinflammatory Disorders in Single Tertiary Care Center.

Autoinflammatory diseases (AIDs) are disorders with an inborn error of innate immunity, characterized by recurrent episodes of fever and inflammatory attacks. The spectrum of AIDs is expanding, but there are no standardized clinical criteria for the diagnosis of the patients. This study aims at establishing the first autoinflammatory registry of an Iranian population focusing on the clinical and laboratory features that may help clinicians for a better understanding and diagnosis of these disorders. Clinical and laboratory characteristics of patients who were clinically and or genetically diagnosed with AIDs were collected during 15 years. The updated version of classification criteria from the Eurofever Registry was used for the clinical diagnosis. Twenty-eight patients (16 males and 12 females) with the mean±SD age of 28.03±14.49 years (from 2 to 68 years) were entered this study. About 29% were genetically diagnosed. Familial Mediterranean fever (FMF) was the most common diagnosis of the patients. Fever duration episodes were between 1-10 days. Some of the clinical manifestations from the most to the least common were as follows: arthralgia and arthritis (80%), myalgia (76%), coughs and shortness of breath (68%), fatigue (60%), abdominal pain (56%), increased erythrocyte sedimentation rate(ESR) (48%), and splenomegaly (24%). Here, we presented the most common clinical manifestations of Iranian AIDs who have registered in our AID registry which would be a useful guide for managing the same patients and also designing the future studies.

Joint together: The etiology and pathogenesis of ankylosing spondylitis.

Spondyloarthritis (SpA) refers to a group of diseases with inflammation in joints and spines. In this family, ankylosing spondylitis (AS) is a rare but classic form that mainly involves the spine and sacroiliac joint, leading to the loss of flexibility and fusion of the spine. Compared to other diseases in SpA, AS has a very distinct hereditary disposition and pattern of involvement, and several hypotheses about its etiopathogenesis have been proposed. In spite of significant advances made in Th17 dynamics and AS treatment, the underlying mechanism remains concealed. To this end, we covered several topics, including the nature of the immune response, the microenvironment in the articulation that is behind the disease's progression, and the split between the hypotheses and the evidence on how the intestine affects arthritis. In this review, we describe the current findings of AS and SpA, with the aim of providing an integrated view of the initiation of inflammation and the development of the disease.

The relation between C-reactive protein and serum amyloid A in patients with autoinflammatory diseases.

BACKGROUND: Autoinflammatory diseases are rare disorders of the innate immune system characterized by fever and other signs of inflammation. A feared complication of autoinflammatory diseases is the development of AA amyloidosis. AA amyloidosis is caused by extracellular deposition of soluble serum amyloid A (SAA) proteins as insoluble amyloid fibrils leading to organ damage. Prolonged high levels of SAA are a prerequisite to develop AA amyloidosis. Since measurement of SAA is relatively expensive and sometimes unavailable, C-reactive protein (CRP) is often used as a surrogacy marker to test for inflammation. OBJECTIVE: The aim of this research is to evaluate the possible relation between CRP and SAA. METHODS: A retrospective cohort of patients with autoinflammatory diseases (n = 99) where SAA and CRP blood testing was performed in the period between 2015 and 2021 in the University Medical Centre in Groningen was used to investigate the correlation between CRP and SAA. RESULTS: CRP and SAA have a high correlation (rho = 0.755, p < 0.001). A CRP value below 0.45 mg/L results in 100% sensitivity for SAA below 4 mg/L. CRP below 5 mg/L is a good predictor of SAA below 4 mg/L with 85.4% sensitivity and 83.6% specificity. Only prednisone and erythrocyte sedimentation rate (ESR) significantly influence the relation between CRP and log10SAA. CONCLUSION: There was a significant correlation between CRP and SAA in our retrospective cohort. CRP levels below 5 mg/L proved to be highly predictive of SAA levels below 4 mg/L. This may not be true for patients on steroids.

A Novel Pathogenic NOD2 Variant in a Mother and Daughter with Blau Syndrome.

BACKGROUND: Blau syndrome (BS) is a rare dominantly-inherited autoinflammatory disorder characterized by the triad of arthritis, uveitis and dermatitis that is consequence of gain-of-function NOD2 mutations. We describe the clinical features and genetic basis of a family with two affected members in consecutive generations affected with childhood onset arthritis and uveitis. MATERIALS AND METHODS: Clinical features were retrospectively collected from clinical records. Genetic studies were performed using the Sanger method of DNA sequencing. RESULTS: The proband is a 44 years-old female, who was diagnosed with juvenile onset arthritis at the age of 9 years. She subsequently developed uveitis at age 12 and since then she was managed between the uveitis and rheumatology services. The proband's daughter developed episcleritis at the age of 7 years, and arthritis with bilateral intermediate uveitis two years later. NOD2 analyses revealed in both patients the heterozygous c.1494A>C transversion, predicted to lead the novel, missense p.E498D variant in the NOD2 protein. Additional studies including databases searches and in silico bioinformatic predictions strongly support the "likely pathogenic" classification for this novel variant. CONCLUSIONS: We report a novel pathogenic NOD2 variant in a multiplex family with clinical features compatible with the BS diagnosis. This condition is inherited as a dominant trait in its familial form and should be considered in patients with granulomatous uveitis in association with arthritis and/or dermatitis. Further insight into NOD2 variants and their downstream effects may have implications in the treatment of BS and other inflammatory granulomatous diseases.