Monogenic Autoinflammatory Diseases Research Articles

Deficiency of adenosine deaminase 2 (DADA2) presented with bilateral renal subcapsular hematoma: a case report and literature review

Introduction and importance: Adenosine deaminase 2 (DADA2) deficiency is a monogenic autoinflammatory disease caused by biallelic mutations in the ADA2 gene. Small- and medium-sized vessels may be involved and can cause various clinical symptoms, including features resembling polyarteritis nodosa (PAN). In this article, the authors discuss a unique case of DADA2 disease in which a patient presented with a bilateral renal subcapsular hematoma. Case presentation: An 18-year-old female patient with a history of recurrent optic neuritis presented with a sudden onset of right flank pain as well as nausea, vomiting, weight loss, fever, and elevated arterial blood pressure. Comprehensive abdominal imaging revealed the presence of a bilateral renal subcapsular hematoma. A laboratory test revealed a positive ANA, negative C-ANCA and P-ANCA, and high ESR and CRP. This finding indicated the presence of systemic inflammation. The authors considered DADA2 based on the patient’s clinical features and her family’s history of autoimmune diseases. A genetic study of the patient revealed the presence of a homozygous ADA2 mutation at chromosomal position 22:17182609, which confirmed the presence of adenosine deaminase 2 deficiency. Clinical discussion: The authors present a rare case of DADA2 disease successfully treated with immunosuppressive therapy. As the authors suspected of having known autoimmune diseases, the patient’s clinical and laboratory results improved with corticosteroids and etanercept treatment, leading to notable remission. Under continuous CT imaging, the subcapsular hematoma shrank significantly over two months, decreasing from 8.3 to 5 cm in size for the right-sided hematoma and completely disappearing for the left-sided hematoma. Conclusion: The clinical features of DADA2 may be fatal, but DADA2 may also be curable; therefore, early diagnosis and treatment are essential.

Factors Associated With Successful Withdrawal of Biologic Agents in Children With Colchicine-Resistant Familial Mediterranean Fever.

Familial Mediterranean fever (FMF) is a monogenic autoinflammatory disease, and colchicine is the mainstay of treatment. Approximately 5%-10% of patients may respond inadequately to colchicine, and anti-interleukin-1 (anti-IL-1) agents are important treatment options in these patients. The aim of this study was to see whether there is any factor associated with the withdrawal of these anti-IL-1 agents and to investigate the characteristics of colchicine-resistant FMF patients who needed biological therapy. Demographic, clinical characteristics, and disease severity of patients, at 2 referral centers, between 2012 and 2022, in whom anti-IL-1 treatment was continued and discontinued, were compared in this study. The international severity scoring system for FMF (ISSF) was used for disease severity assessment. In 64 colchicine-resistant FMF patients, the median (interquartile range) duration of biological treatment was 39 (45) months. Treatment of 26 patients (40.6%) was started with anakinra and 38 (59.4%) with canakinumab. During follow-up, anti-IL-1 treatment was discontinued in 23 patients (35.9%). High ISSF scores before biological treatment, presence of exertional leg pain, subclinical inflammation, and comorbidity were found to be statistically more frequent in the group whose biological therapy could not be discontinued (p = 0.009, p = 0.006, p = 0.026, p = 0.001, respectively). Low ISSF scores before biological treatment with no accompanying exertional leg pain, subclinical inflammation, and comorbidities may be stated as an associated factors in terms of the discontinuation of biological agents in colchicine-resistant pediatric FMF patients.

Transition to Adult Care in Autoinflammatory Diseases: A Cohort of 111 French Patients.

Transitioning from pediatric to adult care is a critical step for individuals with autoinflammatory diseases, requiring effective programs to ensure continuity of care and disease management. Despite various recommendations, the effectiveness of transition programs, particularly in monogenic autoinflammatory diseases, remains understudied. A single-center medical records review study was conducted at the French National Reference Center for Adult Autoinflammatory Diseases in Tenon Hospital from 2017 to 2023. All patients who had consulted for the first time between the ages of 15 and 30 years and had received care for an autoinflammatory disease during childhood were included. The patients were classified according to whether they had undergone a transition, defined as either no transition, simple transition (referral letter), or joint transition (pediatrician and adult physician consultation). One hundred eleven patients (median age, 18 years) were included. Patients who consulted without transition started adult follow-up and were followed up less regularly than those who underwent the transition process ( p < 0.001 and p = 0.028). In patients with familial Mediterranean fever, the absence of a formal transition was associated with poorer disease control at baseline ( p = 0.019). The type of transition did not impact disease control during follow-up. Participation in a transition program is associated with earlier and more regular follow-up in adulthood. Although transition type did not significantly impact disease control during follow-up in familial Mediterranean fever, the potential benefit of joint consultation extends beyond consultation frequency and disease outcomes, encompassing patient perspectives and self-management abilities. This study highlights the significance of collaborative transition programs in AIDs.

New and future perspectives in familial Mediterranean fever and other autoinflammatory diseases.

Systemic autoinflammatory diseases are a group of disorders characterized by sterile episodes of inflammation resulting from defects in the innate immune system. In contrast to classical autoimmune diseases, where circulating autoantibodies and the adaptive immune system are involved, these conditions involve excessive presence of proinflammatory cytokines leading to inflammatory attacks. Excessive cytokine production, functional mutations in regulatory pathways, excessive interferon production, defects in the nuclear factor-kappa B signaling pathway, abnorARCHmal protein folding, and complement activation are the mechanisms leading to autoinflammatory diseases. A defect in the mTOR pathway and trained immunity are newly discovered possible causes in pathogenesis. Early onset and severe forms of classical rheumatological diseases have been more frequently associated with autoinflammatory diseases in the last decade. Therefore, monogenic autoinflammatory diseases should be considered in rheumatic diseases with family history, consanguinity, early onset, and severe disease. The combination of functional and genotyping research will help to identify unclassified patients. The optimal treatment strategy remains uncertain, functional studies such as interferon signature and cytokine profiling, may prove valuable in guiding the treatment process. Stem cell transplantation strategies in autoinflammatory diseases with partial response to biological therapies can be considered. Autoinflammatory diseases are becoming increasingly complex and are bringing new perspectives to already known rheumatic diseases. Although we have effective treatments, we are still far from personalized recommendations.

The Impact of Different MEFV Genotypes on Clinical Phenotype of Patients with Familial Mediterranean Fever: Special Emphasis on Joint Involvement

Familial Mediterranean Fever (FMF) is the most common monogenic autoinflammatory disease worldwide. In this retrospective cohort study, we aimed to assess the effects of various MEFV genotypes on the clinical characteristics of the patients, with a special focus on the joint involvement. In total, 782 patients with FMF were categorized into 3 groups according to the MEFV mutation; Group 1: Patients homozygous for M694V; Group 2: Patients carrying other pathogenic MEFV variants in exon 10 in homozygous or compound heterozygous states; and Group 3: FMF patients with other variants or without mutations. Clinical and demographic findings were compared between groups. Among the 782 FMF patients, total frequency of arthritis was 237 (30.3%): 207 (26.4%) were acute monoarthritis and 67 (8.5%) were chronic arthritis. Both the frequency of arthritis (acute and/or chronic) (40.4% vs. 24.8% vs. 26.7%; p:0.001) and acute monoarthritis (35.4% vs. 20% vs. 23.7%; p:0.001) were significantly higher in Group 1 than in the other groups. FMF patients with chronic arthritis showed a distinct juvenile idiopathic arthritis (JIA) distribution pattern with a more frequent enthesitis-related arthritis (ERA) subtype (43.2%). HLA-B27 was positive in 24% of the ERA patients.Conclusion: Homozygous M694V mutation is associated with a more frequent and longer acute monoarthritis comparing to other MEFV genotypes. In addition, the risk of chronic arthritis seems not related to the MEFV mutations. However, FMF patients with chronic arthritis show a distinct ILAR JIA distribution pattern with a more frequent ERA and undifferentiated arthritis subtype.What is known:• Homozygous M694V mutation is associated with a more frequent and longer acute monoarthritisWhat is new:• FMF patients with chronic arthritis show a distinct ILAR JIA distribution pattern with a more frequent ERA subtype• ERA patients with negative HLA-B27 antigen should also be assessed for polyserositis episodes of FMF, especially in countries with high FMF carrier frequency

Sacroiliitis in familial Mediterranean fever: A rare joint involvement of the disease.

Familial Mediterranean fever (FMF) is a monogenic autoinflammatory disease characterised by recurrent episodes of fever and polyserositis. Sacroiliac joint involvement is rare in FMF patients. The purpose of this study was to evaluate the demographic, clinical, laboratory and imaging findings of patients with FMF who developed sacroiliitis. The files of paediatric patients aged 0-18 years who were followed up with a diagnosis of FMF were retrospectively reviewed. FMF patients with evidence of sacroiliitis on magnetic resonance imaging (MRI) were included in the study. Among 1062 FMF patients, 22 (12 males; median age 8.5) (2.1%) of them were found to have sacroiliitis. FMF was diagnosed before sacroiliitis in nine (40.9%) patients and after in 13 (59.1%) patients. The most common symptom in patients with sacroiliitis was low back pain (n = 21, 95.5%). In MEFV gene analysis, M694V was found in 16 (72.7%) patients and was the most common mutation. MRI showed evidence of sacroiliitis in all patients. All patients were using colchicine. Patients with FMF-associated sacroiliitis, remission was achieved with non-steroidal anti-inflammatory drugs in 12 (54.5%), conventional disease-modifying antirheumatic drugs in six (27.3%) and tumour necrosis factor inhibitor treatment in four (31.8%). Four (31.8%) patients experienced sacroiliitis when colchicine incompatible and four (31.8%) patients experienced sacroiliitis while using biologic agents for colchicine-resistant FMF. FMF-associated sacroiliitis should be considered especially in patients with M694V mutation if they have symptoms such as low back pain. Colchicine-resistant FMF patients should be evaluated for sacroiliitis symptoms at each visit.

Could tocilizumab be used in familial Mediterranean Fever? A systematic review.

Familial Mediterranean fever (FMF) is the most common monogenic autoinflammatory disease characterized by recurrent fever and serosal inflammation. Although colchicine is the primary treatment, around 10% of FMF patients do not respond to it, necessitating alternative therapies. Biologic treatments, such as interleukin-1β (IL-1β), TNF-α, and interleukin-6 (IL-6) inhibitors, have been considered. However, the accessibility and cost of IL-1β inhibitors may limit their use in certain regions. Tocilizumab (TCZ), an IL-6 receptor inhibitor, offers an alternative, but its efficacy in FMF is not well-documented. To evaluate the efficacy and safety of tocilizumab in the treatment of FMF. Following PRISMA guidelines, we identified 237 articles on the use of TCZ in FMF. After selection, 14 articles were included: 2 double-blind RCTs, 2 retrospective studies, and 10 case reports. Multicentre double-blind RCTs reported mixed results in FMF patients without AA amyloidosis due to genetic/classification heterogeneity of the available studies, possible misdiagnosed FMF patients and study design. Retrospective studies suggest that TCZ may benefit FMF patients with established renal AA amyloidosis, potentially preventing progression and managing flares more effectively. TCZ showed a safe profile with no specific adverse events, but data on its use during pregnancy or breastfeeding are lacking. There was no available data on the use of TCZ in pediatric FMF. This review summarizes the current state of research, safety and efficacy of TCZ in FMF. While IL1β inhibitors remain the first choice for colchicine-resistant or intolerant FMF patients, TCZ might be of interest in some selected FMF patients with established AA amyloidosis and resistance to colchicine and interleukin 1 inhibitors.

РАЗВИТИЕ ХРОНИЧЕСКОГО МУЛЬТИОЧАГОВОГО НЕБАКТЕРИАЛЬНОГО ОСТЕОМИЕЛИТА У ПАЦИЕНТА С ИСХОДНО ДИАГНОСТИРОВАННЫМ СИСТЕМНЫМ ЮВЕНИЛЬНЫМ АРТРИТОМ: КЛИНИЧЕСКОЕ НАБЛЮДЕНИЕ

Systemic juvenile arthritis (sJA) is a special variant of chronic arthritis in children belonging to the spectrum of polygenic autoinflammatory diseases whose main features are persistent febrile fever, skin rashes, other systemic manifestations (serositis, lymphadenopathy, hepatosplenomegaly) as well as the presence of joint damage with the frequent development of destructive polyarthritis and osteonecrosis, high laboratory indicators of systemic inflammation either at the disease onset or delayed. The list of differentiated conditions includes many diseases such as infections, cancer, primary immunodeficiencies, monogenic autoinflammatory diseases etc. Authors represent a clinical case of a patient with sJA manifestations who was diagnosed with chronic multifocal nonbacterial osteomyelitis (CMNO), that demonstrates the great difficulties in diagnosis and the variability of the course of rheumatic diseases in childhood, which in its turn causes a delay in the timely prescription of effective therapy. Thus, patients with manifestations of a systemic inflammatory process, joint changes, especially those with an atypical course of the disease, pain in the bones and joints of a nocturnal nature, as well as an insufficient response to the therapy even long-term, are in need of conducting of a differential diagnostic search with the inclusion of CMNO, the ‘whole body’ mode magnetic-resonance tomography prescribed by a rheumatologist practitioner.

Genetic and Clinical Manifestations of Familial Mediterranean Fever in Children from the Central North of Iran

Background: Familial Mediterranean fever (FMF) is one of the most common monogenic autoinflammatory diseases in the Middle East. The disease is characterized by recurrent attacks of fever and serositis, and the clinical presentation varies across different ages, ethnicities, and genotypes. Objectives: In this study, we determined the types of gene mutations in patients with FMF and their relationship with clinical symptoms in the Central North of Iran. Methods: This was an analytical cross-sectional study conducted on all patients with FMF who were referred to 17 Shahrivar Hospital in Rasht. Demographic information, clinical data, and genetic test results were collected. Results: The mean age of patients at the onset of symptoms was 3.57 ± 2.79 years. In this study, 62.5% of patients were male and 37.5% were female. The most common clinical symptoms were fever, abdominal pain, nausea, vomiting, chest pain, joint pain, headache, and diarrhea, respectively. In genetic studies, 12.50% of patients were homozygous, 47.50% were compound heterozygous, 20% were heterozygous, 2.50% had complex genotypes, and 17.50% had no mutation. The most common gene mutations were R761H, M694V, E148Q, and M680I alleles, respectively. Conclusions: In our study, we found different clinical and genetic patterns in patients with Familial Mediterranean fever. These results highlight the importance of conducting further studies in different regions to help clinicians manage their patients accurately.

The most frequent febrile syndromes and autoinflammatory diseases in adulthood

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, X‑linked, 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.

Relapsing polychondritis: clinical updates and new differential diagnoses.

Relapsing polychondritis is a rare inflammatory disease characterized by recurrent inflammation of cartilaginous structures, mainly of the ears, nose and respiratory tract, with a broad spectrum of accompanying systemic features. Despite its rarity, prompt recognition and accurate diagnosis of relapsing polychondritis is crucial for appropriate management and optimal outcomes. Our understanding of relapsing polychondritis has changed markedly in the past couple of years with the identification of three distinct patient clusters that have different clinical manifestations and prognostic outcomes. With the progress of pangenomic sequencing and the discovery of new somatic and monogenic autoinflammatory diseases, new differential diagnoses have emerged, notably thevacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS)syndrome, autoinflammatory diseases and immune checkpoint inhibitor-related adverse events. In this Review, we present a detailed update of the newly identified clusters and highlight red flags that should raise suspicion of these alternative diagnoses. The identification of these different clusters and mimickers has a direct impact on the management, follow-up and prognosis of patients with relapsing polychondritis and autoinflammatory syndromes.

Physical fitness in adolescent patients with familial Mediterranean fever.

Familial Mediterranean fever (FMF) is the most frequent monogenic auto-inflammatory disease worldwide responsible for episodes of fever, serositis and musculoskeletal symptoms. Inflammatory attacks are responsible for sedentary behavior and FMF patients may be at increased cardiovascular risk. Cardiorespiratory Fitness (CRF) and physical capacities during adolescence are associated with cardiovascular mortality in adulthood. In this study, we aimed to describe the physical fitness of FMF adolescents. A monocentric retrospective study at the Versailles Hospital between January 2020 and June 2023. All FMF patients over 14-year-old who had completed a routine physical test were included. Clinical and physical data including results of the 6-minute walking test, timed unipedal stance test, Ruffier-Dickson index, 30-seconds chair-stand test and sit-and-reach test were extracted from medical records. Results were compared with previously published normative reference values and criterion-referenced standards for healthy subjects. Eighteen FMF patients (12 girls, 6 boys) were included. The median age was 16 years old [14-18]. Clinical history included joint symptoms (n = 11), chest pleuritis (n = 8), and leg pain (n = 11). Estimated VO2max was below the recommended thresholds in 13 patients, which predicts cardiovascular risk. Cardiovascular adaptation was poor in 11 patients. Low VO2max was associated with CRP > 5mg/l on test day and history of joint symptoms. FMF patients displayed altered physical capacities compared to normative values of healthy subjects. History of musculoskeletal pain, systemic inflammation and sedentary behavior may participate in impaired physical abilities and promote cardiovascular diseases in adulthood. Specific exercise programs could benefit patients for disease control and cardiovascular risk reduction.

Monogenic Autoinflammatory Disease Due to Blau Syndrome with Nucleotide Oligomerization Domain 2 Gene Mutation in an Indian Family

Background: Blau syndrome is a monogenic disease resulting from mutations in nucleotide oligomerization domain 2 (NOD2) and is phenotypically characterized by a triad of dermatitis, arthritis, and uveitis. We report Blau syndrome in a child who had been symptomatic for years, without the typical clinical triad. Clinical Description: A 7-year-old girl child presented with bilateral knee, wrist, and ankle joint swelling since the age of 2 years. She had recently developed a rash on the body. Her mother, mother’s identical twin sister, and the latter’s 5-year-old daughter had similar joint pain and swellings since childhood. In view of the strong positive family history of polyarthritis, monogenic cause of arthritis was suspected. Management and Outcome: Complete blood count was unremarkable. Erythrocyte sedimentation rate was 20 mm at C-reactive protein was 36 mg/L, antinuclear antibody and rheumatoid arthritis factor were negative. X-ray of the knee joints and wrist joints showed soft-tissue swellings around the knee and lumbar scoliosis. A heterozygous pathogenic variant in NOD2 gene confirmed the diagnosis of Blau syndrome. After receiving the genetic report, the girl was started on prednisolone and weekly methotrexate. Conclusion: Early-onset arthritis, with recurrent episodes of fever, is not to be ignored if autoimmune markers are negative. Knowledge about the clinical features of autoinflammatory diseases and the spectrum of NOD2 variants will enable physicians to carry out specific investigations, especially genetic analysis for confirmation of the diagnosis and hence administer the right treatment.

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.

Genetic and epigenetic dysregulation of innate immune mechanisms in autoinflammatory diseases.

Dysregulation and hyperactivation of innate immune responses can lead to the onset of systemic autoinflammatory diseases. Monogenic autoinflammatory diseases are caused by inborn genetic errors and based on molecular mechanisms at play, can be divided into inflammasomopathies, interferonopathies, relopathies, protein misfolding, and endogenous antagonist deficiencies. On the other hand, more common autoinflammatory diseases are multifactorial, with both genetic and non-genetic factors playing an important role. During the last decade, long-term memory characteristics of innate immune responses have been described (also called trained immunity) that in physiological conditions provide enhanced host protection from pathogenic re-infection. However, if dysregulated, induction of trained immunity can become maladaptive, perpetuating chronic inflammatory activation. Here, we describe the mechanisms of genetic and epigenetic dysregulation of the innate immune system and maladaptive trained immunity that leads to the onset and perpetuation of the most common and recently described systemic autoinflammatory diseases.

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.

Familial Mediterranean fever in Armenian children with inflammatory bowel disease.

Inflammatory bowel disease (IBD) and familial Mediterranean fever (FMF) are inflammatory diseases with complex interactions among genetic, immune, and environmental factors. FMF is a monogenic autoinflammatory disease, characterized by recurrent febrile attacks and polyserositis, and is manifested mainly in childhood. FMF is widespread in Armenia. There are reports on the concurrent occurrence of FMF and IBD. MEFV gene mutations may have a disease-modifying effect on IBD. We have investigated the frequency of MEFV mutations and FMF in Armenian children with IBD and their influence on the clinical course. A total of 69 untreated IBD patients under 18 years of age were enrolled: 52.1% (36) had ulcerative colitis (UC), 21.7% (15) had Crohn's disease (CD), and 26.0% (18) had unclassified colitis (IBD-U). The frequency of FMF among them was 36.2% (25/69), and MEFV mutations were identified in 53.6% (37/69). The highest rate of MEFV mutations and FMF was in UC patients (61.1% and 41.6% respectively). In all, 56.7% (21/37) of IBD patients with MEFV mutations had M694V mutated alleles, mainly in compound heterozygous and heterozygous states. There were no associations in the group of IBD patients with coexisting FMF (25), either between any MEFV mutation and type of IBD or coexistence of FMF. Overall, 36.0% (9/25) of them developed VEO IBD and carried mainly the M694V mutation. We concluded that the carrier frequency of MEFV mutations among Armenian pediatric IBD patients was rather high (53.6%), especially for UC. It was suggested that the MEFV gene is not necessarily a susceptibility gene but most likely modifies the course of IBD. MEFV genetic testing was recommended for Armenian pediatric IBD patients, especially for VEO UC and IBD-U, atypical IBD course, or resistance to the conventional treatment. They should also be asked for isolated febrile attacks, recurrent arthritis, and family history, even in the absence of FMF typical symptoms, to rule out FMF and its complications.

Long-term safety and effectiveness of canakinumab in patients with monogenic autoinflammatory diseases: results from the interim analysis of the RELIANCE registry

ObjectiveInterim analysis of the RELIANCE registry, an on-going, non-interventional, open-label, multicentre, prospective study evaluating the long-term safety, dosing regimens and effectiveness of canakinumab in patients with cryopyrin-associated periodic syndromes (CAPS),...

Anakinra in idiopathic recurrent pericarditis: acomprehensive case series and literature review.

Idiopathic recurrent pericarditis (IRP) is defined by recurring episodes of pericardial inflammation without aknown cause. This study investigates the safety and efficacy of anakinra, an interleukin‑1 inhibitor, as asuccessful therapy for IRP in cases resistant to conventional treatment. Aretrospective evaluation of patients treated at our autoinflammatory center between 2011 and 2023 was conducted. Patient files were examined for demographic, clinical, and treatment response data, including nonsteroid anti-inflammatory drugs (NSAIDs), corticosteroids, and colchicine. Monogenic autoinflammatory disease screening was performed for Mediterranean Fever (MEFV), tumor necrosis factor receptor-associated periodic syndrome (TRAPS), mevalonate kinase (MVK), nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3), and nucleotide-binding oligomerization domain-containing protein 2 (NOD2). Patients who experienced multiple episodes of pericarditis were diagnosed with recurrent pericarditis. The study evaluated anakinra treatment in IRP patients unresponsive to conventional therapy. The study included 21participants, 9(42.9%) female and 12(57.1%) male. The average age of the participants was 43.1 ± 16.5years. The MEFV mutation analysis revealed that 2(9.5%) had amutation in exon10 and4 (19.0%) had one in exon2. Out of the 16cases, 15successfully discontinued steroid treatment. Four patients (19.0%) experienced injection site reactions. C‑reactive protein (CRP) levels were measured at an average of 196 ± 67.8 mg/l before and 2.6 ± 3.15 mg/l after anakinra treatment. In conclusion, the study adds to the growing evidence for the efficacy of interleukin-1inhibitors, such as anakinra, as apromising treatment modality for IRP in cases resistant to conventional treatment.

Autoinflammatory Contributors to Cytokine Storm.

Cytokine Storm is a complex and heterogeneous state of life-threatening systemic inflammation and immunopathology. Autoinflammation is a mechanistic category of immune dysregulation wherein immunopathology originates due to poor regulation of innate immunity. The growing family of monogenic Systemic Autoinflammatory Diseases (SAIDs) has been a wellspring for pathogenic insights and proof-of-principle targeted therapeutic interventions. There is surprisingly little overlap between SAID and Cytokine Storm Syndromes, and there is a great deal to be inferred from thoseSAID that do, and do not, consistently lead to Cytokine Storm. This chapter will summarize how illustrations of the autoinflammatory paradigm have advanced the understanding of human inflammation, including the role of autoinflammation in familial HLH. Next, it will draw from monogenic SAID, both those with strong associations with cytokine storm and those without, to illustrate how the cytokine IL-18 linksinnate immune dysregulation and cytokine storm.