Performance of Recent PRINTO Criteria Versus Current ILAR Criteria for Systemic Juvenile Idiopathic Arthritis: A Single-Center Experience

Objectives The purpose of this study is to evaluate the performances of recently proposed Pediatric Rheumatology International Trials Organization (PRINTO) criteria versus current International League of Associations for Rheumatology (ILAR) criteria, for systemic juvenile idiopathic arthritis (sJIA). Methods The study was performed at the Department of Pediatric Rheumatology in Istanbul Faculty of Medicine with a retrospective design, covering the date range 2010 to 2021. Patients being followed-up with a diagnosis of sJIA, Kawasaki disease (control group-1), and common autoinflammatory diseases (control group-2) were included in the study. Both the ILAR and PRINTO classification criteria were applied to each patient and compared against expert rheumatologist diagnosis. Results Eighty-two patients with a diagnosis of sJIA compared against 189 [74 Kawasaki disease, 83 familial Mediterranean fever (FMF), 16 mevalonate kinase deficiency (MKD), 10 cryopyrin-associated periodic syndromes (CAPS), 6 tumor necrosis factor receptor-associated periodic fever syndrome (TRAPS)] patients. The PRINTO criteria demonstrated higher sensitivity (62.2% vs 80.5%, p=0.003), but comparable specificity (90.5% vs 91%) as regards the ILAR criteria. Conclusions The revised criteria appear to enhance the ability to provide early recognition and pertinent classification of sJIA. The two criteria were not superior to each other in segregating sJIA from common autoinflammatory diseases and Kawasaki disease, namely in terms of specificity.

Vasculitis in a patient with mevalonate kinase deficiency (MKD): a case report

Background Mevalonate kinase deficiency (MKD) is a rare autoinflammatory condition caused by biallelic loss-of-function (LOF) mutations in mevalonate kinase (MVK) gene encoding the enzyme mevalonate kinase. Patients with MKD display a variety of non-specific clinical manifestations, which can lead to diagnostic delay. We report the case of a child presenting with vasculitis that was found by genetic testing to be caused by MKD, and now add this autoinflammatory disease to the ever-expanding list of causes of monogenic vasculitides. Case presentation A 2-year-old male presented with an acute 7-day history of high-grade fever, abdominal pain, diarrhoea, rectal bleeding and extensive purpuric and necrotic lesions, predominantly affecting the lower limbs. He had been suffering from recurrent episodes of fever from early in infancy, associated with maculopapular/petechial rashes triggered by intercurrent infection, and after vaccines. Extensive infection screen was negative. Skin biopsy revealed small vessel vasculitis. Visceral digital subtraction arteriography was normal. With a diagnosis of severe idiopathic cutaneous vasculitis, he was treated with corticosteroids and mycophenolate mofetil. Despite that his acute phase reactants remained elevated, fever persisted and the vasculitic lesions progressed. Next-generation sequencing revealed compound heterozygous mutation in MVK c.928G > A (p.V310M) and c.1129G > A (p.V377I) while reduced mevalonate enzyme activity was confirmed suggesting a diagnosis of MKD as a cause of the severe vasculitis. Prompt targeted treatment with IL-1 blockade was initiated preventing escalation to more toxic vasculitis therapies and reducing unnecessary exposure to cytotoxic treatment. Conclusions Our report highlights the broad clinical phenotype of MKD that includes severe cutaneous vasculitis and emphasizes the need to consider early genetic screening for young children presenting with vasculitis to exclude a monogenic vasculitis which may be amenable to targeted treatment.

Real-Life Indications of Interleukin-1 Blocking Agents in Hereditary Recurrent Fevers: Data From the JIRcohort and a Literature Review

BackgroundInterleukin (IL)-1 inhibitors represent the main treatment in patients with colchicine-resistant/intolerant familial Mediterranean fever (crFMF), mevalonate kinase deficiency (MKD), and tumor necrosis factor receptor-associated periodic syndrome (TRAPS). However, the reasons for the use of IL-1 inhibitors in these diseases are still not completely clarified.ObjectiveIdentify real-life situations that led to initiating anakinra or canakinumab treatment in hereditary recurrent fevers (HRFs), combining data from an international registry and an up-to-date literature review.Patients and MethodsData were extracted from the JIRcohort, in which clinical information (demographic data, treatment, disease activity, and quality of life) on patients with FMF, MKD, and TRAPS was retrospectively collected. A literature search was conducted using Medline, EMBASE, and Cochrane databases.ResultsComplete data of 93 patients with HRF (53.8% FMF, 31.2% MKD, and 15.1% TRAPS) were analyzed. Data from both the registry and the literature review confirmed that the main reasons for use of IL-1 blockers were the following: failure of previous treatment (n = 57, 61.3% and n = 964, 75.3%, respectively), persistence of disease activity with frequent attacks (n = 44, 47.3% and n = 1,023, 79.9%) and/or uncontrolled inflammatory syndrome (n = 46, 49.5% and n = 398, 31.1%), severe disease complication or associated comorbidities (n = 38, 40.9% and n = 390, 30.4%), and worsening of patients’ quality of life (n = 36, 38.7% and n = 100, 7,8%). No reasons were specified for 12 (16.4%) JIRcohort patients and 154 (12%) patients in the literature.ConclusionIn the absence of standardized indications for IL-1 inhibitors in crFMF, MKD, and TRAPS, these results could serve as a basis for developing a treat-to-target strategy that would help clinicians codify the therapeutic escalation with IL-1 inhibitors.

P084 Recurrent fever in children: why not a mevalonate kinase deficiency?

Background Mevalonate kinase deficiency (MKD) is a rare autosomal recessive auto inflammatory disease. The clinical spectrum of this disease is a continuum ranging from the moderate form of Hyper-IgD syndrome (HIDS) to lethal forms of mevalonic aciduria (MA). An autoinflammatory disease should be considered in children with recurrent fever of unexplained origin. Case report M, 28 months old boy from a non-consanguineous marriage of Algerian parents, presented since the age of two months’ episodes of unexplained fever resistant to antibiotics and requiring several hospitalizations. Family history found that the mother and a maternal uncle experienced an unexplained recurrent fever. Personal history found episodes of fever lasting in average 6 days, with no obvious cause and recurring every 15–20 days; associated with bilateral cervical adenopathy, mouth ulcers, arthralgia, abdominal pain with vomiting and diarrhea. Clinical examination confirmed the fever with temperature of 38.7°, Chills and irritability, Multiple cervical adenopathy oral aphthae, tongue of geographical aspect, cervical pain and large joint arthralgia, tender abdomen with no organomegaly. Biologic workups found major inflammatory syndrome with hyper leucocytosis at 14X103/mm3 predominantly polynuclear, high CRP level, high ESR at 110 mm. Blood cultures and viral serologies were negative. Immunoelectrophoresis found elevated IgA, IgG and IgM with a normal IgD level. Chest X-ray and abdominal ultrasound were normal. The diagnosis of MKD in its moderate form was supported by elevated urinary mevalonic acid excretion to 5.1 mmol/mol during the febrile episode and subsequently confirmed by a 2nd contributory urine assay during another febrile episode. Conclusion MKD is a rare disease. The clinical spectrum of this condition is variable and could benefit of an effective treatment. Our patient developed a moderate form with a better long-term prognosis.

O007. Register of hereditary auto-inflammatory diseases in a pediatric rheumatology unit

Background Autoinflammatory diseases (AID) are a group of genetic syndromes resulting from an excessive activation of the innate immune system, caused by mutations in genes regulating the inflammatory pathways and can involve several organs. The aim of this study is to evaluate the clinical, paraclinical, epidemiogical and genetic data of Moroccan patients with confirmed AID, in order to allow a first experience of AID registry in our unit. Material We have retrospectively analyzed 30 cases of patients in our unit over a period of 13 years (between 2006 and 2019), according to inclusion criterias (recurrent fever > 3 episodes and a CRP > 40mg/L) and having excluded immune deficiency, autoimmune disease, neoplasia and infectious diseases. Results The mean age of our patients at 1st consultation was 6.9 years (with extremes ranging from 8 months to 14 years). Consanguinity was reported in 16 cases, and unknown in one case of an adopted child. The patients were classified as follows: 66% of cases with Familial Mediterranean Fever (FMF) including 1 case with a characteristic phenotype of Marshall/Periodic Fever Aphtous Pharyngitis Adenitis (PFAPA) syndrome, 16% of cases with Mevalonate Kinase Deficiency (MKD), 10% of cases with Chronic Recurrent Multifocal Osteomyelitis (CRMO), 1 patient with Familial Pustular Psoriasis (FPP) and another symptomatic patient with Muckle Wells syndrome. An association with Henoch Schonlein purpura was reported in 30% of cases and with periarteritis nodosa in 1 case in FMF patients. The mean diagnostic delay was 3 years (with extremes ranging from 1 month to 12 years). The main clinical features found in our patients included fever (83%), abdominal pain (90%), arthralgia (83%), arthritis (46%), adenopathies (40%), aphtous (30%) and other specific signs. Genetic analysis revealed that M694V was the most frequent mutation (60%), followed by A744S (15%), E148Q (10%), K695R (10%) and P369S/ R408Q (5%) in all FMF patients, and V337I found in 1 patient with MKD while the 4 others were confirmed basing on a high rate of urinary mevalonic acid. CRMO patients were confirmed by radiological and histological analysis. The case of FPP was confirmed histologically by skin biopsy and the patients with Muckle Wells and PFAPA syndroms were diagnosed basing on characteristic clinical features. Therapeutically, all FMF patients were treated with colchicine in addition of corticosteroids in 1 case of PFAPA syndrome. Patients with MKD received targeted therapy (Anakinra, Etanercept) and Ibuprofen in 1 case. CRMO patients were treated with targeted therapy and NSAIDs. The case of FPP was treated with Methotrexate combined with Etanercept and the patient with Muckel Wells Syndrome received corticosteroid therapy combined with Azathioprine and then Anakinra. The clinical and biological evolution was considered favorable in 76% of cases, partial in 13% of cases and 3 death cases were reported. Conclusion AIDs remain rare genetic syndromes whose lack of knowledge explains the late diagnostic delay. Therefore, it is necessary for any pediatrician to know how to evoke an AID in front of recurrent fever with free intervals, clinical features and inflammatory syndrome, in order to choose the optimal treatment as well as to make the genetic counseling. Abbreviations AID: Auto-Inflammatory Disease CAPS: Cryopyrin Associated Periodic Syndromes CARD14: Caspase Recruitment Domain Family Member 14 CIAS1: Cold-Induced Autoinflammatory Syndrome 1 CRMO: Chronic Recurrent Multifocal Osteomyelitis CRP: C-Reactive Protein CT scan: Computerized Tomography scan DNA: DeoxyriboNucleic Acid ESR: Erythrocyte Sedimentation Rate FMF: Familial Mediterranean Fever FPP: Familial Pustular Psoriasis IL-1β: Interleukine-1beta IL-17A: Interleukine 17A MEFV: Mediterranean fever gene MKD: Mevalonate Kinase Deficiency MVK: Mevalonate Kinase MW: Muckle Wells NALP3: NAcht Leucine-rich repeat Protein 3 NLRP3: NOD-like receptor family, pyrin domain containing 3 NSAID: Non-Steroidal Anti Inflammatory Drugs PFAPA: Periodic Fever Aphtous Pharyngitis Adenitis PRINTO: Pediatric Rheumatology INternational Trials Organization SAA: Serum Amyloid A TRAPS: TNF Receptor Associated Periodic Syndroms TNF: Tumor Necrosis Factor

An Atypical Presentation of Mevalonate Kinase Deficiency in Response to Colchicine Treatment

Mevalonate kinase deficiency (MKD) is a periodic fever syndrome. Nonsteroidal anti-inflammatory drugs, corticosteroids, and anakinra are the most common treatments. However, colchicine is considered insufficient in disease control. In this case report, we present an 8-month-old infant with an atypical presentation of MKD. She had recurrent fever episodes, diarrhea, and lethargy. Elevated mevalonic acid was not detected in the urine. However, the genetic investigation showed a novel pathogenic heterozygous c.925G&#x3e;C (p.Gly309Arg) variant and a heterozygous c.1129G&#x3e;A (p.Val377Ile) mutation in the <i>MVK</i> gene. The patient was treated with colchicine for 8 months. During treatment, no further fever episode had been observed. It should be kept in mind that mevalonic acid excretion may not be present in the urine with mild MKD. Colchicine may be a reasonable option in mild MKD patients for a longer duration of treatment due to favorable adverse event profiles.

Mevalonate Kinase Deficiency and Squalene Synthase Inhibitor (TAK-475): The Balance to Extinguish the Inflammation

Mevalonate Kinase Deficiency (MKD) is a rare inborn disease belonging to the family of periodic fever syndromes. The MKD phenotype is characterized by systemic inflammation involving multiple organs, including the nervous system. Current anti-inflammatory approaches to MKD are only partially effective and do not act specifically on neural inflammation. According to the new emerging pharmacology trends, the repositioning of drugs from the indication for which they were originally intended to another one can make mechanistic-based medications easily available to treat rare diseases. According to this perspective, the squalene synthase inhibitor Lapaquistat (TAK-475), originally developed as a cholesterol-lowering drug, might find a new indication in MKD, by modulating the mevalonate cholesterol pathway, increasing the availability of anti-inflammatory isoprenoid intermediates. Using an in vitro model for MKD, we mimicked the blockade of the cholesterol pathway and evaluated the potential anti-inflammatory effect of Lapaquistat. The results obtained showed anti-inflammatory effects of Lapaquistat in association with a low blockade of the metabolic pathway, while this effect did not remain with a tighter blockade. On these bases, Lapaquistat could be configured as an effective treatment for MKD’s mild forms, in which the residual enzymatic activity is only reduced and not almost completely absent as in the severe forms.

Expanding Contributions of Monogenic Very Early Onset Inflammatory Bowel Disease

Currently over 70 genes known to be causative in very early onset inflammatory bowel disease (VEOIBD) have been identified. In the current issue of Inflammatory Bowel Diseases, 2 articles describing monogenetic forms of VEOIBD are highlighted. One describes a patient with life-threatening VEOIBD and a mutation in ITGA6, illustrating the importance of the epithelial barrier in maintaining mucosal homeostasis. The other describes the presentation and management of 10 patients with VEOIBD secondary to damaging mutations in MVK, resulting in mevalonate kinase deficiency. Though most monogenic causes of VEOIBD remain “private,” understanding the different categories of pathways affected in children with VEOIBD is critical and has already resulted in invaluable insight in the management of patients with VEOIBD and may hold strong implications for the care of IBD overall.

Mevalonate Kinase Deficiency: A Cause of Severe Very-Early-Onset Inflammatory Bowel Disease

Mevalonate kinase deficiency should be considered in patients with severe very-early-onset inflammatory bowel disease (IBD), especially in patients with a history of recurrent or chronic fever, peritoneal adhesions, and atypical IBD pathology. Anti-interleukin-1 therapy may be efficacious in these patients with monogenic very-early-onset IBD.

Compromised Protein Prenylation as Pathogenic Mechanism in Mevalonate Kinase Deficiency

Mevalonate kinase deficiency (MKD) is an autoinflammatory metabolic disorder characterized by life-long recurring episodes of fever and inflammation, often without clear cause. MKD is caused by bi-allelic pathogenic variants in the MVK gene, resulting in a decreased activity of the encoded enzyme mevalonate kinase (MK). MK is an essential enzyme in the isoprenoid biosynthesis pathway, which generates both non-sterol and sterol isoprenoids. The inflammatory symptoms of patients with MKD point to a major role for isoprenoids in the regulation of the innate immune system. In particular a temporary shortage of the non-sterol isoprenoid geranylgeranyl pyrophosphate (GGPP) is increasingly linked with inflammation in MKD. The shortage of GGPP compromises protein prenylation, which is thought to be one of the main causes leading to the inflammatory episodes in MKD. In this review, we discuss current views and the state of knowledge of the pathogenetic mechanisms in MKD, with particular focus on the role of compromised protein prenylation.