Newborn-onset chronic urticaria as the first manifestation of NLRP3 mosaicism

Objectives: A 7-month-old boy presented with generalized urticaria since the first week of life, without any other clinical manifestation. Cow's milk allergy was ruled out. His development was normal for his age. Maternal history was significant for COVID-19 infection in the third trimester of pregnancy with mild symptoms. Family history was significant for dermatographism in a maternal uncle. Hives were migratory with no single lesion persisting more than 24 h. There were no recognizable triggers and only relieved for 1-2 days after each vaccination. Patient was treated with optimal doses of antihistamines without improvement. Method(s): Laboratory tests and further studies were performed Results: Laboratory tests were normal including complete blood testing, circulating autoantibodies and infectious studies. C-reactive protein level and erythrocyte sedimentation rate were elevated. Due to chronic urticaria of newborn onset unresponsive to antihistamines a monogenic autoinflammatory disease was suspected. A targeted gene panel covering causative genes revealed the unreported p.Gly307Ala variant in the NLRP3 gene with a variant allele frequency (VAF) of 3% compatible with gene mosaicism. NLRP3 variant was classified as "likely pathogenic" based on its location, where a different variant has been reported as causing a severe form of cryopyrin-associated periodic syndromes (CAPS), and bioinformatic analyses. As expected, the variant was absent in patient's parents supporting for its de novo nature. Vision and hearing exams were normal. Treatment with canakinumab will start soon. Discussion(s): CAPS are dominantly-inherited autoinflammatory diseases caused by gain-of-function NLRP3 variants. These variants are often germline, but in some reported cases the variants are postzygotic causing gene mosaicism as in the patient here described. We believe that the mild presentation in our patient, despite having a likely pathogenic variant, may be explained by the low VAF. The genetic diagnosis in our patient allowed early initiation of anti-IL-1 treatment, which probably will prevent the development of other CAPS manifestations.

Clinical efficacy and safety of interleukin-1 blockade in the treatment of patients with COVID-19: a systematic review and meta-analysis of randomized controlled trials.

OBJECTIVE: This study evaluated the clinical efficacy and safety of interleukin-1 (IL-1) blockade for patients with COVID-19. METHODS: The PubMed, Web of Science, Ovid Medline, Embase and Cochrane Library databases were searched for relevant articles from their inception to 25 September 2022. Only randomized clinical trials (RCTs) that assessed the clinical efficacy and safety of IL-1 blockade in the treatment of patients with COVID-19 were included. RESULTS: This meta-analysis included seven RCTs. No significant difference in the all-cause mortality rate of patients with COVID-19 was observed between the IL-1 blockade and control groups (7.7 vs. 10.5%, odds ratio [OR] = 0.83, 95% confidence interval [CI] 0.57-1.22; I2 = 18%). However, the study group was at significantly lower risk of requiring mechanical ventilation (MV) compared with the control group (OR = 0.53, 95% CI 0.32-0.86; I2 = 24%). Finally, the risk of adverse events was similar between the two groups. CONCLUSIONS: IL-1 blockade does not provide increased survival benefits in hospitalized patients with COVID-19, but it may reduce the need for MV. Furthermore, it is a safe agent for use in the treatment of COVID-19.>.

This systematic review and meta-analysis of randomized clinical trials (RCTs) evaluated the clinical efficacy and safety of interleukin-1 (IL-1) blockade for patients with COVID-19.Based on the analysis of six RCTs, no significant difference in the all-cause mortality rate of patients with COVID-19 was observed between the IL-1 blockade and control groups.The study group using IL1 was associated with a significantly lower risk of requiring mechanical ventilation compared with the control group.The risk of adverse events was similar between the study and the control groups.

ADULT STILL'S DISEASE: NEW HORIZONS.

Still's disease in children (systemic juvenile idiopathic arthritis - JIA) and adult Still's disease (ASD) are considered as systemic autoinflammatory diseases of unknown etiology, which are based on similar immunopathogenetic mechanisms associated with genetically determined disorders of the mechanisms of innate immunity. ASD was first described 50 years ago by the English rheumatologist Eric George Lapthorne Bywaters. The molecular basis of ASD immunopathogenesis is the activation of innate immunity associated with NLRP3 inflammasome-dependent mechanisms of inflammation, characterized by the overproduction of "pro-inflammatory" cytokines - interleukin (IL) 1 and IL-18, inducing the synthesis of other proinflammatory inflammatory mediators. A review of new data concerning the mechanisms of immunopathology, clinical polymorphism, laboratory biomarkers and the possibilities of ASD pharmacotherapy is presented. Particular attention is paid to the prospects for the use of monoclonal antibodies to IL-1beta - canakinumab. The problems associated with the generality of clinical and laboratory disorders, pathogenetic mechanisms and pharmacotherapy of ASD and coronavirus disease 2019 (COVID-19) are considered.Copyright © 2021 Authors. All rights reserved.

ADULT STILL'S DISEASE: NEW HORIZONS.

Still's disease in children (systemic juvenile idiopathic arthritis - JIA) and adult Still's disease (ASD) are considered as systemic autoinflammatory diseases of unknown etiology, which are based on similar immunopathogenetic mechanisms associated with genetically determined disorders of the mechanisms of innate immunity. ASD was first described 50 years ago by the English rheumatologist Eric George Lapthorne Bywaters. The molecular basis of ASD immunopathogenesis is the activation of innate immunity associated with NLRP3 inflammasome-dependent mechanisms of inflammation, characterized by the overproduction of "pro-inflammatory" cytokines - interleukin (IL) 1 and IL-18, inducing the synthesis of other proinflammatory inflammatory mediators. A review of new data concerning the mechanisms of immunopathology, clinical polymorphism, laboratory biomarkers and the possibilities of ASD pharmacotherapy is presented. Particular attention is paid to the prospects for the use of monoclonal antibodies to IL-1beta - canakinumab. The problems associated with the generality of clinical and laboratory disorders, pathogenetic mechanisms and pharmacotherapy of ASD and coronavirus disease 2019 (COVID-19) are considered.Copyright © 2021 Authors. All rights reserved.

Covid-19: All facts, no myth

On December 31, 2019, the China Health Authority alerted WHO about 27 cases of pneumonia of unknown etiology in Wuhan City. It was subsequently named Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) and the disease as Coronavirus Disease 2019 (COVID-19). The disease has now become pandemic. Current review was done to summarize information on COVID-19 published in various scientific works. Electronic databases containing medical articles viz., MEDLINE/PubMed, Google Scholar etc were searched using the Medical Subject Headings 'COVID-19', '2019-nCoV', 'coronavirus' and 'SARS-CoV-2' during antecedent one year. All study designs were incorporated to harvest clinical, laboratory, imaging, and hospital course data. The intermediate host of the virus is still unknown. Respiratory droplets produced by the patient is main source of transmission. SARS-CoV-2 invades the airway epithelium by binding to angiotensin-converting enzyme-2 (ACE2) receptor with Coronavirus spike (S) protein. Most common symptoms are fever (98%), dry cough (77%), and dyspnea (63.5%). Later, complications like acute respiratory distress syndrome, septic shock etc may occur. Advanced age and co-morbidities like Diabetes have higher mortality otherwise Case Fatality Rate is 2-3%. RT-PCR is the diagnosis of choice. Since no universally accepted registered drug or FDA approved vaccine has come by now, prevention is the key. Hands should be regularly cleaned with soap or alcohol based sanitizer and in public, Nose and Mouth should be covered with face-mask and social distance of one meter should be maintained. While Vaccines are expected by early 2021, we should not forget to take comprehensive measures to prevent future outbreaks of zoonotic origin. Copyright © 2020, Kathmandu University. All rights reserved.

Pharmacological treatment of COVID-19: an opinion paper.

The precocity and efficacy of the vaccines developed so far against COVID-19 has been the most significant and saving advance against the pandemic. The development of vaccines has not prevented, during the whole period of the pandemic, the constant search for therapeutic medicines, both among existing drugs with different indications and in the development of new drugs. The Scientific Committee of the COVID-19 of the Illustrious College of Physicians of Madrid wanted to offer an early, simplified and critical approach to these new drugs, to new developments in immunotherapy and to what has been learned from the immune response modulators already known and which have proven effective against the virus, in order to help understand the current situation.

Current Evidence on Vaccinations in Pediatric and Adult Patients with Systemic Autoinflammatory Diseases.

Systemic autoinflammatory diseases (SAIDs) are defined by recurrent febrile attacks associated with protean manifestations involving joints, the gastrointestinal tract, skin, and the central nervous system, combined with elevated inflammatory markers, and are caused by a dysregulation of the innate immune system. From a clinical standpoint, the most known SAIDs are familial Mediterranean fever (FMF); cryopyrin-associated periodic syndrome (CAPS); mevalonate kinase deficiency (MKD); and periodic fever, aphthosis, pharyngitis, and adenitis (PFAPA) syndrome. Current guidelines recommend the regular sequential administration of vaccines for all individuals with SAIDs. However, these patients have a much lower vaccination coverage rates in 'real-world' epidemiological studies than the general population. The main purpose of this review was to evaluate the scientific evidence available on both the efficacy and safety of vaccines in patients with SAIDs. From this analysis, neither serious adverse effects nor poorer antibody responses have been observed after vaccination in patients with SAIDs on treatment with biologic agents. More specifically, no new-onset immune-mediated complications have been observed following immunizations. Post-vaccination acute flares were significantly less frequent in FMF patients treated with colchicine alone than in those treated with both colchicine and canakinumab. Conversely, a decreased risk of SARS-CoV-2 infection has been proved for patients with FMF after vaccination with the mRNA-based BNT162b2 vaccine. Canakinumab did not appear to affect the ability to produce antibodies against non-live vaccines in patients with CAPS, especially if administered with a time lag from the vaccination. On the other hand, our analysis has shown that immunization against Streptococcus pneumoniae, specifically with the pneumococcal polysaccharide vaccine, was associated with a higher incidence of adverse reactions in CAPS patients. In addition, disease flares might be elicited by vaccinations in children with MKD, though no adverse events have been noted despite concurrent treatment with either anakinra or canakinumab. PFAPA patients seem to be less responsive to measles, mumps, and rubella-vaccine, but have shown higher antibody response than healthy controls following vaccination against hepatitis A. In consideration of the clinical frailty of both children and adults with SAIDs, all vaccinations remain 'highly' recommended in this category of patients despite the paucity of data available.

Autoinflammatory Manifestations In Adult Patients.

Autoinflammatory diseases represent a family of immune-mediated conditions characterized by the unchecked activation of innate immunity. These conditions share common clinical features such as recurrent fever, inflammatory arthritis and elevation of acute phase reactants, in the absence of an identified infectious etiology, generally without detectable serum autoantibodies, with variable response to glucocorticoids and in some cases colchicine, which represented the mainstay of treatment until cytokine blockade therapies became available. The first autoinflammatory diseases to be described were monogenic disorders caused by missense mutations in inflammasome components and were recognized predominantly during childhood or early adulthood. However, the progress of genetic analyses and a more detailed immunological phenotyping capacity led to the discovery a wide spectrum of diseases, often becoming manifest or being diagnosed in the adult population. The beneficial role of targeting hyperinflammation via interleukin 1 in complex non-immune mediated diseases is a field of growing clinical interest. We provide an overview of the autoinflammatory diseases of interest to physicians treating adult patients and to analyze the contribution of hyperinflammation in non-immune-mediated diseases; the result is intended to provide a roadmap to orient scientists and clinicians in this broad area.

Interleukin-1 and the NLRP3 inflammasome in COVID-19: Pathogenetic and therapeutic implications.

A hyperinflammatory response during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection crucially worsens clinical evolution of coronavirus disease 2019 (COVID-19). The interaction between SARS-CoV-2 and angiotensin-converting enzyme 2 (ACE2) triggers the activation of the NACHT, leucine-rich repeat, and pyrin domain-containing protein 3 (NLRP3) inflammasome. Enhanced inflammasome activity has been associated with increased disease severity and poor prognosis. Evidence suggests that inflammasome activation and interleukin-1ß (IL-1ß) release aggravate pulmonary injury and induce hypercoagulability, favoring progression to respiratory failure and widespread thrombosis eventually leading to multiorgan failure and death. Observational studies with the IL-1 blockers anakinra and canakinumab provided promising results. In the SAVE-MORE trial, early treatment with anakinra significantly shortened hospital stay and improved survival in patients with moderate-to-severe COVID-19. In this review, we summarize current evidence supporting the pathogenetic role of the NLRP3 inflammasome and IL-1ß in COVID-19, and discuss clinical trials testing IL-1 inhibition in COVID-19.

LONG-TERM SAFETY of CANAKINUMAB in PATIENTS with AUTOINFLAMMATORY DISEASES-INTERIM ANALYSIS of the RELIANCE REGISTRY

Background: Autoinfammatory diseases (AID) are characterized by severe systemic and organ infammation as well as high burden of disease for patients and their families. Treatment with the monoclonal antibody canakinumab (CAN), an interleukin-1β inhibitor, has been proven to be safe and effective in clinical trials and real-life. Objectives: The present study explores the long-term efficacy and safety of CAN in routine clinical practice conditions in pediatric (age ≥2 years) and adult patients with CAPS (cryopyrin-associated periodic syndromes), FMF (familial Mediterranean fever), TRAPS (tumor necrosis factor receptor-associated periodic syndrome) and HIDS/MKD (hyperimmunoglobulinemia D syndrome/meva-lonate kinase defciency). Methods: RELIANCE is a prospective, non-interventional, observational study based in Germany. Patients with clinically confrmed diagnoses of AID routinely receiving CAN are enrolled. Besides efficacy parameters regarding disease activity and remission, safety parameters were recorded at baseline and assessed at 6-monthly intervals. Results: Here, we present the interim analysis of patients with AID (N=199) enrolled in the RELIANCE Registry between October 2017 and December 2021. Mean age in this cohort was 24.4 years (2-79 years) and the proportion of female patients was 53% (N=104). At baseline, median duration of prior CAN treatment was 2 years (0-12 years). A total of 123 patients (62%) experienced any AE (N=653) among which naso-pharyngitis, increase of infammatory markers and pyrexia were the most frequent AE with incidence rates per 100 patient years (IR) of 8.3, 6.2, and 6.2, respectively. 29 patients (15%) were affected by severe AE (SAE, total number N=90) including 11 patients (6%) with SAE suspected to be drug-related (SADR;total number N=30) with IR from 0.2 to 0.7 (Table 1). Overall, 16 AE comprised upper respiratory tract infections (URI). One death (COVID-19, not related) and one malignancy (skin papilloma, not related) were reported. No vertigo and no hyper-sensitivity reactions were observed. N=10 (IR 2.36) vaccination reactions were reported (no SAE). Conclusion: The interim data from the RELIANCE study, the longest running real-life canakinumab registry, confrm safety of long-term canakinumab treatment across the entire study population. A trend for dose-related increase of SAE/SADR requires continuous close monitoring and awareness in patient groups (children, severe phenotypes, certain genotypes) requiring greater than standard dose treatment regimens.

EVALUATION of the SAFETY PROFILE of COVID-19 VACCINES in CHILD PATIENTS USING BIOLOGICAL THERAPY

Background: Coronavirus vaccines have been widely applied all over the world after the coronavirus pandemic. There are inactivated vaccines and mRNA vaccines in our country. There is no clear guideline for the vaccination programs of patients receiving immunosuppressive therapy, especially childhood. Objectives: For this reason, we wanted to evaluate the frequency of side effects developed after covid-19 vaccine in pediatric patients diagnosed with rheumatic disease using biological therapy and nonbiologic disease modifying drugs Methods: A total of 226 patients over the age of 12, who were followed up in the pediatric rheumatology clinic of the University of Health Sciences, Umraniye Training and Research Hospital, using biological therapy and were vaccinated against Covid-19, were included in the study. The standard questionnaire forms were flled in face-to-face after each administration for both vaccines. The patient, who had any serious side effects, was followed up in the hospital. Results: Of the 226 patients included in the study, 97 were male and 128 were female. Their mean age was 16.4 + 2.4. It was determined that 88.4% (n=200) of the patients had mRNA vaccine and 11.6% (n=26) had inactivated vaccine. 105 of the patients were using biologic drugs during vaccination. Of these, 63 (27.9%) patients were treated with anti-TNF drugs (46 adalimumab, 10 etanercept, 6 infix-mab), 32 patients were anti-il-1 (30 canakinumab, 2 anakirna), 4 patients were anti-il-6, 3 patients were anti-il-17, 3 patient was receiving abatacept and 1 patient was receiving rituximab. 121 patients were using DMARDs. Of these, 61 were using colchicine. 26.5% (n=60) of the patients had covid infection before vaccination. Side effects were observed in 180 of our patients. No side effects were observed in 46 patients. Pain at the injection site was the most common among them, 72.6% (n=164). Headache was seen in 16.8% (n=38) of the patients, myalgia in 18.1% (n=41), fever in 16.4% (n=37) and arthralgia in 6.6% (n=15). The frequency of serious adverse events was determined as 0.9%(n=2). Both patients were followed up in the ward. When the patients were compared in terms of covid infection and gender, there was no signifcant difference in the frequency of side effects. When the vaccines were compared, the incidence of side effects in the mRNA vaccine was statistically signifcantly higher (p=0.001). Pain at the injection site was signifcantly less frequent in the inactivated vaccine (p=0.004). In terms of drug distribution, there was no signifcant difference in the frequency of side effects between patients using biologic drugs and DMARDs. p=0.004) There was no statistically signifcant difference in the frequency of side effects when the patients using dmard were compared as colcicine and other dmards. Conclusion: In our study, we have shown that the use of vaccines in individuals with adolescent rheumatological diseases is safe and that the biological treatments used by the patients do not cause an increase in the risk of vaccine side effects. In addition;We have shown in our study that the side-effect profile of the inactivated vaccine used in our country is milder than the mRNA vaccine, and that it affects daily life less. Another result of our study was that anti-TNF drugs could cause a decrease in pain sensation due to the relationship of anti-TNF with pain pathways.

RETROSPECTIVE STUDY of the COVID-19 COURSE in CHILDREN with RHEUMATIC DISEASES: SINGLE CENTER EXPERIENCE

Background: The study of the features of the course and mutual influence of the new coronavirus disease COVID-19 and various rheumatic diseases (RD) in children can still give us new lessons, warnings and fears. Objectives: To update the analysis in a retrospective study the course of covid-19 in children with RD based on the results of two years of the pandemic. To analyze the impact of COVID-19 on the course of RD in children. Methods: Retrospective analysis based on data from single center. The study included patients with RD and confirmed COVID-19 for 2 years (2020-2021). Results: Were registered 320 cases of COVID-19 in children with RD. 158 (49%) patients were asymptomatically infected, 162 (51%) had clinical symptoms. A detailed description of the groups is presented in Table 1. Clinical symptoms were fever (67%), anosmia (47%), rhinitis (34%), cough (19%), arthralgia/myalgia (16%), dyspepsia (5%), rash (2.5%), pneumonia (3%). In the majority of cases (98%), COVID-19 proceeded in mild to moderate severity. Hospitalization due to COVID-19 was required just in 5 cases. 2 children were admitted to the intensive care unit. First, an 11-year-old girl with sJIA with the history of recurrent episodes of MAS resolved by regular administration of canakinumab. 2nd, a 12-year-old girl with Sjogren's syndrome, who received Rituximab and 1 month later she developed the COVID-19 with MIS-like clinical picture, pneumonia with 25%CT lessions. Both cases have a favorable outcome. The clinical characteristics of the patients are presented in Table 1. COVID-19 didǹt affect the course of RD in the 86% of pts. However, 15% developed a fare of the RD with average of 3 months after COVID-19. In this group for 13 pts (girls mostly F/M-9/4, mean age 15 years [9;16]), COVID-19 triggered the new onset of RD (non-systemic JIA-4, Uveitis-1, non-bacterial osteomyelitis-3, systemic JIA-2, Scleroderma-2, Sjögren's syndrome-1. 12 from 13 these children had clinical symptoms on COVID-19. Whether this is Long-COVID syndrome or an independent RD is not known. Conclusion: Our study suggests that the new coronavirus infection in most cases in children with RD, had mild or asymptomatic course, regardless of therapy with immunosuppressive drugs and bDMARD, except of 1 observation with the previous therapy of Rituximab. Worsening of RD after coronavirus infection developed in 15% of cases, regardless of its clinical manifestations. In 13 patients, the RD were started just after COVID-19. The explosive increasing of the incidence of a new strain of COVID-19 for a past month may change the current results and conclusions.

SARS-COV-2 COURSE and OUTCOME in PATIENTS with SYSTEMIC AUTOINFLAMMATORY DISEASES (SAID) TREATED with IL-1 INHIBITORS and COLCHICINE

Background: The spread of COVID-19 had a strong impact in north-east Italy especially during 2020 and in the frst months of 2021. Patients affected by rheumatological disorders are at high risk of infections due to immunosuppressant therapies and a clear immunological imbalance. However, some anti-cytokines such as IL-1 inhibitors proved to be effective in curbing the cytokine storm, frequent feature of severe COVID-19. Objectives: We assessed the SARS-CoV-2 clinical course in 28 patients affected by autoinfammatory diseases, referring to the Autoinfammatory Outpatient Clinic of Padova University;in particular we observed if patients undertaking IL-1 inhibitors (group-1) had a diverse outcome compared to those not on anti-IL-1 drugs (group-2). Methods: Through telephone or e-mail consultancy, 28 patients (18 females, mean age 39.5±15), confrmed to have contracted COVID-19 between March 2020 and January 2022. Twelve patients (42.8%) were affected by periodic fevers (FMF/TRAPS), 10/28 (35.7%) had Adult-Onset Still's Disease, 3/28 (10.7%) had Undiffer-entiated Autoinfammatory Diseases, while 2/28 (7.1%) were affected by BehÇet Disease and one patient had Schnitzler Syndrome. 12 out of 28 patients (42.8%) were undertaking IL-1 inhibitors;8/28 (28.5%) were in therapy with colchicine;2 patients were in therapy with methotrexate and abatacept respectively, and 6/28 (21.4%) received no therapy. All were diagnosed with COVID-19 after molecular nasopharyn-geal swab performed either for the presence of symptoms or close contact with a positive subject. 5/28 patients had the infection after receiving the second vaccine shot, two after the booster dose. All the others had COVID-19 before the vaccine injection. GraphPad5 was used for statistical analysis and Fisher's test was applied. Results: COVID-19 clinical course was benign in 27 out of 28 patients (96.4%);a total of 29 infections were counted due to a case of re-infection;2 patients discontinued the therapy;all the others continued their medications (92.8%). Two patients (7.1%) of the entire cohort were hospitalized, one died. Regarding the major symptoms (fever ≥ 38 C°, cough/respiratory or gastro-intestinal symptoms) no difference was noticed between group-1 and group-2 (p=0.449);despite group-1 required less symptomatic therapy than group-2, the difference was not signifcant (p=0.471). Table 1 summarizes the clinical features exhibited by the patients and the therapies undertaken during the infection. Conclusion: Despite the low sample size, our study is of interest since it proves that the inhibition of IL-1 with both anakinra or canakinumab and the employment of colchicine, an important infammasome regulator, may curb the hyperinfammation typical of COVID-19. Given the promising results obtained with anti-IL-1 and colchi-cine in treating severe COVID-19, it is conceivable a 'protective' role of these drugs in preventing a massive cytokine release. Unsurprisingly, none of our patients but one, had a severe course or fatal outcome after SARS-CoV-2 infection.

Double-blind randomized proof-of-concept trial of canakinumab in patients with COVID-19 associated cardiac injury and heightened inflammation.

Aims: In coronavirus disease 2019 (COVID-19), myocardial injury is associated with systemic inflammation and higher mortality. Our aim was to perform a proof of concept trial with canakinumab, a monoclonal antibody to interleukin-1ß, in patients with COVID-19, myocardial injury, and heightened inflammation. Methods and results: This trial required hospitalization due to COVID-19, elevated troponin, and a C-reactive protein concentration more than 50 mg/L. The primary endpoint was time to clinical improvement at Day 14, defined as either an improvement of two points on a seven-category ordinal scale or discharge from the hospital. The secondary endpoint was mortality at Day 28. Forty-five patients were randomly assigned to canakinumab 600 mg (n = 15), canakinumab 300 mg (n = 14), or placebo (n = 16). There was no difference in time to clinical improvement compared to placebo [recovery rate ratio (RRR) for canakinumab 600 mg 1.15, 95% confidence interval (CI) 0.46-2.91; RRR for canakinumab 300 mg 0.61, 95% CI 0.23-1.64]. At Day 28, 3 (18.8%) of 15 patients had died in the placebo group, compared with 3 (21.4%) of 14 patients with 300 mg canakinumab, and 1 (6.7%) of 15 patients with 600 mg canakinumab. There were no treatment-related deaths, and adverse events were similar between groups. Conclusion: There was no difference in time to clinical improvement at Day 14 in patients treated with canakinumab, and no safety concerns were identified. Future studies could focus on high dose canakinumab in the treatment arm and assess efficacy outcomes at Day 28.

Familial mediterranean fever (FMF) in Apulia: rare, or actually not? A 14 year experience as Internist

Familial Mediterranean fever (FMF) is a hereditary autoinflammatory disorder characterized by recurrent attacks of fever and serosal inflammation. The clinical features consist of especially abdominal pain, chest pain and arthralgias, plus erysipelas-like manifestations. According to the available literature, most patients with FMF experience their first attack in early childhood, before the ages of 10 and 20 years in 65 and 90% of cases, respectively. Rarely, the initial attack can occur in individuals older than 50 years of age. We report our experience with FMF during the last 14 yrs [1], following case #1 aged 36 yrs. [2]. In the regions of Apulia and Basilicata, we could identify several family clusters due to historical and geographical roots. In the initial series of 60 cases, the five most frequent MEFV variants were E148Q/R761H (41.9%, compound heterozygosity), K695R (10.2%, heterozygosity), E148Q (8.2%, heterozygosity), E148Q/R761H/A744S (6.1% compound heterozygosity), and P369S (6.1%, heterozygosity). Notably, the mean disease onset was 22 yrs and the diagnostic delay was 15 yrs. The severity of symptoms was generally mild/intermediate but about 30% of this initial series had undergone unnecessary abdominal surgery. Females were significantly older than males (median 40 vs. 30 yrs., respectively, P = 0.03). Symptoms including fever were largely responsive to the average dose of colchicine 1 mg/day ad libitum. Only one case required canakinumab for resistance/intolerance to colchicine. We did not observe severe cases of secondary amyloidosis and kidney damage. Later, we extended our observations and concluded that the combination of available expert information with sensitive predictor tools could result in a more accurate interpretation of clinical consequences of MEFV gene variants, and a better genetic counselling and patient management, with respect to symptom severity as well [3, 4]. We recently reported the rare case of a very late onset of FMF symptoms in a patient aged 86 [5]. Further studies in FMF have focused the attention on environmental factors including intestinal microbiota [6], COVID-19 pandemic [7], blood-based test for diagnosis and functional subtyping of FMF by the ex vivo colchicine assay [8], and histopathological characteristics of synovitis in FMF [9]. Following these seminal observations, we conclude that the Apulia region represents a new endemic area for FMF, a puzzling inherited autoinflammatory disorder. Clinical presentation of FMF can be misleading and requires a complete and early workup to recognize the disease and avoid unjustified surgery. Colchicine remains the gold standard therapy to prevent FMF attacks and fatal long-term complications [10, 11].