Low-dose colchicine for atherosclerosis: long-term safety.

Low-dose colchicine (0.5 mg daily) is now FDA-approved for secondary prevention in patients with coronary disease and will be increasingly prescribed in clinical practice. In this State-of-the-Art Review, data were collated from contemporary systemic reviews of case reports, drug registries, and placebo-controlled trials that assessed specific issues of safety related to the continuous use of colchicine in a range of clinical settings to inform physicians, pharmacists, and patients of the absolute risks of continuous use of low-dose colchicine, including among individuals taking statin therapy. Based upon these collective data, it is concluded that aside mild diarrhoea on initiation of colchicine that typically subsides in the vast majority of patients within a week of therapy, continuous use of low-dose colchicine is well tolerated and very safe. It does not affect renal, liver, or cognitive function, has no adverse effects on bleeding, wound healing, fertility, or pregnancy, and does not increase risks of cancer, serious infection, or cause-specific mortality. When appropriately prescribed to patients without significant renal or hepatic impairment, reports of myelosuppression, myotoxicity, and serious drug-drug interactions are rare and no more frequent than placebo, including in patients taking statin therapy. Physicians, pharmacists, and patients can be reassured that in the absence of significant renal or hepatic impairment continuous use of low-dose colchicine can be used safely in patients with atherosclerosis for the purpose of reducing cardiovascular risk.

Multi-Dimensional Validation of the Integration of Syntactic and Semantic Distance Measures for Clustering Fibromyalgia Patients in the Rheumatic Monitor Big Data Study.

This study primarily aimed at developing a novel multi-dimensional methodology to discover and validate the optimal number of clusters. The secondary objective was to deploy it for the task of clustering fibromyalgia patients. We present a comprehensive methodology that includes the use of several different clustering algorithms, quality assessment using several syntactic distance measures (the Silhouette Index (SI), Calinski-Harabasz index (CHI), and Davies-Bouldin index (DBI)), stability assessment using the adjusted Rand index (ARI), and the validation of the internal semantic consistency of each clustering option via the performance of multiple clustering iterations after the repeated bagging of the data to select multiple partial data sets. Then, we perform a statistical analysis of the (clinical) semantics of the most stable clustering options using the full data set. Finally, the results are validated through a supervised machine learning (ML) model that classifies the patients back into the discovered clusters and is interpreted by calculating the Shapley additive explanations (SHAP) values of the model. Thus, we refer to our methodology as the clustering, distance measures and iterative statistical and semantic validation (CDI-SSV) methodology. We applied our method to the analysis of a comprehensive data set acquired from 1370 fibromyalgia patients. The results demonstrate that the K-means was highly robust in the syntactic and the internal consistent semantics analysis phases and was therefore followed by a semantic assessment to determine the optimal number of clusters (k), which suggested k = 3 as a more clinically meaningful solution, representing three distinct severity levels. the random forest model validated the results by classification into the discovered clusters with high accuracy (AUC: 0.994; accuracy: 0.946). SHAP analysis emphasized the clinical relevance of "functional problems" in distinguishing the most severe condition. In conclusion, the CDI-SSV methodology offers significant potential for improving the classification of complex patients. Our findings suggest a classification system for different profiles of fibromyalgia patients, which has the potential to improve clinical care, by providing clinical markers for the evidence-based personalized diagnosis, management, and prognosis of fibromyalgia patients.

Old paradigms and new concepts in familial Mediterranean fever (FMF): an update 2023.

Familial Mediterranean fever (FMF) is a hereditary autoinflammatory disease characterized by recurrent attacks of fever and polyserositis. Its first description as a new entity was published by Siegal in 1945. Colchicine has been the treatment of choice for this disease since 1972. Significant progress has been made over the years in understanding FMF's clinical features, diagnosis, mode of inheritance, pathogenesis and therapeutic approach. However, many old paradigms related to FMF have proven inaccurate, leading to the emergence of new concepts that provide more precise insights. The term 'FMF' is no longer appropriate as the disease is found beyond the Mediterranean basin. The concept of diagnosis based only upon clinical ground proved to be wrong. The paradigm that MEFV mutations in FMF lead to loss of function of the encoded peptide pyrin turned out to be a gain of function mutation. Finally, the concept that as a genetic disease FMF should be treated for life was found to be inaccurate for the subpopulation of the heterozygote patients. Thus, the breakthroughs of identifying the gene associated with the disease (MEFV) and the deciphering of its pathogenesis revolutionized our old paradigms and replaced them with new and more precise insights.

IL-1 inhibition in familial Mediterranean fever: clinical outcomes and expectations.

Familial Mediterranean fever (FMF) is a hereditary auto-inflammatory disease, characterised by recurrent episodes of fever and serositis. Since 1972, colchicine is the drug of choice for FMF. It is effective in preventing the attacks and withholding amyloidosis in most patients with FMF. Colchicine blood and tissue levels are regulated by a glycoprotein pump (GLP) and by Cytochrome P450 3A4 (CYP450 3A4). It is secreted through the bile system and the kidneys. Over the years several problems have been raised following the use of colchicine in FMF. These include potential side effects (particularly gastrointestinal), non-compliance, inefficacy due to drug resistance, many drug-drug interactions and high risk for intoxication due to a narrow therapeutic range. In addition, colchicine does not prevent protracted febrile myalgia or exertional leg pain. Based upon our current understanding of the pathogenesis of FMF, it seems that anti-interleukin-1 (anti-IL-1) agents can solve many of the aforementioned problems related to colchicine therapy. The gastrointestinal side effects of colchicine are extremely uncommon with anti-IL-1 biologics. Drug-drug interactions are also unlikely, and their therapeutic window is not narrow. The once daily injection of anakinra, the once weekly injection of rilonacept, and the once monthly injection of canakinumab result in a better compliance to therapy. Nevertheless, there are no controlled trials showing the efficacy of anti-IL-1 agents in preventing amyloidosis or their safety in pregnancy. Therefore, it is still needed to give IL-1 blockers with concomitant colchicine in its tolerable dose effective in preventing amyloidosis (1.5 mg daily in adult).

Palindromic rheumatism following COVID-19 infection evolved to rheumatoid arthritis after COVID-19 reinfection.

A 33-year-old woman developed palindromic rheumatism (PLR) several weeks following an infection with severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2). Three months later, she developed full blown seropositive rheumatoid arthritis (RA) following COVID-19 reinfection. Although the occurrence of the joint diseases and the COVID-19 infections maybe fortuitous, knowing the enormous effects of COVID-19 infection on the human immune system, it is difficult to ignore the temporal relationship between the appearance of PLR after the first COVID-19 infection and the transition to full blown RA following her COVID-19 re-infection.

Incidence and course of COVID-19 hospitalizations among patients with familial Mediterranean fever.

OBJECTIVES: To evaluate the incidence of hospitalization for coronavirus disease 2019 (COVID-19) in patients with FMF, as compared with the general population, and to compare the disease course between FMF inpatients, and age-, sex-, ethnicity- and comorbidity-matched non-FMF COVID-19 inpatients. METHODS: We used electronic medical records to obtain data about the total number of the insured population and the number of FMF patients in the two largest health management organizations in Jerusalem, Clalit and Meuhedet. The total number of COVID-19 inpatients at the Hadassah Medical Center, including those with FMF, for the period between 1 February 2020 and 10March 2021, was retrieved from the electronic medical records of Hadassah. COVID-19 course was compared between the FMF inpatient group and age-, sex-, ethnicity- and comorbidity-matched non-FMF COVID-19 inpatients. Each FMF inpatient was matched with two non-FMF controls. RESULTS: We found no statistically significant difference in the odds of hospitalization for COVID-19 between FMF patients and the non-FMF population (0.46% vs 0.41%, P = 0.73). Furthermore, we found similar disease severity and therapeutic approach in FMF COVID-19 inpatients and matched non-FMF COVID-19 inpatients. CONCLUSIONS: Neither FMF nor baseline colchicine therapy, appear to affect the incidence of hospitalization for COVID-19 or the disease course, in terms of severity and therapeutic approach.

Infertility Causes and Pregnancy Outcome in Patients With Familial Mediterranean Fever and Controls.

OBJECTIVE: Recurrent attacks of peritonitis due to familial Mediterranean fever (FMF) may lead to peritoneal adhesions and fallopian tube obstruction. Colchicine, which is the treatment of choice for FMF, may disturb cell division. Secondary amyloidosis, a complication of untreated FMF, may involve the testes and ovaries. Thus, FMF and colchicine may potentially affect fertility and pregnancy in patients with FMF. The aims of the study are to evaluate the causes of infertility and pregnancy outcome in FMF patients and to compare them with 2 groups: non-FMF patients with peritoneal female genital tuberculosis (FGTB) and normal healthy controls. METHODS: This is a retrospective study in which FMF patients with reproductive disorders were recruited from the National Center of Medical Genetics and Primary Health Care in Yerevan, Armenia. The patients with FGTB and the healthy controls with reproductive problems were recruited successively from a large gynecology clinic in Yerevan. Genetic analyses for FMF were performed using ViennaLab StripAssay. RESULTS: The FMF group (211 patients) resembles the FGTB group (127 patients) regarding etiologies of infertility. However, in vitro fertilization (IVF) success rate and pregnancy outcome were comparable between the FMF patients and the control group (162 patients). Infertility in patients with FMF was clearly associated with a more severe disease and a lack of adequate colchicine treatment. CONCLUSIONS: Colchicine medication and controlled FMF disease do not adversely affect the reproductive system and pregnancy outcome. However, a lack of an appropriate colchicine treatment may cause infertility and poor pregnancy outcome.

Defining colchicine resistance/intolerance in patients with familial Mediterranean fever: a modified-Delphi consensus approach.

OBJECTIVES: Colchicine is the main treatment for FMF. Although a number of individuals with FMF are intolerant/resistant to colchicine, there is no standard definition of colchicine resistance/intolerance. We developed a set of evidence-based core statements defining colchicine resistance/intolerance in patients with FMF that may serve as a guide for clinicians and health authorities. METHODS: A set of statements was identified using a modified-Delphi consensus-based approach. The process involved development of an initial colchicine resistance/intolerance-related questionnaire derived from a systematic literature review. The questionnaire, which was completed by an international panel of 11 adult and paediatric rheumatologists with expertise in FMF, was analysed anonymously. The results informed draft consensus statements that were discussed by a round-table expert panel, using a nominal group technique to agree on the selection and wording of the final statements. RESULTS: Consensus among the panel was achieved on eight core statements defining colchicine resistance/intolerance in patients with FMF. A definition of resistance was agreed upon that included recurrent clinical attacks (average one or more attacks per month over a 3-month period) or persistent laboratory inflammation in between attacks. Other core statements recognize the importance of assessing treatment adherence, and the impact of active disease and intolerance to colchicine on quality of life. CONCLUSION: Based on expert opinion, a set of evidence-based core statements defining colchicine resistance/intolerance in patients with FMF were identified to help guide clinicians and health authorities in the management of patients with FMF.

Serological and hematological characteristics of Sjogren's syndrome and dry eye syndrome patients using a novel immune serology technique.

OBJECTIVES: To compare hematologic and serological parameters among patients with Sjogren's syndrome (SS), dry eye syndrome (DES) and controls, and validate a novel multiplex-serology method for identifying auto-antibodies in these populations. METHODS: In a clinic-based case-control study a total of 422 participants were recruited, including 91 with SS, 120 DES, and 211 controls (age and sex frequency-matched). We measured blood counts, anti-nuclear-antibodies (ANA), anti-SSA/SSB, anti-ribonucleoprotein (RNP), anti-double-stranded-DNA (DS-DNA), and rheumatoid factor (RF) using the "Immunodot" qualitative-ELISA assay. Immunoglobulins, C3 and C4 were measured by immune-fluorescence. Autoantibodies were also quantified with a newly-developed method using glutathione-S-transferase fusion proteins of SSA/Ro 52 and 60kD and SSB/La (multiplex-serology), measuring median fluorescence intensity (MFI). RESULTS: Among DES patients, only 2% (95%CI: 0.36-6.3) had positive immune serology. SS patients had lower lymphocyte, hemoglobin and C3 levels but higher prevalence of RF, ANA, anti-SSA/B and higher IgG and MFI levels, compared to DES and controls (P<0.001). Presence of anti-SSA/Ro-52kD was associated with SS [odds ratio (OR) = 2.05, 95% confidence interval (CI): 1.46-2.88]. Anti-SSB/La was inversely associated with DES (OR = 0.81, 95%CI: 0.65-1.00) compared to controls. Positivity to RF (adjusted for age, gender and ethnicity OR = 5.03, 95%CI: 1.78-14.21), ANA (OR = 14.75, 95%CI: 4.09-53.17), or combination of anti-SSA/B (OR = 20.97, 95%CI: 4.60-95.54) were more likely in SS compared to DES. The novel multiplex-serology method correctly identified anti-SSA/B autoantibodies by ELISA among SS, DES patients and controls (sensitivity = 1.0, negative-predictive-value = 1.0). CONCLUSIONS: Serologic parameters distinguish SS from DES patients and controls. A newly-developed multiplex-serology technique may be useful to detect autoantibodies in large epidemiologic studies.

ISSAID/EMQN Best Practice Guidelines for the Genetic Diagnosis of Monogenic Autoinflammatory Diseases in the Next-Generation Sequencing Era.

BACKGROUND: Monogenic autoinflammatory diseases are caused by pathogenic variants in genes that regulate innate immune responses, and are characterized by sterile systemic inflammatory episodes. Since symptoms can overlap within this rapidly expanding disease category, accurate genetic diagnosis is of the utmost importance to initiate early inflammation-targeted treatment and prevent clinically significant or life-threatening complications. Initial recommendations for the genetic diagnosis of autoinflammatory diseases were limited to a gene-by-gene diagnosis strategy based on the Sanger method, and restricted to the 4 prototypic recurrent fevers (MEFV, MVK, TNFRSF1A, and NLRP3 genes). The development of best practices guidelines integrating critical recent discoveries has become essential. METHODS: The preparatory steps included 2 online surveys and pathogenicity annotation of newly recommended genes. The current guidelines were drafted by European Molecular Genetics Quality Network members, then discussed by a panel of experts of the International Society for Systemic Autoinflammatory Diseases during a consensus meeting. RESULTS: In these guidelines, we combine the diagnostic strength of next-generation sequencing and recommendations to 4 more recently identified genes (ADA2, NOD2, PSTPIP1, and TNFAIP3), nonclassical pathogenic genetic alterations, and atypical phenotypes. We present a referral-based decision tree for test scope and method (Sanger versus next-generation sequencing) and recommend on complementary explorations for mosaicism, copy-number variants, and gene dose. A genotype table based on the 5-category variant pathogenicity classification provides the clinical significance of prototypic genotypes per gene and disease. CONCLUSIONS: These guidelines will orient and assist geneticists and health practitioners in providing up-to-date and appropriate diagnosis to their patients.

SNP variations in IL10, TNFα and TNFAIP3 genes in patients with dry eye syndrome and Sjogren's syndrome.

BACKGROUND: Cytokines are known to be key players in dry eye syndrome (DES) and Sjogren's syndrome (SS) pathogenesis. In this study we compared single nucleotide polymorphism (SNP) variations in genes encoding cytokine levels among SS and DES patients in Israel. METHODS: We recruited 180 subjects, 82 with SS and 98 with DES. Using a candidate gene approach and allele-specific PCR technique for genotyping, proportions of risk alleles in Tumor Necrosis Factor α (TNFα) (rs1800629), IinterLeukin-10 (IL-10) (rs1800896) and TNFAIP3 (rs2230926) SNPs were compared between study groups. RESULTS: Allelic distribution was found very similar to Caucasian (CEU - Utah residents with Northern and Western European roots) population distributions in these SNPs. While none of the SNPs' variants were significantly associated with SS or DES in a recessive model, in an additive model the TNFα G risk allele was found higher among SS patients compared to DES (Homozygote-G: 84.2% vs. 70.8%; Heterozygote: 26.9% vs. 11.2%, respectively, p = 0.02). After adjustment for age, gender and ethnicity, these variants weren't associated with SS. Genetic scoring reveals that SS patients are more likely to present variants of all three SNPs than DES subjects. CONCLUSIONS: This is the first study evaluating these SNP variations among both patients with DES and patients with SS. We found the allelic distribution in each SNP to be very similar to that found in healthy Caucasian populations presented in the HapMap project. We found the TNFα allele significantly associated with DES for homozygotes, and associated with SS for heterozygotes in the additive model.

Shared Medical and Environmental Risk Factors in Dry Eye Syndrome, Sjogren's Syndrome, and B-Cell Non-Hodgkin Lymphoma: A Case-Control Study.

OBJECTIVES: To assess whether there are shared exposures associated with Sjogren's syndrome (SS), dry eye syndrome (DES), and B-cell non-Hodgkin lymphoma (B-NHL), in order to determine whether they are etiologically related. METHODS: In a clinic-based case-control study, 702 participants (91 SS, 120 DES, 211 (age and sex frequency-matched) controls, and 280 B-NHL cases) were recruited and interviewed regarding exposures, medical history, and family history. RESULTS: Female predominance was noted in SS (ratio 9.2 : 1). Eye dryness was severest in SS compared to DES and controls (P < 0.001). Compared to controls, alcohol consumption was inversely associated with NHL, DES, and SS (odds ratio (OR) = 0.47, 95% confidence interval (CI): 0.31-0.71; OR = 0.54, 95% CI: 0.33-0.88; and OR = 0.26, 95% CI: 0.14-0.49, respectively), while a previous history of infection requiring hospitalization was positively associated with all three conditions: NHL (OR = 1.92; 95% CI: 1.23-2.99), DES (OR = 3.29; 95% CI: 1.97-5.47), and SS (OR = 4.74; 95% CI: 2.66-8.44). NHL patients were more likely to report first-degree relatives with hematologic cancer, while having first-degree relatives with an autoimmune disease (AID) was associated with SS (OR = 5.25; 95% CI: 2.59-10.63) and DES (OR = 3.55; 95% CI: 1.83-6.91) compared to controls. CONCLUSIONS: Some exposures are associated with all three conditions (such as an inverse association with alcohol consumption and a positive association with serious past infection), while a family history of AID appears to be shared by DES and SS, but not NHL subjects. Shared risk factors for all three conditions indicate possible mutual etiological pathways.

An International Delphi Survey for the Definition of New Classification Criteria for Familial Mediterranean Fever, Mevalonate Kinase Deficiency, TNF Receptor-associated Periodic Fever Syndromes, and Cryopyrin-associated Periodic Syndrome.

OBJECTIVE: Provisional evidence-based classification criteria for hereditary periodic fever (HPF) have been recently developed. However, no consensus on how to combine clinical criteria, laboratory tests, and results of molecular analysis has been reached. The objective of this study is to understand which variables physicians consider important for the classification of patients with HPF. METHODS: Two Delphi surveys were sent to health professionals in the field of autoinflammation. In the first open survey, 124 researchers could list all the variables they consider useful for the diagnosis of each monogenic periodic fever. The variables could be of any type and each researcher could complete the survey for 1 or more diseases. In the second survey, 162 researchers were asked to select, from a list of items coming from the first survey, the 10 top variables and to rank them by assigning a score from 10 to 1. RESULTS: The response rates to the Delphi surveys were 85% for the first session and 87% for the second. The variables selected for each disease (corresponding to the third quartile, considering the total score obtained by the variables after the second Delphi survey) were 21 for mevalonate kinase deficiency, 22 for cryopyrinopathies, 18 for familial Mediterranean fever, and 20 for tumor necrosis factor receptor-associated periodic fever syndrome. A positive genetic test reached the top rank in all the HPF. CONCLUSION: Our process led to the identification of those features considered the most important as candidate variables to be included in a new set of evidence-based classification criteria for HPF.