Update on the Role of Colchicine in Cardiovascular Disease.

PURPOSE OF REVIEW: This review focuses on the use of colchicine to target inflammation to prevent cardiovascular events among those at-risk for or with established coronary artery disease. RECENT FINDINGS: Colchicine is an anti-inflammatory drug that reduces cardiovascular events through its effect on the IL-1ß/IL-6/CRP pathway, which promotes the progression and rupture of atherosclerotic plaques. Clinical trials have demonstrated that colchicine reduces cardiovascular events by 31% among those with chronic coronary disease, and by 23% among those with recent myocardial infarction. Its ability to dampen inflammation during an acute injury may broaden its scope of use in patients at risk for cardiovascular events after major non-cardiac surgery. Colchicine is an effective anti-inflammatory therapy in the prevention of acute coronary syndrome. Ongoing studies aim to assess when, and in whom, colchicine is most effective to prevent cardiovascular events in patients at-risk for or with established coronary artery disease.

Unraveling the genome: Familial Mediterranean fever.

ABSTRACT: Familial Mediterranean fever (FMF) is an inherited, autoinflammatory disease with a high prevalence in Middle Eastern and Mediterranean populations including Turks, Iranian, Spanish, Sephardic Jews, Arabs, and other Mediterranean ethnic groups. Autoinflammatory diseases are genetically predetermined disorders with multisystem effects primarily caused by defects in innate immunity. Although primarily known for an autosomal recessive mode of inheritance, there are increasing case reports associated with single Mediterranean fever (MEFV) mutation or dominant transmission. There have been over 300 variants identified in the MEFV gene; however, roughly 9-11 variants are responsible for the phenotypical expression seen with FMF. Symptoms include recurrent episodes of fever of unknown origin, abdominal, chest, or joint pain because of serosal inflammation. Persistent elevations in serum amyloid A can lead to complications like renal amyloidosis, kidney dysfunction, and end-stage kidney disease. Familial Mediterranean fever is diagnosed clinically using the Tel-Hashomer criteria and confirmed through genetic testing. Treatment includes initiation of colchicine with the goal of stopping attacks and preventing renal dysfunction and end-stage kidney disease. Genetic testing helps to identify the specific mutation allowing the provider to create a patient-specific treatment plan, monitor for complications such as renal amyloidosis, and enhance knowledge on the genetic heterogeneity and possible epigenetic factors.

Empagliflozin and colchicine in patients with reduced left ventricular ejection fraction following ST-elevation myocardial infarction: a randomized, double-blinded, three-arm parallel-group, controlled trial.

PURPOSE: There is accumulating evidence regarding the potential benefits of empagliflozin in individuals with acute myocardial infarction (MI). Based on the literature, colchicine could also reduce the risk of MI and death in individuals with cardiovascular disease (CVD). However, trials investigating the effects of the combination of empagliflozin with colchicine and high-dose empagliflozin monotherapy in this setting are lacking. METHODS: In this trial, 106 non-diabetic participants with reduced left ventricular ejection fraction (LVEF) following recent ST-elevation MI were randomly assigned to empagliflozin 10 mg/day, empagliflozin 10 mg/day plus colchicine 0.5 mg twice daily, or empagliflozin 25 mg/day groups within 72 h after primary percutaneous coronary intervention (PCI). The study's primary outcomes were the changes in New York Heart Association (NYHA) functional class and high-sensitivity C-reactive protein (hs-CRP) over 12 weeks. RESULTS: The baseline characteristics of individuals were statistically similar between the study groups. Changes in NYHA functional class over 12 weeks were not significantly different between the study groups. hs-CRP was significantly reduced in all groups (all P < 0.001); however, there was no significant change between the groups over the study period. Changes in tumor necrosis factor-alpha (TNF-α), LVEF, and left ventricular end-diastolic dimension (LVEDD) during the research period did not differ significantly between groups. CONCLUSION: This study showed that neither the combination treatment of empagliflozin 10 mg/day with colchicine nor the monotherapy of empagliflozin 25 mg/day was superior to empagliflozin 10 mg/day in terms of changes in clinical, inflammatory, and echocardiographic outcome parameters in patients with recent MI with reduced LVEF over 3 months. Further studies are warranted to confirm the findings. TRIAL REGISTRATION: Clinical trial ID: IRCT20111206008307N39. Registration date: 27 October 2022. https://www.irct.ir/trial/66216.

Inflammatory comorbidities in the largest pediatric Familial Mediterranean fever cohort: a multicenter retrospective study of Pediatric Rheumatology Academy (PeRA)-Research Group (RG).

AIM: The aim of this study was to investigate the frequency and type of FMF-associated inflammatory diseases in a large FMF pediatric patients and to compare them to those FMF patients without concomitant inflammatory diseases. MATERIALS AND METHODS: Familial Mediterranean fever patients enrolled in the Pediatric Rheumatology Academy (PeRA)-Research Group (RG) were included. The patients were divided into two groups according to concomitant inflammatory disease as FMF patients who had a concomitant inflammatory disease (group 1) and FMF patients who did not have a concomitant inflammatory disease (group 1). The clinical findings and treatments were compared between the two groups. RESULTS: The study group comprised 3475 patients with FMF. There were 294 patients (8.5%) in group 1 and 3181 patients (91.5%) in group 2. Juvenile idiopathic arthritis (n = 136) was the most common accompanying inflammatory disease. Arthritis, M694V homozygosity, and the need for biological therapy were more frequently observed in Group 1 (p < 0.05). Fever and abdominal pain were more frequently detected in Group 2 (p < 0.05). FMF patients with concomitant inflammatory diseas more frequently demonstrated colchicine resistance. There were no significant differences in the median attack frequency, chest pain, amyloidosis, erysipelas-like erythema, or family history of FMF between the two patient groups. CONCLUSION: To the best of our knowledge, this is the largest pediatric cohort reviewed to date. FMF patients may have different clinical profiles and colchicine responses if they have with concomitant inflammatory diseases. Key points • FMF is associated with some inflammatory comorbidities diseases. • To the best of our knowledge, this is the largest cohort evlauated pediatric FMF associated inflammatory comorbidities diseases reviewed to date.

Cleavage-resistant RIPK1-induced autoinflammatory syndrome-A report of three generations with periodic fever and clinical response to colchicine.

The clinical syndrome caused by cleavage-resistant RIPK1 is known as CRIA (Cleavage-resistant RIPK1-induced autoinflammatory) syndrome. We present a family with three generations affected by CRIA syndrome. Our index patient (P1), a boy born of a non-consanguineous marriage, developed recurrent episodes of fever after 5 months of age, with variable periodicity. His father (P2) and paternal grandmother also had periodic fever. At 23 months of age, P1 was diagnosed with renal biopsy-proven steroid-responsive nephrotic syndrome. His first visit to our center was at 2 years of age. At presentation, he had failure to thrive, microcytic hypochromic anemia, and elevated inflammatory markers and interleukin-6 levels. Amyloid A protein was elevated, serum creatinine was normal, and proteinuria resolved after addition of steroids. Next-generation sequencing showed heterozygous mutation (c.970G>A, p.Asp324His) in RIPK1. This mutation has been reported to cause CRIA syndrome. P2 and P1's asymptomatic younger brother had the same mutation. All the affected members showed variability with respect to frequency and duration of periodic fever as well as the age of onset. Both P1 and P2 had elevated amyloid A, with no evidence of renal dysfunction. P1 and P2 showed improvement in the intensity of fever spikes with colchicine treatment; however, both continue to have periodic fever.

Cancer incidence in Familial Mediterranean Fever: A retrospective analysis.

OBJECTIVES: Familial Mediterranean Fever (FMF) is the most common hereditary monogenic fever syndrome that is characterized by recurrent attacks of fever and polyserositis. Anti-inflammatory drugs, with colchicine being the first-line therapy, have been used in the management of FMF. This study aims to evaluate the risk of cancer in Turkish FMF patients. METHODS: We retrospectively screened the cancer-related outcomes of our study group which consisted of Turkish FMF patients registered at our division. Cancer estimates of the Turkish population were published by the Turkish Ministry of Health in the Turkey Cancer Statistics Report 2018. Standardized incidence rates (SIR) were calculated to compare the cancer incidence observed in our study group with the expected cancer incidence of the Turkish population. Subgroup analyses were conducted on the subgroups, based on gender and usage of biological agents. RESULTS: Our study included 1734 FMF patients, 1054 (60.8 %) of whom were females. The total follow-up was 68,784 person-years. Cancer was observed in 35 (2 %) of these patients. Turkish FMF patients had a significantly lower incidence of cancer, compared with the overall Turkish population [SIR 0.64 (95 % CI 0.46-0.89), p < 0.01]. No significant association was found between cancer and biological agent therapies in FMF patients. CONCLUSIONS: Findings from our study indicate that the risk of cancer was decreased by 36 % in Turkish patients with FMF, compared with the outcomes of the overall Turkish population. Life-long exposure to anti-inflammatory drugs, primarily colchicine, may be the underlying reason for this outcome. Further studies are needed for the confirmation and explanation of this association.

French protocol for the diagnosis and management of familial Mediterranean fever.

Familial Mediterranean fever is the most common monogenic auto-inflammatory disease in the world. It mainly affects people originating from the Mediterranean region. The mutated gene is MEFV, which codes for pyrin. Transmission is autosomal recessive. Patients present with recurrent attacks of fever since childhood associated with abdominal and/or thoracic pain lasting an average of 2-3days and a biological inflammatory syndrome. Other symptoms include arthralgia or arthritis in large joints such as the knees and ankles, myalgia in the lower limbs and pseudo-erysipelas in the ankles. The most serious complication is inflammatory amyloidosis, which can lead to kidney failure. Treatment is based on colchicine, which helps to prevent flares and the onset of renal amyloidosis. This paper proposes national guidelines for the diagnosis, management and follow-up of familial Mediterranean fever in France, where we estimate there are between 5000 and 10,000 patients with the disease at all stages of life. The diagnosis is suspected on the basis of clinical and anamnestic factors and confirmed by genetic analysis. These guidelines also suggest a "treat-to-target" approach to disease management, particularly in case of suspected colchicine resistance - a very rare situation that should remain a diagnosis of elimination, especially after colchicine compliance has been verified. Two special situations are also addressed in these guidelines: kidney failure and pregnancy.

NLRP12-associated autoinflammatory disease: much more than the FCAS phenotype.

OBJECTIVES: NLRP12-associated autoinflammatory disease (NLRP12-AID) is a rarely seen periodic fever syndrome also known as familial cold autoinflammatory syndrome-2 (FCAS2), caused by autosomal dominant inherited mutations in the NLRP12 gene. We aimed to present our clinical experience constituting one of the largest paediatric NLRP12-AID cohort. METHODS: The patients with preliminary diagnosis of systemic autoinflammatory disease (SAID) other than familial Mediterranean fever (FMF) and PFAPA syndrome were evaluated with the next-generation-sequence (NGS) genetic-panel analysis between January-2016 and January-2022. Among children carrying NLRP12-variant, patients with recurrent episodes of autoinflammatory disease manifestations were diagnosed with NLRP12-AID. Demographic, clinical and laboratory data, treatments and outcomes of patients were presented. RESULTS: Seventeen patients were diagnosed with NLRP12-AID. The mean age at diagnosis was 114.7±69.5 months. The most frequently seen clinical manifestations were respectively; fever (100%), arthritis/arthralgia (58.8%), rash (52.9%), abdominal pain (52.9%), diarrhoea (41.2%), myalgia/fatigue (53.2%) and, conjunctivitis (11.7%). Clinical manifestations were triggered by cold exposure in three patients (17.6%). Seven patients had pathogenic, one had likely pathogenic, seven had VUS, and two had novel heterozygous variants. The most common defined variant in the NLRP12 gene was R352C. Complete response was achieved in 5 patients and partial response was in 6 with colchicine treatment. Attacks were prevented with anti-IL-1 treatments in 6 patients unresponsive to colchicine. CONCLUSIONS: In conclusion, the disease can cause effects on various tissues, especially the musculoskeletal and gastrointestinal systems, apart from FCAS symptoms. We think that a patient who can be defined as syndrome of undifferentiated recurrent fever should also be evaluated genetically in terms of NLRP12 previously.

Drug metabolism and inflammation related distinct miRNA signature of colchicine resistant familial Mediterranean fever patients.

OBJECTIVE: Colchicine is the primary treatment for familial Mediterranean fever (FMF). Although colchicine is safe and effective in FMF patients, around 5-10% of patients show resistance to the drug. This study investigates the possibility of a link between colchicine resistance and the distinct miRNA profiles in colchicine resistant FMF patients. METHODS: Differentially expressed miRNAs in colchicine resistant FMF patients were detected by Affymetrix 4.0 miRNA array analysis. These miRNAs were then categorized based on the role of their target genes in drug metabolism and inflammation related pathways. qRT-PCR was used to validate candidate miRNAs selected by Enrichr, a gene enrichment analysis system based on the relevance of possible target genes in drug metabolism pathways. Expression levels of these miRNAs' potential target genes were investigated by qRT-PCR. Then, a colchicine resistant hepatoblastoma cell line (HEPG2) was established, and the differentially expressed miRNAs and genes identified in patients were also analyzed in this colchicine-resistant cell line. RESULTS: 25 differentially expressed miRNAs were detected in colchicine resistant FMF patients. miR-183-5p, miR-15b-5p, miR-505-5p, and miR-125a-5p were identified to be associated with drug resistance and inflammatory pathways and thus chosen for further validation. miR-183-5p, miR-15b-5p, miR-505-5p miRNAs showed significantly differential expression in qRT-PCR. NFKB1, NR3C1, PPARα - drug absorption, distribution, metabolism, and excretion (ADME) genes were predicted to be targeted by these miRNAs. Among these targets, NFKB1 and NR3C1 were differentially over expressed in colchicine resistant FMF patients. These findings were validated in the colchicine resistant hepatoblastoma cell line (HEPG2). CONCLUSION: This is the first study evaluating the role of miRNAs in colchicine resistant patients with FMF. Their differential expression may result in resistance to standard colchicine treatment by affecting the expression of genes that take place in drug absorption, distribution, metabolism, and excretion (ADME) or nuclear receptors that regulate ADME genes, thus potentially playing a role in both drug metabolism and inflammation.

LOSS OF EFFICACY OF ADALIMUMAB IN HIDRADENITIS SUPPURATIVA: FOCUS ON ALTERNATIVES.

The loss of efficacy of adalimumab, one of the most commonly used biologics for the treatment of hidradenitis suppurativa/acne inversa, is not news to the scientific community, and it should be noted that the number of cases not responding to this agent has been progressively increasing in recent years. We present a 45-year-old patient with hidradenitis suppurativa/acne inversa (Hurley II-III) with a complaint duration of 3 years who has been on adalimumab 40 mg weekly for 9 months. The lack of improvement in the clinical condition as well as the progression of the disease within the ongoing biologic therapy led to the need for repeated hospitalizations and the additional introduction of intravenous treatment with a regimen of antibiotics (Ertapenem, Metronizadol, Ceftriaxone), zinc, colchicine, and pain relievers. During these hospitalizations, a partial improvement was found, which was not durable and required the parallel administration of antibiotics, colchicine and zinc in combination with adalimumab in an outpatient regimen. Several attempts at surgical treatment/incision in non-specialized units were also made, and these too remained generally unsuccessful or with a nondurable, unsatisfactory clinical outcome. Due to the subsequent consecutive worsening of the symptomatology, the patient was admitted for evaluation of the clinical condition and optimization of treatment. Surgical treatment was performed by surgical deroofing under general anaesthesia, concurrent with discontinuation of adalimumab/antibiotic application and long-term remission was achieved. Surgical deroofing has also been shown to be an effective therapeutic option in the loss/lack of efficacy of adalimumab in patients with hidradenitis suppurativa (Hurley II-III). In the case of therapeutic resistance or worsening of symptomatology in patients with acne inversa within adalimumab therapy, other advanced alternatives such as golimumab, anakinra, etanercept are available. The efficacy of these second-line agents is also questionable due to the development of resistance to them as well, which in turn necessitates the frequent switch to third-line agents such as: Ustekinumab, Tildarkizumab, Certolizumab or Ixekizumab. The future will show to what extent this "trust" could be justified and whether in practice the surgical approach will once again displace the so-called "modern options" as the reasonable next basic and reliable alternative. The disadvantage of modern biological therapy is mainly due to the loss of efficacy/development of resistance over time, multiple side effects and frequent recurrence after discontinuation of treatment. In contrast, in the case of specific, stage-oriented, specialized surgical treatment of hidradenitis suppurativa/ acne inversa, in the form of surgical deroofing, for example, the results are long-lasting and in the case of recurrences: the latter are much more easily managed by dermatosurgery/surgery again. The effect achieved after this type of manipulation is essential for the patients' quality of life and guarantees to a large extent also prevention of the development of keratinocyte tumours in the areas affected by chronic inflammation. Precisely because of the aforementioned facts, in a serious number of patients this type of treatment could be considered as a priority. The rethinking of the guideline and the staging of surgical modalities as first-line therapy could, in a serious number of patients, have a positive effect. Swap for surgery seems to be a good alternative.

Gray zone in the spectrum of autoinflammatory diseases: familial Mediterranean fever accompanying periodic fever, aphthous stomatitis, pharyngitis, and adenitis syndrome: single-center experience.

Despite the advanced knowledge concerning autoinflammatory diseases (AID), more data regarding the optimal treatment options and outcomes of the children who met the criteria of more than one AID are required. This study aimed to describe the demographic and clinical characteristics of children from familial Mediterranean fever (FMF)-endemic countries who meet both the FMF and the periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome criteria. Moreover, we aimed to measure the response rates to colchicine and tonsillectomy and evaluate the factors affecting the colchicine response in these patients. The study was conducted at pediatric rheumatology tertiary centre. A total of 131 patients (58 females; 73 males) who met both the modified Marshall and pediatric FMF criteria were included. The median age at onset was 18 months (1-77 months), and the mean age at diagnosis was 47 ± 21.88 months. The median interval between episodes was 21 (7-90) days. The median disease duration was 46 (6-128) months. Consanguineous marriage was detected in 17 (13%) of the patients. The most common clinical finding was fever (100%), followed by exudative pharyngitis (88.5%), abdominal pain (86.3%), arthralgia (61.8%), stomatitis (51.1%), adenitis (42%), myalgia (28.7%), chest pain (16%), maculopapular rash (12.2%), arthritis (8.4%), and erysipelas-like rash (4.6%). MEFV gene variants were identified in 106 (80.9%) patients. The most common variants were M694V heterozygous (29%). We found that patients with tonsillopharyngitis, aphthous stomatitis, and PFAPA family history were more likely to be colchicine-resistant and tonsillectomy responsive, while those with exon 10 MEFV gene mutations were more prone to have a favorable response to colchicine.     Conclusion: PFAPA syndrome patients with exon 10 MEFV gene mutation, showing typical FMF symptoms, should be treated with colchicine, even after tonsillectomy. In multivariate analysis, PFAPA family history and lack of exon 10 MEFV gene mutations were independent risk factors for colchicine resistance. Thus, tonsillectomy may be recommended as a possible treatment option for these patients. It has yet to be clarified when colchicine treatment will be discontinued in patients whose attacks ceased after tonsillectomy that was performed due to colchicine unresponsiveness. What is Known: • A certain number of patients with periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome concomitantly fulfill the familial Mediterranean fever (FMF) criteria. • While colchicine is proposed as a first treatment choice in familial Mediterranean fever (FMF), corticosteroids are recommended as a first-line treatment in PFAPA syndrome patients. What is New: • In patients with concomitant PFAPA syndrome and FMF, PFAPA family history and lack of exon 10 MEFV gene mutation are predictive factors of colchicine resistance. • The presence of exon 10 MEFV gene mutations in patients with concomitant FMF and PFAPA syndrome has a favourable effect on response to colchicine treatment.

Is colchicine prophylaxis required with start-low go-slow allopurinol dose escalation in gout? A non-inferiority randomised double-blind placebo-controlled trial.

OBJECTIVES: To determine whether placebo is non-inferior to low-dose colchicine for reducing gout flares during the first 6 months of allopurinol using the 'start-low go-slow' dose approach. METHODS: A 12-month double-blind, placebo-controlled non-inferiority trial was undertaken. Adults with at least one gout flare in the preceding 6 months, fulfilling the American College of Rheumatology (ACR) recommendations for starting urate-lowering therapy and serum urate ≥0.36 mmol/L were recruited. Participants were randomised 1:1 to colchicine 0.5 mg daily or placebo for the first 6 months. All participants commenced allopurinol, increasing monthly to achieve target urate <0.36 mmol/L. The primary efficacy outcome was the mean number of gout flares/month between 0 and 6 months, with a prespecified non-inferiority margin of 0.12 gout flares/month. The primary safety outcome was adverse events over the first 6 months. RESULTS: Two hundred participants were randomised. The mean (95% CI) number of gout flares/month between baseline and month 6 was 0.61 (0.47 to 0.74) in the placebo group compared with 0.35 (0.22 to 0.49) in the colchicine group, mean difference 0.25 (0.07 to 0.44), non-inferiority p=0.92. There was no difference in the mean number of gout flares/month between randomised groups over the 12-month period (p=0.68). There were 11 serious adverse events in 7 participants receiving colchicine and 3 in 2 receiving placebo. CONCLUSIONS: Placebo is not non-inferior to colchicine in prevention of gout flares in the first 6 months of starting allopurinol using the 'start-low go-slow' strategy. After stopping colchicine, gout flares rise with no difference in the mean number of gout flares/month between groups over a 12-month period. TRIAL REGISTRATION NUMBER: ACTRN 12618001179224.

Familial Mediterranean Fever-Related Amyloidosis in Turkey: A Need for a Familial Mediterranean Fever Registry.

Amyloidosis has been well known since Rudolph Virchow named the condition in the 19th century. Most physicians were aware of the association between amyloidosis to chronic suppurative conditions and multiple myeloma. However, familial Mediterranean fever, although probably as ancient as the Galenic era, was appropriately identified only in the 21st century. The nomenclature was variable throughout history, but the name "FMF" has been universally adopted since the report from Heller and colleagues in 1958. In 1967, Sokmen and Ozdemir of Ankara University published a report on 194 patients, of whom 64 had amyloidosis. Familial Mediterranean fever constituted the cause in half of the cases. Goldfinger and Ozkan demonstrated efficacy of colchicine for treatment of familial Mediterranean fever in 1972, and further studies revealed that colchicine is also efficient for prevention of amyloidosis. However, since then, several single-center and multicenter amyloid A amyloidosis studies from Turkey have been published. Almost invariably, familial Mediterranean fever is the most common cause of systemic amyloidosis. No downward trends in percentages have been observed. Recent studies have shown that cases of amyloidosis in patients with familial Mediterranean fever are decreasing. Also, cases of amyloidosis in conjunction with suppurative conditions are on the decrease worldwide. However, according to registry data from the Turkish Society of Nephrology, the percentage of incident hemodialysis patients with amyloidosis is not decreasing. The question arises: Why is a complication that is 98% preventable still causing end-stage renal disease? We believe the lack of a stable and comprehensive registry for familial Mediterranean fever, including associated cases of amyloidosis, is the reason we cannot properly answer this question. In this work, we use a historical approach to present why a familial Mediterranean fever registry is direly needed.

Analysis of appropriate duration of colchicine prophylaxis to maximize the persistence of xanthine oxidase inhibitors as the first-line urate-lowering therapy in patients with gout using the Korean Health Insurance Review and Assessment Service database.

INTRODUCTION: We investigated the appropriate duration of colchicine prophylaxis to maximize the persistence of xanthine oxidase inhibitors (XOIs) as first-line urate-lowering therapy (ULT) in patients with gout. This was a nationwide population-based retrospective cohort study using the Korean Health Insurance Review and Assessment database. METHODS: Patients with gout aged ≥20 years who were newly initiated on XOIs, such as allopurinol or febuxostat, from July 2015 to June 2017 and received these medications for ≥6 months were analyzed and followed up until June 2019. Persistence of XOIs was compared according to the 6-month duration of colchicine prophylaxis. For additional subgroup analysis, we also compared the persistence of XOIs according to the 3-month duration of colchicine prophylaxis. RESULTS: This study included 43 926 patients. The frequencies of patients with gout receiving colchicine prophylaxis for ≥6 months and ≥3 months were 6.3% and 7.6%, respectively. Allopurinol (65.2%) was prescribed more frequently than febuxostat (34.8%). During the study period, 23 475 patients (53.4%) stopped using XOIs. Colchicine prophylaxis for ≥6 months did not significantly reduce the risk of XOI discontinuation in multivariable Cox regression models. Colchicine prophylaxis for ≥3 months was significantly associated with a lower risk of non-persistence to XOIs after adjusting for confounding factors (hazard ratio = 0.95, p = .041). CONCLUSION: Our data suggest that at least 3 months of colchicine prophylaxis may be more appropriate than at least 6 months in terms of maximizing the persistence of XOIs in patients with gout.

Evaluation of mandibular cortical and trabecular radiomorphometry in familial Mediterranean fever patients.

OBJECTIVE: The objective of this retrospective study was to evaluate the mandibular cortical and trabecular morphology and microarchitecture of patients with familial Mediterranean fever (FMF) and compare them to those of healthy individuals by examining radiomorphometric indices on panoramic radiographs. STUDY DESIGN: We examined a group of 56 FMF patients aged 5 to 71 years and an age- and sex-matched control group of individuals with no systemic diseases. We classified the FMF and control groups according to age and sex and the FMF group according to colchicine use. We evaluated the quantitative radiomorphometic indices of gonial index, antegonial index, molar cortical thickness, mental index, panoramic mandibular index, and lacunarity, and the qualitative mandibular cortical index on all panoramic radiographs and performed between and within group analysis. RESULTS: Mean gonial index, antegonial index, and molar cortical thickness values of the FMF group were significantly smaller than those of the control group. Significantly fewer patients in the FMF group were classified as mandibular cortical index type 1 compared to the control group. There were no significant differences in quantitative index values according to colchicine use in the FMF group or regarding the categorical parameters of age, sex, and mandibular cortical index classification. CONCLUSIONS: Radiomorphometric values of the mandibular basal cortex posterior to the mental foramen differ significantly in FMF patients compared to healthy counterparts. Dentists should note mandibular morphologic changes indicative of low bone density when examining panoramic images of patients with this disease.

An Update on Familial Mediterranean Fever.

(1) Background: Familial Mediterranean Fever (FMF) is the prototypal autoinflammatory disease, characterized by recurrent bursts of neutrophilic inflammation. (2) Methods: In this study we look at the most recent literature on this condition and integrate it with novel information on treatment resistance and compliance. (3) Results: The canonical clinical presentation of FMF is in children with self-limited episodes of fever and polyserositis, associated with severe long-term complications, such as renal amyloidosis. It has been described anecdotally since ancient times, however only recently it has been characterized more accurately. We propose an updated overview on the main aspects of pathophysiology, genetics, diagnosis and treatment of this intriguing disease. (4) Conclusions: Overall, this review presents the all the main aspects, including real life outcome of the latest recommendation on treatment resistance of FMF, a disease, that not only helped understanding the pathophysiology of the auto inflammatory process but also the functioning of the innate immune system itself.

Changes in Prescription Drug and Health Care Use Over 9 Years After the Large Drug Price Increase for Colchicine.

Importance: Prescription drug prices are a leading concern among patients and policy makers. There have been large and sharp price increases for some drugs, but the long-term implications of large drug price increases remain poorly understood. Objective: To examine the association of the large 2010 price increase in colchicine, a common treatment for gout, with long-term changes in colchicine use, substitution with other drugs, and health care use. Design, Setting, and Participants: This retrospective cohort study examined MarketScan data from a longitudinal cohort of patients with gout with employer-sponsored insurance from 2007 through 2019. Exposures: The US Food and Drug Administration's discontinuation of lower-priced versions of colchicine from the market in 2010. Main Outcomes and Measures: Mean price of colchicine; use of colchicine, allopurinol, and oral corticosteroids; and emergency department (ED) and rheumatology visits for gout in year 1 and over the first decade of the policy (through 2019) were calculated. Data were analyzed between November 16, 2021, and January 17, 2023. Results: A total of 2 723 327 patient-year observations were examined from 2007 through 2019 (mean [SD] age of patients, 57.0 [13.8] years; 20.9% documented as female; 79.1% documented as male). The mean price per prescription of colchicine increased sharply from $11.25 (95% CI, $11.23-$11.28) in 2009 to $190.49 (95% CI, $190.07-$190.91) in 2011, a 15.9-fold increase, with the mean out-of-pocket price increasing 4.4-fold from $7.37 (95% CI, $7.37-$7.38) to $39.49 (95% CI, $39.42-$39.56). At the same time, colchicine use declined from 35.0 (95% CI, 34.6-35.5) to 27.3 (95% CI, 26.9-27.6) pills per patient in year 1 and to 22.6 (95% CI, 22.2-23.0) pills per patient in 2019. Adjusted analyses showed a 16.7% reduction in year 1 and a 27.0% reduction over the decade (P < .001). Meanwhile, adjusted allopurinol use rose by 7.8 (95% CI, 6.9-8.7) pills per patient in year 1, a 7.6% increase from baseline, and by 33.1 (95% CI, 32.6-33.7) pills per patient through 2019, a 32.0% increase from baseline over the decade (P < .001). Moreover, adjusted oral corticosteroid use exhibited no significant change in the first year, then increased by 1.5 (95% CI, 1.3-1.7) pills per patient through 2019, an 8.3% increase from baseline over the decade. Adjusted ED visits for gout rose by 0.02 (95% CI, 0.02-0.03) per patient in year 1, a 21.5% increase, and by 0.05 (95% CI, 0.04-0.05) per patient through 2019, a 39.8% increase over the decade (P < .001). Adjusted rheumatology visits for gout increased by 0.02 (95% CI, 0.02-0.03) per patient through 2019, a 10.5% increase over the decade (P < .001). Conclusions and Relevance: In this cohort study among individuals with gout, the large increase in colchicine prices in 2010 was associated with an immediate decrease in colchicine use that persisted over approximately a decade. Substitution with allopurinol and oral corticosteroids was also evident. Increased ED and rheumatology visits for gout over the same period suggest poorer disease control.