Colitis in a patient with familial Mediterranean fever: Is it Crohn's disease or ulcerative colitis?

A 24-year-old woman was referred to our hospital with joint pain, fever, abdominal pain, and diarrhea. A colonoscopy revealed longitudinal ulcers with a cobblestone appearance throughout the entire colon, suggestive of Crohn's disease. However, treatment with 5-aminosalicylic acid, azathioprine, and infliximab failed to achieve clinical remission. A colonoscopy 5 months later revealed a diffusely spreading granular mucosa without visible vasculature, compatible with active ulcerative colitis. Based on these serial changes in colonic lesions, we tested the patient for MEFV gene mutations and found variants E148Q and L110P in exon 2. Administration of colchicine resulted in complete clinical remission. Our experience suggests that drastic changes in the features of colonic inflammation may be a clue to the diagnosis of enterocolitis associated with familial Mediterranean fever.

Diagnostic delays in familial Mediterranean fever: a Juvenile Inflammatory Rheumatism (JIR) cohort study.

Several studies reported that Familial Mediterranean Fever (FMF) diagnosis may be missed or delayed even in countries with a high FMF prevalence. Our aim was to study on a large cohort of European FMF patients the frequency and associated factors of diagnosis delay. Clinical data were extracted from the Juvenile Inflammatory Rheumatism (JIR)-cohort. All FMF patients fulfilled Livneh Criteria and had been sequenced for MEFV exon 10. FMF-diagnostic delay (d-FMF) was defined as the duration between the onset of the symptoms and the diagnosis of more than 10 years. 960 FMF patients were enrolled: delayed diagnosis (d-FMF) was noted in 200 patients (20%). d-FMF patients were significantly older compared to non d-FMF with a median age of 46.4 years old vs. 15.5 (p < 0.0001). Women displayed more d-FMF compared to men (56 vs. 47%, p = 0.03). Clinical presentation during attacks was not statistically significant except for erysipelas-like erythema, which was higher among d-FMF patients (33 vs. 22%, p = 0.0003). The presence of one or two pathogenic MEFV mutation was not different between patients. Compared to other FMF, d-FMF patients displayed significantly more AA amyloidosis (10 vs. 2.6%, p < 0.0001) and received more biotherapy (18 vs. 3.8%, p < 0.0001). Twenty percent of FMF patients had a diagnostic delay >10 years, including more women. The differential diagnosis of abdominal attacks with menstrual pain may be an explanation, and erysipelas-like erythema may not be recognized as FMF by all practitioners.

Successful Management of Pyoderma Gangrenosum in a Patient With Concurrent Behçet's Disease and Familial Mediterranean Fever: A Case Report.

Pyoderma gangrenosum (PG) is a rare ulcerative skin condition. Familial Mediterranean fever (FMF) and Behçet's disease (BD) are autoinflammatory disorders common in Mediterranean populations. The coexistence of FMF and BD is unusual, and the presence of PG alongside both is even rarer. We present a case of a 51-year-old male diagnosed with both BD and FMF who developed PG during treatment. His PG lesion was managed with a tailored regimen that included topical hydrocortisone acetate with fusidic acid, colchicine, topical tacrolimus, oral prednisone, and intravenous infliximab, which led to the successful healing of the PG lesion. This case underscores the need for specialized approaches to manage overlapping autoinflammatory conditions.

Heterozygous MEFV Mutation Leading to Renal Failure: A Case Study.

Familial Mediterranean fever (FMF) is an autosomal recessive disorder, particularly common in the Mediterranean area. Mutations in the MEVF gene cause it. AA Amyloidosis is the most severe complication of FMF leading to chronic renal failure. We describe a rare pediatric case of a phenotype I familial Mediterranean fever with V726A heterozygous mutation. The diagnosis was made at chronic kidney disease. We discuss through this case the importance of the early diagnosis of FMF heterozygous children which is not usually evident in some phenotypes. It will surely avoid fatal complications, inappropriate therapeutic approaches and higher healthcare costs.

Implementation of long-read sequencing for routine molecular diagnosis of familial mediterranean fever.

Background: Long-read sequencing technology, widely used in research, is proving useful in clinical diagnosis, especially for infectious diseases. Despite recent advances, it hasn't been routinely applied to constitutional human diseases. Long-read sequencing detects intronic variants and phases variants, crucial for identifying recessive diseases. Methods: We integrated long-read sequencing into the clinical diagnostic workflow for the MEFV gene, responsible for familial Mediterranean fever (FMF), using a Nanopore-based workflow. This involved long-range PCR amplification, native barcoding kit library preparation, GridION sequencing, and in-house bioinformatics. We compared this new workflow against our validated method using 39 patient samples and 3 samples from an external quality assessment scheme to ensure compliance with ISO15189 standards. Results: Our evaluation demonstrated excellent performance, meeting ISO15189 requirements for reproducibility, repeatability, sensitivity, and specificity. Since October 2022, 150 patient samples were successfully analyzed with no failures. Among these samples, we identified 13 heterozygous carriers of likely pathogenic (LP) or pathogenic (P) variants, 1 patient with a homozygous LP/P variant in MEFV, and 4 patients with compound heterozygous variants. Conclusion: This study represents the first integration of long-read sequencing for FMF clinical diagnosis, achieving 100 % sensitivity and specificity. Our findings highlight its potential to identify pathogenic variants without parental segregation analysis, offering faster, cost-effective, and accurate clinical diagnosis. This successful implementation lays the groundwork for future applications in other constitutional human diseases, advancing precision medicine.

Interleukin-21 and Interleukin-23 levels in familial Mediterranean Fever before and after treatment: the role of cytokines in disease pathogenesis.

In a previous study, it has been shown that the population of Th17 lymphocytes was increased in patients with FMF. IL-21 and IL-23 play significant roles in the production and differentiation of Th17 cells. In this study, we aimed to evaluate serum levels of IL-21 and IL-23 in FMF patients both at diagnosis and after treatment, and to compare these levels with those of healthy controls. Twenty-seven newly diagnosed patients with FMF in attack-free periods and twenty-seven healthy volunteers enrolled in the study. The groups were comparable with respect to age and gender. IL-21 and IL-23 levels in serum samples from patients at the time of diagnosis, in remission after treatment, and from the control groups were analysed using the ELISA method. There was no significant difference between the cytokine levels of the patient group at the time of diagnosis and the cytokine levels of the control group (for IL-21, p: 0.28 and for IL-23, p: 0.56). Similarly, there was no significant difference between the patients' cytokine levels at the time of diagnosis and after treatment (for IL-21, p: 0.99 and for IL-23, p: 0.08). Interleukin levels at the time of diagnosis did not differ among patient groups based on the presence of clinical findings or the M694V genotype. Our results suggest that IL-21 and IL-23 do not play a role in the pathogenesis of the disease. However, while interpreting these findings, it should be considered that patients with active episodes were excluded and cytokine levels were not measured in tissue samples.

Pregnancy occurring in AA amyloidosis: a series of 27 patients including 3 new French cases.

BACKGROUND: AA amyloidosis (AAA) is a multisystem disease related to the deposition in tissues of serum amyloid A protein which complicates chronic inflammation. It is a potentially fatal complication.  Renal involvement is the most common manifestation of AAA. Pregnancy in women with chronic kidney disease  is considered to be at risk for specific pregnancy complications and the worsening of their underlying renal dysfunction. Our aim was to report pregnancy in our AAA patients and discuss the outcome through a literature review. METHODS: French cases were identified through the Reference Center for Auto-Inflammatory Diseases and Amyloidosis and a systematic literature review was performed. RESULTS: Three new patients were identified: two with Familial Mediterranean fever (FMF) and one with cryopyrin-associated periodic syndrome; one was under anakinra therapy and one had received a kidney transplantation before her pregnancy. One patient was diagnosed with AAA following the detection of post-partum nephrotic syndrome. Among the 27 patients from literature and our case, FMF was the main cause of AAA (69%). Eight of the patients were diagnosed with AAA during their pregnancy or in immediate post-partum and gestational complications appeared in 23/25 cases, mostly intrauterine growth retardation (n = 10), prematurity (n = 11) and preeclampsia (n = 4). No bleeding complication was reported. CONCLUSION: Pregnancy can occur in patients (eight overall) with AAA and the diagnosis is frequently made during pregnancy. Pregnant women with AAA are at risk for adverse pregnancy-associated outcomes and require special and closer monitoring.

The Potential Role of Cell-Death Mechanisms in the Pathogenesis of Familial Mediterranean Fever Attacks: Granzyme A and Beyond.

BACKGROUND: FMF is the most common autoinflammatory disease. The activation of the pyrin inflammasome is the mainstay of the pathogenesis, which might lead to a specific cell-death mechanism, pyroptosis. Pyroptosis is a programmed inflammatory cell death mediated by gasdermin proteins, featuring cell swelling, membrane rupture, and release of inflammatory contents Aim: In this study we aimed to analyze the cell-death mechanisms in the pathogenesis of FMF attacks. METHODS: Twenty-five FMF patients were included, and PFAPA patients (n = 10) and healthy controls (HC, n = 10) served as controls. We collected plasma samples from FMF and PFAPA patients during the attack and the attack-free period. We measured the soluble plasma levels of sFas, sFasL, granzyme A, granzyme B, perforin, granulysin, IL-2, IL-4, IL-10, IL-6, IL-17A, TNF-α, and IFN-γ by commercial pre-defined cytometric bead array kits. RESULTS: There was no significant difference between groups in terms of sex and age between FMF patients and HCs, but PFAPA patients were younger than other groups due to the nature of the disease. We then analyzed the components of apoptosis and pyroptosis. The levels of sFasL (p = 0.035) and granzyme A (p = 0.038) in FMF patients were significantly increased during the attack period and decreased to levels comparable to HCs during the attack-free period. This increase was not seen in the PFAPA patients, with comparable levels with the HC group both during attack period and attack-free period. During the attack period of FMF patients, granzyme B (p = 0.145) and perforin (p = 0.203) levels were also increased; however, the differences were not statistically significant. The levels of sFasL, granzyme A, granzyme B, and perforin were closely correlated with each other during the attack period of FMF patients. CONCLUSIONS: Our study on death pathways during an FMF attack, suggests an upregulation in both pyroptosis through the granzyme-gasdermin pathway and apoptosis with the increased FasL and perforin levels, which was different from PFAPA patients. These findings might shed light on the reason for the nature of self-limited attacks, but further studies are needed to prove this hypothesis.

Solving a diagnostic dilemma in a patient with periodic fever-When the pieces of the puzzle finally fit.

The lack of pediatric subspecialists locally prior to 5 years ago, meant that some of our patients with rare, relapsing conditions were left behind. Familial Mediterranean fever can be diagnosed clinically and supported via genetic panel studies. Although neurological symptoms can be non-specific, this system symptomatology may lead patients and carers to seek medical attention. When neurological symptoms progress, seemingly refractory to first-line treatment, or suggestive of colchicine resistance, CNS demyelination should be considered by the neurologist. Abstract: Familial Mediterranean fever (FMF) is an inherited disorder with episodic fevers accompanied by pain in the abdomen, joints, or chest. It is a clinical entity that can be confirmed with a specific genetic mutation. Neurological symptoms have not been a focal point in clinical case descriptions. We aim to present the long road to diagnosing our patient, where the diagnostic clues centered around her neurological symptoms.

The increased chromosomal DNA damage in patients with Familial Mediterranean Fever.

Familial Mediterranean Fever (FMF) is an inherited autoinflammatory disease. In this study, we aimed to assess chromosomal DNA damage and cell proliferation by using cytokinesis-block micronucleus cytome (CBMN-cyt) assay in the peripheral blood lymphocytes of untreated FMF patients carrying M694V and R202Q mutations, which are the most common MEFV gene mutations in Turkish society. The study included 20 untreated FMF patients with M694V and R202Q mutations and 20 healthy individuals of similar age and sex as the control group. Micronucleus (MN), nucleoplasmic bridges (NPBs), and nuclear buds (NBUDs) were scored in the obtained bi-nucleated (BN) cells. Additionally, the nuclear division index (NDI) was calculated using the scores of mononuclear, binuclear, and multinuclear cells. We found that MN and NPBs frequencies in FMF patients were significantly higher than in controls, and number of metaphases was significantly lower (respectively, p < 0.05, p < 0.01, and p < 0.01). However, there was no significant difference in NBUDs frequencies and NDI values between FMF patients and controls (p > 0.05). Our study is the first to evaluate FMF patients' lymphocytes using the CBMN-cyt assay, as no previous research has been found in this respect. Increased MN and NPB frequencies may be useful as biomarkers for chromosomal DNA damage, and may indicate a potential for elevated cancer risk in untreated FMF patients.