Familial Mediterranean fever (FMF) is the most common monogenic autoinflammatory disease, but many rheumatologists are not well acquainted with its management. The objective of this report is to ...produce evidence-based recommendations to guide rheumatologists and other health professionals in the treatment and follow-up of patients with FMF. A multidisciplinary panel, including rheumatologists, internists, paediatricians, a nurse, a methodologist and a patient representative, was assembled. Panellists came from the Eastern Mediterranean area, Europe and North America. A preliminary systematic literature search on the pharmacological treatment of FMF was performed following which the expert group convened to define aims, scope and users of the guidelines and established the need for additional reviews on controversial topics. In a second meeting, recommendations were discussed and refined in light of available evidence. Finally, agreement with the recommendations was obtained from a larger group of experts through a Delphi survey. The level of evidence (LoE) and grade of recommendation (GR) were then incorporated. The final document comprises 18 recommendations, each presented with its degree of agreement (0-10), LoE, GR and rationale. The degree of agreement was greater than 7/10 in all instances. The more controversial statements were those related to follow-up and dose change, for which supporting evidence is limited. A set of widely accepted recommendations for the treatment and monitoring of FMF is presented, supported by the best available evidence and expert opinion. It is believed that these recommendations will be useful in guiding physicians in the care of patients with FMF.
Systemic lupus erythematosus (SLE) is a clinically and genetically heterogeneous autoimmune disease. The etiology of lupus and the contribution of genetic, environmental, infectious and hormonal ...factors to this phenotype have yet to be elucidated. The most straightforward approach to unravel the molecular pathogenesis of lupus may rely on studies of patients who present with early-onset severe phenotypes. Typically, they have at least one of the following clinical features: childhood onset of severe disease (<5 years), parental consanguinity, and presence of family history for autoimmune diseases in a first-degree relative. These patients account for a small proportion of patients with lupus but they inform considerable knowledge about cellular pathways contributing to this inflammatory phenotype. In recent years with the aid of new sequencing technologies, novel or rare pathogenic variants have been reported in over 30 genes predisposing to SLE and SLE-like diseases. Future studies will likely discover many more genes with private variants associated to lupus-like phenotypes. In addition, genome-wide association studies (GWAS) have identified a number of common alleles (SNPs), which increase the risk of developing lupus in adult age. Discovery of a possible shared immune pathway in SLE patients, either with rare or common variants, can provide important clues to better understand this complex disorder, it's prognosis and can help guide new therapeutic approaches. The aim of this review is to summarize the current knowledge of the clinical presentation, genetic diagnosis and mechanisms of disease in patents with lupus and lupus-related phenotypes.
Systemic autoinflammatory diseases are caused by mutations in genes that function in innate immunity. Here, we report an autoinflammatory disease caused by loss-of-function mutations in OTULIN ...(FAM105B), encoding a deubiquitinase with linear linkage specificity. We identified two missense and one frameshift mutations in one Pakistani and two Turkish families with four affected patients. Patients presented with neonatal-onset fever, neutrophilic dermatitis/panniculitis, and failure to thrive, but without obvious primary immunodeficiency. HEK293 cells transfected with mutated OTULIN had decreased enzyme activity relative to cells transfected with WT OTULIN, and showed a substantial defect in the linear deubiquitination of target molecules. Stimulated patients’ fibroblasts and peripheral blood mononuclear cells showed evidence for increased signaling in the canonical NF-κB pathway and accumulated linear ubiquitin aggregates. Levels of proinflammatory cytokines were significantly increased in the supernatants of stimulated primary cells and serum samples. This discovery adds to the emerging spectrum of human diseases caused by defects in the ubiquitin pathway and suggests a role for targeted cytokine therapies.
To develop widely accepted international severity score for children and adult patients with familial Mediterranean fever (FMF) that can be easily applied, in research and clinical practice.
...Candidate severity criteria were suggested by several FMF expert physicians. After three rounds of Delphi survey, the candidate criteria, defined by the survey, were discussed by experts in a consensus meeting. Each expert brought data of clinical manifestations, laboratory findings and physician's global assessments (PGAs) of minimum 20 patients from their centres. We used the PGAs for disease severity as a gold standard. Logistic regression analysis was used to evaluate the predicting value of each item, and receiver operating characteristic curve analysis was performed to demonstrate the success of the criteria set.
A total of 281 patients consist of 162 children and 119 adults with FMF were enrolled and available for validity analysis: Nine domains were included in the final core set of variables for the evaluation of disease severity in FMF. The International Severity Score for FMF (ISSF) may reach a maximum of 10 if all items are maximally scored. The threshold values to determine: severe disease ≥6, intermediate disease 3-5, mild disease ≤2. Area under the curve was calculated as 0.825 for this set in the whole group.
The initial validity of ISSF both in children and adult with FMF was demonstrated. We anticipate that it will provide a robust tool to objectively define disease severity for clinical trials, future research as well as for therapeutic decisions in managing patients with FMF.
While the pathophysiology of chronic disorders varies there are three basic mechanisms - inflammation, oxidative stress and endothelial dysfunction - that are common in many chronic diseases. ...However, the failure of these mechanisms to work synchronously can lead to morbidity complicating the course of many chronic diseases. We analyzed data of 178 patients from cohorts with selected chronic diseases in this quasi-experimental study. Endothelial dysfunction was determined by flow-mediated dilatation (FMD) and asymmetric dimethylarginine (ADMA) levels. Serum ADMA, high sensitive C-reactive protein (hs-CRP), serum PTX3, malondialdehyde (MDA), Cu/Zn-superoxide dismutase (Cu/Zn-SOD), glutathione peroxidase (GSH-Px) levels and FMD were studied in baseline and after 12 weeks of Morinda citrifolia (anti-atherosclerotic liquid- AAL), omega-3 (anti-inflammatory capsules- AIC) and extract with Alaskan blueberry (anti-oxidant liquid- AOL). Stepwise multivariate regression analysis was used to evaluate the association of FMD with clinical and serologic parameters. Serum ADMA, MDA, PTX3, hsCRP and albumin levels, and proteinuria were significantly decreased while CuZn-SOD, GSH-Px and FMD levels were significantly increased following AAL, AIC and AOL therapies. The FMD was negatively correlated with serum ADMA, MDA, PTX3, and hsCRP levels and positively correlated with CuZn-SOD and eGFR levels. ADMA and PTX3 levels were independently related to FMD both before and after AAL, AIC and AOL therapies. Our study shows that serum ADMA, MDA, PTX3 levels are associated with endothelial dysfunction in patients with selected chronic diseases. In addition, short-term AAL, AIC and AOL therapies significantly improves a number of parameters in our cohort and can normalize ADMA, PTX3, hsCRP and MDA levels.
Neonatal systemic vasculitis syndromes have been reported in infants born to mothers with systemic lupus erythematosus, Sjögren's syndrome, Behҫet's disease, cutaneous polyarteritis nodosa and ...anti-neutrophil cytoplasmic antibody-associated vasculitides. Here we report a novel association of a case of new-onset maternal seronegative inflammatory arthritis associated with a transient systemic vasculitis in a neonate.
In the first 24 h of life, a preterm Caucasian baby boy was noted to have blue discoloration to all four extremities. Despite antibiotics, fresh frozen plasma and anticoagulation, the discoloration remained, particularly in the left index finger. This was associated with fever and a maximum C-reactive protein (CRP) of 148 mg/L. Intravenous immunoglobulin (IVIG) was given with short-term improvement. Initial echocardiogram showed enlarged coronary arteries with normalization on repeat 1 week later. Clinical signs and symptoms responded to high dose oral steroid administration. MRI angiography (MRA) of the body and heart showed tortuosity of arteries in the upper and lower extremities with gadolinium uptake, suggestive of vasculitis. Autoantibody profile negative. Genetic panel for hereditary autoinflammatory diseases was negative as was whole exome sequencing performed on the trio. The baby was weaned off steroids by 5 months of age. A small distal autoamputation of the left index finger occurred. He was born to a 28-year-old woman who developed new onset severe symmetrical polyarthritis at 8 weeks gestation. This was presumed a reactive arthritis secondary to a dental infection. Infectious work up and autoantibodies were negative. She was treated with high dose prednisone for the remainder of her pregnancy. The mother was weaned off prednisone, treated with hydroxychloroquine for 8 months post-partum and remains in remission. A repeat MRA done at 1 year old showed mild residual tortuosities of the arteries in the forearms. The remainder of the medium and large vessels were within normal limits with no gadolinium enhancement to suggest active disease. The child is now 4 years old with normal growth and development.
This is a unique case of new-onset seronegative presumed reactive arthritis in a mother with the rare development of a successfully treated medium vessel vasculitis in an infant.
Familial Mediterranean fever (FMF) is an autoinflammatory disease, which can be well controlled with lifelong use of colchicine. Since studies dealing with the efficacy and safety of colchicine were ...conducted mainly in the sixties and seventies of the previous century, it seems that this topic needs to be updated. Recently, an international expert panel was undertaken for the establishment of recommendations on how to manage FMF. We aimed to summarize the efficacy and safety of the current treatments available to prevent FMF attacks and to avert the appearance of amyloidosis secondary to FMF. A systematic review was performed. Two reviewers and methodologist established the protocol of the review and the epidemiological questions in PICO terms. MEDLINE through PubMed, Embase, and Cochrane Central Trials Register all up to May 31, 2014, were searched, and only randomized controlled trials or quasicontrolled trials were accepted. For each study, a judgment on risk of bias was then rated as high, moderate, or low. Of 1222 initially captured publications, 153 articles were studied in detail. Finally, only seven studies met all criteria and were included. Among these seven studies, four were randomized crossover clinical trials of colchicine including a total of 57 patients, one RCT of
Andrographis paniculata
Herba Nees extract employed in 24 patients, one randomized crossover clinical trial of Rilonacept used in 12 patients, and one RCT of interferon treating 34 acute abdominal attacks in 22 patients. The quality of the colchicine trials was low compared with the other drugs trials. Safety was not clearly mentioned in the trials. Colchicine is an effective treatment in FMF.
Familial Mediterranean fever (FMF) is an autoinflammatory disease caused by mutations of the MEFV gene. We analyse the impact of ethnic, environmental and genetic factors on the severity of disease ...presentation in a large international registry.
Demographic, genetic and clinical data from validated paediatric FMF patients enrolled in the Eurofever registry were analysed. Three subgroups were considered: (i) patients living in the eastern Mediterranean countries; (ii) patients with an eastern Mediterranean ancestry living in western Europe; (iii) Caucasian patients living in western European countries. A score for disease severity at presentation was elaborated.
Since November 2009, 346 FMF paediatric patients were enrolled in the Eurofever registry. The genetic and demographic features (ethnicity, age of onset, age at diagnosis) were similar among eastern Mediterranean patients whether they lived in their countries or western European countries. European patients had a lower frequency of the high penetrance M694V mutation and a significant delay of diagnosis (p<0.002). Patients living in eastern Mediterranean countries had a higher frequency of fever episodes/year and more frequent arthritis, pericarditis, chest pain, abdominal pain and vomiting compared to the other two groups. Multivariate analysis showed that the variables independently associated with severity of disease presentation were country of residence, presence of M694V mutation and positive family history.
Eastern Mediterranean FMF patients have a milder disease phenotype once they migrate to Europe, reflecting the effect of environment on the expression of a monogenic disease.
Chronic inflammation and proteinuria is a risk factor for cardiovascular disease (CVD) in patients with chronic kidney diseases and rheumatologic disorders. Our aim was to investigate the CVD events ...(CVDEs) and survival between the patients with FMF-related AA amyloidosis and glomerulonephropathies (GN) to define possible predictors for CVDEs. A prospective follow-up study with FMF-amyloidosis and glomerulonephropathy (GN) was performed and patients were followed for CVDEs. Flow-mediated dilatation (FMD), FGF-23, serum lipid, hsCRP levels, BMI and HOMA were assessed. A Cox regression analysis was performed to evaluate the risk factors for CVDEs. There were 107 patients in the FMF-amyloidosis group and 126 patients with GN group. Forty-seven CVDEs were observed during the 4.2-years follow up; all 28 patients in the FMF-amyloidosis group and 14/19 patients with GN developed CVDEs before the age of 40 (p = 0.002). CVD mortality was 2.8 times higher (95% CI 1.02-7.76) in patients with FMF-amyloidosis. Across both groups, FMD and FGF23 (p < 0.001) levels were independently associated with the risk of CVDEs. Patients with FMF-amyloidosis are at increased risk of early CVDEs with premature mortality age. FGF 23, FMD and hsCRP can stratify the risk of early CVD in patients with FMF-related AA amyloidosis.
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