EULAR recommendations for the management of familial Mediterranean fever.

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.

What is the best acute phase reactant for familial Mediterranean fever follow-up and its role in the prediction of complications? A systematic review.

The most dreaded complication of familial Mediterranean fever (FMF) is amyloidosis; controversy exists as to what acute phase reactant (APR) should be monitored in these patients. To analyze the best acute phase reactant for FMF follow-up to help guide physicians to decide on what APR parameter to use, we also attempted to define the best APR in predicting the complications of FMF, specifically the development of amyloidosis. Systematic review based on a sensitive search to capture studies that: (1) included FMF patients; (2) measured serum amyloid A (SAA), CRP (C-reactive protein), proteinuria, or ESR (erythrocyte sedimentation rate); (3) amyloidosis were the outcome measure; (4) sensitivity, specificity, predictive value, and other performance parameters could be calculated; and (5) had a longitudinal design. Of 1905 captured items, 26 were selected for detailed review, of which only two finally met the criteria, and the quality was only moderate; the articles did not analyzed the performance by means of sensitivity and specificity to predict, or even detect, amyloidosis, and thus had to be calculated based on text. The 26 screened studies were very heterogeneous in designs, parameters measured, and results, despite being set from research questions similar to ours. They were mainly descriptive, and it was very difficult to interpret the true performance of the tests. The correlation between the various APR is low. The evidence supporting the monitoring of FMF with any APR over the others is limited. Well designed longitudinal studies with a mixture of outcomes should be undertaken. Until them, recommending an APR over other would be based on expert opinion and indirect evidence.

Efficacy and safety of treatments in Familial Mediterranean fever: a systematic review.

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.

The rate and significance of type 1/type 2 serum amyloid A protein gene polymorphisms in patients with ankylosing spondylitis and amyloidosis.

A relationship between the presence of amyloidosis and SAA1 genotype has been shown in recent studies of (principally) familial Mediterranean fever patients. We found that the SAA1 rs12218 polymorphism was significantly more prevalent in ankylosing spondylitis patients with amyloidosis.

Osteoporosis and osteopathy markers in patients with mastocytosis.

OBJECTIVE: Osteoporosis, osteosclerosis, and lytic bone lesions have been observed in patients with systemic mastocytosis (SM). We examined bone mineral density (BMD) biochemical turnover markers and serum tryptase levels in SM, which is considered a rare disease. MATERIALS AND METHODS: Seventeen adult patients (5 females, 12 males; median age: 33 years, range: 20-64) with mastocytosis were included in this study. We investigated the value of quantitative ultrasound (QUS) of the calcaneus in the assessment of BMD in SM patients, as well as BMD of the lumbar spine (L1-L4), femoral neck, and distal radius using dual energy x-ray absorptiometry (DXA) and plasma tryptase levels, biochemical markers of bone turnover. RESULTS: At lumbar spine L1-L4, the femoral neck, and the distal radius or as calcaneus stiffness, 12 of 17 patients had T-scores of less than -1 at least at 1 site, reflecting osteopenia. Three of 17 patients had T-scores showing osteoporosis (T-score <-2.5). There was no relationship between DXA and bone lesion severity. We also found a significant positive correlation between tryptase levels and disease severity, as well as between disease severity and pyridinoline (p<0.01 by Spearman's test). CONCLUSION: DXA and calcaneal QUS may not be appropriate techniques to assess bone involvement in SM patients because of the effects of osteosclerosis. This study further shows that the osteoclastic marker pyridinoline is helpful in patients with severe disease activity and sclerotic bone lesions to show bone demineralization.

Small bowel mucosal damage in familial Mediterranean fever: results of capsule endoscopy screening.

OBJECTIVE: Familial Mediterranean fever (FMF) is the most common form of autoinflammatory diseases. We aimed to evaluate the small bowel mucosa by capsule endoscopy (CE) in FMF patients for investigation of other possible causes of abdominal pain. MATERIAL AND METHODS: The study group consisted of 41 patients with FMF. A standard questionnaire was used to record the gastrointestinal symptoms, other clinical findings, Mediterranean fever gene (MEFV) mutations, and history of medications including non-steroidal anti-inflammatory drugs (NSAIDs). Gastroscopy, colonoscopy and small bowel CE were performed in all patients, and biopsies were taken from terminal ileum and duodenum. RESULTS: The mean age of the patients was 34 ± 11 years, 63% of them were female, and 76.5% of them were carrying MEFV exon 10 mutations. Only one patient used NSAIDs in addition to colchicine. In endoscopic investigations, gastric erosion was detected in only one patient, and no significant findings were detected in colonoscopy. CE showed small bowel mucosal defects in 44% (erosions in 26.8%, ulcer in 17.1%) and edema in 29.3% of the patients. Most (64%) of the ulcer and erosions were localized to jejunum, and only 24% were in ileum. Mitotic changes as an indirect finding of colchicine toxicity were not different from the changes observed in samples of independent group of patients with irritable bowel syndrome. CONCLUSION: Mucosal defect was observed in half of the FMF patients, which may be associated with underlying inflammation or chronic colchicine exposure. Detection of nonspecific chronic inflammation without mitotic changes supports that mucosal defects may be associated with the autoinflammatory process.

Re-evaluation of 129 patients with systemic necrotizing vasculitides by using classification algorithm according to consensus methodology.

Recently, a new classification algorithm (CA) for systemic necrotizing vasculitides was proposed by Watts et al. (Annals Rheum Dis 66:222-227, 2007) by using the American College of Rheumatology (ACR), Chapel Hill Consensus Criteria (CHCC) and Sorensen surrogate markers (So). We aimed to validate CA in our patients. One hundred twenty-nine patients followed up in our vasculitis clinic were reclassified according to CA in different categories (ACR or Lanham criteria in "1" for Churg-Strauss Syndrome (CSS); ACR in "2a"; CHCC-Wegener's granulomatosis (WG) in "2b"; CHCC-microscopic polyangiitis (MPA), So-WG in "2c"; So-WG, proteinase 3 (PR3) or myeloperoxidase antineutrophil cytoplasmic antibody (MPO ANCA) serology in "2d" for WG; clinical features and histology compatible with small vessel vasculitis without So-WG in "3a"; So-MPA, PR3 or MPO ANCA serology in "3b" for MPA; CHCC-classic-polyarteritis nodosa (c-PAN) or typical angiographic features in "4" for c-PAN; unclassifiable in "5"). Kappa statistic was used to analyse the agreement of the criteria that formed the algorithm. All of 12 CSS, 91% of 69 WG, 78% of 18 MPA and 93% of 26 c-PAN patients remained in their previous diagnosis. WG patients were placed in 2a (83%), 2c (3%), 2d (14%) categories. Four WG (6%) and four MPA (22%) patients were categorized as MPA (in 3a (75%), 3b (25%)) and WG (in 2c (75%), 2d (25%)), respectively. Three of four unclassified patients could be classified as c-PAN (two) and MPA (one). Significant agreement was demonstrated only for ACR and So criteria in WG (κ = 0.62, p < 0.001). The majority of our patients stayed on their previous diagnosis in "CA". Our findings suggest that this algorithm is helpful and practical for epidemiological studies. Poor correlation of defined criteria was thought to be related to the fact that each criteria mainly consist of different characteristics of vasculitides such as clinical, histopathological and serological features.

Unusual cause of right ventricular outflow tract compression: mediastinal lipomatosis.

Mediastinal lipomatosis (ML) is a benign condition characterized by the accumulation of mature adipose tissue within the mediastinum. ML is usually associated with Cushing syndrome and obesity. Most patients are asymptomatic, but some have thoracic pain, dyspnea, cough, dysphonia, dysphagia, and supraventricular tachycardia. We report a case of ML compressing the right ventricular outflow tract in a patient with Behçet disease.

The platelet functions in patients with ankylosing spondylitis: anti-TNF-alpha therapy decreases the mean platelet volume and platelet mass.

The present study was designed to investigate the interaction between platelet indices (mean platelet volume (MPV), platelet count (PLC) and platelet mass (PLM)), inflammatory markers and disease activity in ankylosing spondylitis (AS) subjects. The effects of anti-TNF-alpha therapy and conventional treatment on platelet indices were also compared. We studied 68 patients with AS (group I, 46 men, age: 36.4 +/- 6.9 years) and as control group 34 age and sex-matched healty subjects. All patients received conventional therapy (CT) at the beginning (Group I). The patients were reevaluated after 3 months according to Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score. Group II consisted of 35 subjects who responded to the CT and continued to take the same therapy for 3 months additionally. Group III consisted of 33 subjects who had a high disease activity score (BASDAI > 4) after 3 months and were accepted refractory to the CT therapy. In Group III the treatment was switched to infliximab and continued for 3 months at the standard intravenous dose. Significantly higher baseline MPV, PLC and PLM was reported as compared to controls decreased by therapy (9.12 +/- 1.20 vs. 8.35 +/- 0.94 fl, p < 0.001, 340 +/- 69 vs. 251 +/- 56 (x 10(3)/ microL) p < 0.0001, 3096 +/- 736 vs. 2110 +/- 384; p < 0.0001, respectively). In the same way, they were substantially lowered by both treatments in group II and group III. PLC and PLM were positively correlated with WBC and ESR (r : 0.44; p < 0.0001, r : 0.41; p = 0.001, r : 0.52; p < 0.0001, r : 0.41; p = 0.001), respectively) in AS patients. Additionally, MPV and PLM were positively correlated with BASDAI score (r : 0.41; p < 0.001, r = 0.29; p < 0.001 respectively). We have found that increased platelet activity reduced by therapy in AS patients. Additionally, it was correlated with inflammatory markers and disease activity. According to these results, it can be suggested that both anti-TNF-alpha and conventional therapy might contribute to a decrease in the risk of cardiovascular morbidity and mortality in AS patients.

Predictors of damage and survival in patients with Wegener's granulomatosis: analysis of 50 patients.

OBJECTIVE: To evaluate damage features and impact on survival by Vasculitis Damage Index (VDI) in a cohort of Turkish patients with Wegener's granulomatosis (WG). METHODS: We enrolled 50 (25 female) patients with WG according to ACR criteria. Birmingham Vasculitis Activity Score (BVAS) and VDI were used to analyze disease activity and damage. RESULTS: Patients had kidney (82%), upper airway (72%), lung (70%), and nervous system (15%) involvement. Median age at diagnosis was 45 years, time to diagnosis was 3.5 months, and total followup time was 35.5 months. All but one patient was positive for antineutrophil cytoplasmic antibodies (ANCA). Mean final dose and duration of corticosteroid and cyclophosphamide was 15 +/- 14 g, 39 +/- 33 months and 36 +/- 34 g, 21 +/- 2 months, respectively. Mean early (e) BVAS were 20.2 +/- 7.1 (4-38) (median 21). Mean e-BVAS and e-VDI scores at presentation and final (f)-VDI scores at last visit were 20.2 +/- 7.1 (4-38), 3.1 +/- 1.7 (median 3) (0-7) and 4.4 +/- 2.6 (0-12), consecutively. Disease related damage was prominent in kidneys (50%) and upper airways (27%). Amenorrhea (90%), cataract (28%), and diabetes (24%) were the most frequent treatment related damages. Rapidly progressive glomerulonephritis at presentation (42%) progressed to endstage renal failure in 20%. Relapses occurred in 25% with mean BVAS of 6.5 +/- 2.3 (4-11). Survival rate was 77% at 37 months. Deaths occurred early (90% in the first year). f-VDI was high in patients who relapsed (6 +/- 3 vs 3.8 +/- 2.1, p = 0.03). Logistic regression analysis demonstrated that age at time of diagnosis and e-VDI were lower in survivors with OR = 0.9 (p = 0.06, 95% CI: 0.78-1) and OR = 0.5 (p = 0.04, 95%CI: 0.25-0.98), respectively. In this cohort, e-VDI score of 5 or more was related to death with 98% sensitivity and 56% specificity (p = 0.004) (CI: 0.66-0.95). CONCLUSION: Disease related damage outweighed treatment related damage in our cohort of predominantly generalized disease activity. Early damage and older age were found to be predictors of final damage and death.

Assessment of adenosine deaminase levels in rheumatoid arthritis patients receiving anti-TNF-alpha therapy.

Anti-TNF-alpha agents are increasingly used in rheumatoid arthritis (RA) treatment and that is known to increase the risk of tuberculosis (TB) reactivation. Adenosine deaminase (ADA) levels are shown to increase to high levels in TB patients. Our aim is to investigate the serum ADA levels in RA patients being treated with anti-TNF-alpha and to compare the results with the patients on DMARD therapy. The study groups comprised of 56 RA patients (45 female, mean age 49) who were treated either with two or three DMARDs, 32 RA patients with anti-TNF-alpha treatment (26 female, mean age 46) and 20 healthy controls (10 female, mean age 48). All patients fulfilled the 1987 ACR criteria for RA. DAS28 score was calculated for all subjects. When compared to healthy controls, ADA levels were measured statistically higher both in patient groups (P = 0.046, 0.002). ADA levels in anti-TNF-alpha group were similar to conventional therapy (11.3 +/- 2.7, 10.9 +/- 4.01; P = 0.76). PPD was positive in 17 RA patients in the anti-TNF-alpha treatment group (%53). The ADA levels were found to be similar in the anti-TNF-alpha group when compared according to the PPD positivity (positive, 12.4 +/- 3.7; negative, 10.5 +/- 2.1; P = 0.02). No correlation was found between the ADA levels and age, disease duration, ESR, CRP, DAS 28 and HAQ score. In this study, we observed that RA patients at remission taking DMARD or anti-TNF-alpha therapy have similar levels of serum ADA. Although serum ADA levels during TB infection increase much higher, in our study, ADA levels of all RA patients were lower than 15 IU/L. Elevated ADA levels may be a clue for diagnosis of TB in patients who were on anti-TNF-alpha therapy.

Doxycycline-induced ulceration mimicking esophageal cancer.

INTRODUCTION: Doxycycline-induced esophageal ulcer patients are mostly young persons with no history of esophageal dysfunction. Heartburn, midsternal pain and dysphagia are the most common symptoms. It has generally a benign course. The present case is the first report of doxycycline-induced extensive ulcerations, mimicking esophageal cancer in two esophageal segments alongside, in the literature. CASE PRESENTATION: This report describes a 16-year-old Caucasian girl who, while taking doxycycline capsules100 mg twice a day for acne vulgaris for 3 months, developed these symptoms. An upper endoscopy revealed multiple circumferential deep ulcerations surrounding fragile, irregular, hyperemic and hypertrophic mucosa at the level of the mid-esophagus and concomitantly in the lower esophageal sphincter. The lesions were biopsied to exclude esophageal carcinoma because of the suspicious appearance in the endoscopic examination. The histopathological examination, haematoxylin and eosin stained sections showed ulceration with a mixed inflammatory infiltrate. Doxycycline was discontinued and she was given sucralfate 1 g qid and omeprazole 20 mg bid orally. All symptoms of the patient were resolved on the third day of the treatment. After 4 weeks of the therapy, an upper endoscopic control examination demonstrated normal findings. CONCLUSION: The present case has been an uncommon presentation of doxycycline-induced extensive ulcerations, mimicking esophageal cancer in two esophageal segments, concomitantly. Even the lesions were biopsied to exclude esophageal carcinoma. A modification on the behavior of taking drugs can prevent these unpleasant complications.

Leptin in nonalcoholic fatty liver disease.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a prevalent condition associated with obesity and insulin resistance (IR). Leptin plays a key role in the control of energy balance, and insulin sensitivity. In this study, we aimed to examine whether serum leptin levels correlate with insulin resistance, oxidative stress parameters and the severity of histological changes in NAFLD. METHODS: Fifty-two patients (M/F: 28/24) with no alcohol intake and biopsy-proven diagnosis of NAFLD were studied. Serum leptin levels were measured by radioimmunoassay. HOMA (homeostasis model assessment) IR index was calculated. Comparisons between the patients with NAFLD and non-alcoholic steatohepatitis (NASH) were performed using the Student's t test. Multivariate regression analysis and the area under the receiver operating characteristic (ROC) curve were used to identify the independent predictors for NASH. RESULTS: We found no association between serum leptin, fasting insulin levels, and oxidative stress parameters. ROC curve and multiple regression analysis revealed no association between the severity of histological changes and serum leptin levels. During six months followed-up period only NASH group with elevated leptin levels had significant reductions of ALT and AST values (p = 0.03, and 0.005, respectively). CONCLUSION: Our findings show a preventive effect of leptin against progressive liver injury in NAFLD.

Safety of high-dose intravenous immunoglobulin in systemic autoimmune diseases.

It is reported that the usage of high-dose intravenous immunoglobulin (HD-IVIG) in systemic autoimmune diseases is associated with various adverse events in a wide range of severity. We aimed to investigate the frequency and profile of adverse events in a group of patients with diffuse connective tissue diseases and Wegener's granulomatosis (WG) who were administrated HD-IVIG for different indications. We recorded the data of 38 patients (25 females and 13 males) aged 38 +/- 15 (12-75) years who were followed up with the diagnosis of systemic autoimmune diseases between 1994 and 2006 according to a predefined protocol. Patients with active disease were treated with HD-IVIG and standard immunosuppressives concomitantly. We evaluated the occurrence of allergy, acute renal failure, thromboembolic events, neutropenia, hemolytic anemia, aseptic meningitis, and vasculitis during infusion therapy of HD-IVIG and in the following 3 weeks. We commenced a total of 130 infusions of HD-IVIG. Patients were administrated 1-12 (3.4 +/- 2.6) infusions of HD-IVIG as needed. Indications for HD-IVIG were unresponsiveness or partial response to standard treatment, severe infections along with disease activity, and severe thrombocytopenia in the preoperative period in 97, 23, and 5% of patients, respectively. Minor adverse events were seen in two patients during HD-IVIG infusions. One patient with WG developed rapidly progressive renal failure during severe disease flare between HD-IVIG infusions. Another patient with WG developed recurrence of deep-vein thrombosis during severe disease flare 3 months after HD-IVIG. Both events were attributed to severe disease activity. Adverse events like allergy, acute renal failure, thromboembolic events, hematological problems, aseptic meningitis, and vasculitis are reported in different frequencies (1-81%) in patients who were administered HD-IVIG for systemic autoimmune diseases. HD-IVIG is considered a safe treatment in selected patients assuring adequate infusion precautions.

The Outcome of Large B-Cell Lymphoma Evolving in a Hematopoietic Stem Cell Transplant Patient During Treatment of Chronic Graft-Versus-Host Disease.

Immunosuppression is a risk factor for the development of posttransplant lymphoproliferative disorder. This type of malignancy developed in an immunocompromised man. The patient presented with focal convulsion starting from right face and right arm followed by two generalized convulsions with one minute interval. Diagnosis was made by computed tomographic (CT) scan of the cranium following oral and intravenous administration of contrast dyes which revealedmass leisons in the frontotemporal lobe and by stereotaxic biopsy. Tissue sections showed a malignant tumor cell infiltration with large areas of necrosis and many mitoses. Many tumor cells were positive for CD 20 and CD 10. These findings were consistent with large B-cell lymphoma. Central nervous system radiation with a dose of 56 Gy was given with clinical and radiological improvement. The patient died due to multiorgan failure. Finally, the immunocompromised patients should be closely followed for the development of lymphoproliferative disorder.

Fasting insulin levels independently associated with coronary heart disease in non-diabetic Turkish men and women.

BACKGROUND: Levels of plasma insulin have been recognized as a weak risk indicator for coronary or cardiovascular risk in the general population with ethnic background and gender modifying this relationship. We assessed whether insulin concentrations are associated with or would serve as a marker of prevalent coronary heart disease risk in a cross-sectional study of a population having low cholesterol levels (just under 5 mmol/l) but higher prevalence of components of the metabolic syndrome. METHODS: In 688 participants of the Turkish Adult Risk Factor Survey in 2001, plasma insulin values as well as other risk variables were evaluated, and coronary heart disease was diagnosed based on clinical findings and Minnesota coding of resting electrocardiograms. Nearly equal numbers of men and women (>30 years of age) constituted the population sample from the two largest regions of Turkey. Concentrations of insulin were determined by the chemiluminescent immunometric method. RESULTS: Geometric mean value was 50 pmol/l (interquartile range 37-68 pmol/l), without revealing a significant difference in genders. Fasting insulin was correlated in both genders with many variables, notably those involving central obesity, triglycerides, blood pressure, physical inactivity and, inversely, with high-density lipoprotein (HDL)-cholesterol. In a regression model, waist circumference and body mass index were strongly associated with log insulin, after controlling for age and presence of coronary heart disease. The age- and obesity-adjusted odds ratio for coronary heart disease in the highest as opposed to the lowest quartile was 2-fold in both genders (P<0.05). Even after adjustment for dyslipidemia, blood pressure, glucose intolerance, physical activity and smoking status, an over 2-fold increased coronary heart disease risk still persisted with regard to hyperinsulinemia (>or=10 mU/l, 69.5 pmol/l). When C-reactive protein which was correlated with fasting insulin only in women, was added to the model, the impact of hyperinsulinemia on coronary heart disease risk remained unchanged. CONCLUSION: Hyperinsulinemia (i) may provide information on the coronary heart disease likelihood over and above that provided by the other risk factors, including HDL-cholesterol, and (ii) may contribute, within the frame of insulin resistance, to the coronary heart disease risk independently of the classical risk factors.