Serdal Ugurlu

Canakinumab in a patient with juvenile Behçet's syndrome with refractory eye disease

Behcets syndrome (BS) causes panuveitis and retinal vasculitis in about 50% of patients. Despite intensive treatment, up to 20% of patients may lose useful vision.1 Treatment consists of corticosteroids, immunosuppressive agents such as azathioprine (AZA) and ciclosporin A (CycA),1 and biological agents such as interferon-α (IFN) and antitumour necrosis factor agents.2 ,3 We describe a patient with juvenile BS whose refractory eye disease was treated successfully with canakinumab, a fully human anti-interleukin-1β antibody. Figure 1 shows the different treatment regimes used during the follow-up period. Figure 1 Different treatment regimes and eye flares during the follow-up period. A 16-year-old girl was diagnosed with BS at the age of 9 years because …

Targeted resequencing implicates the familial Mediterranean fever gene MEFV and the toll-like receptor 4 gene TLR4 in Behçet disease

Genome-wide association studies (GWAS) are a powerful means of identifying genes with disease-associated common variants, but they are not well-suited to detecting genes with disease-associated rare and low-frequency variants. In the current study of Behçet disease (BD), nonsynonymous variants (NSVs) identified by deep exonic resequencing of 10 genes found by GWAS (IL10, IL23R, CCR1, STAT4, KLRK1, KLRC1, KLRC2, KLRC3, KLRC4, and ERAP1) and 11 genes selected for their role in innate immunity (IL1B, IL1R1, IL1RN, NLRP3, MEFV, TNFRSF1A, PSTPIP1, CASP1, PYCARD, NOD2, and TLR4) were evaluated for BD association. A differential distribution of the rare and low-frequency NSVs of a gene in 2,461 BD cases compared with 2,458 controls indicated their collective association with disease. By stringent criteria requiring at least a single burden test with study-wide significance and a corroborating test with at least nominal significance, rare and low-frequency NSVs in one GWAS-identified gene, IL23R (P = 6.9 × 10−5), and one gene involved in innate immunity, TLR4 (P = 8.0 × 10−4), were associated with BD. In addition, damaging or rare damaging NOD2 variants were nominally significant across all three burden tests applied (P = 0.0063–0.045). Furthermore, carriage of the familial Mediterranean fever gene (MEFV) mutation Met694Val, which is known to cause recessively inherited familial Mediterranean fever, conferred BD risk in the Turkish population (OR, 2.65; P = 1.8 × 10−12). The disease-associated NSVs in MEFV and TLR4 implicate innate immune and bacterial sensing mechanisms in BD pathogenesis.

Vascular involvement in Behçet’s syndrome: a retrospective analysis of associations and the time course

OBJECTIVE Some features of Behçets syndrome (BS) tend to go together. We aimed to explore the association and timing of various vascular events in both the venous and the arterial vascular tree. METHODS We conducted a chart survey on the type and time of vascular involvement of BS. The cross-relationships of involvement were assessed by phi correlation coefficients. Multiple correspondence analysis was used to identify patterns of vascular involvement. The risk of vascular recurrence was also estimated. RESULTS We identified 882 patients with vascular involvement among 5970 BS patients (14.7%). Deep vein thrombosis (DVT), almost always in the legs, was the most frequent single vascular event (592/882; 67.1%). The cumulative risk of a recurrent vascular event was 38.4% at 5 years. Patients with extrapulmonary artery involvement (EPAI) were significantly older than those with venous and pulmonary artery involvement (PAI). There were significant correlations between dural sinus thrombosis (DST) and PAI, Budd-Chiari syndrome (BCS) and inferior vena cava syndrome (IVCS) and between IVCS and superior vena cava syndrome (SVCS). Multiple correspondence analysis further indicated clustering of PAI, DST, BCS, IVCS and SVCS. However, EPAI and DVT clustered separately from forms of vascular disease, the separate clustering of the DVT being attributed to its propensity to occur solo. CONCLUSION The most common type of vascular involvement in BS is solo DVT, almost always occurring in the legs. Various forms of venous disease in BS segregate together and PAI is included in this group. EPAI segregates separately.

Behçet Syndrome: Is It One Condition?

Behçets syndrome (BS) is a disease of unknown etiology, and as such, there have been efforts to classify BS within the popular nosological identities of the times such as seronegative spondarthritides, autoimmune, and more recently autoinflammatory diseases. Current evidence suggests that BS does not easily fit into any one of these lumps, while on occasion, it might be impossible to tell BS from Crohns disease, especially when the main clinical presentation is intestinal ulceration. There are distinct regional differences in disease expression of BS with fewer cases of intestinal disease in the Mediterranean basin and less severe eye disease and less frequent skin pathergy among patients reported from northern Europe or America. The clustering of symptoms, especially with the recently described increased frequency of the acne/arthritis cluster in familial cases, suggests that more than one pathological pathway is involved in what we call BS today. Supportive evidence for this contention also comes from the observations that (a) the genetic component is very complex with perhaps different genetic modes of inheritance in the adult and in the pediatric patients; and (b) there are differing organ responses to one same drug. For example, the anti-TNF agents successfully control the oral ulcers while they have no effect on the pathergy reaction.

Efficacy and safety of canakinumab in adolescents and adults with colchicine-resistant familial Mediterranean fever

IntroductionThis open-label pilot study aimed to investigate the efficacy of canakinumab in colchicine-resistant familial Mediterranean fever (FMF) patients.MethodPatients with one or more attacks in a month in the preceding 3 months despite colchicine were eligible to enter a 30-day run-in period. Patients who had an attack during the first run-in period advanced to a second 30-day period. At the first attack, patients started to receive three canakinumab 150 mg subcutaneous injections at 4-week intervals, and were then followed for an additional 2 months. Primary efficacy outcome measure was the proportion of patients with 50 % or more reduction in attack frequency. Secondary outcome measures included time to next attack following last canakinumab dose and changes in quality of life assessed by SF-36.ResultsThirteen patients were enrolled in the run-in period and 9 advanced to the treatment period. All 9 patients achieved a 50 % or more reduction in attack frequency, and only one patient had an attack during the treatment period. C-reactive protein and serum amyloid A protein levels remained low throughout the treatment period. Significant improvement was observed in both physical and mental component scores of the Short Form-36 at Day 8. Five patients had an attack during the 2-month follow-up, occurring median 71 (range, 31 to 78) days after the last dose. Adverse events were similar to those observed in the previous canakinumab trials.ConclusionCanakinumab was effective at controlling the attack recurrence in patients with FMF resistant to colchicine. Further investigations are warranted to explore canakinumab’s potential in the treatment of patients with colchicine resistant FMF.Trial registrationClinicalTrials.gov NCT01088880. Registered 16 March 2010.

Screening for Cushing's syndrome in obese patients.

OBJECTIVES: The aim of this study was to examine the frequency of Cushing’s syndrome (CS) in obese patients devoid of specific clinical symptoms of Cushing’s syndrome. METHODS: A total of 150 obese patients (129 female, 21 male; mean age 44.41 ± 13.34 yr; mean BMI 35.76 ± 7.13) were included in the study. As a first screening step, we measured 24-h urinary free cortisol (UFC). An overnight 1-mg dexamethasone suppression test was also performed on all patients. Urinary free cortisol levels above 100 μg/24 h were considered to be abnormal. Suppression of serum cortisol <1.8 μg/dL after administration of 1 mg dexamethasone was the cut-off point for normal suppression. The suppression of the serum cortisol levels failed in all of the patients. RESULTS: Measured laboratory values were as follows: ACTH, median level 28 pg/ml, interquartile range (IQR) 14–59 pg/ml; fasting glucose, 100 (91–113) mg/dL; insulin, 15.7 (7.57–24.45) mU/ml; fT4, 1.17 (1.05–1.4) ng/dL; TSH, 1.70 (0.91–2.90) mIU/L; total cholesterol, 209 (170.5–250) mg/dL; LDL-c, 136 (97.7–163) mg/dL; HDL-c, 44 (37.25–50.75) mg/dL; VLDL-c, 24 (17–36) mg/dL; triglycerides, 120.5 (86–165) mg/dL. The median UFC level of the patients was 30 μg/24 h (IQR 16–103). High levels of UFC (>100 μg/24 h) were recorded in 37 patients (24%). Cushing’s syndrome was diagnosed in 14 of the 150 patients (9.33%). Etiologic reasons for Cushing’s syndrome were pituitary microadenoma (9 patients), adrenocortical adenoma (3 patients), and adrenocortical carcinoma (1 patient). CONCLUSION: A significant proportion (9.33%) of patients with simple obesity were found to have Cushing’s syndrome. These findings argue that obese patients should be routinely screened for Cushing’s syndrome.

Mushroom poisoning: retrospective analysis of 294 cases

OBJECTIVE The objective of this study was to present special clinical and laboratory features of 294 cases of mushroom poisoning. MATERIALS AND METHODS In this retrospective study, 294 patients admitted to the Pediatric and Adult Emergency, Internal Medicine and ICU Departments of Cumhuriyet University Hospital were investigated. RESULTS Of 294 patients between the ages of 3 and 72 (28.97 ± 19.32), 173 were female, 121 were male and 90 were under the age of 16 years. One hundred seventy-three patients (58.8%) had consumed the mushrooms in the early summer. The onset of mushroom toxicity symptoms was divided into early (within 6 h after ingestion) and delayed (6 h to 20 d). Two hundred eighty-eight patients (97.9%) and six (2.1%) patients had early and delayed toxicity symptoms, respectively. The onset of symptoms was within two hours for 101 patients (34.3%). The most common first-noticed symptoms were in the gastrointestinal system. The patients were discharged within one to ten days. Three patients suffering from poisoning caused by wild mushrooms died from fulminant hepatic failure. CONCLUSION Education of the public about the consumption of mushrooms and education of health personnel working in health centers regarding early treatment and transfer to hospitals with appropriate facilities are important for decreasing the mortality.

Intima–media thickening in patients with familial Mediterranean fever

OBJECTIVE The aim of this study was to assess the frequency of atherosclerotic plaques and intima-media thickness (IMT) in patients with FMF and suitable controls. METHODS We studied 100 (46 males, 54 females; mean age: 40 +/- 6 years) patients with FMF. Also 94 (15 males, 79 females; mean age: 41 +/- 7 years) patients with SLE and 103 (44 males, 59 females; mean age: 40 +/- 5 years) apparently healthy volunteers were included as the control groups. Subclinical atherosclerosis was assessed by investigating atherosclerotic plaques and measuring IMT from carotid and common femoral arteries using B-mode ultrasonography (USG). Traditional atherosclerotic risk factors were also assessed. RESULTS Both FMF and SLE patients had significantly higher carotid (C-IMT) and femoral artery IMT (F-IMT) compared with healthy controls. This was also true after adjustment for atherosclerotic risk factors. Only patients with SLE were found to have higher frequency of atherosclerotic plaques in the carotid and in the carotid and/or femoral artery. When all atherosclerotic risk factors were adjusted, again only patients with SLE were found to have risk for atherosclerotic plaques. In FMF, whereas the presence of atherosclerotic plaques was only associated significantly with diabetes mellitus; C-IMT was correlated with age, BMI and fasting glucose; and F-IMT with age and BMI. CONCLUSIONS Increased atherosclerosis defined as the presence of plaques was not observed in patients with FMF. The significance of increased C- and F-IMT among patients with FMF must be further assessed.

Prevalence of angina, myocardial infarction and intermittent claudication assessed by Rose Questionnaire among patients with Behcet's syndrome

OBJECTIVE To determine the risk of clinical cardiovascular disease in middle-aged patients with Behcets syndrome (BS) compared with gender-matched non-BS subjects. METHODS The prevalence of angina, myocardial infarction (MI), doctor diagnosed ischaemic heart disease (IHD) and intermittent claudication were sought by the Rose Angina Questionnaire in 225 (141 M/84 F) BS patients (mean age: 52 +/- 8) with BS and 117 (74 M/43 F) controls (mean age: 50 +/- 5). Information on atherosclerotic risk factors was also collected. RESULTS The prevalence of angina, MI and doctor-diagnosed IHD were not different between BS patients and non-BS controls in the whole study population and when males and females were separately analysed. Angina tended to be more common among females compared with males among both patients and controls. Intermittent claudication was found to be significantly more common among BS patients, especially in males with venous disease. CONCLUSIONS The findings in this cross-sectional clinical study are in line with previous observations not indicating accelerated atherosclerosis in BS. Intermittent claudication might not be a suitable tool for the detection of peripheral atherosclerotic disease especially among BS patients having venous disease.

Pulmonary artery involvement in Behçet׳s syndrome: Effects of anti-Tnf treatment

OBJECTIVES Anti-TNF agents are being increasingly used in patients with Behçet׳s syndrome (BS) when conventional immunosuppressives fail. However, experience with anti-TNF treatment on pulmonary artery involvement (PAI) of BS is limited. METHODS A chart review revealed 13 patients with PAI (all men) treated with anti-TNF agents (12 infliximab and 1 adalimumab) following an inadequate response to immunosuppressives for 12.2 ± 9.5 SD months and 2 male patients who developed PAI while receiving infliximab for large vein thrombosis for 10 months and for parenchymal central nervous system involvement for 2 years, respectively. RESULTS The first patient developing PAI while receiving infliximab responded to cyclophosphamide and prednisolone but the second died with hemoptysis within 1 month. At the end of the survey, 6 of the 13 patients with PAI were continuing these agents for 25.5 ± 16.2 SD months with good response, 4 stopped anti-TNF treatment after a mean of 23 ± 9.8 SD months after achieving clinical and radiologic response and 1 patient with good response went to another center after receiving infliximab for 10 months and the remaining 2 experienced serious infections (lung tuberculosis and aspergillosis) necessitating early withdrawal. Two patients relapsed within 3 years after stopping anti-TNF agents and concomitant azathioprine. One developed mesenteric vein thrombosis necessitating bowel resection and the second developed new PAI that was controlled with cyclophosphamide and prednisolone after short courses of infliximab, adalimumab, and canakinumab. CONCLUSION Anti-TNF treatment seems to be effective for refractory PAI of BS but may not prevent its development. Relapses can be seen after withdrawal. Caution is required for their serious adverse effects.