Polymorphisms in the Growth Differentiation Factor 5 (GDF 5) Gene in Knee Osteoarthritis.

OBJECTIVE: To identify the frequency of the rs143383 SNPin the GDF5 gene, which is located in the 5'-untranslated region of Turkish population with knee osteoarthritis (OA). STUDY DESIGN: Acase-control study. PLACE AND DURATION OF STUDY: Orthopedics and Traumatology Department, Bozok University Medical Faculty, Yozgat, Turkey, from 2012 to 2014. METHODOLOGY: Patients diagnosed with OA(n=94) and patients who did not have joint complaints (n=279) were enrolled in this study. Patients diagnosed with osteoarthritis according to the 1986 American College of Rheumatology osteoarthritis criteria and Kellgren and Lawrence scores were investigated, based on age, gender, and X-ray findings. Blood samples were taken for the identification of GDF5 (rs143383) SNPs by PCR/RFLP, according to a standard protocol. RESULTS: This study included 373 patients. The OAgroup (25.2%; n=94) was characterized by specific genotypes: TT (39.4%; n=37); heterozygotes (TC; 45.7%; n=43); and homozygotes (CC; 14.9%; n=14). The control group (74.8%; n=279) was comprised of TT(26.5%; n=74), TC (54.8%; n=153), and CC (18.6%; n=52) genotypes. An analysis of rs143383 SNP of the GDF5 gene polymorphism revealed that the rs143383 TTgenotype had a higher risk for OA(crude OR=1.798, 95% CI=1.010-2.941, p=0.021). CONCLUSION: This study demonstrated that there is a correlation of +104T/C polymorphism in the 5'-UTR of GDF5 with knee OAin a Turkish population.

Functional gastrointestinal disorders in patients with familial Mediterranean fever.

AIM: Familial Mediterranean fever (FMF) is an autosomal recessive autoinflammatory disease characterised by recurrent episodes of fever and polyserositis. To date, insufficient data regarding the prevalence of functional gastrointestinal disorders such as irritable bowel syndrome (IBS) and functional dyspepsia (FD) have been reported in patients with FMF. This study aimed to determine the prevalence of functional gastrointestinal disorders in patients with FMF. METHODS: This study included 122 patients with FMF and a control group of 122 healthy volunteers who were similar with respect to age and sex. Clinical data were collected and gastrointestinal complaints were evaluated according to the Rome III criteria. RESULTS: IBS was found in 18% of the patients and 10.7% of the controls (P > 0.05). Dyspepsia was reported in 37.7% of the patients and 35.2% of the controls. Constipation was significantly higher in the control group (15.6% vs. 7.4%, P = 0.045), whereas diarrhoea was reported significantly more often in patients with FMF (P = 0.001). CONCLUSIONS: IBS and dyspepsia were not increased in patients with FMF, whereas diarrhoea was more frequently reported.

Neutrophil-lymphocyte ratio in patients with familial Mediterranean fever.

BACKGROUND: Blood neutrophil-to-lymphocyte (N/L) ratio is an indicator of the overall inflammatory status of the body, and an alteration in N/L ratio may be found in patients with familial Mediterranean fever (FMF). The aim of this study was to investigate the interrelationship between N/L ratio and FMF. METHODS: One hundred and fifteen patients and controls were enrolled in the study. The cases in the study were categorized as FMF with attack, FMF with attack-free period, and controls. The neutrophil and lymphocyte counts were recorded, and the N/L ratio was calculated from these parameters. All patients were diagnosed according to Tel Hashomer criteria. RESULTS: A total of 79 FMF patients were included in the study and all subjects were receiving colchicine treatment at the time. The serum N/L ratios of active patients were significantly higher than those of attack-free FMF patients and controls (P < 0.001). The optimum N/L ratio cut-off point for active FMF was 2.63 with sensitivity, specificity, positive predictive value, and negative predictive value of 0.62 (0.41-0.80), 0.85 (0.72-0.93), 0.67 (0.44-0.85), and 0.82 (0.69-0.91), respectively. The overall accuracy of the N/L ratio in determination of FMF patients during attack was 71%. CONCLUSION: Our results demonstrate that N/L ratio is higher in patients with active FMF compared with FMF patients in remission and controls, and a cut-off value of 2.63 can be used to identify patients with active FMF.

Does rheumatoid arthritis have an effect on audiovestibular tests?

The study aimed to determine the characteristics of hearing loss, vestibular responses and the incidence of vestibular disturbances in RA patients. This prospective study was performed at the Otolaryngology Department of Bozok University School of Medicine between May and November 2012. Eighty-one RA patients (69 women and 12 men) with a mean age of 40.8 ± 13.4 years (23-67 years) and 81 healthy controls (67 women and 14 men) with a mean age of 41.3 ± 13.8 years (24-66 years). Each subject was tested with low and high-frequency audiometry by a single experienced investigator under standard audiometric testing conditions. For each set of tests, mean values of air and bone conduction at each frequency and tympanometric values were calculated for the study groups. Videonystagmography (VNG) including smooth pursuit, saccade, positional, and caloric tests were also performed. The mean air conduction threshold values at high frequencies (4,000, 6,000, and 8,000 Hz) in RA group were lower than control groups. The difference between mean air conduction threshold values of the control groups against RA group at high frequencies were statistically significant (p < 0.05). There was no statistically significance between the two groups in tympanometric values (p < 0.05). VNG testing revealed central abnormalities in twenty patients (24.69%), peripheral abnormalities in five patients (6.17%), and mixed abnormalities in six patients (7.4%). There was no association between VNG abnormalities in patients with RA and age, sex, duration of disease, accompanying vertigo complaint, the laboratory findings and hearing levels (p < 0.05). Our findings suggest an association of RA and audiovestibular system dysfunction regardless clinical and demographic situation of patients. We assume the hearing and vestibular disturbances in RA are more prevalent than previously recognized. Also hearing losses in high frequencies in RA patients may be considered as an indicator of cochlear involvement in this disease.

The impact of ankylosing spondylitis on audiovestibular functions.

In this study, we aimed to evaluate the audiovestibular functions in the patients with ankylosing spondylitis (AS). This prospective study was performed in collaboration by the Otolaryngology and Rheumatology Departments of Bozok University School of Medicine between May 1, 2012, and January 1, 2013. We studied 80 subjects consisting of 40 AS patients (37 men and 3 women) in whom the diagnosis confirmed by the criteria of New York and 40 healthy controls (35 men and 5 women). All participants were evaluated by routine audiologic (including tympanometric evaluation, pure-tone audiograms, speech tests) and vestibular studies (including spontaneous nystagmus, gaze, optokinetic, saccadic movements, smooth pursuit, caloric test and Dix-Hallpike tests). The tympanometric values did not show a statistically significant difference between the AS group and the healthy subjects (p > 0.05). At low frequencies (250, 500, 1,000, and 2,000 Hz) pure-tone audiologic evaluations also proved statistically non-significant results at mean air conduction thresholds (ACT) and bone conduction thresholds (BCT) between the AS and control groups (p > 0.05). At high frequencies (4,000, 6,000, and 8,000 Hz), the ACTs and BCTs in AS group were lower than control group which was statistically significant (p < 0.05). The results of spontaneous nystagmus, gaze, optokinetic, canal paresis and saccadic movement tests between the two groups were statistically insignificant (p > 0.05). The comparison of smooth pursuit and Dix-Hallpike tests reached statistical significance (p < 0.05). Videonystagmographic test (VNG) revealed central abnormalities in 7 patients (17.5 %), peripheral abnormalities in 16 patients (40 %), and mixed abnormalities in 3 patients (7.5 %). Our findings suggest a possible association between AS and audiovestibular system dysfunction. We assume that the hearing and vestibular disturbances in AS are more prevalent than previously recognized.

Efficacy of treatment with glucosamine sulfate in patients with knee effusion due to osteoarthritis.

OBJECTIVE: Evaluation of anti-inflammatory effect of Glucosamine sulfate (GS) versus diclofenac sodium (DS) in effusion of osteoarthritic knees. METHODOLOGY: In this study, patients were included in this study from 2007-2010 based on American College of Rheumatology criteria with OA and physical examination in effusion of osteoarthritic knees. The patients were divided into two groups. First group (27 patients) DS was given in doses 75 mg twice daily for ten day. In the group II (25 patients) GS was used in doses of 1500 mg two times daily over the first 12 weeks of the study. A closed aspiration was performed. The knee circumference was measured in patients before and 12 week after treatment. Before and after 12 weeks of treatments, both groups of patients were assessed according to the WOMAC questionnaire of knee pain and function scores. RESULTS: Comparison of knee mean circumference between the two groups was not statistically significant before treatment (p=0.938), but significant after treatment (p<0.001). At the end of the 12 week, there was 66.6% complete resolution of effusion in the DS group (18 patients) and 24.0% (6 patients) in the GS group, this was statistically significant (P<0.001). DS groups, results of the beginning and at the end of 12 week measurement showed significant differences in WOMAC pain mean score (P < 0.001) but GS groups not statistically significant (P=0.160). The WOMAC function mean scores in pre and post-treatment periods of follow-up showed significant variation between the two groups (P< 0.001, P<0.001). CONCLUSIONS: Our observations suggest that GS is not able to suppress the progression of adjuvant arthritis in OA with effusion of knee osteoarthritis. GS should not be expected as anti-inflammatory influence as DF in the treatment of OA-related effusion.

Surgical synovectomy combined with yttrium 90 in patients with recurrent joint synovitis.

Radiation synovectomy (RS) is one of many therapeutic options used for recurrent joint synovitis. Our aim was to analyze the effect of the surgical synovectomy combined with yttrium 90 ((90)Y) in the treatment for recurrent joint synovitis. A surgical combined RS procedure was used on 32 knees of 30 patients. They were divided into two groups. Group 1 consisted of 7 knees of 7 patients (5 women and 2 men) with a mean age of 40.7 years in whom RS was combined with the open synovectomy. Group 2 consisted of 25 knees of 23 patients (21 men and 2 women) with a mean age of 45.5 years in whom RS was combined with the arthroscopic synovectomy. Arthroscopic synovectomy or open surgery biopsy was carried out for all cases who diagnosed of having synovitis. A scintigraphic examination was conducted within 24 h after the RS procedure to investigate the systemic leakage of (90)Y in all patients. The outcome of treatment was assessed based on self-reporting using the visual analogue scale (VAS) of night pain, rest pain, activity pain, effusion, and satisfactory scores. The average follow-up period was 4.15 years. There was a significant difference between before and after treatment in terms of outcome parameters' VAS scores in both groups (p < 0.05). But there was no statistically significant difference between open and arthroscopic synovectomy groups in terms of outcome parameters (p > 0.05). Satisfactory outcome was excellent in 3 patients (42.8 %) in group 1 and 8 patients (32 %) in group 2. Surgical synovectomy with combined (90)Y could treat recurrent joint synovitis successfully. There was no statistically significant difference between open and arthroscopic synovectomy techniques combined with RS procedure.

Is there a predisposition for the development of autoimmune diseases in patients with fibromyalgia? Retrospective analysis with long term follow-up.

The objectives of the study were to evaluate the prevalence of antinuclear antibodies (ANA) in patients with fibromyalgia (FM) and the probability of the development of clinically overt connective tissue diseases. Four hundred and fifty FM patients were compared to 129 healthy matched blood donors. ANA testing was performed by immunofluorescence on rat tissue sections; in case of highly positive results, ANA were specified further by ELISA and immunodiffusion. All ANA positive FM patients were invited for a control examination. The ANA negative patients received a questionnaire, which was designed to identify those patients with possible connective tissue diseases (CTD). There was no significant difference in the frequency of ANA or thyroid antibodies between patients and controls (11.6% vs. 7%). Two patients had developed SLE: one was already ANA/anti-dsDNA positive at time of first diagnosis of FM; in the other, specific antibodies and SLE-related symptoms developed after 4.5 years. The probability for FM patients to develop CTD (SLE) within one year is 0.0027%, which is comparable to the incidence of SLE in the general population (0.005%). The risk of CTD is not increased in FM. The detection of ANA does not predict the development of CTD. However, in individual cases, FM may be an early sign of an autoimmune disease.

Anakinra in patients with treatment-resistant adult-onset Still's disease: four case reports with serial cytokine measurements and a review of the literature.

OBJECTIVE: To determine the efficacy of the interleukin (IL)-1-receptor antagonist (IL-1RA) anakinra in patients with adult-onset Still's disease (AOSD) refractory to standard treatments such as glucocorticosteroids (GC), immunosuppressive drugs, and tumor necrosis factor (TNF)-antagonists; to verify disease remission objectively by serial cytokine measurements; and to review the current literature on anakinra for this indication. METHODS: Four patients with AOSD--2 with acute flares of the chronic form of the disease and 2 with intermittent disease--were treated with prednisolone and methotrexate. One was also treated with several other immunosuppressive drugs including etanercept and infliximab. One patient had life-threatening symptoms (toxic megacolon, pneumonitis, disseminated intravascular coagulation) despite high-dose prednisolone. Treatment with anakinra 100 mg/d subcutaneously was initiated. White blood cells (WBC), C-reactive protein (CRP) levels, erythrocyte sedimentation rate (ESR), liver enzymes, ferritin levels, and serum cytokines were analyzed. The current literature on the efficacy of anakinra for AOSD is reviewed. RESULTS: Patients with chronic AOSD quickly responded to anakinra treatment (1 day to 3 days). GC could be tapered. ESR, CRP, WBC, ferritin, and liver enzymes returned to normal. Serum cytokine measurements revealed moderately elevated IL-1beta levels and highly elevated IL-18 levels in active disease, which normalized with anakinra. TNF-alpha and IL-6 were moderately elevated only in the 2 patients with chronic AOSD. In the literature, 17 similar cases have been reported to date. CONCLUSIONS: Anakinra is effective in treatment-resistant and in life-threatening AOSD. IL-18 serum levels, in addition to CRP, ESR, liver enzymes, ferritin, and WBC, may be helpful in assessing disease activity and response to treatment.

CNS involvement occurs more frequently in patients with Behçet's disease under cyclosporin A (CSA) than under other medications--results of a retrospective analysis of 117 cases.

The aim of this study was to evaluate the incidence of neurological manifestations of Behçet's disease (BD) in patients on cyclosporin A (CSA) compared with those on other medications. The records of 117 patients with BD who visited our hospital between 1990 and 2003 were reviewed with respect to symptoms and medication. All episodes of constant therapy prior to central nervous system (CNS) involvement were counted, and then the associations were analysed by the exact Fisher-Freeman-Halton test and adjusted for multiple tests by the Bonferroni-Holm method. We observed ten new cases of CNS manifestations in our patients with BD being regularly seen and treated in our tertiary care centre. The overall prevalence of neuro-BD in our patient group was 8.5%. In a retrospective analysis, the incidence of new-onset neurological disease (neuro-BD) in all patients with BD who regularly visited our hospital was significantly higher in patients on CSA than in those on other medications (6 of 21 vs 0 of 175 episodes, P<0.0001). This contrasts the obvious efficacy of CSA on extracerebral manifestations of BD, such as severe ocular disease, mucocutaneous lesions or arthritis. CSA exerts differential efficacy on various manifestations of BD. It is very effective for severe ocular and other moderate to severe manifestations of BD, but its efficacy for the prevention of neuro-BD seems to be inferior to that of other medications used in BD, such as azathioprine or interferon-alpha. The reasons for this are unclear, but the potential toxic effects of CSA on the CNS may be a predisposing factor for CNS vasculitis in BD.

Efficacy and safety of willow bark extract in the treatment of osteoarthritis and rheumatoid arthritis: results of 2 randomized double-blind controlled trials.

OBJECTIVE: To investigate the efficacy and safety of a standardized willow bark extract in patients with osteoarthritis (OA) and rheumatoid arthritis (RA). METHODS: We studied 127 outpatients with hip or knee OA and a WOMAC pain score of at least 30 mm and 26 outpatients with active RA in 2 randomized, controlled, double-blind trials with followup for 6 weeks. OA trial: Patients were randomized to receive willow bark extract, corresponding to 240 mg of salicin/day, diclofenac 100 mg/day, or placebo (n = 43, 43, and 41, respectively). Main outcome measure was the pain subscore of the WOMAC OA Index. RA trial: Patients were randomized to receive willow bark extract, corresponding to 240 mg salicin/day (n = 13) or placebo (n = 13). Main outcome measure was the patient's assessment of pain rated on a 100 mm visual analog scale (VAS). RESULTS: OA trial: WOMAC pain scores decreased by 8 mm (17%) in the willow bark group and by 23 mm (47%) in the diclofenac group, compared with 5 mm (10%) in the placebo group. The difference between willow bark extract and placebo was not statistically significant (-2.8 mm; 95% CI -12.1 to 6.4 mm; p = 0.55, ANCOVA), but the difference between diclofenac and placebo was highly significant (-18.0 mm; 95% CI -27.2 to -8.8 mm; p = 0.0002, ANCOVA). RA trial: The mean reduction of pain on the VAS was -8 mm (15%) in the willow bark group compared with -2 mm (4%) in the placebo group. The difference was not statistically significant (estimated difference -0.8 mm; 95% CI -20.9 to 19.3 mm; p = 0.93, ANCOVA). CONCLUSION: The OA study suggested that the willow bark extract showed no relevant efficacy in patients with OA. Similarly, the RA trial did not indicate efficacy of this extract in patients with RA.

Differential efficacy of human recombinant interferon-alpha2a on ocular and extraocular manifestations of Behçet disease: results of an open 4-center trial.

OBJECTIVE: Behçet disease (BD) is a multisystem vasculitis of unknown origin. Standard treatment mainly comprises systemic immunosuppressive agents. In a study primarily designed for refractory ocular disease, we additionally evaluated the efficacy of recombinant human interferon-alpha2a (rhIFN-alpha2a) on the extraocular manifestations of BD. METHODS: Fifty patients were included in the study. RhIFN-alpha2a was applied at a dose of 6 x 10(6) units subcutaneously daily. Dose reduction was performed according to a decision tree until discontinuation. Disease activity was evaluated by the Behçet's Disease Activity Scoring System and the Uveitis Scoring System. RESULTS: Response rate of the ocular manifestations was 92%. Visual acuity rose significantly from 0.56 to 0.84 at week 24 (P <.0001). Mean Behçet's Disease Activity Score fell in a dose-dependent fashion by 1.2 points in the first week (P <.0001) and from 5.8 to 3.3 at week 24 and further to 2.8 at week 52. After a mean observation period of 36.4 months, 17 patients have been off treatment and disease-free for 29.5 months (mean). In the other patients, maintenance IFN dosage is 3 million units 3 times weekly. Whereas extraocular manifestations such as genital ulcerations, arthritis, and skin lesions remitted with IFN, only 36% of oral aphthous ulcers responded. CONCLUSIONS: RhIFN-alpha2a is effective in ocular BD, resulting in significant improvement of vision and complete remission of ocular vasculitis in the majority of patients. It is also beneficial for the extraocular manifestations of the disease, although less so for oral aphthous ulcers.

The use of interferon alpha in Behçet disease: review of the literature.

OBJECTIVES: To evaluate the efficacy and safety of interferon (IFN) alpha for the treatment of Behçet's disease (BD) and discuss its possible mechanisms of action. METHODS: Reports published until July 2002 in all languages were identified by the PubMed Database and the BD conference proceedings and abstract booklets. The indexing terms used were "Behçet" and "interferon." RESULTS: Thirty-two original reports and 4 selected abstracts were included in the analysis. Systemic IFN-alpha was administered to 338 patients. One hundred eighty-two patients with acute ocular disease were treated with IFN-alpha. Two hundred sixty-four patients received IFN-alpha2a, and 74 received IFN-alpha2b. Eighty-six percent of the patients with mucocutaneous symptoms, 96% with arthritis, and 94% with uveitis exhibited a partial or complete response. Higher IFN doses were more effective than low-dose regimens and led to up to 56% long-term remissions after discontinuation of IFN-alpha were reported. IFN-alpha2a apparently was superior to IFN-alpha2b, with more complete remissions, but this probably was the result of a bias caused by the larger number of patients treated with IFN-alpha2a. Side effects were dose-dependent and similar to those noted in patients with hepatitis C. CONCLUSIONS: Although the comparability of the studies is hampered because of different study designs, IFN-alpha is effective for the treatment of BD. It was beneficial even in resistant posterior uveitis, in which long-term remissions with preservation of visual acuity was achieved. In contrast, mostly partial remissions were reported for mucocutaneous symptoms.

Behçet's disease in patients of German and Turkish origin living in Germany: a comparative analysis.

OBJECTIVE: To evaluate the relationship between ethnic origin and manifestations of Behçet's disease (BD) in patients of German and Turkish origin living in Germany. METHODS: Between 1995 and 2000, 32 patients of German and 33 patients of Turkish origin living in Germany were evaluated for the entire spectrum of disease manifestations, disease severity, HLA associations, sex, age at disease manifestation, and time to diagnosis. RESULTS: There were no statistically significant differences between German and Turkish patients. There was no association of sex or HLA-B51 with any manifestation of BD. The only significant difference between the 2 groups was the median time from the first manifestation of the disease to diagnosis, which was 0 years for the Turkish, but 3.5 years for the German patients (p = 0.0005). Additionally, 4 patients of German origin had been misdiagnosed as having spondyloarthropathy (SpA) before the final diagnosis of BD was made (12%). In comparison to Turkish patients living in Turkey (data from the literature), only 2 differences were found: one concerned the frequency of ocular involvement (lower in the patients in Turkey), and the other the male to female ratio, which was reported as 1.03:1 in Turkey, but 3.7:1 in Germany. CONCLUSION: Our results do not favor an ethnic influence on the expression of BD. Environmental influences may be responsible for the higher frequency of ocular manifestations and the higher male to female ratio in patients living in Germany compared to those living in Turkey.