Rheumatoid Arthritis: Pay S

Simsek I, Erdem H, Pay S, Sobaci G, Dinc A. · Gulhane Military School of Medicine, Division of Rheumatology, Ankara, Turkey. · Ann Rheum Dis. · Pubmed #17456525 No free full text.

Abstract: OBJECTIVE: Various demyelinating disorders have been reported in association with anti-tumour necrosis factor alpha (TNFalpha) agents. The objective of this study was to review the occurrence, clinical features and outcome of optic neuritis (ON) during treatment with anti-TNFalpha agents. METHODS: A PubMed search was conducted to identify literature addressing the potential association between anti-TNFalpha agents and ON, following our experience with a patient having rheumatoid arthritis in whom ON developed while being treated with infliximab. RESULTS: 15 patients including the case presented here with ON in whom the symptoms developed following TNFalpha antagonist therapy were evaluated. Eight of these patients had received infliximab, five had received etanercept and two patients had received adalimumab. Among them, nine patients experienced complete resolution, and two patients had partial resolution, while four patients continued to have symptoms. DISCUSSION: Patients being treated with a TNFalpha antagonist should be closely monitored for the development of ophthalmological or neurological signs and symptoms. Furthermore, consideration should be given to avoiding such therapies in patients with a history of demyelinating disease. If clinical evaluation leads to the diagnosis of ON, discontinuation of the medication and institution of steroid treatment should be a priority.

Saruhan-Direskeneli G, Inanc M, Fresko I, Akkoc N, Dalkilic E, Erken E, Karaaslan Y, Kinikli G, Oksel F, Pay S, Yucel E, Yentür SP, Duymaz-Tozkir J, Yilmaz V, Inanc N, Yazici H, Konice M, Direskeneli H. · Department of Physiology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey. · Rheumatology (Oxford). · Pubmed #18032542 No free full text.

Abstract: OBJECTIVES: To investigate the role of shared epitope (SE) alleles in the short-term clinical response to leflunomide for the treatment of active RA. METHODS: In an open-label, multi-centre study of 16-weeks duration, 93 patients (82% female) fulfilling ARA 1987 RA criteria were treated with leflunomide (100 mg loading dose for 3 days, then 20 mg/day as the maintenance dose). The primary efficacy criterion was the response status according to the European League Against Rheumatism (EULAR) response criteria using Disease Activity Score-28 (DAS28) activity measure. SE determinations have been undertaken by polymerase chain reaction and sequence-specific oligonucleotide genotyping methods. RESULTS: The mean (s.d.) Disease Activity Score-28 (DAS28) was 5.1 (1.3) before the treatment, which was significantly decreased after 16 weeks [3.0 (1.1), P < 0.001]. According to the EULAR response criteria, 55 patients (59.1%) were classified as good responders. SE was positive in 51 (54.8%) of the patients, with 13 (13.9%) having SE homozygosity or carrying any two SE alleles. Among SE-positive patients, 68.6% (35/51) were good responders, compared with 47.6% (20/42) in SE negatives (P = 0.04). No difference was present according to SE hetero- or homozygosity (68.4 vs 69.2%). RF was also present significantly more frequently in the SE-positive group compared with negatives (78.4 vs 57.1%, P = 0.03). However, no significant difference was observed in the prevalence of RF positivity in patients with a good clinical response (72.7 vs 63.2%, P = 0.32). CONCLUSIONS: The results suggest that HLA-DRB1 SE presence may favourably affect the outcome of leflunomide monotherapy in an unselected group of RA patients with an active disease and naive to leflunomide.

Calgüneri M, Pay S, Calişkaner Z, Apraş S, Kiraz S, Ertenli I, Cobankara V. · Hacettepe University School of Medicine, Department of Rheumatology, Ankara, Turkey. · Clin Exp Rheumatol. · Pubmed #10609068 No free full text.

Abstract: OBJECTIVE: The response to single disease modifying antirheumatic drug (DMARD) is often suboptimal in patients with rheumatoid arthritis (RA). Thus, despite the limited data on the therapeutic efficacy of combination therapies, many patients are currently treated with a combination of DMARDs. METHODS: We studied prospectively the efficacy of combination therapy with DMARDs. The study was designed as a randomized trial and a single DMARD or two or three DMARD combinations were administered to 180 consecutive, age- and sex-matched patients with active RA, each of whom was followed up for a period of 2 years under treatment. Patients were divided into 3 groups which did not differ with regard to demographic, clinical and laboratory parameters. Patients in group I were treated with a single DMARD [methotrexate (MTX) 7.5-15 mg/week or sulfasalazine (SSZ) 1-2 g/day or hydroxychloroquine (HCQ) 200 mg/day], group II with MTX + SSZ or MTX + HCQ, and group III with a combination of all three drugs. Patients were re-evaluated at regular intervals by means of clinical and biochemical tests designed to detect specific rheumatic activity. Radiological assessments were also performed and scored according to Larsen by the same radiologist who was blinded to the treatment groups. RESULTS: At the end of the trial there were significant improvements in the clinical and laboratory parameters in all 3 groups. However, improvements were greater and much more significant in the patients who were given combination therapies. The combination of MTX + SSZ + HCQ was more effective than both monotherapy and the two-drug combinations. CONCLUSION: In conclusion, we suggest that patients with RA should be treated with combinations of DMARDs.

Sari I, Simsek I, Guvenc I, Sanal HT, Erdem H, Pay S, Dinc A. · Department of Medicine, Division of Rheumatology, Gulhane Military School of Medicine, Ankara, Turkey. · Rheumatol Int. · Pubmed #18696073 No free full text.

Abstract: Osteopoikilosis (OPK) is a rare benign sclerosing disease of the skeleton and inherited as an autosomal dominant trait. OPK is associated with inflammatory rheumatic disorders, such as rheumatoid arthritis, scleroderma, reactive arthritis and familial Mediterranean fever (FMF). We report a rare case of OPK coexistent with ankylosing spondylitis and FMF. The patient presented multiple sclerotic lesions within and around the sacroiliac joints and a series of radiological diagnostic challenges.

Pay S, Musabak U, Simsek I, Erdem H, Pekel A, Sengul A, Dinc A. · Division of Rheumatology, Gulhane Military School of Medicine, Ankara, Turkey. · Clin Exp Rheumatol. · Pubmed #17949547 No free full text.

Abstract: OBJECTIVE: Lymphoid neogenesis seems to play an important role in the persistence of chronic inflammation and has been shown in various disorders characterized by chronic inflammation including rheumatoid arthritis. Arthritis of Behçet's disease is characterized by non-erosive arthritis in which the disease course is considered to be subacute and self limiting. However, molecular mechanisms underlying those features of Behçet's arthritis have not been defined yet. In order to determine the contribution of lymphoid neogenesis in the disease course of Behçet's arthritis, we investigated the synovial fluid (SF) levels of CXCL 12, CXCL 13, CCL 21 homeostatic chemokines and the percentage of SF naive lymphocytes expressing their receptors such as CXCR4+ and CCR7+. We further measured the SF TGF-Beta and INF-Beta levels which are known to contribute lymphoid neogenesis via leading persistent expression of CXCR4 on T cells and inhibiting T cell apoptosis, respectively. METHODS: Fifty-one [15 BD, 17 RA, and 19 osteoarthritis (OA)] patients with at least one- sided knee arthritis were enrolled in the study. Patients with BD constituted the study group, and RA, OA patients were used as positive and negative control groups, respectively. The SF levels of CXCL 12, CXCL 13, CCL 21, TGF-Beta and INF-Beta were measured by ELISA. CXCR4, CCR7 chemokine receptors on SF lymphocytes were tested by Flow- cytometry. Kruskal-Wallis test and Mann-Whitney U test were used for statistical analysis where appropriate. RESULTS: Synovial fluid CCL 21 levels were found to be increased in RA patients as compared to BD and OA patients (p = 0.003, and p = 0.013, respectively). No significant difference was detected between BD and OA patients with respect to CCL 21 levels. Both CXCL 12 and CXCL 13 SF levels were found to be higher in RA and BD patients as compared to OA patients (CXCL-12; p = 0.012, and p = 0.024), (CXCL 13; p < 0.001, and p = 0.007). However, no difference with regard to SF levels of both CXCL 12 and CXCL 13 were found between RA and BD patients. Percentages of both CD3+CXCR4+ lymphocytes and CD3+CCR7+ lymphocytes in the SF of RA patients were detected to be increased as compared to those of BD and OA patients (CD3+CXCR4+; p = 0.019, p = 0.048, respectively), (CD3+CCR7+; p = 0.023, p = 0.001, respectively). However, no differences with respect to the percentages of SF lymphocytes expressing CD3+CXCR4+ or CD3+CCR7+ were found between BD and OA patients. Both TGF-Beta and INF-Beta SF levels were found to be higher in RA patients as compared to BD and OA patients (TGF-Beta; p = 0.041, and p = 0.003), (INF-Beta; p = 0.012, and p = 0.016). However, no differences with regard to SF levels of both TGF-Beta and INF-Beta were found between BD and OA patients. CONCLUSION: Considering the subacute, self limiting and non-erosive course of arthritis observed in BD, our finding of detection of lower levels of CCL21 and TGF-Beta1 and IFN-Beta in BD patients, seems to prevent the development of LN and chronic inflammation in Behçet's synovitis. In support of this view, percentages of SF naïve T lymphocytes were found to be lower in BD patients comparing with those of the RA. Absence of tertiary lymphoid structures in BD patients, may explain the spontaneous resolution of Behçet's arthritis in most of the cases.

Erdem H, Pay S, Musabak U, Simsek I, Dinc A, Pekel A, Sengul A. · Division of Rheumatology, Gulhane Military School of Medicine, Ankara, Turkey. · Rheumatol Int. · Pubmed #17265155 No free full text.

Abstract: In our previous studies, we found higher synovial fluid (SF) levels of angiogenic ELR(+) CXC chemokines such as CXCL1, CXCL5, CXCL6 and CXCL8, which play an important role in neutrophil migration and angiogenesis, and more abundant synovial CXCR2 chemokine receptor expression in patients with rheumatoid arthritis (RA) than those with Behçet's disease (BD), familial Mediterranean fever and osteoarthritis (OA). As a continuation of our previous studies, we investigated synovial levels of angiostatic non-ELR CXC chemokines (CXCL4, CXCL9 and CXCL10) in patients with RA, BD, spondyloarthritis (SpA), and OA. Seventy (17 RA, 15 BD, 19 SpA, and 19 OA) patients were enrolled in the study. The levels of CXCL4, CXCL9, and CXCL10 were measured by ELISA. The SF levels of CXCL4 in patients with RA were higher than those of the patients with BD, SpA, and OA (P = 0.007, P = 0.022, and P = 0.017, respectively). No difference was found with respect to CXCL4 levels among the BD, SpA, and OA patients. The synovial CXCL9 levels of patients with RA and SpA were found to be higher than those of the patients with OA (P = 0.002 and P = 0.005, respectively), while no statistically significant difference was detected among the other groups. With regard to SF CXCL10 levels, patients with RA had higher levels as compared to patients with OA (P = 0.002), but no significant difference was found among the other groups. CXCL9 correlated with CXCL4 and CXCL10 (P < 0.05 for both) in patients with RA. No correlation was found in other parameters. The angiostatic non-ELR CXC chemokines were expressed in synovial inflammation. We proposed that angiostatic non-ELR CXC chemokines may increase to balance angiogenic ELR (+) CXC chemokines in which increased levels were shown in patients with inflammatory arthritides and CXCL4 may contribute to designate the chronicity of synovitis in patients with RA. In addition, as CXCL-9 and CXCL-10 play crucial role in inflammation characterized by Th1 polarization, we suggested that they may contribute to the commencement and the perpetuation of synovitis seen in these groups of arthritides.

Pay S, Musabak U, Simşek I, Pekel A, Erdem H, Dinç A, Sengül A. · Division of Rheumatology of Department of Medicine, Gülhane Military School of Medicine, Etlik/Ankara 06018 Turkey. · Joint Bone Spine. · Pubmed #16987681 No free full text.

Abstract: OBJECTIVE: To analyze the CXCR-1 and CXCR-2 chemokine receptor expression on peripheral blood neutrophils (PBN) and synovial fluid neutrophils (SFN) of patients with rheumatoid arthritis (RA) and Behçet's disease (BD) (characterized by erosive and non-erosive arthritis, respectively), and to compare them with those of patients with osteoarthritis (OA). METHODS: We used flow cytometry to investigate the expression of CXCR-1 and CXCR-2 chemokine receptors on PBN and SFN of fifty-five (22 RA, 22 BD and 11 OA) age and sex-matched patients. RESULTS: In respect to chemokine receptor expression on neutrophils isolated from patients with RA, mean fluorescein intensity (MFI) of CXCR-1 chemokine receptors on PBN from active and inactive RA patients, and SFN from patients with RA were 151 (90-395), 129 (81-539) and 136 (64-220), respectively, and there were not statistically significant difference each other. But MFI of CXCR-2 chemokine receptors on SFN of patients with RA was 18 (10-32), and significantly higher than PBN of active and inactive RA patients (MFI: 10 (6-15) and 12 (7-16), P=0.002 and 0.037, respectively). In respect to chemokine receptor expression on neutrophils isolated from patients with BD, MFI of CXCR-1 chemokine receptors on PBN of active BD patients was 245 (97-844), and higher than PBN of active RA patients and SFN of BD patients (MFI: 151 (90-395) and 134 (61-231), P=0.047 and 0.017, respectively). MFI of CXCR-2 chemokine receptors on PBN of active and inactive BD patients, and SFN of patients BD were 10 (6-14), 10 (2-16), and 12 (8-24), respectively, there were not statistically significant difference each other. MFI of CXCR-1 chemokine receptors on SFN from patients with RA, BD, and OA were 136 (64-220), 134 (61-231), and 114 (60-180), respectively, and there was no difference between the study groups. MFI of CXCR-2 chemokine receptors on SFN of patients with RA was 18 (10-32), and higher than patients with BD and OA (MFI: 12 (8-24) and 11 (9-18), P=0.037 and 0.005, respectively), though there was no difference between last two groups. CONCLUSION: Our study points that CXCR-1 and CXCR-2 chemokine receptors of SFN may have diverse functions in the course of inflammatory arthritides. These results indicate that CXCR-2 chemokine receptor might play more critical role in long lasting accumulation of neutrophils within the synovial fluid of patients with RA.

Pay S, Türkçapar N, Kalyoncu M, Simşek I, Beyan E, Ertenli I, Oztürk MA, Düzgün N, Erdem H, Ozbalkan Z, Kiraz S, Kinikli G, Besbas N, Dinç A, Ateş A, Olmez U, Calgüneri M, Aydintuğ OT, Bakkaloğlu A, Turan M, Turgay M, Karaaslan Y, Topaloğlu R, Duman M, Ozen S, Anonymous00040. · Division of Rheumatology, Gulhane Military School of Medicine, Ankara, Turkey. · Clin Rheumatol. · Pubmed #16365690 No free full text.

Abstract: Adult-onset Still's disease (AOSD) has often been regarded as the adult spectrum of systemic juvenile idiopathic arthritis (sJIA). The present study aims to compare the clinical and laboratory features, the disease course and the response to treatment in patients having AOSD with those having sJIA. Retrospective review of all available data that were filled out by adult and paediatric rheumatologists from six centers using a standard data extraction form was performed. A total of 95 patients with AOSD and 25 patients with sJIA were recruited for the study. The frequency of fever, rash, myalgia, weight loss and sore throat was higher in patients with AOSD. The pattern of joint involvement differed slightly. Laboratory findings were similar in both groups, except that liver dysfunction and neutrophilia were more common among adults. A multiphasic pattern dominated the childhood cases, whereas the most frequent course was a chronic one in adults. Corticosteroids and methotrexate were the most commonly employed therapy; however, chloroquine was another popular therapy in the adult group. We showed a difference in the rate of clinical and laboratory features between patients with AOSD and those with sJIA. AOSD and sJIA may still be the same disease, and children may simply be reacting differently as the result of the first encounter of the putative antigens with the immune system.

Pay S, Erdem H, Pekel A, Simsek I, Musabak U, Sengul A, Dinc A. · Division of Rheumatology, Department of Medicine, Gülhane Military School of Medicine, Etlik/Ankara 06018, Turkey. · Rheumatol Int. · Pubmed #16205926 No free full text.

Abstract: The objective of this study has been the well established fact that proinflammatory cytokines and metalloproteinases play a crucial role in the pathogenesis of chronic arthritis as well as the development of pannus, with the eventual erosive changes. Among the proinflammatory cytokines, interleukin-18 (IL-18) has been shown to contribute to the pathogenesis of chronic synovitis by increasing the secretion of interleukin-1beta (IL-1beta) and the tumor necrosis factor-alpha (TNF-alpha) and also stimulating angiogenesis. The aim of this study is to investigate the synovial IL-18, IL-1beta, TNF-alpha and matrix metalloproteinase-3 (MMP-3) levels in patients with Behçet's disease (BD), and compare them with the levels of patients with rheumatoid arthritis (RA) and osteoarthritis (OA). 30 patients with BD, 20 with RA, and 20 with OA were included in the study. The synovial levels of IL-18, IL-1beta, TNF-alpha and MMP-3 were detected using the two-step sandwich ELISA method. The synovial IL-18, TNF-alpha and MMP-3 levels were significantly higher in RA patients than patients with BD (P=0.004, 0.019, 0.025, respectively) and with OA (P=0.004, 0.045, 0.032, respectively). There were no differences, with respect to the cytokine levels, when patients with BD were compared with those with OA. Patients with RA and BD had higher IL-1beta levels than patients with OA (P=0.017, 0.013, respectively). However, no such difference was found for IL-1beta between BD and RA patients. Among patients with RA, positive correlations were found between TNF-alpha and MMP-3 (r=0.683, P=0.001). Our results showed that MMP-3 and proinflammatory cytokines, except IL-1beta, were expressed in relatively small quantities in Behçet's synovitis. Detection of the lower levels of these cytokines and metalloproteinases might explain the non-erosive character of Behçet's arthritis. We suggest that IL-1beta may be involved in the pathogenesis of Behçet's synovitis.

Cobankara V, Oztürk MA, Kiraz S, Ertenli I, Haznedaroglu IC, Pay S, Calgüneri M. · Department of Rheumatology, Pamukkale University School of Medicine, Denizli, Turkey. · Rheumatol Int. · Pubmed #15761728 No free full text.

Abstract: Local functional renin-angiotensin systems (RAS) have been demonstrated in many organ and tissue systems. Angiotensins, the effector growth factors of the RAS, are essentially cytokines and growth factors which actively contribute to many inflammatory reactions. Among the components of RAS, angiotensin-converting enzyme (ACE) and renin have been previously investigated separately in RA. In this study, ACE levels and renin concentrations were measured in the sera of 16 patients with RA (median age: 45 (26-69), male/female: 3/13), 13 patients with osteoarthritis (OA) (median age: 55 (28-72), male/female: 5/8), and 11 healthy adults (median age: 44 (35-70), male/female: 6/5). Synovial ACE levels and renin concentrations were also measured concurrently in patients with RA and OA. Serum ACE levels were comparable between the groups. However, synovial fluid ACE levels were significantly higher in the patients with RA than in patients with OA. Likewise, synovial fluid renin concentrations were higher in RA patients than in OA patients, while serum renin concentrations were similar in patients with RA and OA and in healthy controls. Moreover, there was a significant negative correlation between the duration of the disease and synovial renin concentrations in RA patients. In conclusion, locally-generated active renin and ACE could contribute to joint destruction in rheumatoid arthritis.

Erdem H, Pay S, Serdar M, Simşek I, Dinç A, Muşabak U, Pekel A, Turan M. · Department of Rheumatology, Gülhane Military School of Medicine, Etlik, Ankara 06018, Turkey. · Rheumatol Int. · Pubmed #15672235 No free full text.

Abstract: The aim of the present study was to determine synovial levels of ELR (+) CXC chemokines, known to attract mainly neutrophils to inflamed tissues by binding the neutrophil chemokine receptors CXCR1 and CXCR2 and promoting neovascularization in patients with various inflammatory disorders. The study group consisted of 14 patients with Behçet's disease and nine with familial Mediterranean fever. Fourteen patients with rheumatoid arthritis and 16 with osteoarthritis served as controls. Synovial chemokine levels were measured by two-step sandwich enzyme-linked immunosorbent assay, and significant differences were found in the various chemokines studied. In addition to its angiogenic properties, increased synovial levels of interleukin-8 by attraction of more neutrophils to synovial fluids might also be responsible for the acute synovitis in patients with Behçet's disease. However, the absence of chronic changes with the eventual development of pannus and erosions might result from relatively lower expression of interleukin-8 and the transient, short-lived nature of the arthritis observed in these patients.

Pay S, Erdem H, Serdar M, Dinç A, Simşek I, Turan M. · Gülhane Military Medical Academy, Ankara, Turkey. · Clin Rheumatol. · Pubmed #12447637 No free full text.

Abstract: The purpose of this study was to investigate synovial levels of matrix metalloproteinase-1 (MMP-1), known to break down collagen, and tissue inhibitor of metalloproteinase (TIMP-1), its natural antagonist, in patients with various inflammatory disorders. Eighty-five patients with different inflammatory arthritides (20 Behçet's disease, 20 familial Mediterranean fever, 26 rheumatoid arthritis and 19 osteoarthritis) were enrolled in the study. Synovial MMP-1 and TIMP-1 levels were measured by two-step sandwich ELISA. There were significant differences between study and control groups regarding erythrocyte sedimentation rate, C-reactive protein, MMP-1 and TIMP-1 values. The synovial MMP-1 levels of patients with Behçet's disease and familial Mediterranean fever were no different from those in patients with rheumatoid arthritis, but significantly higher than those of patients with osteoarthritis. The synovial TIMP-1 levels in patients with osteoarthritis were higher than those of patients with the other three diseases, among which the difference was not statistically significant, and the difference between osteoarthritis and the others was statistically significant. Because of the detection of similar levels of synovial MMP-1 in patients with familial Mediterranean fever, Behçet's disease and rheumatoid arthritis, we conclude that the absence of erosions in patients with familial Mediterranean fever and Behçet's disease may be explained by MMP-1 being a marker of cytokine-driven inflammation, or by the short-lived and transient nature of the arthritis observed in these patients.

Pay S, Dinc A, Simsek I, Can C, Erdem H. · GATA Romatoloji Bilim Dah, Etlik, Ankara, Turkey. · Rheumatol Int. · Pubmed #11149657 No free full text.

Abstract: We describe a patient with juvenile chronic arthritis who developed reactive angioimmunoblastic lymphadenopathy, induced by sulfasalazine. Development of angioimmunoblastic lymphadenopathy although rare, is a very serious side effect of sulfasalazine treatment, and patients treated with this drug should be watched carefully.

Akkoc N, Sari I, Birlik M, Pay S, Binicier O, Akar S, Onen F. · No affiliation provided · Rheumatology (Oxford). · Pubmed #18658204 No free full text.

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