Rheumatoid Arthritis: Voulgari PV

Voulgari PV. · University of Ioannina, Rheumatology Clinic, Department of Internal Medicine, Medical school, 45 110 Ioannina, Greece. · Expert Opin Emerg Drugs. · Pubmed #18321156 No free full text.

Abstract: BACKGROUND: Rheumatoid arthritis (RA) is a chronic, inflammatory, systemic, autoimmune disease characterized by symmetric arthritis of diarthrodial joints leading to progressive erosion of cartilage and bone. The individual and social impacts of RA are of great importance. OBJECTIVE: To investigate the development of new therapies for RA treatment. METHODS: Various databases have been searched for new drugs in clinical trials (Phase I - III) and experimental future therapeutic agents for RA. RESULTS/CONCLUSION: The current management of the disease includes the use of disease modifying anti-rheumatic drugs and the biologic therapies. Progress in our understanding of RA pathophysiology led to the identification of new therapeutic targets. These include pro-inflammatory cytokines, T and B cells, adhesion molecules, chemokines and intra- and extracellular signaling pathways. Therapeutic modulation of the above targets can provide new treatment strategies. This article reviews a few of the new treatment strategies currently being evaluated.

Voulgari PV, Drosos AA. · University of Ioannina Medical School, Rheumatology Clinic, Department of Internal Medicine, 45110 Ioannina, Greece. · Expert Opin Biol Ther. · Pubmed #17223742 No free full text.

Abstract: In the last few years significant advances have been made in our understanding of the molecular mechanisms underlying rheumatoid arthritis pathogenesis. Pro-inflammatory cytokines, such as TNF-alpha, play a pivotal role in its pathogenesis. Anti-TNF-alpha biological agents are considered a major advance in the treatment of rheumatoid arthritis. Adalimumab is a fully human monoclonal antibody that binds specifically to TNF-alpha, thereby neutralising its activity. It had significant efficacy in well-designed, placebo-controlled trials in patients suffering from rheumatoid arthritis, both as monotherapy and in combination with various disease-modifying antirheumatic drugs, including methotrexate. Adalimumab was generally well tolerated during both concomitant therapy with methotrexate or standard antirheumatic therapy and monotherapy. In addition, the radiographic progression of structural joint damage was significantly inhibited by adalimumab and improved quality of life. This review summarises the recent available data.

Alamanos Y, Voulgari PV, Drosos AA. · Department of Hygiene and Epidemiology, Medical School, University of Ioannina, Ioannina, Greece. · Semin Arthritis Rheum. · Pubmed #17045630 No free full text.

Abstract: OBJECTIVES: To conduct a systematic review of incidence and prevalence studies of rheumatoid arthritis (RA), based on the 1987 revised American College of Rheumatology (ACR) criteria, to compare their methodologies and summarize their results, and to investigate the possible geographic variations and changes over time in the frequency of the disease. METHODS: We conducted a Medline search between January 1988 and December 2005. Studies reporting the incidence and prevalence of RA in adult populations (16 to 20 years and over), based on 1987 ACR criteria, were eligible for inclusion. From each study included, we extracted the country, year of publication, type of study (retrospective, prospective, or cross-sectional), and incidence or prevalence rates. The study areas were grouped into (a) North American countries; (b) north European countries; (c) south European countries; and (d) developing countries. We examined the geographical differences of prevalence and incidence rates using the Mann-Whitney and the Kruskall-Wallis tests. RESULTS: A total of 28 studies were identified meeting the inclusion criteria. Nine were incidence studies, 17 were prevalence studies, and 2 estimated both prevalence and incidence rates. Incidence studies were not available from developing countries. There is a significant difference of prevalence estimates between northern European and American countries and developing countries. South European countries have lower median incidence rates than North American and north European countries. As concerning the time trends of RA occurrence, only 3 incidence studies provided secular data from the same study area, based on ACR criteria, using the same methods of case ascertainment. Two of these studies indicate a decreasing incidence of RA in Finland and United States of America. CONCLUSIONS: The occurrence of RA varies among countries and areas of the world. A decreasing trend has been observed in countries characterized by high rates of RA incidence and prevalence. However, the relatively small number of studies for most areas of the world and the lack of incidence studies for the developing countries limits the understanding of worldwide RA epidemiology.

Alamanos Y, Tsifetaki N, Voulgari PV, Venetsanopoulou AI, Siozos C, Drosos AA. · Rheumatology Clinic, Department of Internal Medicine, Medical School, University of Ioannina, 45110 Ioannina, Greece. · Rheumatology (Oxford). · Pubmed #16332955 links to  free full text

Abstract: OBJECTIVES: To investigate the incidence and prevalence, as well as the mortality and survival rates, of primary Sjögren's syndrome (pSS) in a defined area of north-west Greece with a population of about 500 000 inhabitants. METHODS: Cases were recorded from the following sources: (i) in- and out-patients referred to the rheumatology clinics of the Ioannina University Hospital and the Ioannina General Hospital; and (ii) patients referred to private rheumatologists practising in the study area. All patients diagnosed between 1 January 1982 and 31 December 2003 who were resident in the study area were included as incident cases. Diagnosis was based on the American-European consensus criteria for SS. Incidence and prevalence rates were calculated as numbers of cases per 10(5) inhabitants. Population data were based on the National Censuses of 1981, 1991 and 2001. RESULTS: A total of 422 incident cases were identified for the study period 1982-2003. Age-adjusted mean annual incidence rate for this period was 5.3 (95% confidence interval [CI] 4.5-6.1) cases per 10(5) adult inhabitants. The female/male ratio of incident cases was about 20/1. The age-adjusted prevalence rate for the adult population was 92.8 (95% CI 83.7-101.9) cases per 10(5) inhabitants on 31 December 2003. The 5-yr survival rate in the incidence cohort was 96.6% and the 10-yr survival rate 92.8%. The standardized mortality ratio in comparison with the general population of the study area was 1.02 (95% CI 0.4-2.0). The main causes of death were cardiovascular diseases and cancer. The occurrence of the disease shows a slightly decreasing, but not statistically significant, trend with time. CONCLUSIONS: The estimated incidence and prevalence of pSS in this study were slightly higher in comparison with data from other studies based on physician-diagnosed cases. The prevalence was significantly lower when compared with the findings of studies based on the examination of a sample of the general population. Mortality rates did not differ significantly between pSS patients and the general population.

Kozanidou VI, Theocharis AD, Georgiadis A, Voulgari PV, Drosos AA, Karamanos NK. · Laboratory of Biochemistry, Department of Chemistry, University of Patras, 26110 Patras, Greece. · Curr Drug Targets Immune Endocr Metabol Disord. · Pubmed #15777203 No free full text.

Abstract: Rheumatoid arthritis (RA) is a chronic and destructive arthropathy with systemic features, the etiopathogenesis of which remains unclear. It is characterized by relapsing and remitting inflammation and hyperplasia of synovial cells. Proinflammatory cytokines, such as interleukin-2 (IL-2), play an important role in maintaining cartilage damage and severe destruction of the joints due to an uncontrolled activation of cellular immunity. An imbalance between proinflammatory and anti-inflammatory mediators is likely to contribute to the chronicity of the disease. Therefore, insight into the activation state of T-cells in different stages of the disease may be important to understand pathogenetic mechanisms underlying RA and could be a lead for the design of future therapeutic strategies. Because of the central role of the IL-2/IL-2 receptor (IL-2R) system in mediation of the immune system, monitoring and manipulation of this system has important diagnostic and therapeutic implications. New approaches in RA therapy with anticytokine agents, which block cytokines and their receptors, are now used as antirheumatic drugs in clinical practice.

Voulgari PV, Papazisi D, Bai M, Zagorianakou P, Assimakopoulos D, Drosos AA. · Rheumatology Clinic, Department of Internal Medicine, Medical School, University of Ioannina, 45110 Ioannina, Greece. · Rheumatol Int. · Pubmed #15761726 No free full text.

Abstract: Rheumatoid arthritis (RA) is a chronic inflammatory disease affecting the synovial membrane, which causes joint damage and bone destruction. Extra-articular manifestations are numerous, involving multiple organ systems. Rheumatoid nodules are common extra-articular findings occurring in 20% RA patients. They develop most commonly in pressure areas (elbows and finger joints) and may occasionally affect internal organs including pleura, lungs, meninges, larynx, and others. Furthermore, RA affects the ear, nose, and throat, causing various otorhinolaryngological symptoms. In this report we describe two patients with RA and laryngeal involvement, mostly rheumatoid nodule formation, with a review of the literature.

Zikou AK, Argyropoulou MI, Voulgari PV, Xydis VG, Nikas SN, Efremidis SC, Drosos AA. · Department of Radiology and the Rheumatology Clinic, Department of Internal Medicine, Medical School, University of Ioannina, Greece. · J Rheumatol. · Pubmed #16465650 No free full text.

Abstract: OBJECTIVE: To investigate the clinical response and to evaluate by magnetic resonance imaging (MRI) the inflammatory tissue changes in patients with refractory rheumatoid arthritis (RA) treated with adalimumab. METHODS: Thirteen patients with refractory RA who were treated with adalimumab (40 mg every 2 weeks subcutaneously) were examined with MRI of the dominant affected wrist and hand before treatment and one year after therapy. The volume of the enhanced inflammatory tissue (VEIT) was evaluated in fat-suppressed contrast-enhanced T1-weighted MRI images using the Analyse 4.0 software. Disease activity was evaluated using the Disease Activity Score 28-joint (DAS-28). Clinical improvement was evaluated according to the American College of Rheumatology 20% response criteria (ACR20%). RESULTS: We studied 12 women and one man, with mean age 52.0 +/- 10.9 years and mean disease duration 13.0 +/- 8.5 years. Eight patients had positive IgM rheumatoid factor. One year after treatment, 11 (84.6%) patients showed a decrease of the VEIT. Moreover the values of C-reactive protein (CRP; 4.3 +/- 6.6 mg/l), the erythrocyte sedimentation rate (ESR; 26.3 +/- 19.5 mm/h), the DAS-28 (3.5 +/- 1.1), and the VEIT (21.6 +/- 10.7 cm3) after treatment were significantly lower compared to the corresponding values before treatment (CRP 41.6 +/- 39.2), (ESR 54.3 +/- 28.6) (DAS-28 5.8 +/- 0.8), and (VEIT 36.9 +/- 16.8) (p < 0.01). All but 3 (76.9%) patients with RA achieved the ACR20% response, while 7 (53.8%) and 5 (38.5%) patients achieved ACR50% and ACR70% response, respectively. A positive correlation between VEIT, swollen joint count, and ESR was found before treatment (r = 0.59, r = 0.64, respectively; p < 0.05). CONCLUSION: In patients with refractory RA, treatment with adalimumab resulted in improvement of clinical, laboratory, and MRI findings. MRI assessment of the VEIT may represent an additional tool for investigation of joint disease activity and responsiveness to treatment.

Tsifetaki N, Kitsos G, Paschides CA, Alamanos Y, Eftaxias V, Voulgari PV, Psilas K, Drosos AA. · Rheumatology Clinic, Department of Internal Medicine, Medical School, University of Ioannina, Ioannina, Greece. · Ann Rheum Dis. · Pubmed #14644860 links to  free full text

Abstract: OBJECTIVE: To evaluate the efficacy and side effects of oral pilocarpine for the treatment of ocular symptoms in patients with primary Sjögren's syndrome (SS). METHODS: A 12 week, single centre, randomised controlled study was performed. Twenty nine patients were randomly assigned to receive oral pilocarpine (5 mg twice a day), 28 only artificial tears, and 28 inferior puncta occlusion. Patients receiving oral pilocarpine and those with inferior puncta occlusion also received artificial tears. Patients were evaluated at baseline and throughout the study for their subjective global assessment of dry eyes and for their objective assessment of dry eyes (Schirmer's-I test, rose bengal test, and imprint test). RESULTS: Patients taking oral pilocarpine had significant improvement in subjective global assessment of dry eyes, as was evaluated by improvement of >55 mm on a visual analogue scale (VAS) for responses to the eye questionnaire, compared with patients treated with artificial tears (p<0.001) and those with inferior puncta occlusion (p<0.05). Furthermore, patients receiving oral pilocarpine also showed greater objective improvement, as measured by the rose bengal test (p<0.05), while Schirmer's-I test showed no differences between the treated groups. Commonly reported adverse events were headache, increased sweating, nausea, and vomiting in the pilocarpine group, while one patient in the inferior puncta occlusion group had blepharitis and was withdrawn from the study. CONCLUSION: 10 mg of pilocarpine daily given to patients with SS for 12 weeks had a beneficial effect on subjective eye symptoms, as evaluated by improvement >55 mm on a VAS. Additionally, an improvement of rose bengal staining was noted, but an increase in tear production, as measured by the Schirmer-I test, was not substantiated.

Temekonidis TI, Georgiadis AN, Alamanos Y, Bougias DV, Voulgari PV, Drosos AA. · Department of Internal Medicine, Medical School, University of Ioannina, Ioannina, Greece. · Ann Rheum Dis. · Pubmed #12176808 links to  free full text

Abstract: OBJECTIVE: To investigate whether infliximab can be used in combination with cyclosporin A (CsA) in patients with refractory rheumatoid arthritis (RA) who cannot tolerate methotrexate (MTX). MATERIALS AND METHODS: Eighteen patients with refractory RA receiving low dose CsA (2 mg/kg/day) and prednisone (5 mg/day) were treated with intravenous infliximab. The patients were given infliximab (3 mg/kg weight) at 0, two, six, and every eight weeks thereafter for a total period of 12 months. Clinical improvement was evaluated according to the American College of Rheumatology (ACR) 20% response criteria. RESULTS: Eighty per cent of patients receiving the combination treatment with CsA and infliximab achieved the 20% ACR criteria for response to treatment, whereas 39% satisfied the 50% response criteria. In addition, a 76% reduction in swollen and tender joint count was found. Finally, a reduction in C reactive protein and erythrocyte sedimentation rate was maintained throughout the study. In general, treatment was well tolerated, with minimal adverse drug reactions. Two patients dropped out; one because of an immediate hypersensitivity reaction and the other because of the development of pulmonary tuberculosis. CONCLUSION: Multiple infusions of infliximab and low doses of CsA improve patients with refractory RA. It seems that CsA may be an alternative disease modifying drug to be used in combination with infliximab in patients with refractory RA who cannot tolerate MTX.

Drosos AA, Voulgari PV, Katsaraki A, Zikou AK. · Department of Internal Medicine, Medical School, University of Ioannina, Greece. · Rheumatol Int. · Pubmed #10776690 No free full text.

Abstract: The aim of this study was to evaluate whether cyclosporin A (CsA) influences the radiological disease progression in early rheumatoid arthritis (RA) patients in comparison with other disease-modifying drugs (DMARDs). A total of 103 early RA patients, without prior use of DMARDs, were randomized to receive CsA (3 mg/kg per day) or methotrexate (MTX) (0.15 mg/kg per week). In addition, all patients received prednisone (7.5 mg/day). After 42 months of treatment, pairs of hand and wrist radiographs of 41 patients treated with CsA and 42 treated with MTX were evaluated blindly and separately by two investigators, using reference radiographs for scoring. A scale scoring similar to Larsen's standard radiographs with minor modifications was used. The studied radiographs were obtained at the beginning and 42 months after therapy in both groups. Patients in both groups responded beneficially to the above treatment regimens. In the CsA group, 37 patients (71 %) remained radiographically stable and 4 worsened, while in the MTX group 39 patients (76%) remained stable and 3 deteriorated. No significant radiological worsening was found in the CsA-treated patients as compared to those treated with MTX. Early immuno-intervention in RA patients appears to be crucial for the future development of joint damage: CsA can delay radiological disease progression and may inhibit joint damage deterioration in early RA patients.

Voulgari PV, Efremidis SC, Drosos AA. · Department of Internal Medicine, Medical School, University of Ioannina, Greece. · Clin Exp Rheumatol. · Pubmed #10464562 No free full text.

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Drosos AA, Voulgari PV, Psychos DN, Tsifetaki N, Bai M. · Department of Internal Medicine, Medical School, University of Ioannina, Greece. · Rheumatol Int. · Pubmed #10399792 No free full text.

Abstract: Out of 134, 12 sarcoidosis patients with symptoms of mucosal dryness as the first clinical manifestation were identified and compared with 30 consecutive unselected Sjögren's syndrome (SS) patients. Sicca manifestations were similar among the two groups, while parotid gland enlargement (PGE) was more frequently found in sarcoidosis patients (P < 0.05). Patients with sarcoidosis had mainly pulmonary (P < 0.001) and skin involvement (P < 0.05), while SS patients presented more frequently with Raynaud's phenomenon (P < 0.05). Autoantibody profile was more often found in SS patients compared to sarcoidosis (P < 0.0025). The histopathological findings of minor salivary gland biopsy (MSGB) revealed noncaseating granulomas (NCG) in 58% of patients with sarcoidosis, while in SS, MSGB showed focal sialadenitis in the majority of the patients. Transbronchial lung biopsy (TBLB), which was performed in 10 sarcoidosis patients, revealed the presence of NCG in all patients. In patients with sarcoidosis and sicca symptoms as the presenting syndrome, PGE is a useful clinical finding. Searching for pulmonary involvement is a determining factor to differentiate sarcoidosis from SS. The absence of autoantibodies is another useful tool for the diagnosis of sarcoidosis. Finally, MSGB is very helpful to discriminate between sarcoidosis and SS and when MSGB is not specific, then TBLB is valuable to confirm the diagnosis.

Voulgari PV, Drosos AA. · Rheumatology Clinic, Department of Internal Medicine, Medical School, University of Ioannina, Ioannina, Greece. · J Rheumatol. · Pubmed #18843757 No free full text.

This publication has no abstract.

Chatzikyriakidou A, Georgiou I, Voulgari PV, Georgiadis AN, Argyriou ES, Drosos AA. · Genetics Unit, Department of Obstetrics and Gynaecology, Medical School, University of Ioannina, Ioannina, Greece. · Scand J Rheumatol. · Pubmed #18830906 No free full text.

Abstract: OBJECTIVES: Deregulation of glucocorticoid (GC) secretion could be associated with rheumatoid arthritis (RA). The GC receptor (GR) has two isoforms. In the present study, we explored the role of GR-alpha polymorphisms rs33388, rs33389, and Bcl I, and the GR-beta variant rs6198 in RA susceptibility. METHODS: One hundred and thirty-six RA patients and 148 ethnic matching controls were studied. Polymorphisms rs33388 and Bcl I were genotyped by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP), and variants rs33389 and rs6198 by polymerase chain reaction single-strand conformation polymorphism (PCR-SSCP) coupled with sequencing. Arlequin and SPSS softwares were used in the statistical analysis. RESULTS: The polymorphisms studied were in Hardy-Weinberg equilibrium in both groups. A marginally statistical significant difference was observed in the distribution of rs33388 genotypes between RA patients and controls (p = 0.053). When the A and T alleles were compared, the statistical significance was p = 0.025. Specific complex genotypes were also differentially distributed: the GR-alpha complex genotypes (a) [homozygote (homo) wild-type (wt) rs33388-homo wt rs33389] (11% RA vs. 21% controls; p = 0.023), (b) [homo wt rs33388-homo wt rs33389-homo non-wt Bcl I] (0.7% RA vs. 4.7% controls; p = 0.042), and (c) the GR-beta complex genotype [homo wt rs33388-homo wt rs33389-homo non-wt Bcl I-homo wt rs6198] (0.7% RA vs. 4.7% controls; p = 0.042). CONCLUSIONS: GR-alpha and GR-beta polymorphisms are potentially associated with RA susceptibility. However, additional studies in larger and other ethnic groups of patients are needed to confirm the results of the present study.

Voulgari PV, Alamanos Y, Drosos AA. · Rheumatology Clinic, Department of Internal Medicine, Medical School, University of Ioannina, Ioannina, Greece. · Curr Clin Pharmacol. · Pubmed #18666381 No free full text.

Abstract: Infliximab, a chimeric monoclonal anti-tumor necrosis factor alpha antibody is approved for the treatment of patients with rheumatoid arthritis (RA) who had an inadequate response to methotrexate (MTX) therapy. This report provides analyses by using infliximab in combination with various disease modifying anti-rheumatic drugs, infliximab "survival" over a period of three years, and its effectiveness on synovial tissue damage using magnetic resonance (MR) imaging. The study was started in 1999 as an open label study using infliximab in combination with cyclosporin A (CsA) in refractory RA patients who were unable to tolerate MTX. A total of 18 RA patients were investigated. After a year of treatment, 80% of patients achieved the 20% American College of Rheumatology Response criteria. Two patients dropped out; one because of an immediate hypersensitivity reaction and the other because of the development of pulmonary tuberculosis. In a subsequent study we investigated infliximab "survival" over a period of 3 years. A total of 84 RA patients were included in the study. After 3 years of therapy, 59% of patients still continued receiving infliximab. The factor that was associated with infliximab "survival" was the concomitant use of MTX. A total of 28 (33%) patients discontinued this study. More specifically, 16 (19%) presented adverse drug reactions, 9 (11%) had drug failure, and 3 (3%) were lost from follow-up. Finally, to evaluate by MR imaging the inflammatory tissue changes in refractory RA patients treated with infliximab, 16 patients were examined with MR imaging of the dominant affected wrist and hand before and one year after therapy. The volume of the enhancing inflammatory tissue (VEIT) was evaluated. A significant decrease of VEIT was observed in 88% of patients after therapy. We conclude that in refractory RA patients infliximab was proved to be efficacious and well tolerated in combination with CsA. The clinical response of infliximab was persistent over a 3-year period and was associated with the concomitant use of MTX. This clinical improvement was also associated with the reduction of inflammatory disease tissue damage.

Georgiadis AN, Voulgari PV, Argyropoulou MI, Alamanos Y, Elisaf M, Tselepis AD, Drosos AA. · Department of Internal Medicine, Medical School, University of Ioannina, Ioannina, Greece. · Semin Arthritis Rheum. · Pubmed #18191989 No free full text.

Abstract: OBJECTIVE: To investigate subclinical atherosclerosis and the effect of treatment in patients with early rheumatoid arthritis (RA). PATIENTS AND METHODS: Forty patients with early RA who met the revised American College of Rheumatology (ACR) criteria and disease duration of <1 year were included in the study. Smokers and patients with classical risk factors for atherosclerosis were excluded. The serum levels of total cholesterol (TC), triglycerides, high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol were determined in all patients before and after 1 year of therapy. Carotid artery intima-media thickness (IMT) and carotid plaque were measured before and after treatment. RA disease activity was measured using the 28 joint indices score (DAS-28) and clinical improvement was determined by the ACR response criteria. Forty-five age- and sex-matched nonsmoking volunteers were used as controls. All patients were treated with methotrexate and prednisone. RESULTS: RA patients had a baseline mild dyslipidemia characterized by a decrease in serum HDL-C levels and a high TC/HDL-C atherogenic ratio compared with controls. Both lipid parameters were significantly improved after treatment (P<0.01). Common carotid artery IMTs at baseline were higher in RA patients compared with controls (P<0.05). After 1 year of therapy there was a significant decrease in the IMTs (P<0.001). Thirty-five patients (88%) achieved the ACR 20%, while 30 (75%) reached the ACR 50% response criteria. A significant decrease of DAS-28 was observed after treatment (P<0.03). CONCLUSIONS: The atherogenic lipid profile and subclinical atherosclerosis are features of early RA, which improved after therapy. Early intervention and control of the disease activity may reduce the risk of atherosclerosis and cardiovascular events in patients with RA.

Voulgari PV, Markatseli TE, Exarchou SA, Zioga A, Drosos AA. · Rheumatology Clinic, Department of Internal Medicine, Medical School, University of Ioannina, Ioannina, Greece. · Ann Rheum Dis. · Pubmed #17728330 No free full text.

Abstract: OBJECTIVE: To describe granuloma annulare (GA) skin lesion development in patients during anti-tumour necrosis factor (TNF) therapy. METHODS: 199 patients with rheumatoid arthritis and 127 suffering from spondyloarthropathies treated with anti-TNF antagonists were analysed to identify skin lesions suggesting GA. RESULTS: Nine cases of GA during anti-TNF therapy (123 treated with infliximab, 57 with adalimumab and 17 with etanercept) for rheumatoid arthritis were identified. Two have been treated with infliximab, six with adalimumab and one with etanercept, and here the development of GA was 4.5%. No patient with spondyloarthropathies developed such skin lesions. All patients developed the generalised form of GA. None had or developed diseases, or conditions known to be associated with GA. In seven patients the skin eruptions developed during the first year of anti-TNF treatment, while they developed in two patients during the second year. Two patients had to stop anti-TNF therapy due to the extent of skin lesions. All patients responded well to the local corticosteroid therapy. CONCLUSIONS: Our series strongly supports a link between TNF inhibition and the development of GA in some patients. When dealing with patients on these agents physicians should be aware of possible adverse events and the potential development of such complications.

Hyphantis TN, Tsifetaki N, Siafaka V, Voulgari PV, Pappa C, Bai M, Palieraki K, Venetsanopoulou A, Mavreas V, Drosos AA. · Department of Psychiatry, Medical School, University of Ioannina, Ioannina, Greece. · Semin Arthritis Rheum. · Pubmed #17512572 No free full text.

Abstract: OBJECTIVE: To access health-related quality of life (HRQOL) in systemic sclerosis (SSc) patients using the World Health Organization Quality of Life Instrument, Short-Form (WHOQOL-BREF), and to identify the association between clinical, psychopathological, and personality parameters and SSc patients' HRQOL. METHODS: Fifty-six patients with SSc were compared with 72 patients with rheumatoid arthritis (RA), 43 with systemic lupus erythematosus (SLE), 34 with Sjögren syndrome (SS), and 74 healthy controls. A wide range of clinical information was collected and the following self-report instruments were used: the WHOQOL-BREF, the General Health Questionnaire, the Symptom Distress Check List, the Hostility and Direction of Hostility Questionnaire, the Defense Style Questionnaire, and the Sense of Coherence scale. RESULTS: HRQOL perceived by SSc patients was significantly impaired compared with healthy controls. Initial examination of HRQOL across groups of rheumatology patients revealed similar HRQOL, but when age, pain, psychopathology, and coping strategies were taken into account, SSc patients had impaired physical health QOL in comparison with RA, SLE, and SS patients. Arthritis-related pain was closely associated with SSc patients' HRQOL. Elevated psychological distress symptoms as well as certain personality traits, such as maladaptive defenses and lower sense of coherence, were also associated with diminished HRQOL. CONCLUSIONS: Impaired psychological functioning is associated with diminished HRQOL in SSc, and consequently, treatment of depressive symptoms should be considered a priority. Moreover, assessment of HRQOL should only be used in conjunction with specific psychological distress measurements, to detect the influence of psychopathology on HRQOL.

Chatzikyriakidou A, Georgiou I, Voulgari PV, Papadopoulos CG, Tzavaras T, Drosos AA. · Genetics Unit, Department of Obstetrics and Gynaecology, Medical School, University of Ioannina, 45110 Ioannina, Greece. · Rheumatol Int. · Pubmed #17404734 No free full text.

Abstract: The reduced folate carrier (RFC) protein (SLC19A1-gene) has central role in the uptake and intracellular accumulation of folates. In this respect, we investigate whether SLC19A1 genetic variations could affect rheumatoid arthritis (RA) patient response to antifolate treatment. One hundred six unrelated RA patients were enrolled in this study. Polymerase chain reaction (PCR)-single strand conformation polymorphism (SSCP) was used as the screening method for genetic variants. Unusual SSCP patterns were characterized by direct sequencing of the PCR products and subsequently restriction assays were established. Western blot analysis of RFC protein was performed in respect of the identified SLC19A1 genotypes. Patient response to methotrexate (MTX) was evaluated using disease activity for 28 joint indices score, American College of Rheumatology 20% and 50% scores. No mutation was found in the SLC19A1 gene, but three polymorphic variants: the -43T>C in the 5'-flanking sequence to the ATG-transcription start site; and the 80G>A (R27H) and 696C>T (P232P) in the coding gene sequence. The wild type alleles of the three polymorphisms were in strict linkage disequilibrium. Western blot analysis revealed that the non-wild type allele of polymorphism -43T>C is associated with low RFC protein expression levels. Furthermore, the genotypic analysis of the functional polymorphic variant -43T>C revealed to be insufficient to predict patient response to MTX therapy. According to recent literature, several transport systems account for folate membrane transport. Additionally, in previous studies discrepancies have been reported to exist between the same genetic variants and their use in prediction of patient response to MTX therapy. Therefore, the present genotypic-phenotypic association study of a functional polymorphism revealed the need of a complex genotypic analysis in order to predict patient response to folate antagonists' therapy.

Nikas SN, Voulgari PV, Drosos AA. · Rheumatology Clinic, Department of Internal Medicine, Medical School, University of Ioannina, 45110, Ioannina, Greece. · Clin Rheumatol. · Pubmed #16421645 No free full text.

Abstract: Specific inhibition of the cytokine tumor necrosis factor alpha has resulted in significant clinical and laboratory improvement of patients with chronic inflammatory diseases of Th1 phenotype. Etanercept is a recombinant fusion protein of two p75 soluble receptors, while infliximab is a chimeric monoclonal antibody. Both have been considered to be immunogenic and cause various immune-mediated skin reactions. On the other hand, adalimumab, a human monoclonal antibody, was expected to cause little or no immune-mediated skin reactions. Herein, we report a patient with rheumatoid arthritis treated with adalimumab, who after the seventh injection, developed angiedema affecting the lips and face, as well as an urticaria-like skin reaction affecting the trunk. These reactions were followed by hypotension. The patient was treated appropriately and after 2 h, the rashes and the edema disappeared and the patient gradually recovered completely. Adalimumab was discontinued.

Papadopoulos NG, Alamanos Y, Voulgari PV, Epagelis EK, Tsifetaki N, Drosos AA. · Rheumatology Clinic, Department of Internal Medicine, Medical School, University of Ioannina, Ioannina, Greece. · Clin Exp Rheumatol. · Pubmed #16396705 No free full text.

Abstract: OBJECTIVE: To investigate the association of cigarette smoking with clinical expression, disease activity and severity in a cohort of Greek patients with early rheumatoid arthritis (RA). METHODS: From January 1993 until December 2002, 293 patients with early RA were diagnosed and followed up in our rheumatology clinic. All patients fulfilled the American College of Rheumatology criteria for RA, had disease duration of less than one year, without prior treatment of disease modifying anti-rheumatic drugs (DMARDs) or steroids. The patients were treated with at least one DMARD, and 287 of them had a last follow up during the year 2004. The demographic, personal, clinical, laboratory, radiological and therapeutic features were compared at entry and at the last follow-up, according to their smoking habits at entry. RESULTS: Among the 293 patients, 6 were lost to follow-up, thus 287 patients were evaluated. There were 200 females (67.7%) and 87 males (30.3%). Eighty-two (28.6%) were current smokers, 21 (7.3%) ex-smokers and 184 (64.1%) non-smokers at presentation. RA smoker patients displayed the disease at a younger age than the non-smokers. Additionally, the smokers presented at disease onset more prominent features of articular involvement as was evaluated by the higher number of total joint count with tenderness and swelling and by the higher disease activity for 28 joint indices score (DAS-28). Smokers also presented a higher Larsen's score and higher frequency of IgM and IgA rheumatoid factors as compared to non-smokers. At the end of the study, the smoker patients presented more active and severe disease as evaluated by the higher total number of tender and swelling joint count, the higher DAS-28, and higher Larsen's score as compared to non-smokers. Furthermore, the smokers more frequently had rheumatoid nodules than the ex-smokers and non-smokers. The association of smoking with disease activity and severity was independent of sex, age, educational level, alcohol consumption, and follow-up duration. Finally, no significant differences were observed concerning the therapeutic procedure among the three groups. CONCLUSIONS: In our early RA patients, cigarette smoking was associated with increased disease activity, and severity, independently of several other possible confounders and despite the early disease treatment.

Argyropoulou MI, Glatzouni A, Voulgari PV, Xydis VG, Nikas SN, Efremidis SC, Drosos AA. · Department of Radiology Medical School, University of Ioannina, Ioannina, Greece. · Joint Bone Spine. · Pubmed #16376805 No free full text.

Abstract: AIM: To investigate the clinical response and to evaluate by magnetic resonance imaging the inflammatory tissue changes in refractory rheumatoid arthritis patients treated with infliximab. METHODS: Sixteen refractory rheumatoid arthritis patients who were treated with intravenous infliximab (3 mg/kg) at weeks 0, 2, 6 and every 8 weeks thereafter were examined with magnetic resonance imaging of the dominant affected wrist and hand before treatment and 1 year after therapy. The volume of the enhancing inflammatory tissue was evaluated in fat suppressed contrast enhanced T1-weighted images by using the Analyse 4.0 software. Disease activity was evaluated by assessing the disease activity score for 28 joint indices. The clinical improvement was evaluated according to the American College of Rheumatology 20% response criteria. RESULTS: There were 13 females and 3 males with mean age 49.5 (17.0) years and mean disease duration 10.5 (8.0) years. Ten patients had positive IgM rheumatoid factor. One year after treatment, a significant reduction of the erythrocyte sedimentation rate, the C-reactive protein, the disease activity score for 28 joint indices and the volume of the enhancing inflammatory tissue was observed. All but two of the rheumatoid arthritis patients achieved the American College of Rheumatology 20% response criteria, while 9 (56.25%) and 5 (31.25%) patients achieved the 50% and 70% American College of Rheumatology response criteria, respectively. A positive correlation among the volume of the enhancing inflammatory tissue, swollen joint count, tender joint count, as well as disease activity score for 28 joint indices (r=0.66, r=0.79, r=0.57 respectively) was found before treatment. CONCLUSIONS: In refractory rheumatoid arthritis patients, the addition of infliximab therapy may result in clinical, laboratory and magnetic resonance imaging improvement. Magnetic resonance imaging assessment of the volume of the enhancing inflammatory tissue may represent an additional tool for the investigation of joint disease activity and responsiveness to treatment.

Dalavanga YA, Voulgari PV, Georgiadis AN, Leontaridi C, Katsenos S, Vassiliou M, Drosos AA, Constantopoulos SH. · Department of Anatomy, Medical School, University of Ioannina, 45110 Ioannina, Greece. · Rheumatol Int. · Pubmed #16344933 No free full text.

Abstract: Twelve years ago we reported that lymphocytic alveolitis [or bronchoalveolar lavage (BAL) lymphocytosis] correlates with clinical pulmonary involvement in primary Sjogren's syndrome (pSS). Our thesis was based on subtle clinical and functional evidence of interstitial lung disease (ILD) in pSS patients with "high lymphocytic alveolitis" (>15% lymphocytes in BAL). This report is a follow-up study of these patients. Basic clinical and functional re-evaluation of the 22 patients with pSS, studied in 1991, emphasized the differences between those with alveolitis and those without alveolitis. There was no significant functional decline. There were, however, two statistically significant differences between the two groups: (1) only patients with BAL lymphocytosis had to be treated with steroids (5/12 vs. 0/10, P < 0.05) and (2) only patients with BAL lymphocytosis had died in the mean time (6/12 vs. 0/10, P < 0.01). The causes of death were various. On only two occasions were they related to respiratory infections while there were no deaths from respiratory failure secondary to ILD. BAL lymphocytosis appears to be a surprisingly serious index of dismal prognosis in patients with pSS. We offer no unifying pathophysiologic mechanism for it and, therefore, all we propose is that BAL is performed early, in as many patients with pSS as possible. These patients should then be followed up systematically, in order to evaluate if BAL lymphocytosis has any pathophysiologic importance in the development of clinically serious pSS, which is serious enough to lead to death.

Hyphantis TN, Bai M, Siafaka V, Georgiadis AN, Voulgari PV, Mavreas V, Drosos AA. · Department of Psychiatry, Medical School, University of Ioannina, 45110 Ioannina, Greece. · Rheumatol Int. · Pubmed #16341699 No free full text.

Abstract: OBJECTIVES: To investigate psychiatric manifestations, personality traits, and ego mechanisms of defense involved in early rheumatoid arthritis (RA). METHODS: Twenty-two unselected early RA outpatients with disease duration less than 1 year participated in the study. The majority of participants were females (72.7%), married (81.8%), aged 51.0+/-14.6 years. Thirty-four subjects matched for age, sex and educational level served as "healthy" controls. General Heath Questionnaire, Symptom Distress Checklist, Defense Style Questionnaire and Hostility and Direction of Hostility Questionnaire were used; disease activity was estimated by disease activity for 28-joint indices score. RESULTS: Seven patients (31.8%) presented psychological distress scores indicative of possible psychiatric caseness, expressing obsessive-compulsive symptoms and depression, as compared to six (17.6%) of controls. Social dysfunction distress and somatization were prominent psychiatric manifestations in early RA group. Early RA patients tend to adopt a less adaptive defense style than controls. Although disease activity was not correlated to psychological distress, a significant association between disease activity and patients' defensive style was observed: as the disease is exacerbated, there was a shift from "non-adaptive" to "immature image distorting or borderline" defense style, suggesting a rather fragile underlying personality structure. CONCLUSION: Psychological distress is a relatively common experience in early RA. Social dysfunction, along with the less adaptive defense style, which under the stress of the disease exacerbation turns to "borderline", underlines the importance of a careful assessment and consultation in early RA patients in order to face the distress shortly after diagnosis and highlights potential risk factors for future adaptation to exacerbations of the disease.

Zikou AK, Argyropoulou MI, Alamanos Y, Tsifetaki N, Tsampoulas C, Voulgari PV, Efremidis SC, Drosos AA. · Department of Radiology, Medical School, University of Ioannina, Ioannina, Greece. · Clin Exp Rheumatol. · Pubmed #16173243 No free full text.

Abstract: OBJECTIVES: To investigate by magnetic resonance (MR) imaging the occurrence of cervical spine (CS) involvement in rheumatoid arthritis (RA) patients. METHODS: Fifty-one consecutive unselected patients, who fulfilled the revised American College of Rheumatology criteria for RA, were investigated. All patients had a complete physical and laboratory evaluation. Radiological evaluation included hand and wrist x-rays, as well as CS radiographs in anteroposterior, lateral and lateral in full flexion views. In addition, MR (Spin Echo T2-weighted sagittal scans [neutral and flexion position], plain and contrast enhanced T1-weighted sagittal and axial scans) was performed in all patients. Hand x-rays were evaluated according to the Larsen's criteria, while CS radiographs were evaluated according to Winfield classification. Disease activity was assessed by disease activity score for 28 joint indices (DAS-28). RESULTS: There were 42 females and 9 males with a mean age of 56.5 +/- 10.4 years and mean disease duration 12.4 +/- 8.5 years. Thirty-three patients (64.7%) had positive IgM rheumatoid factor (RF). Thirty patients presented clinical findings, mainly cervical pain and stiffness of CS (25 with positive and 5 with negative MR), while, radiological findings of CS involvement were found in 40 patients. Forty-four patients (86.2%) presented MR findings of CS involvement (peridental pannus 88%; dens erosion 23.5%; atlantoaxial subluxation 13.7%; subaxial subluxations 10%; brainstem compression 5.9%). Peridental pannus correlated with high DAS-28, positive IgM RF and advanced erosive changes of the wrist and hand (p < 0.05) in the univariate analysis. However, multivariate logistic regression analysis did not confirm such correlation. CONCLUSIONS: We conclude that the frequency of CS involvement in Greek RA patients is high but the destructive changes are mild. However, in patients with active erosive peripheral disease it is very probable to also have some changes in CS. These may be clinically important and in such cases, MR may offer valuable information.