The frequency of arthritis in Adamantiades-Behçet's disease in Greek patients.

BACKGROUND/OBJECTIVES: Musculoskeletal manifestations are frequent in Adamantiades-Behçet's disease (ABD) but only represent non-specific clinical findings. They have not been included in the two commonly used sets of classification criteria. The occurrence of musculoskeletal manifestations at ABD onset may even delay or obscure the diagnosis; therefore, detailed knowledge of the different musculoskeletal manifestations is essential. Our objective was to describe musculoskeletal signs and their clinical course in Greek ABD patients. METHODS: We conducted a retrospective cohort study, which included all patients with ABD, who had been examined in our Rheumatology Outpatient Division from 1995 to 2010. The study included 224 ABD patients (140 male, 84 female) that fulfilled the International Criteria for the diagnosis of BD. For statistical analysis, we have used chi-square and Fisher's exact tests. RESULTS: Arthritis as a presenting sign was seen in 10.2% of our patients. During the follow-up period, the frequency of arthritis was 58.4%. Monoarthritis was found in 32.8% and 22.6% of male and female patients, respectively (ns). During the follow-up period, polyarthritis was only occasionally observed in male patients (2.14%). Oligoarthritis was assessed in 20.0% and 41.6% of male and female patients, respectively (P < 0.001), and was the only significantly different manifestation between sexes. CONCLUSIONS: Musculoskeletal manifestations are common in ABD both at presentation and during the disease course. The most frequent sign is mooarthritis. Oligoarthritis was the only significantly different articular manifestation between sexes (more common in women) in our study group.

Greek rheumatoid arthritis patients have elevated levels of antibodies against antigens from Proteus mirabilis.

Patients with rheumatoid arthritis (RA) from different ethnic groups present elevated levels of antibodies against Proteus mirabilis. This finding implicates P. mirabilis in the development of RA. The aim of this study was to investigate the importance of P. mirabilis in the etiopathogenesis of RA in Greek RA patients. In this study, 63 patients with RA and 38 healthy controls were included. Class-specific antibodies IgM, IgG, and IgA against three human cross-reactive and non-cross-reactive synthetic peptides from P. mirabilis-hemolysin (HpmB), urease C (UreC), and urease F (UreF)-were performed in all subjects, using the ELISA method. RA patients had elevated levels of IgM, IgG, and IgA antibodies against HpmB and UreC Proteus peptide which are significantly different compared to healthy controls: p = 0.005, p < 0.001, and p = 0.003 and p = 0.007, p = 0.002, and p < 0.001, correspondingly. Also, elevated levels of IgM, IgG, and IgA antibodies against the UreF Proteus peptide-which are non-cross-reactive with human tissue antigens-were observed and their significant difference compared to healthy controls (p = 0.007, p < 0.001, p < 0.001). Anti-peptide antibodies in RA patients showed a significant correlation with rheumatoid factors (Rf), erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP), especially when patients were divided into subgroups according to the receiving treatment. Greek RA patients present elevated levels of antibodies against P. mirabilis antigenic epitopes, such as in North European populations, albeit Greek RA patients presenting the cross-reaction antigen in a low percentage. These results indicate that P. mirabilis through the molecular mimicry mechanism leads to inflammation and damage of the joints in RA.

Toll-like receptors pathways implication in common autoimmune diseases and therapeutic perspectives.

Toll-like receptors (TLRs) are a category of receptors that recognize and activate their signaling pathways to defend against the pathogen factors. However, an alteration in the proper activation might occurr, resulting in the production of proinflammatory cytokines. This improper activation is the beginning of an autoimmune disease. The inhibition of the implicated receptors or their pathways may prevent the induction of autoimmunity. This paper describes in detail new therapeutic opportunities based on the alteration of the TLR activation for rheumatoid arthritis and systemic lupus erythematosus.

Mediterranean fever gene mutations in Greek patients with Behcet's disease.

OBJECTIVE: It is known that clinical similarities between Behcet's disease and Familial Mediterranean Fever have led to the hypothesis of a common pathogenesis. Familial Mediterranean Fever is caused by MEFV gene mutations coding for pyrin. Therefore, we examined whether these pyrin mutations are also associated with Behcet's disease. METHODS: Molecular testing for pyrin mutations was performed in 96 unrelated Greek patients with an established diagnosis of Behcets disease. The results were compared with an analysis for pyrin mutations in 140 unrelated healthy Greek controls. RESULTS: We found no pyrin mutations among the Behcet cases tested; this result is comparable with the control group. CONCLUSIONS: Pyrin gene mutations in Greek patients with Behcet's disease are not more common than those in the general population. This finding is not in agreement with the findings in other populations. It is suggested that screening for pyrin mutations not be included in the evaluation of Greeks suspected to have Behcet's disease.

Abnormal spatial QRS-T angle, a marker of ventricular repolarisation, predicts serious ventricular arrhythmia in systemic sclerosis.

OBJECTIVES: Cardiac involvement may be under-diagnosed in asymptomatic patients with systemic sclerosis (SSc). Standard electrocardiography-derived spatial QRS-T angle (spQRS-Ta) is an established marker of ventricular repolarisation heterogeneity, and a strong independent predictor of cardiac morbidity and mortality, including sudden death, in the general population. We examined whether spQRS-Ta is abnormal in asymptomatic SSc patients and assessed its predictive value for possibly concurrent, serious ventricular arrhythmia. METHODS: SpQRS-Ta and 24-hour Holter recordings were obtained from 69 SSc patients (aged 51±13 years, 63 women) without clinically evident cardiac involvement and having left ventricular ejection fraction at least 50% by echocardiography. 'Healthy' subjects matched 1:1 with patients for age, gender and body mass index served as controls. RESULTS: SpQRS-Ta was wider in SSc (median value 15.6°, interquartile range 10.6-24.3°) than controls (10.5°, 7.3-13.5°, p=0.0001) and not associated with skin fibrosis extent or specific clinical manifestations and autoantibodies. Twenty-four-hour Holter recordings revealed couplets of ventricular beats in six (Lown class IVa) and non-sustained ventricular tachycardia in five patients (Lown class IVb); spQRS-Ta was wider in those eleven patients with serious ventricular arrhythmia than the remaining patients (24.9°, 14.9-31.3° vs. 14.4°, 9.6-22.3°; p=0.02). A spQRS-Ta>19.3° demonstrated 80% sensitivity and 68% specificity (area under the curve 0.81, p=0.02) to predict the presence of non-sustained ventricular tachycardia in Holter monitoring. CONCLUSIONS: Ventricular repolarisation heterogeneity, as reflected by wider spQRS-Ta, is common in SSc. Increased spQRS-Ta could serve as a simple screening test for further investigation to identify patients at risk or prone to develop life-threatening ventricular arrhythmia.

Mediterranean fever gene mutations in greek patients with Behcet's disease / Mutacionesen el gen de la fiebre mediterránea en pacientes griegos con la enfermedadde Behçet

OBJECTIVE: It is known that clinical similarities between Behcet's disease and Familial Mediterranean Fever have led to the hypothesis of a common pathogenesis. Familial Mediterranean Fever is caused by MEFV gene mutations coding for pyrin. Therefore, we examined whether these pyrin mutations are also associated with Behcet's disease. METHODS: Molecular testing for pyrin mutations was performed in 96 unrelated Greek patients with an established diagnosis of Behcet's disease. The results were compared with an analysis for pyrin mutations in 140 unrelated healthy Greek controls. RESULTS:We found no pyrin mutations among the Behcet cases tested; this result is comparable with the control group. CONCLUSIONS: Pyrin gene mutations in Greek patients with Behcet's disease are not more common than those in the general population. This finding is not in agreement with the findings in other populations. It is suggested that screening for pyrin mutations not be included in the evaluation of Greeks suspected to have Behcet's disease.

OBJETIVO:Se sabe que las similitudes clínicas entre la enfermedad de Behçet y la fiebre mediterránea familiar han llevado a la hipótesis de una patogénesis común. La fiebre mediterránea familiar es causada por mutaciones en el gen MEFV que codifica la pirina. Por lo tanto, examinamos si estas mutaciones de la pirina se hallan también asociadas con la enfermedad de Behçet. MÉTODOS: La prueba molecular para la detección de las mutaciones de la pirina se realizó en 96 pacientes griegos no relacionados, y diagnosticados con la enfermedad de Behçet. Los resultados se compararon con un análisis de las mutaciones de la pirina en 140 controles formados por individuos griegos saludables. RESULTADOS: No se encontraron mutaciones de pirina entre los casos de Behçet sometidos a prueba. Este resultado es comparable con el grupo control. CONCLUSIONES: Las mutaciones del gen de la pirina en los pacientes griegos con la enfermedad de Behçet no son más comunes que las de la población general. Este hallazgo no concuerda con los hallazgos en otras poblaciones. Se sugiere que el tamizaje para la detección de las mutaciones de pirina no se incluya en la evaluación de pacientes griegos sospechosos de padecer la enfermedad de Behçet.

The spectrum of mucocutaneous manifestations in Adamantiades-Behçet's disease in Greece.

BACKGROUND: This is the largest specific demographic and clinical study performed until now in Greece. OBJECTIVES: To analyse the spectrum of mucocutaneous manifestations in 202 patients with Adamantiades-Behçet's disease (ABD) in Greece. METHODS: Any mucocutaneous symptom at disease onset and during the follow-up was recorded in a particular questionnaire that included 58 items. All patients fulfilled the International Study Group Criteria for BD. RESULTS: Consecutive patients (130 men and 72 women) were included in this study. Their mean age was 42.03 +/- 12.41 and 44.96 +/- 11.99 years for male and female patients respectively. Pathergy test was positive in 38%, whereas HLA-B5 (51) positivity was evident in 76% of patients. Onset signs: oral aphthous ulcers were found in 64.36%, genital ulcers in 6.93%, skin lesions in 8.91%, erythema nodosum in 7.42% and pseudofolliculitis in 1.5%. One patient had leg ulcers. During the follow-up, oral aphthous ulcers were found in 100%, genital ulcers in 65.4% and in 51.4%, erythema nodosum in 42.9% and in 78.1%, whereas pseudofolliculitis in 57.1% and in 21.9% in men and women respectively. Significant differences pointing to a different course of mucocutaneous disease were found between men and women. CONCLUSIONS: The nature and frequency of mucocutaneous manifestations at presentation are important for the diagnosis of ABD, whereas significant differences were found between genders in this Greek patient cohort. Significant differences were also observed when our results were compared with those of four other series, probably explained by genetic and environmental factors.

Are clusters of patients with distinct clinical expression present in Behçet's disease?

OBJECTIVE: Studies from Israel and Turkey have proposed that patient clusters with discriminating clinical features may exist in Behçet's disease (BD); such clusters could help to better understand pathogenetic mechanisms and guide therapeutic decisions. Herein, we searched for specific associations between each disease manifestation to all other manifestations in Greek patients with BD. METHODS: Specific clinical features were retrospectively recorded in 142 consecutive patients (80 men) fulfilling the International Study Group criteria, seen between 2000-2008 in our Departments (mean follow-up of 37 months). All possible associations between distinct clinical features were examined; further analysis in relation to HLA-B51 status and pathergy test positivity, available in 89 patients, was performed. RESULTS: No significant associations between various manifestations of BD were found, either among all patients, or among men or women analysed separately. Uveitis was present more frequently in men, but not women, who were HLA-B51 carriers (p<0.02). A positive pathergy reaction was associated with oral ulcers (p<0.001) and central nervous involvement (p=0.008) in women, and folliculitis in men (p=0.046). CONCLUSION: In contrast to studies from other countries, no subgroups of patients with distinct positive or negative associations between clinical features were found. HLA-B51 may have some prognostic significance in men only. Whether differences in disease expression between geographical areas may reflect different triggers of pathogenetic mechanisms operating among ethnic groups could be further explored in comparative studies.

Coexistence of Behcet's disease and chronic myelomonocyte leukemia with trisomy 8: a case report and review of the literature.

Behçet's disease (BD) is a multisystem inflammatory vasculitis of unknown etiology and pathogenesis. Coexistence of BD along with hematological malignancies is extremely rare. We describe a patient diagnosed with BD and chronic myelomonocytic leukaemia (CMML) with trisomy 8. This case suggests that trisomy 8 may be involved in the concurrent manifestation of myelodysplastic syndrome (MDS) and BD with gastrointestinal ulcers.

Cardiac sarcoidosis.

Sarcoidosis is a systemic disease which affects many organs, including the heart. Cardiac sarcoidosis has a reported incidence of about 25 % and carries a poor prognosis. It can occur in the form of conduction abnormalities, pericardial and valvular heart disease, congestive heart failure, arrhythmias and sudden cardiac death. The diagnosis of cardiac sarcoidosis is difficult, requiring a high index of suspicion and the use of electrocardiography, echocardiography, nuclear medicine imaging, myocardial biopsy and magnetic resonance imaging. Corticosteroids have been the cornerstone of treatment of cardiac sarcoidosis, but other immunosuppressives have also been used, along with standard heart failure therapy, antiarrhythmic medications, pacemakers and implantable defibrillators. Cardiac transplantation is an option for patients who do not respond to medical treatment. We briefly review the current armamentarium for the diagnosis and treatment of cardiac sarcoidosis.

Adjunctive anakinra in patients with active rheumatoid arthritis despite methotrexate, or leflunomide, or cyclosporin-A monotherapy: a 48-week, comparative, prospective study.

OBJECTIVE: To assess the efficacy and safety of anakinra (ANK) as an add-on therapy in RA patients with inadequate response to monotherapy with non-biological DMARDs. METHODS: A 48-week comparative, prospective study of patients with active RA [mean 28-joint disease activity score (DAS28): 6.81], despite MTX (n = 48), or LEF (n = 42), or CSA (n = 38) treatment, in whom ANK (100 mg/daily SC) was given with corticosteroid cream topical application. RESULTS: At 24 and 48 weeks the patient percentages meeting the ACR20 response criteria were 57 and 73%, respectively, 33 and 41% met ACR50, while 15 and 23% met ACR70. Significant improvements in number of swollen and tender joints, HAQ, pain, global disease assessment, CRP and haemoglobin from baseline to 24 and 48 weeks were evident. DAS28 decreased at 24 weeks (- 1.68; 95% CI - 1.46, - 1.90; P < 0.0001), as well as at study end (- 2.24; 95% CI - 2.01, - 2.47; P < 0.0001). Subgroup analysis revealed a significantly weaker response in terms of pain and DAS28 in patients treated with concomitant CSA. The most common ANK-related adverse event was injection-site reaction (29%), being less frequent in male patients, as well as in patients treated with CSA. There were 17 withdrawals, 6 of them due to inefficacy. No opportunistic infections or new safety signals were observed. CONCLUSION: Considering the limitations of an open-label study, addition of ANK appears to be an effective and well-tolerated treatment option for many RA patients with inadequate responses to non-biologic DMARDs in clinical practice.

Impaired aortic elastic properties in patients with systemic sarcoidosis.

BACKGROUND: Systemic sarcoidosis (Sar) is a granulomatous disorder involving multiple organs. Widespread vascular involvement and microangiopathy are common in patients with Sar. In addition, subclinical cardiac involvement is increasingly recognized in patients with Sar. However, data on the effect of Sar on the elastic properties of the arteries and myocardial performance are limited. In this study we looked for differences in aortic distensibility (AoD) which is an index of aortic elasticity, and myocardial performance of the ventricles, between patients with Sar and healthy subjects. In addition, we examined potential associations between AoD and clinical, respiratory and echocardiographic findings in patients with Sar. MATERIALS AND METHODS: A total of 83 consecutive patients (26 male/57 female, mean age 51.1 +/- 13.3 years) with Sar, without cardiac symptoms, were included. All patients underwent echocardiographic and respiratory evaluation including lung function tests. Additionally, 83 age- and sex-matched healthy subjects served as controls. AoD was determined non-invasively by ultrasonography. RESULTS: AoD was lower in the Sar compared to the control group (2.29 +/- 0.26 vs. 2.45 +/- 0.20 .10(-) (6) cm2 x dyn(-1), P < 0.01), while left ventricular mass (LVM) was higher in the Sar group (221.3 +/- 50.2 vs. 195.6 +/- 31.3 g, P = 0.007). Furthermore, myocardial performance of both ventricles was impaired in the Sar group. Multivariate linear regression analysis in the total sample population demonstrated a significant and independent inverse relationship between AoD and the presence of Sar (P < 0.001). The same analysis in the Sar patients showed that AoD was associated significantly and independently with the stage of Sar, age, systolic blood pressure, LVM and myocardial performance of both ventricles. No significant relationship was found between AoD and disease duration, pulmonary artery pressure or lung function tests. CONCLUSIONS: Presence and severity of Sar are associated with reduced aortic distensibility, irrespective of the disease duration, pulmonary artery pressure and lung function. In addition, patients with Sar have increased LVM and impaired myocardial performance.

Infliximab treatment-induced formation of autoantibodies is common in Behçet's disease.

OBJECTIVE: To study autoantibody formation in patients with Behçet's disease (BD) who received long-term treatment with the anti-TNF monoclonal antibody infliximab. METHODS: Serial sera from infliximab-treated patients (5 mg/kg at weeks 0, 4, 8, and every 6-8 weeks thereafter) were tested for various autoantibodies, using commercially available methods, at baseline and at 6 months (n = 20), at 12 months (n = 16), and at 18 months post-baseline (n = 12). Thirty-five age- and sex-matched BD patients, not treated with infliximab, served as controls. RESULTS: Autoantibodies were rarely seen in controls, as well as in infliximab treated patients at baseline. Formation of antinuclear antibodies (ANA) at low titers was evident in 13/20 (65%) patients at 6 months post-baseline; one additional patient developed anti-beta2 glycoprotein-I IgM antibodies (anti-beta(2)GPI). Of the 13 ANA-positive sera, low titers-IgM of anti-dsDNA or anti-beta(2)GPI were detected in 7 (35%) and 6 (30%) patients, respectively. Additional measurements at 12 and 18 months showed that the persistence and/or increasing titers of these autoantibodies depended on continuation of treatment. Antibodies to extractable nuclear antigens (anti-RNP, anti-SS-A/Ro, anti-SS-B/La, anti-Sm), rheumatoid factors, anti-cyclic citrullinated peptide antibodies and antineutrophil cytoplasmic antibodies, were never detected. No antibody-related symptoms, lupus-like disease, or thrombosis were observed in any patient up to 18 months of follow-up. CONCLUSION: Early induction of ANA and specific autoantibodies is common in BD patients treated with infliximab, including low titers of non-pathogenic anti-dsDNA and anti-Beta2GPI antibodies. A possible clinical significance of these findings needs to be documented in further studies, including more patients and longer follow-up periods.

Serum ceruloplasmin as a marker in prostate cancer.

AIM: Serum acid phosphatase and prostate specific antigen have been utilized as disease markers in prostate cancer, one of the commonest cancers of the elderly. Serum ceruloplasmin (Cp) increases in cancer patients; it may be a reliable marker for prostate cancer, but few data are available on specificity and sensitivity of Cp values. METHODS: Serum prostate specific antigen (PSA) and Cp was determined in Greek patients suffering from histologically proven prostate carcinoma or benign hyperplasia. The results were compared with those in controls matched for sex and age. RESULTS: In all studied subjects with a prostate cancer, serum Cp values were higher than age-matched healthy controls; they were also higher in cases with benign hyperplasia. No difference in serum Cp was noted among patients with earlier and advanced stages of the tumor. No difference in Cp was also found between benign hyperplasia and normal controls. There exists a significant difference in serum PSA between both prostate cancer and benign hyperplasia cases. There exists also a difference between benign hyperplasia cases and controls. CONCLUSION: It is suggested that serum Cp may complement the biochemical screening in prostate carcinoma, especially in cases where this cancer is not accompanied by elevation of serum PSA. However, it is not of help in differentiating prostate cancer from prostate benign hyperplasia.

Raynaud's phenomenon is correlated with elevated systolic pulmonary arterial pressure in patients with systemic lupus erythematosus.

In patients with Systemic lupus erythematosus (SLE), Raynaud phenomenon (RP) is frequently present and associated with pulmonary hypertension (PHT). Elevated pulmonary artery systolic pressure (PASP) is an indicator of PHT and can be estimated noninvasively. We attempt to explore the significance of RP in SLE and to correlate it with clinical and serological parameters of the disease. The study population consisted of 34 patients (age, sex and disease duration matched) who fulfilled the revised SLE criteria of the American College of Rheumatology, and were categorized into two groups: Group 1 had patients having SLE and RP (2 males/15 females, mean age 45 +/- 18 years) and group 2 had patients with SLE but without RP (3 males/14 females, mean age 40 +/- 14 years. Detailed cardiac ultrasound was performed including measurement of PASP, while clinical and serological features of both groups were collected and correlated. Significant differences were shown in the presence of arterial hypertension (P < 0.05), arthralgias (P < 0.005), arthritis (P < 0.05), myalgias (P < 0.05), alopecia (P < 0.05) and PASP (P < 0.0001). No difference was observed among the cardiac ultrasound indices and the ejection fraction between the two groups. PASP was significantly correlated with RP, while no correlation was observed regarding the disease duration. In patients with SLE, the presence of RP was associated with elevation in PASP. Further investigation is needed to clarify the significance of this relation.

Heterophilic antibodies causing falsely high serum calcitonin values.

Heterophilic antibodies (HA) may interfere in some immunoassays, causing falsely high hormone values, of which practitioners should be aware when measuring calcitonin (CT) used as tumor marker for medullary thyroid carcinoma (MTC). We studied four patients with thyroid nodules, three of whom underwent surgical neck exploration, after an erroneous diagnosis of MTC because of falsely high serum CT eventually proved to be due to HA. One patient had a lingual thyroid, two autoimmune thyroiditis and the fourth a colloid goiter. The minimal incremental CT response to calcium infusion raised our suspicion of possible false high CT values due to HA. There was no linearity of the CT values obtained by testing serial dilutions of the sera in the CT assay, which employs two monoclonal mouse anti-CT antibodies. Addition of normal mouse gamma globulin eliminated the interference by HA in the sera of two patients. Serum assayed in a polyclonal radioimmunoassay using goat anti-CT antibodies gave normal CT values. Finally, incubation of the sera in Heterophilic Blocking Tubes (HBT) eliminated the false CT immunoreactivity. A spontaneous change of the CT serum concentrations was noticed in three patients over several months, apparently due to changing titles of HA. We suggest that, in patients a) whose CT response to calcium or pentagastrin infusion is minimal despite high basal CT values, b) with autoimmune thyroiditis and c) in whom an unexpected change in serum CT concentrations occurs, the possibility of spuriously high CT values because of circulating HA should be considered.

Temozolomide in combination with celecoxib in patients with advanced melanoma. A phase II study of the Hellenic Cooperative Oncology Group.

BACKGROUND: There is now increasing evidence that a constitutive expression of cyclooxygenase (COX)-2 plays a role in the development and progression of malignant epithelial tumors. Expression of COX-2 is seen in 93% of melanomas, as determined by immunohistochemistry. Temozolomide (TMZ) has demonstrated activity against melanoma and has been investigated as single agent or in combination. We designed a phase II study to assess the efficacy and toxicity of the combination of TMZ and celecoxib (a COX-2 inhibitor) in patients with advanced melanoma. PATIENTS AND METHODS: From January 2003 to July 2004, 52 patients were enrolled in the study. Nineteen patients were M1a, six M1b and 27 M1c. Patients received TMZ 200 mg/m(2) per day p.o. for 5 consecutive days every 4 weeks and celecoxib 400 mg b.i.d. p.o. for a maximum of six cycles. Celecoxib was continued until progression. RESULTS: The median age was 63 years. There were 29 males and 23 females. Among 50 assessable patients, there were 11 (21.5%) objective responses including five complete responses and six partial responses. Twenty patients (38.5%) had stabilization of their disease, and 19 (36.5%) progressed. The median time to progression was 4.6 months and the median survival 9.5 months. Twenty-two patients (41.5%) completed all cycles of treatment. Median relative dose intensity of TMZ was 0.99 (range 0.6-1.2). Most commonly seen toxic effects included anemia (27.5%), neutropenia (17.5%), thrombocytopenia (33%), nausea/vomiting (75%), gastrointestinal (52%) and fatigue (46.5%). One patient discontinued due to severe toxicity. COX-2 was determined by immunohistochemistry and was expressed in all cases. CONCLUSION: The combination of TMZ and celecoxib is safe and potentially effective in the treatment of metastatic melanoma. Randomized studies are needed to explore the role of celecoxib in combination with chemotherapy or as maintenance treatment in these patients.