Rheumatoid Arthritis: Fonseca JE

Canhão H, Santos MJ, Costa L, Bogas M, Mourão AF, Machado P, Fonseca JE, Silva JA, Anonymous00048. · Serviço de Reumatologia, Centro Hospitalar Lisboa Norte, Hospital de Santa Maria, Lisboa. · Acta Reumatol Port. · Pubmed #19377402 No free full text.

Abstract: OBJECTIVES: To develop Portuguese evidence-based recommendations for the use of methotrexate (MTX) in daily clinical practice in rheumatic disorders. METHODS: The Portuguese project was integrated in the multinational 3E Initiative (Evidence, Expertise, Exchange) 2007-2008 where a total of 751 rheumatologists from 17 countries have participated. Ten clinical questions concerning the use of MTX in rheumatic diseases were formulated and the Portuguese group added three more questions. A systematic literature search in Medline, Embase, Cochrane Library and 2005-2007 ACR/EULAR meeting abstracts was conducted. Selected articles were systematically reviewed and the evidence was appraised according to the Oxford Levels of Evidence. In Portugal, a national meeting was held in Obidos on February 15th and 16th, 2008, involving 50 rheumatologists who discussed and voted by Dephi method the recommendations. Finally, the agreement among the rheumatologists and the potential impact on their clinical practice was assessed. RESULTS: Thirteen national key recommendations on the use of MTX were formulated: work-up before starting MTX, optimal dosage and route of administration, use of folic acid, monitoring, management of hepatotoxicity, long-term safety, mono versus combination therapy, management in the peri-operative period, during infections, before/during pregnancy and after clinical remission, screening and treatment of tuberculosis and the role of MTX as a steroid-sparing agent in rheumatic diseases. DISCUSSION: The Portuguese recommendations for the use of MTX in daily clinical practice were developed, which are evidence-based and supported by a panel of 50 rheumatologists, enhancing their validity and practical use. This project was integrated in a multinational initiative that led to the recent publication of ten multinational recommendations which differ from ours in some specific aspects.

Santos MJ, Fonseca JE, Canhão H, Conde M, José Vieira M, Costa L, Costa M, Salgado M, Melo Gomes JA, Anonymous00046. · Sociedade Portuguesa de Reumatologia, Lisboa. · Acta Reumatol Port. · Pubmed #17450764 links to  free full text

Abstract: The Pediatric RheumatologyWorking Group of the Portuguese Society of Rheumatology recommends the use of biological treatments in children with polyarticular course Juvenile Idiopathic Arthritis (JIA) with active disease (5 or more active joints) refractory to subcutaneous or intramuscular methotrexate (MTX) 15 mg/m(2)/week during 3 to 6 months. If toxicity occurs, or if there is contraindication for the use of MTX in this optimum dose, biological treatment can be started, as a first option, or the use of other conventional Disease ModifyingAnti Rheumatic Drug (DMARD) either alone or in combination with MTX might be considered. Prior to starting treatment, children should be screened for latent tuberculosis through clinical evaluation, chest X ray and PPD skin test. The suspension of the biological treatment should be considered if the American College of Rheumatology (ACR) definition of improvement in JIA is not fulfilled in two consecutive visits 3 months apart. Etanercept is the only biological agent currently approved for JIA in Portugal. In refractory cases the use of infliximab is accepted, in accordance with preliminary published evidence. In case of systemic manifestations of JIA refractory to conventional treatment, anakinra can be considered.

Fonseca JE, Lucas H, Canhão H, Duarte R, Santos MJ, Villar M, Faustino A, Raymundo E, Anonymous00188, Anonymous00189. · Grupo de Estudos de Artrite Reumatóide, Sociedade Portuguesa de Reumatologia, Rua D. Estefânia 177, 1 D1000-154 Lisbon. · Rev Port Pneumol. · Pubmed #17117328 No free full text.

Abstract: The Portuguese Society of Rheumatology (SPR) and the Portuguese Society of Pulmonology (SPP) have developed guidelines for the diagnosis and treatment of latent tuberculosis infection (LTBI) and active tuberculosis (AT) in patients with inflammatory joint diseases (IJD), namely rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis, treated with tumour necrosis factor alpha (TNF-a) antagonists. Due to the high risk of tuberculosis (TB) in patients with IJD, LTBI and AT screening should be performed as soon as possible, ideally at the moment of IJD diagnosis. Even if TB screening was performed at the beginning of the disease, the evaluation should be repeated before starting anti-TNF-a therapy. When TB (LTBI or AT) treatment is indicated, it should be performed before the beginning of anti-TNF-a therapy. If the IJD activity requires urgent anti-TNF-a therapy, these drugs can be started after two months of antituberculosis therapy in AT cases, or after one month in LTBI cases. Chest X-ray is mandatory for all patients. If abnormal, e.g. Gohn complex, the patient should be treated as LTBI; residual lesions require the exclusion of AT and patients with history of untreated or incomplete TB treatment should be treated as LTBI. In cases of suspected active lesions, AT diagnosis should be confirmed and adequate therapy initiated. Tuberculin skin test (TST), with two units of RT23, should be performed in all patients. If induration is less than 5 mm, the test should be repeated after 1 to 2 weeks, on the opposite forearm, and should be considered negative if the result is again inferior to 5 mm. Positive TST implicates LTBI treatment. If TST is performed in immunosuppressed IJD patients, LTBI treatment should be offered to the patient before starting anti-TNF-a therapy, even in the presence of a negative test.

Fonseca JE, Lucas H, Canhão H, Duarte R, Santos MJ, Villar M, Faustino A, Raymundo E, Anonymous00298, Anonymous00299. · Grupo de Estudos de Artrite Reumatóide da Sociedade Portuguesa de Reumatologia. · Acta Reumatol Port. · Pubmed #17094335 links to  free full text

Abstract: The Portuguese Society of Rheumatology (SPR) and the Portuguese Society of Pulmonology (SPP) have developed guidelines for the diagnosis and treatment of latent tuberculosis infection (LTBI) and active tuberculosis (AT) in patients with inflammatory joint diseases (IJD), namely rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis, treated with tumour necrosis factor alpha (TNF-alpha) antagonists. Due to the high risk of tuberculosis (TB) in patients with IJD, LTBI and AT screening should be performed as soon as possible, ideally at the moment of IJD diagnosis. Even if TB screening was performed at the beginning of the disease, the evaluation should be repeated before starting anti-TNF-alpha therapy. When TB (LTBI orAT) treatment is indicated, it should be performed before the beginning of anti-TNF-alpha therapy. If the IJD activity requires urgent anti-TNF-alpha therapy, these drugs can be started after two months of antituberculosis therapy in AT cases, or after one month in LTBI cases. Chest X-ray is mandatory for all patients. If abnormal, e.g. Gohn complex, the patient should be treated as LTBI; residual lesions require the exclusion of AT and patients with history of untreated or incomplete TB treatment should be treated as LTBI. In cases of suspected active lesions, AT diagnosis should be confirmed and adequate therapy initiated. Tuberculin skin test (TST), with two units of RT23, should be performed in all patients. If induration is less than 5 mm, the test should be repeated after 1 to 2 weeks, on the opposite forearm, and should be considered negative if the result is again inferior to 5 mm. Positive TST implicates LTBI treatment. IfTST is performed in immunosupressed IJD patients, LTBI treatment should be offered to the patient before starting anti-TNFalpha therapy, even in the presence of a negative test.

Fonseca JE. · No affiliation provided · Acta Reumatol Port. · Pubmed #17572647 links to  free full text

This publication has no abstract.

Fonseca JE, Lucas H, Canhão H, Duarte R, Santos MJ, Villar M, Faustino A, Raymundo E. · Rheumatoid Arthritis Study Group (Grupo de Estudos de Artrite Reumatoide-GEAR) of the Portuguese Society of Rheumatology (Sociedade Portuguesa de Reumatologia-SPR), Lisbon, Portugal. · Acta Reumatol Port. · Pubmed #18344925 links to  free full text

Abstract: The Portuguese Society of Rheumatology and the Portuguese Society of Pulmonology have updated the guidelines for the diagnosis and treatment of latent tuberculosis infection (LTBI) and active tuberculosis (ATB) in patients with inflammatory joint diseases (IJD) that are candidates to therapy with tumour necrosis factor alpha (TNFalpha) antagonists. In order to reduce the risk of tuberculosis (TB) reactivation and the incidence of new infections, TB screening is recommended to be done as soon as possible, ideally at the moment of IJD diagnosis, and patient assessment repeated before starting anti-TNFalpha therapy. Treatment for ATB and LTBI must be done under the care of a TB specialist. When TB treatment is indicated, it should be completed prior to starting anti-TNFalpha therapy. If the IJD activity justifies the need for immediate treatment, anti-TNFalpha therapy can be started two months after antituberculous therapy has been initiated, in the case of ATB, and one month after in the case of LTBI. Chest X-ray is mandatory for all patients. If Gohn s complex is present, the patient should be treated for LTBI; healed lesions require the exclusion of ATB. In cases of suspected active lesions ATB should be excluded/confirmed and adequate therapy initiated. Tuberculin skin test, with two units of RT23, should be performed in all patients. If the induration is <5 mm, the test should be repeated within 1 to 2 weeks, on the opposite forearm, and will be considered negative only if the result is again <5 mm. Positive TST implicates LTBI treatment, unless previous proper treatment was provided. If TST is performed in immunossuppressed IJD patients, LTBI treatment should be offered to the patient before starting anti-TNFalpha therapy, even in the presence of a negative test, after risk/benefit assessment.

Caetano-Lopes J, Henriques R, Canhão H, Duarte J, Amaral PM, Vale M, Moura RA, Pereira PA, Weinmann P, Abdulghani S, Souto-Carneiro M, Rego P, Monteiro J, Sakagushi S, Queiroz MV, Konttinen YT, Graça L, Vaz MF, Fonseca JE. · Rheumatology Research Unit, Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal. · Clin Exp Rheumatol. · Pubmed #19604441 No free full text.

Abstract: OBJECTIVES:Rheumatoid arthritis (RA) is associated with an increased risk of fragility fractures. In RA patients, the direct effect of inflammation on bone is difficult to study because their skeleton is also affected by medication with corticosteroids and other drugs as well as aging and menopause, which contribute to bone fragility. This study used an animal model of chronic arthritis to evaluate the direct impact of chronic inflammation on biomechanical properties and structure of bone.METHODS:In the SKG mouse chronic arthritis model three point bending tests were performed on femoral bones and compression tests on vertebral bodies. Collagen structure was analysed using second-harmonic generation (SHG) imaging with a two-photon microscope, ultramorphology by scanning electron microscopy (SEM) coupled with energy dispersive x-ray spectroscopy (EDS) and bone density using water pycnometer.RESULTS:Arthritic bones had poor biomechanical quality compared to control bones. SHG, SEM and pycnometry disclosed variable signs of impaired collagen organization, poor trabecular architecture and low bone density.CONCLUSION:Present data demonstrate for the first time that chronic inflammation per se, without confounding influence of drugs and aging, leads to impairment of bone biomechanics in terms of stiffness, ductility and ultimate strength (fracture).

Abdulghani S, Caetano-Lopes J, Canhão H, Fonseca JE. · Rheumatology Research Unit, Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal. · Autoimmun Rev. · Pubmed #19223022 No free full text.

Abstract: Inflammatory diseases, such as rheumatoid arthritis (RA), influence the bone remodelling process and increase the risk of fracture. Bone can be viewed as a composite material comprising of two phases: the organic phase, constituted predominantly by collagen type I, and the mineral phase, composed primarily by calcium phosphate, in the form of mineral crystals. The mineral component confers bone with strength and stiffness while the organic phase is responsible for bone toughness and ductility and acts as a scaffold for the mineralisation process. The efficacy of bone as a structural material depends on the balance between these different bone components and their biomechanical properties. The main determinants of mechanical properties of bone are the amount of mineral, the collagen content, the orientation of the collagen fibers and minerals and the accumulation of microcracks in the bone matrix. In a mice model of arthritis mechanical testing has shown that arthritic femurs have a significantly lower Young's modulus, yield stress and work until ultimate stress. This evidence suggests that one of the major explanations for the increased fracture risk in RA is related to the changes on bone components induced by inflammation that result in compromised biomechanical properties.

Mourão AF, Caetano-Lopes J, Costa P, Canhão H, Santos MJ, Pinto P, Brito I, Nicola P, Cavaleiro J, Teles J, Sousa A, Gomes JM, Branco J, da Costa JT, Pedro JG, de Queiroz MV, Fonseca JE. · Rheumatology Research Unit, Instituto de Medicina Molecular, Edifício Egas Moniz, Faculdade de Medicina da Universidade de Lisboa, Av. Professor Egas Moniz, 1649-028 Lisboa, Portugal. · J Rheumatol. · Pubmed #19208590 No free full text.

Abstract: OBJECTIVE: Considering the relevance of tumor necrosis factor-alpha (TNF-alpha) in the pathophysiology of juvenile idiopathic arthritis (JIA), it is likely that polymorphisms in its promoter area may be relevant in disease susceptibility and activity. We investigated if clinical measures of JIA activity and TNF-alpha serum concentrations were associated with TNF-alpha -308 genotypes. METHODS: Portuguese patients with JIA in 5 pediatric rheumatology centers were recruited consecutively, along with a control group of healthy subjects. Demographic and clinical data and blood samples were collected from each patient. DNA was extracted for analysis of TNF-alpha gene promoter polymorphisms at position -308 by restriction fragment-length polymorphism. RESULTS: One hundred fourteen patients and 117 controls were evaluated; 57% of patients presented the oligoarticular subtype, 25% the polyarticular subtype, 8% the systemic subtype, and 9% had enthesitis-related arthritis and 5% psoriatic arthritis. Twenty-four percent of the patients presented the -308 GA/AA genotypes and 76% the -308 GG genotype, similar to findings in controls. Patients with the -308 GA/AA genotype had higher degree of functional impairment, erythrocyte sedimentation rate, 100-mm visual analog scale score for disease activity, and TNF-alpha levels compared to those with the -308 GG genotype. CONCLUSION: TNF-alpha -308 GA/AA genotypes were found to be related to higher inflammatory activity and worse measures of disease activity in Portuguese patients with JIA. They were not associated with susceptibility to JIA.

Fonseca JE, Santos MJ, Canhão H, Choy E. · Rheumatology Research Unit, Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal. · Autoimmun Rev. · Pubmed #19189867 No free full text.

Abstract: Interleukin-6 (IL-6) is a cytokine that can facilitate autoimmune phenomena, amplify acute inflammation and promote the evolution into a chronic inflammatory state. In addition, it is a major promoter of bone resorption in pathological conditions. In particular, IL-6 has a pivotal role in synovitis, bone erosions and in the systemic features of inflammation. This cytokine specifically binds to IL-6 receptor (IL-6R), forming the IL-6/IL-6R complex that binds to gp130, a membrane-bound protein, which is involved in non-ligand-binding signal transduction. Targeting IL-6R in both animal models of arthritis and in rheumatoid arthritis patients with a humanized anti IL-6R monoclonal antibody (tocilizumab) effectively controls local and systemic inflammatory manifestations and blocks cartilage and bone destruction. Given the pleiotropic function of IL-6 it can be anticipated that other inflammatory diseases and bone metabolic conditions might benefit from selective IL-6 signaling inhibition.

Mourão AF, Santos FP, Falcão S, Barros R, Pinto TL, Mendes A, Castelão W, Nero P, Fonseca JE, Matos AA, Branco JC. · Serviço de Reumatologia do Centro Hospitalar de Lisboa Ocidental (CHLO), EPE, Hospital Egas Moniz, Lisboa, Portugal. · Acta Reumatol Port. · Pubmed #19078861 links to  free full text

Abstract: AIM: To verify if the response to TNFalpha inhibitors is influenced by the presence of IgM rheumatoid factor (RF), in patients with RA. MATERIAL AND METHODS: In this study, the patients with the diagnosis of RA treated with TNFa inhibitors followed in our hospital were recruited. A protocol was applied including demographic, clinical and laboratory data, in order to calculate DAS 28. The presence/absence of IgM RF and associated therapies were record. RESULTS: Fifty-seven patients, 52 female, with a mean duration of anti-TNFa treatment of 30,9+/-15,9 months were studied. Twenty-four patients were being treated with infliximab, 17 with adalimumab and 16 with etanercept. Forty-one patients had IgM RF detectable in serum (RF positive group). In the RF positive group, the variation of DAS 28 was -1,75 +/- 1,53 vs -1,04 +/- 1,76 in the RF negative group (p=0,135). The mean duration of anti-TNFalpha treatment was similar in both groups (31,9+/-15,9 vs 29,5+/-16,16 months). Patients who were treated with methotrexate presented a higher variation of DAS 28 (-1,87 +/- 1,70 vs -0,80 +/- 1,09; p=0,041) and this variation was dose dependent (p=0,056). CONCLUSIONS: Despite needing a replication in a larger cohort, our results suggest that the presence of IgM RF in the serum did not interfere with the response to treatment with TNFalpha inhibitors.

Weinmann P, Moura RA, Caetano-Lopes JR, Pereira PA, Canhão H, Queiroz MV, Fonseca JE. · Rheumatology Research Unit, Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal. · Clin Exp Rheumatol. · Pubmed #18173925 No free full text.

Abstract: OBJECTIVES: To analyse the activation state and apoptosis of circulating neutrophils in untreated very early rheumatoid arthritis (VERA) and after exposure to low dose corticosteroids and methotrexate (MTX). METHODS: Neutrophils were isolated from the peripheral blood of VERA patients at 3 different times: before any treatment was started, 2 weeks after starting a low dose of prednisone (5-10 mg) and 4 months after reaching more than 20mg/week of MTX. The expression of different activation markers (CD11b, CD64, CD86 and CD69) in freshly isolated neutrophils was analysed by flow cytometry. Apoptosis was measured by the loss of DNA content, which was analysed by flow cytometry using propidium iodide. RESULTS: Compared to neutrophils from healthy controls, we have found a delayed neutrophil apoptosis within 6 h and 22 h of cultured polymorphonuclear leukocytes (PMN) derived from VERA patients without any treatment or treated with corticosteroids. The delay of PMN apoptosis was restored to control levels after treatment with MTX. CONCLUSION: The treatment of VERA patients with corticosteroids did not affect the delay of neutrophil apoptosis. However, delayed apoptosis was restored to control levels after treatment with low dose MTX, which highlights the importance of early RA treatment with MTX.

Fonseca JE, Canhão H, Reis P, Jesus H, Silva JA, Branco J, Queiroz MV. · Unidade de Investigação em Reumatologia Instituto de Medicina Molecular Faculdade de Medicina da Universidade de Lisboa. · Acta Reumatol Port. · Pubmed #18159204 links to  free full text

Abstract: The authors present the update of a protocol for the clinical follow-up of Rheumatoid Arthritis Patients PMAR which aims to contribute to a standardized clinical observation of these patients particularly when they are being treated with biologic therapies.

Canhão H, Fonseca JE, Santos MJ, Gomes JA. · Serviço de Reumatologia, Hospital de Santa Maria, Lisbon. · Acta Reumatol Port. · Pubmed #17928788 links to  free full text

Abstract: The development of new and more efficacious therapeutic agents, though expensive and potentially toxic, helped to implement objective measures to quantify the improvement and to monitor the evolution of inflammatory rheumatic diseases. The aim of our protocol (PMAIJ) is to supply rheumatologists and paediatricians with a useful tool for follow-up of juvenile arthritis patients using validated instruments for the evaluation of activity, functional capacity and response to treatment. PMAIJ has 2 pages. The first page is filled only at the initial evaluation; the second page is filled at first and in all the appointments after that. The application of this protocol would contribute to the standardization of procedures in different Paediatric Rheumatology Centres and would help to obtain useful information on the clinical evolution of JIA patients followed in Portugal.

Canhao H, Fonseca JE, Caetano-Lopes J, Saldanha C, Queiroz MV. · Rheumatology Research Unit, Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Edifício Egas Moniz. Av. Prof. Egas Moniz, 1649-028, Lisbon, Portugal. · Clin Rheumatol. · Pubmed #17684700 No free full text.

Abstract: The aim of this study was to identify and evaluate laboratory parameters associated with normal bone mineral density (BMD) and to test if -308 tumour necrosis factor (TNF) alpha gene promoter polymorphisms could influence BMD. We performed a comparative cross-sectional study of four main groups: young healthy individuals (20-30 years); subjects aged 50 years or over with normal BMD; osteoporotic subjects aged 50 years or over; osteoporotic women with active rheumatoid arthritis. Variables assessed included anthropometric features, diet intake, lifestyle, calcium-phosphorus balance, markers of bone turnover, sexual hormones, hormones related with body mass and growth, cytokines involved in inflammation and bone turnover, and -308 TNF alpha gene promoter polymorphisms. One hundred fifty-nine subjects were evaluated. Across the four groups, zinc serum levels were higher in men as compared to women. In addition, zinc serum levels were also higher in individuals with normal BMD as compared to osteoporotic subjects. Serum calcium levels were higher in normal BMD group. On the other hand, follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels were significantly higher in normal bone mass postmenopausal women and men as compared to age-matched osteoporotic groups. Finally, leptin was significantly lower in men, after correcting these results for body mass index values. The remaining variables assessed had a similar distribution among the different studied groups. In our population, low serum levels of leptin and high serum levels of zinc, calcium, FSH, and LH were associated with a higher BMD.

Fonseca JE, Cavaleiro J, Teles J, Sousa E, Andreozzi VL, Antunes M, Amaral-Turkman MA, Canhão H, Mourão AF, Lopes J, Caetano-Lopes J, Weinmann P, Sobral M, Nero P, Saavedra MJ, Malcata A, Cruz M, Melo R, Braña A, Miranda L, Patto JV, Barcelos A, da Silva JC, Santos LM, Figueiredo G, Rodrigues M, Jesus H, Quintal A, Carvalho T, da Silva JA, Branco J, Queiroz MV. · Rheumatology Research Unit, Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Av, Professor Egas Moniz, 1649-028, Lisboa, Portugal. · Arthritis Res Ther. · Pubmed #17408492 links to  free full text

Abstract: The objective of this study was to assess whether clinical measures of rheumatoid arthritis activity and severity were influenced by tumor necrosis factor-alpha (TNF-alpha) promoter genotype/haplotype markers. Each patient's disease activity was assessed by the disease activity score using 28 joint counts (DAS28) and functional capacity by the Health Assessment Questionnaire (HAQ) score. Systemic manifestations, radiological damage evaluated by the Sharp/van der Heijde (SvdH) score, disease-modifying anti-rheumatic drug use, joint surgeries, and work disability were also assessed. The promoter region of the TNF-alpha gene, between nucleotides -1,318 and +49, was sequenced using an automated platform. Five hundred fifty-four patients were evaluated and genotyped for 10 single-nucleotide polymorphism (SNP) markers, but 5 of these markers were excluded due to failure to fall within Hardy-Weinberg equilibrium or to monomorphism. Patients with more than 10 years of disease duration (DD) presented significant associations between the -857 SNP and systemic manifestations, as well as joint surgeries. Associations were also found between the -308 SNP and work disability in patients with more than 2 years of DD and radiological damage in patients with less than 10 years of DD. A borderline effect was found between the -238 SNP and HAQ score and radiological damage in patients with 2 to 10 years of DD. An association was also found between haplotypes and the SvdH score for those with more than 10 years of DD. An association was found between some TNF-alpha promoter SNPs and systemic manifestations, radiological progression, HAQ score, work disability, and joint surgeries, particularly in some classes of DD and between haplotypes and radiological progression for those with more than 10 years of DD.

Fonseca JE, Canhão H, Silva C, Miguel C, Mediavilla MJ, Teixeira A, Castelão W, Nero P, Bernardes M, Bernardo A, Mariz E, Godinho F, Santos MJ, Bogas M, Oliveira M, Saavedra MJ, Barcelos A, Cruz M, Santos RA, Maurício L, Rodrigues M, Figueiredo G, Quintal A, Patto JV, Malcata A, da Silva JC, Araújo D, Ventura F, Branco J, Queiroz MV, Anonymous00300. · Serviço de Reumatologia, Hospital de Santa Maria. · Acta Reumatol Port. · Pubmed #17094336 links to  free full text

Abstract: In Portugal, 13 cases of tuberculosis (TB) were reported, in the period between 1999 and 2005, in 960 patients exposed to anti-TNFalpha treatment (1.35%), 8 females and 5 males. Mean age was 46.7 +/- 13.8 years. 9 patients had rheumatoid arthritis (RA), in 639 exposed patients (1.4%), 3 had ankylosing spondylitis (AS), in 200 exposed patients (1.5%) and 1 had psoriatic arthritis (PA), in 101 exposed patients (1%). The anti-TNFa used was in 8 cases infliximab (in 456 patients exposed, 1.5%), in 4 adalimumab (in 171 patients exposed, 2.3%) and in 1 etanercept (in 333 exposed, 0.3%). Treatment with a biological agent was started 11.1 +/- 8.7 months (min 3 and max 50) before TB onset. Tuberculin skin test (TST) was performed in 9 out of the 13 patients (the other 4 had started biological therapy before 2002). In 3 cases the TST response was 0 mm, in 3 less than 10 mm, in one was 14 mm and in two 20 mm. In the 3 cases with a TST response superior to 10 mm, isoniazid treatment 300 mg/d was prescribed, during 9 months. The time between first symptoms and TB diagnosis was 2.6 +/- 2.9 months. TB involvement was pulmonary in 6 patients, lymph node disease in 2, peritoneal and pulmonary in 2, osteoarticular in one case, lymph node disease and splenic in another and miliar TB in the last case. One death was reported; all of the other cases had a good outcome after anti-TB treatment. In two cases (one treated with adalimumab and the other with infliximab), paradoxical response to treatment occurred. None of the patients has restarted biological therapy after TB treatment.

Ligeiro D, Fonseca JE, Abade O, Abreu I, Cruz M, Nero P, Cavaleiro J, Teles J, Trindade H, Caetano JM, Branco J. · Centro de Histocompatibilidade do Sul, Lisboa, Portugal. · Ann Rheum Dis. · Pubmed #16793843 No free full text.

Abstract: OBJECTIVE: To clarify the influence of the HLA-DRB1 locus on the susceptibility to rheumatoid arthritis and the production of anti-cyclic citrullinated peptide antibodies (anti-CCP) in a Portuguese population. METHODS: 141 patients with rheumatoid arthritis fulfilling the American College of Rheumatology 1987 revised criteria for rheumatoid arthritis were compared with 150 healthy controls. Human leucocyte antigen (HLA)-DRB1 locus genotyping was assessed by polymerase chain reaction reverse probing assays and sequence-specific primers. Anti-CCP antibodies were quantified by ELISA in patients with rheumatoid arthritis. Frequencies between groups were compared by the two-sided Fisher's exact test and considered significant if p<0.05. RESULTS: The HLA-DRB1*04 and HLA-DRB1*10 groups were highly associated with rheumatoid arthritis (p<0.001 and p = 0.031, respectively). High titres of anti-CCP antibodies were largely associated with the presence of HLA-DRB1*04/10. CONCLUSION: The well-recognised susceptibility alleles to rheumatoid arthritis, HLA-DRB1*04, were associated with rheumatoid arthritis in Portuguese patients. The relatively rare DRB1*10 was also associated with rheumatoid arthritis, as was described previously in other southern European countries. Both groups were associated with high anti-CCP titres, reinforcing its relevance to disease onset.

Abreu I, Laroche P, Bastos A, Issert V, Cruz M, Nero P, Fonseca JE, Branco J, Machado Caetano JA. · Faculty of Medical Sciences, Department of Immunology, New University of Lisbon, Lisbon, Portugal. · Ann N Y Acad Sci. · Pubmed #16014552 No free full text.

Abstract: Our objective was to (i) compare FIDIS Rheuma, a new multiplexed immunoassay designed for simultaneous detection of IgM class rheumatoid factors (RF) directed against Fc determinants of IgG from humans and animals, with agglutination and ELISA (conventional methods) and (ii) evaluate the clinical sensitivity and specificity of biological markers for rheumatoid arthritis (RA). To do this, FIDIS technology was employed using the Luminex system. It consists of distinct color-coded microsphere sets, a flow cytometer, and digital signal processing hardware and software. Agglutination and ELISA tests were performed with commercial kits. The study included 134 samples from RA patients and 105 from healthy blood donors. For human specificity, we compared FIDIS with latex agglutination and ELISA. Relative sensitivities were 98.9% and 88.5% and specificities were 90.2% and 94.6%, respectively. For animal specificity, we compared FIDIS with Waaler-Rose and ELISA. The results were 84.9% and 71.9% for the sensitivities and 97.5% and 98.4% for the specificities, respectively. Detection of IgG anti-CCP by ELISA and IgG antikeratin by immunofluorescence was also determined in order to compare their clinical sensitivity and specificity with IgM-RF, according to the method used. The results were: IgG anti-CCP 72.3%, 97.2%; IgG antikeratin 36.6%, 100%; latex agglutination 66.4%, 97.2%; Waaler-Rose 55.9%, 96.3%; FIDIS human 73.9%, 92.1%; FIDIS animal 49.2%, 97.2%; ELISA human 93.2%, 95.5%; and ELISA animal 74.6%, 91.3%. The results showed the efficiency of FIDIS with analytical performance equivalent to the conventional methods, but having the advantage of giving quantitative results (IU/mL).

Fonseca JE, Cortez-Dias N, Francisco A, Sobral M, Canhão H, Resende C, Castelão W, Macieira C, Sequeira G, Saraiva F, da Silva JA, Carmo-Fonseca M, Viana Queiroz M. · Rheumatology Department, Santa Maria Hospital, Lisbon, Portugal. · Clin Exp Rheumatol. · Pubmed #15895888 No free full text.

Abstract: OBJECTIVES: To evaluate if the immunofluorescence analysis of synovial tissue (ST) using antibodies against RANKL/OPG, conjugated with the immunophenotyping of lymphocytes and macrophages, could be of diagnostic and prognostic value in rheumatoid arthritis (RA) patients. METHODS: 3-year prospective study of 103 consecutive patients submitted to closed needle biopsy for diagnostic purposes. ST was analyzed with routine histologic techniques and immunofluorescence, using monoclonal antibodies against RANKL, OPG, CD163, CD68, CD4, CD8, interferon-gamma and CD19. Patients were prospectively evaluated with a clinical, laboratorial and radiological protocol. At the end of the follow-up patients were divided according to the final diagnosis. Results of the initial histologic evaluation were compared between the main diagnostic groups and in RA patients histologic data was correlated with clinical and radiologic outcome measures. RESULTS: The RANKL/OPG ratio and the inflammatory infiltrate were significatively higher in RA (n = 25) as compared to the same ratio observed in other inflammatory joint diseases (OIJD, n = 48) and in osteoarthritis (n = 17). The difference between RA and OIJD was specifically confirmed when the comparison involved spondyloarthropathy (n = 26). Final HAQ score and radiologic outcome were correlated with the density of intimal CD68+ macrophages. Radiologic progression was correlated with subintimal CD4+ lymphocytes and CD68+ macrophages and intimal CD68 and CD163+ macrophages. CONCLUSION: The quantification of the RANKL/OPG ratio and of the number of lymphocytes in the ST might be useful to differentiate RA from other inflammatory joint diseases. The ST number of CD4+ lymphocytes and macrophages are probable predictors of radiologic progression in RA patients.

Fonseca JE, Edwards JC, Blades S, Goulding NJ. · University College London, London, UK. · Arthritis Rheum. · Pubmed #12115225 links to  free full text

Abstract: OBJECTIVE: The cell surface glycoprotein CD163 is a member of the cysteine-rich scavenger receptor family, highly specific for leukocytes of the mononuclear phagocyte lineage. In vitro, it is induced by glucocorticoids, interleukin-6 (IL-6), and IL-10 and down-regulated by interferon-gamma (IFNgamma), indicating that it has a role in antiinflammatory or other immunomodulatory pathways. We assessed CD163 expression in microenvironments within rheumatoid arthritis (RA) synovium to clarify the relationships among CD4+ T lymphocytes, IFNgamma, and macrophage function in RA. METHODS: Double immunofluorescence and serial immunoenzymatic studies were performed on normal, osteoarthritic, and RA synovium and tonsil with antibodies to CD163, CD45, CD68, CD14, CD3, CD4, CD8, CD19, and IFNgamma. RESULTS: CD163 was observed on all CD14+ cells in synovium and tonsil with the exception of cells within larger T lymphocyte clusters in synovium and within tonsillar follicles. All brightly CD14+ cells in or around vessel walls (interpreted as immigrant monocytes) were CD163+. CD163 labeled fewer cells than did CD68 in synovial intima, but all CD45+ intimal cells were CD163+. CD4+,IFNgamma+ T lymphocytes in RA synovium were chiefly localized within clusters containing CD68+, CD163- cells. CONCLUSION: Within RA synovium, CD163 has major advantages as a macrophage marker and does not appear to be restricted to "mature" macrophages. CD163 discriminates between synovial macrophages and synovial intimal fibroblasts, which also stain positively for CD68 in diseased tissue.

Fonseca JE, Canhão H, Teixeira da CJ, Pereira da SJ, Queiroz MV. · Unidade de Reumatologia, Medicina IV, Santa Maria Hospital, Lisbon, Portugal. · Clin Rheumatol. · Pubmed #11954881 No free full text.

Abstract: With the aim of clarifying whether patient age could be an additional explanation for the differences in the clinical expression of rheumatoid arthritis (RA) found in different populations, we evaluated the possibility of patient age being a significant factor associated with global functional status, independent from disease duration. Our present results suggest that both disease duration and patient age are major factors in the global functional status of patients with RA, and that patient age is particularly important when a subgroup of patients with more than 60 years of age and more than 20 years of disease duration is considered. These data are relevant when comparing two different RA groups: not only should we have a similar mean age and mean disease duration, but also the subgroups of patients more than 60 years of age and with more than 20 years of disease duration should correspond to equivalent proportions in the populations studied.

Melo-Gomes JA, Ruperto N, Canhao H, Fonseca JE, Quintal A, Salgado M, Santos MJ, Anonymous00079. · Infantile, Adolescent and Young Adult Rheumatology Unit-Instituto Português de Reumatologia, Lisbon, Portugal. · Clin Exp Rheumatol. · Pubmed #11510315 No free full text.

Abstract: We report herein the results of the cross-cultural adaptation and validation into the Portuguese language of the parent's version of two health related quality of life instruments. The Childhood Health Assessment Questionnaire (CHAQ) is a disease specific health instrument that measures functional ability in daily living activities in children with juvenile idiopathic arthritis (JIA). The Child Health Questionnaire (CHQ) is a generic health instrument designed to capture the physical and psychosocial well being of children independently from the underlying disease. The Portuguese CHAQ CHQ were fully validated with 3 forward and 3 backward translations. A total of 130 subjects were enrolled: 69 patients with JIA (32% systemic onset, 19% polyarticular onset, 26% extended oligoarticular subtype, and 23% persistent oligoarticular subtype) and 61 healthy children. The CHAQ clinically discriminated between healthy subjects and JIA patients, with the systemic, polyarticular and extended oligoarticular subtypes having a higher degree of disability, pain, and a lower overall well being when compared to their healthy peers. Also the CHQ clinically discriminated between healthy subjects and JIA patients, with the systemic onset, polyarticular onset and extended oligoarticular subtypes having a lower physical and psychosocial well being when compared to their healthy peers. In conclusion the Portuguese version of the CHAQ-CHQ is a reliable, and valid tool for the functional, physical and psychosocial assessment of children with JIA.

Fonseca JE, Canhão H, Resende C, Saraiva F, da Costa JC, Pimentão JB, Carmo-Fonseca M, da Silva JA, de Queiroz MV. · Rheumatology Unit, Santa Maria Hospital, Lisbon, Portugal. · Clin Exp Rheumatol. · Pubmed #11072594 No free full text.

Abstract: OBJECTIVE: Routine histologic techniques are still the main procedure in the study of the synovial biopsy. The relationship between the typical histological changes of rheumatoid synovium and clinical manifestations has not been studied in detail. METHODS: With the aim of determining whether a simple semiquantitative method of evaluating the changes in closed synovial biopsies was of clinical value in assessing both the diagnosis and prognosis of rheumatoid arthritis (RA) patients, we evaluated retrospectively 72 synovial biopsy specimens (26 RA patients, 30 patients with other inflammatory diseases and 16 osteoarthritis patients). Scores (0-10) were assigned to each biopsy specimen for each of 6 histologic features: synoviocyte hyperplasia; fibrosis in the subsynovial layer; proliferating blood vessels; perivascular infiltrates of lymphocytes; focal aggregates of lymphocytes; and diffuse infiltrates of lymphocytes. Scores were compared between the 3 groups and also between the RA subgroups with early and late disease; positive and negative rheumatoid factor; with and without joint erosions; and with and without systemic disease. RESULTS: Significant differences in the mean global score (mean of the 6 scores) were found both between RA and osteoarthritis and between other inflammatory diseases and osteoarthritis (p < 0.01). The mean global score for RA was higher than the mean global score obtained for the other inflammatory diseases, but the difference was not significant. We found a significantly higher mean global score in the RA patients with erosions in comparison to the RA patients without erosions, this difference being particularly evident for the lymphocyte perivascular infiltrate (p < 0.05). There were no significant differences between the other RA subgroups. CONCLUSION: In this study we have identified differences, using routine histologic techniques, between the rheumatoid synovial membrane of patients with and without erosions. Based on our present observations we suggest that the intensity of inflammatory histological features and, in particular, a high percentage of vessels with perivascular lymphocyte infiltrate might be of prognostic value in RA.

Fonseca JE, Reis P, Saraiva F, Crujo C, Baptista A, da Silva JA, Viana Queiroz M. · Unidade de Reumatologia e Doenças Osseas Metabólicas, Serviço de Medicina IV, Lisboa, Portugal. · Clin Rheumatol. · Pubmed #10524558 No free full text.

Abstract: Liver involvement in patients with systemic lupus erythematosus (SLE) is considered rare. Previous treatment with potentially hepatotoxic drugs or viral hepatitis have usually been implicated as the main causes of liver disease in SLE patients. On the other hand, even after careful exclusion of these aetiologies, the problem remains whether to classify the patient as having a primary liver disease with associated autoimmune clinical and laboratory features resembling SLE, such as autoimmune hepatitis, or as having liver disease as a manifestation of SLE. We report the case of an elderly woman who presented with acute hepatitis, who had been diagnosed with SLE 14 years ago and who also had Sjögren's syndrome and anti-phospholipid's syndrome for several years. The histology depicted chronic active hepatitis and, after drug-induced hepatitis and viral hepatitis were excluded, the serological and clinical features were shown to be typical of liver damage caused by SLE. The patient was treated with azathioprine 100 mg/d and prednisone 30 mg/d. The clinical symptoms resolved in 10 days and the laboratory values were normal at the end of the first month of therapy. Prednisone was progressively reduced, during a period of 4 months, to 10 mg/d but azathioprine was kept to the same dose. One year after the diagnoses the patient is still in remission. Although uncommon, hepatic involvement is well recognised in SLE. The interest of this case lies in the differential diagnosis and recognition of this condition, which deserves an aggressive treatment.