Portuguese guidelines for the use of biological agents in rheumatoid arthritis - October 2011 update.

The authors present the revised version of the Portuguese Society of Rheumatology (SPR) guidelines for the treatment of Rheumatoid Arthritis (RA) with biological therapies. In these guidelines the criteria for introduction and maintenance of biological agents are discussed as well as the contraindications and procedures in the case of nonresponders. Biological treatment (with a tumour necrosis factor antagonist, abatacept or tocilizumab) should be considered in RA patients with a disease activity score 28 (DAS 28) equal to or greater than 3.2 despite treatment with at least 20mg-weekly-dose of methotrexate (MTX) for at least 3 months or, if such treatment is not possible, after 3 months of other conventional disease modifying drug or combination therapy. A DAS 28 score between 2.6 and 3.2 with a significant functional or radiological deterioration under treatment with conventional regimens could also constitute an indication for biological treatment. The treatment goal should be remission or, if that is not achievable, at least a low disease activity, defined by a DAS28 lower than 3.2, without significative functional or radiological worsening. The response criteria, at the end of the first 3 months of treatment, are a decrease of at least 0.6 in the DAS28 score. After 6 months of treatment res­ponse criteria is defined as a decrease greater than 1.2 in the DAS28 score. Non-responders, in accordance to the Rheumatologist's clinical opinion, should try a switch to another biological agent (tumour necrosis factor antagonist, abatacept, rituximab or tocilizumab).

[Practical guide for the use of biological agents in rheumatoid arthritis - December 2011 update]. / Guia prático de utilização de terapêuticas biotecnológicas na artrite reumatóide - actualização de Dezembro 2011.

The authors review the practical aspects of biological therapy use for rheumatoid arthritis patients, commenting safety issues before and after treatment initiation and the best treatment strategies to optimize efficacy.

From a neutrophilic synovial tissue infiltrate to a challenging case of rheumatoid arthritis.

The herein report illustrates how a synovial tissue heavily infiltrated by neutrophils in the first weeks of arthritis, can evolve in few months to a synovial infiltration by lymphocytes with a characteristic pattern of rheumatoid arthritis (RA). This observation suggests a critical initial role of neutrophils in RA onset, which is eventually surpassed by the activation of the adaptive immune system. In addition, this patient, despite the absence of rheumatoid factors and anti-cyclic citrullinated peptide antibodies, progressed to a highly destructive and disabling disease, that was only controlled adequately with rituximab, due to the lack of response to methotrexate and serious adverse effects with TNF blockers therapy.

Portuguese guidelines for the use of biological agents in rheumatoid arthritis - March 2010 update.

The authors present the revised version of the Portuguese Society of Rheumatology (SPR) guidelines for the treatment of rheumatoid arthritis (RA) with biological therapies. In these guidelines the criteria for introduction and maintenance of biological agents are discussed as well as the contraindications and procedures in the case of non-responders. Biological treatment should be considered in RA patients with a disease activity score 28 (DAS 28) superior to 3.2 despite treatment with 20mg/week of methotrexate (MTX) for at least 3 months or, if such treatment is not possible, after 6 months of other conventional disease modifying drug or combination therapy. A DAS 28 score between 2.6 and 3.2 with a significant functional or radiological deterioration under treatment with conventional regimens could also constitute an indication for biological treatment. The treatment goal should be remission or, if that is not achievable, at least a low disease activity, characterized by a DAS28 lower than 3.2, without significative functional or radiological worsening. The response criteria, at the end of the first 3 months of treatment, are a decrease of 0.6 in the DAS28 score. After 6 months of treatment response criteria is defined as a decrease of more than 1.2 in the DAS28 score. Non-responders, in accordance to the Rheumatologist's clinical opinion, should try a switch to another biological agent (tumour necrosis factor antagonist, abatacept, rituximab or tocilizumab).

Ankylosing spondylitis susceptibility and severity--contribution of TNF gene promoter polymorphisms at positions -238 and -308.

Ankylosing spondylitis (AS) is a chronic inflammatory disease in which genetic factors play a central role. The efficacy of TNF blockers has reoriented research in this field in order to explain the influence of TNF in AS pathogenesis. The objective of this study was to access the influence of single nucleotide polymorphisms (SNPs) at positions -308 and -238 of the promoter region of TNF gene on AS susceptibility and prognosis. SNPs were determined by restriction fragment length polymorphisms in patients and controls. AS patients exhibited a decreased frequency of the A allele at position -238 (10%) when compared with controls (18%), suggesting that this could be a protective factor for disease susceptibility. In addition, the -308 GA/AA genotypes were associated with later disease onset in AS patients. These results suggest that TNF gene promoter polymorphisms at positions -238 and -308 could have a small influence on AS susceptibility and prognosis.

Persistent low grade synovitis without erosive progression in magnetic resonance imaging of rheumatoid arthritis patients treated with infliximab over 1 year.

Disease remission is only reached by a minority of rheumatoid arthritis (RA) patients treated with infliximab. Radiological assessment reported in clinical trials support the view that even under persistent inflammatory activity there is no further structural damage. Magnetic resonance imaging (MRI) allows a highly accurate detection of synovitis, bone edema, and erosions, constituting the ideal instrument for the evaluation of treatment response. The goal of this study was to evaluate MRI changes over 1 year in RA patients treated with infliximab. Four RA patients refractory to methotrexate (MTX) therapy were treated with infliximab 3 mg/kg 8/8 weeks and followed up for 1 year. Disease Activity Score (DAS28) was measured in the day of each infliximab administration. MRI was performed at baseline, 3 months, and 1 year. A simplified OMERACT RA MRI scoring (RAMRIS) was applied to the dominant wrist: synovitis (0-3) was measured in the intercarpal-carpometacarpal joints (CMTJ); bone edema (0-39) and erosions (0-130) in the base of the metacarpal and wrist bones. Baseline DAS28 was superior to 3.2 in all patients (ranging from 4.8 up to 6.2). At 14 weeks, DAS28 was still superior to 3.2 (ranging from 3.5 up to 4.6) and at 46 weeks all patients have responded, however without having achieved clinical remission, as DAS28 was still above 2.6 (ranging from 2.6 up to 3.4). MRI showed that synovitis was reduced in all patients to a score of 1, bone edema was slightly reduced (10% reduction), and erosive score was unchanged (baseline values ranging from 2 up to 20). Despite persistent low disease activity, these four RA patients treated with infliximab had stable simplified RAMRIS erosive scores over 1 year. These results support the view that there might be an uncoupling process between inflammation and bone erosions when tumor necrosis factor alpha is targeted in RA.

Tumor necrosis factor-alpha -308 genotypes influence inflammatory activity and TNF-alpha serum concentrations in children with juvenile idiopathic arthritis.

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.

Assessment of laboratory measurements and -308 TNFalpha gene promoter polymorphisms in normal bone mineral density.

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.

[Fibrous dysplasia of bone--a case of polyostotic fibrous dysplasia]. / Displasia fibrosa ósse--um caso clinico de displasia fibrosa poliostótica.

Fibrous Dysplasia FD of bone is a rare non-inheritable congenital disease characterized by a focal proliferation of fibrous tissue in the bone marrow leading to osteolytic lesions deformities and fractures. FD can be presented in a monostotic or polyostotic form this last one is usually more severe. FD primarily affects adolescents and young adults and in some cases in an asymptomatic way. We describe the case of a male patient with long evolution form of polyostotic fibrous dysplasia of bone with delayed clinical presentation. It is also highlighted the importance of an activity and involvement form evaluation as well as possible endocrine abnormalities associated in order to establish the correct treatment and prognosis.

Contribution for new genetic markers of rheumatoid arthritis activity and severity: sequencing of the tumor necrosis factor-alpha gene promoter.

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.

[Tuberculosis in rheumatic patients treated with tumour necrosis factor alpha antagonists: the Portuguese experience]. / Tubereulose em doentes reumáticos tratados com antagonistas do factor de necrose tumoral alfa: a experiência Portuguesa.

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.

[Eating habits and life styles in a Portuguese population--protective and risk factors for osteoporosis]. / Avaliação de hábitos alimentares e estilos de vida numa população portuguesa - factores de risco e de protecção para a osteoporose.

BACKGROUND: Physical activity, calcium intake, coffee, alcohol and tobacco consumption can influence OP risk. These factors can be modifiable and, in some cases, their control may contribute for the OP prevention. OBJECTIVES: To identify and to evaluate associations between modifiable risk or protective factors of OP, age and sex in Portuguese healthy subjects. To assess the knowledge about osteoporosis in the studied population stratified by age and sex. METHODS: Cross-sectional study of randomly selected healthy subjects aged 18 to 29 years or more than 50 years. Information was obtained on demographic, clinical, lifestyle and behavioural characteristics using a standard protocol. Alcohol and tobacco consumption, calcium intake, physical activity and knowledge about osteoporosis were quantified. RESULTS: 301 subjects, 199 females and 102 males were evaluated. They have been separated in four groups stratified by sex and age. All the individuals presented calcium intake below the recommended levels and, except for the group of young males, physical activity was very low. Tobacco consumption was higher in the young female group and had been initiated earlier. Alcohol consumption was higher in male individuals with more than 49 years, being wine the predominant drink, while younger preferred beer. Women older than 49 years presented reduced calcium intake and physical activity. DISCUSSION: Risk factors for OP have been identified in age groups prone to develop OP The differences found in the evaluated parameters between age and sex groups must be considered in campaigns for OP prevention, promoting calcium intake, physical activity and the fight against tobacco consumption.

Diabetes fosforada idiopática do adulto: a propósito de um caso clínico / Acquired hypophosphatemic osteomalacia: case report

O fósforo é elemento essencial e muitas vezes pouco valo rizado na prática clínica. A diabetes fosforada idiopática do adulto (DFIA) é causa de alteraçao da homeostase do fósforo, resultante de defeito da reabsorçao deste elemento no túbulo proximal, de causa nao conhecida. Caracteriza-se clinicamente por raquialgias, radiculalgias, fadiga, dores ósseas e articulares e sintomas neuropsiquiátricos. As características laboratoriais típicas sao: hipofos fatemia, hiperfosfatúria e índices de reabsorçao tubular do fósforo que demons tram diminuiçao da reabsorçao renal desse elemento. A hipofosfatemia moderada que se verifica na DFIA provoca alteraçao do metabolismo ósseo, que resulta em osteopenia. A terapeutica com fósforo e vitamina D leva a normalizaçao da fosfa temia e dos índices de reabsorçao renal de fósforo, a melhoria clínica e o aumento da densidade mineral óssea. Os autores escrevem o caso de paciente com DFIA e discutem alguns pontos de etiopatogenia, clínica e terapeutica dessa doença