Structured and prompt treatment of early arthritis in clinical practice leverages window of opportunity and leads to excellent clinical outcomes: an innovative retrospective cohort study.

OBJECTIVES: With this work, we evaluated the impact of the Lisbon Early ARthritis cliNic (LEARN) on untreated inflammatory arthritis clinical and patient-reported outcomes. METHODS: A retrospective cohort study enrolled patients in LEARN since its inception. Patients were followed for 12 months and treated to achieve disease remission. Clinical, structural, and quality of life outcomes were assessed. The early arthritis module of the Portuguese Rheumatic Diseases Registry (Reuma.pt) is described. RESULTS: We assessed 292 patients between 2015 and 2022. Mean symptom duration and DAS-28-4 V-ESR at baseline were 6.2 ± 3.5 months and 5.6 ± 1.3, respectively. Rheumatoid arthritis (56.4%; 40.1% seropositive) and psoriatic arthritis (12.4%) were the most common diagnoses. Most patients were treated with methotrexate (75.3%) combined with low-dose oral prednisolone (88.1%). At 12 months, a mean ΔDAS28-4 V-ESR improvement of 2.3 ± 0.4 was registered, with 29.5% and 48.9% of patients achieving remission (DAS28-4 V-ESR < 2.6) or low disease activity (DAS28-4 V-ESR < 3.2), respectively. Among RA patients only, these figures were 20.6% and 46.6%, respectively. A clinically meaningful functional improvement was observed in 72.1% of the patients. Structural progression was limited, affecting only 16.1% of the patients. Fatigue, anxiety, depression, and quality of life also improved substantially, translated by improvements in FACIT, HADS, EQ5D, and SF-36 scores. CONCLUSIONS: A structured, dedicated approach to patients with early arthritis resulted in good clinical, structural, and functional outcomes. Furthermore, our findings suggest the window of opportunity for early intervention may have implications for mental health and global well-being. Key Points • Patient assessment is facilitated by reliable electronic clinical records, such as the early arthritis module of the Rheumatic Diseases Portuguese Register (Reuma.pt) which we describe here for the first time. • Inflammatory arthritis was confirmed in the majority of patients observed, but the time to first appointment was above the recommended. • Prompt start of conventional therapy allowed significant disease activity improvement and remission to be achieved in about one-third of the patients. • Key patient-reported outcomes elucidate disease impact and confirm the benefit of early treatment initiation, suggesting a window of opportunity also for mental health and global well-being.

HLA alleles and HLA-B27 haplotypes associated with susceptibility and severity of ankylosing spondylitis in a Portuguese population.

Human leukocyte antigen (HLA)-B27 is the mostly known major histocompatibility complex (MHC) gene associated with ankylosing spondylitis (AS). Nonetheless, there is substantial evidence that other MHC genes appear to be associated with the disease, although it has not yet been established whether these associations are driven by direct associations or by linkage disequilibrium (LD) mechanisms. We aimed to investigate the contributions of HLA class I and II alleles and B27-haplotypes for AS in a case-control study. A total of 188 HLA-B27 AS cases and 189 HLA-B27 healthy controls were selected and typed for HLA class I and II by the Luminex polymerase chain reaction-sequence specific oligonucleotide probe (PCR-SSOP) method. Allelic and haplotypic distributions were estimated by maximum likelihood method using Arlequin v3.11 and statistical analysis were performed by Stata10.1. No associations were found between non-HLA-B27 loci and AS susceptibility, but several associations were observed for phenotypic features of the disease. DRB1*08 was identified as a risk factor for uveitis and DQB1*04 seems to provide protection for AS severity (functional, metrological and radiological indexes). A*02/B27/C*02/DRB1*01/DQB1*05 [P<0.0001; odds ratio (OR) = 39.06; 95% confidence interval (CI) (2.34-651)] is the only haplotype that seems to confer susceptibility to AS. Moreover, the haplotype A*02/B27/C*01/DRB1*08/DQB1*04 seems to provide protection for disease functional and radiological repercussions. Our findings are compatible with the hypothesis that other genes within the HLA region besides HLA-B27 might play some role in AS susceptibility and severity.

Body composition phenotypes in systemic lupus erythematosus and rheumatoid arthritis: a comparative study of Caucasian female patients.

OBJECTIVES: The amount and distribution of fat and lean mass have important implications for health and systemic inflammation may represent a risk for altered body composition. The aim of this study was to analyse whether changes in body composition are similarly associated with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), two inflammatory conditions of different pathogenesis. METHODS: Body mass index (BMI), waist circumference, fat mass (FM) and fat-free mass (FFM) were measured in 92 women with SLE, 89 with RA and 107 controls. Results were compared among the 3 groups and correlations of FM percentage were explored within SLE and RA. RESULTS: Abnormal body composition was more frequent in women with SLE and RA than in non-inflammatory controls, despite having a similar BMI. RA diagnosis was significantly associated with overfat (OR=2.782, 95%CI 1.470-5.264; p=0.002) and central obesity (OR=2.998, 95%CI 1.016-8.841; p=0.04), while sarcopenia was more common among SLE (OR=3.003; 95%CI 1.178-7.676; p=0.01). Sarcopenic obesity, i.e. the coexistence of overfat with sarcopenia, was present in 6.5% of SLE and 5.6% of RA women, but no controls. Independent correlations of FM percentage in women with SLE included smoking, disease activity and CRP. In RA, education, disease activity and cumulative corticosteroid dose were identified as independent predictors of FM percentage. CONCLUSIONS: Women with SLE or RA diagnosis are more likely to have abnormal body composition phenotype, with some differences existing between these two conditions. Changes in body composition are partly explained by the inflammatory burden of disease and its treatment.

Host immune genetic variations influence the risk of developing acute myeloid leukaemia: results from the NuCLEAR consortium.

The purpose of this study was to conduct a two-stage case control association study including 654 acute myeloid leukaemia (AML) patients and 3477 controls ascertained through the NuCLEAR consortium to evaluate the effect of 27 immune-related single nucleotide polymorphisms (SNPs) on AML risk. In a pooled analysis of cohort studies, we found that carriers of the IL13rs1295686A/A genotype had an increased risk of AML (PCorr = 0.0144) whereas carriers of the VEGFArs25648T allele had a decreased risk of developing the disease (PCorr = 0.00086). In addition, we found an association of the IL8rs2227307 SNP with a decreased risk of developing AML that remained marginally significant after multiple testing (PCorr = 0.072). Functional experiments suggested that the effect of the IL13rs1295686 SNP on AML risk might be explained by its role in regulating IL1Ra secretion that modulates AML blast proliferation. Likewise, the protective effect of the IL8rs2227307 SNP might be mediated by TLR2-mediated immune responses that affect AML blast viability, proliferation and chemorresistance. Despite the potential interest of these results, additional functional studies are still warranted to unravel the mechanisms by which these variants modulate the risk of AML. These findings suggested that IL13, VEGFA and IL8 SNPs play a role in modulating AML risk.

Chronic arthritis directly induces quantitative and qualitative bone disturbances leading to compromised biomechanical properties.

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).

Association of IL23R and ERAP1 genes with ankylosing spondylitis in a Portuguese population.

OBJECTIVE: Association between ankylosing spondylitis (AS) and two genes, ERAP1 and IL23R, has recently been reported in North American and British populations. The population attributable risk fraction for ERAP1 in this study was 25%, and for IL23R, 9%. Confirmation of these findings to ERAP1 in other ethnic groups has not yet been demonstrated. We sought to test the association between single nucleotide polymorphisms (SNPs) in these genes and susceptibility to AS among a Portuguese population. We also investigated the role of these genes in clinical manifestations of AS, including age of symptom onset, the Bath Ankylosing Spondylitis Disease Activity, Metrology and Functional Indices, and the modified Stoke Ankylosing Spondylitis Spinal Score. METHODS: The study was conducted on 358 AS cases and 285 ethnically matched Portuguese healthy controls. AS was defined according to the modified New York Criteria. Genotyping of IL23R and ERAP1 allelic variants was carried out with TaqMan allelic discrimination assays. Association analysis was performed using the Cochrane-Armitage and linear regression tests of genotypes as implemented in PLINK for dichotomous and quantitative variables respectively. A meta-analysis for Portuguese and previously published Spanish IL23R data was performed using the StatsDirect Statistical tools, by fixed and random effects models. RESULTS: A total of 14 nsSNPs markers (8 for IL23R, 5 for ERAP1, 1 for LN-PEP) were analysed. Three markers (2 for IL23R and 1 for ERAP1) showed significant single-locus disease associations, confirming that the association of these genes with AS in the Portuguese population. The strongest associated SNP in IL23R was rs1004819 (OR=1.4, p=0.0049), and in ERAP1 was rs30187 (OR=1.26, p=0.035). The population attributable risk fractions in the Portuguese population for these SNPs are 11% and 9.7% respectively. No association was seen with any SNP in LN-PEP, which flanks ERAP1 and was associated with AS in the British population. No association was seen with clinical manifestations of AS. CONCLUSION: These results show that IL23R and ERAP1 genes are also associated with susceptibility to AS in the Portuguese population, and that they contribute a significant proportion of the population risk for this disease.

Rebalancing bone turnover in favour of formation with strontium ranelate: implications for bone strength.

This review updates our current knowledge on the mechanism of action of strontium ranelate and analyses the way it rebalances bone turnover and how it influences bone biomechanics. Strontium ranelate is able to increase pre-osteoblast replication, osteoblast differentiation, collagen type I synthesis and bone matrix mineralization probably through a calcium-sensing receptor (CaR)-dependent mechanism. Paralleling this anabolic effect there is inhibition of osteoclast differentiation and activity mediated by an increase in osteoprotegerin (OPG) and a decrease in RANK ligand (RANKL). The overall effect is a rebalanced bone turnover in favour of improved bone geometry, cortical thickness, trabecular bone morphology and intrinsic bone tissue quality, which translates into enhanced bone strength.

Factors influencing calcaneus quantitative ultrasound measurements in an urban population.

OBJECTIVE: To estimate the effect of demographic, social, behavioural and anthropometric factors on quantitative ultrasound (QUS) parameters in an urban population. METHODS: Cross-sectional evaluation of consecutive subjects selected as part of the EPIPorto study, Portugal. Information was obtained on demographic, social, clinical and behavioural characteristics using a standard protocol. Calcaneus QUS parameters (Broadband Ultrasound Attenuation-BUA, and Speed of Sound-SOS) were obtained for men and women, stratified by age group. Comparisons according to exposure levels were made using the Kruskal-Wallis test and the multivariate effect on QUS parameters was estimated by linear regression. RESULTS: 1482 consecutive subjects (1010 females and 472 males), aged from 18 to 92 years. Higher levels of QUS parameters were found in the younger groups and progressive decrease with age were reported. Men showed higher values as compared to women in all parameters and differences between them increased with age. Differences were significant for BUA after the age of 39 and for SOS after the age of 59. In women, the multivariate model showed that age, body mass index (BMI) and smoking status were independent predictors of BUA and SOS. In men, age, BMI and calcium intake were significantly associated with BUA and SOS. CONCLUSION: The reference values in our Portuguese population are similar to others obtained in Southern European countries. In the Portuguese population, QUS parameters have age, sex and BMI as its major determinants. In addition, BUA and SOS may reflect specific bone characteristics influenced by a different set of independent determinants.

Portuguese recommendations for the prevention, diagnosis and management of primary osteoporosis - 2018 update.

BACKGROUND: Advances in osteoporosis (OP)case definition, treatment options, optimal therapy duration and pharmacoeconomic evidence in the national context motivated the Portuguese Society of Rheumatology (SPR) to update the Portuguese recommendations for the diagnosis and management of osteoporosis published in 2007. METHODS: SPR bone diseases' working group organized meetings involving 55 participants (rheumatologists, rheumatology fellows and one OP specialist nurse) to debate and develop the document. First, the working group selected 11 pertinent clinical questions for the diagnosis and management of osteoporosis in standard clinical practice. Then, each question was investigated through literature review and draft recommendations were built through consensus. When insufficient evidence was available, recommendations were based on experts' opinion and on good clinical practice. At two national meetings, the recommendations were discussed and updated. A draft of the recommendations full text was submitted to critical review among the working group and suggestions were incorporated. A final version was circulated among all Portuguese rheumatologists before publication and the level of agreement was anonymously assessed using an online survey. RESULTS: The 2018 SPR recommendations provide comprehensive guidance on osteoporosis prevention, diagnosis, fracture risk assessment, pharmacological treatment initiation, therapy options and duration of treatment, based on the best available evidence. They attained desirable agreement among Portuguese rheumatologists. As more evidence becomes available, periodic revisions will be performed. Target audience and patient population: The target audience for these guidelines includes all clinicians. The target patient population includes adult Portuguese people. Intended use: These recommendations provide general guidance for typical cases. They may not be appropriate in all situations - clinicians are encouraged to consider this information together with updated evidence and their best clinical judgment in individual cases.

Delayed neutrophil apoptosis in very early rheumatoid arthritis patients is abrogated by methotrexate therapy.

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.

A diagnosis of disseminated tuberculosis based on knee arthroscopic guided synovial biopsy in the context of monoarthritis.

Accounting for 2.2-4.7% of all tuberculosis cases in Europe and USA and around 10-15% of extra-pulmonary tuberculosis cases, osteoarticular tuberculosis tends to be chronic, slowly progressive and destructive. We report the case of an 81-year-old male with 3 weeks of progressively worsening pain, swelling and limited range of motion of the left knee. A knee arthroscopy was performed for synovial biopsy at our department revealing diffuse synovitis with scarce villi formation. The positive polymerase chain reaction assay for Mycobacterium tuberculosis in the synovial tissue allowed the establishment of the diagnosis and synovium histology showed caseating granulomas. A lengthy delay between first symptoms of osteoarticular tuberculosis and the beginning of treatment has been reported. A high index of suspicion, synovial membrane biopsy and appropriate microbiologic testing are fundamental to avoid a delay in diagnosis.

Incidence and predictors of cardiovascular events in a cohort of patients with rheumatoid arthritis.

INTRODUCTION: An excess in cardiovascular (CV) morbidity and mortality has been recognized in Rheumatoid Arthritis (RA) patients when compared to the general population. Given the paucity of prospective data, our aim was to estimate the incidence of CV events and the contribution of traditional CVD risk factors and RA-related parameters to future events. METHODS: Incident fatal and non-fatal CV events (hospitalizations due to unstable angina, myocardial infarction, coronary artery revascularization procedures, stroke, or CV death) were assessed in a prospective cohort of RA women followed since 2007 and without CV events at cohort entry. The presence of traditional CV risk factors, disease characteristics, medication, carotid ultrasound, and biomarkers of inflammation and endothelial activation were evaluated at baseline. Univariate Cox proportional hazard models were used to identify risk factors for CV events. RESULTS: Among 106 women followed over 565 patient-years we identified 4 CV events (1 fatal stroke, 2 myocardial infarction and 1 unstable angina), which contributed to an incidence rate of 7 per 1000 person-years (95%CI 2.0- 13.9). Patients who developed CV events were older, but the distribution of other traditional CV risk factors was otherwise similar in both groups. Also, corticosteroid dosage and proportion of patients with carotid atherosclerotic plaques was higher in those with CV events. Erythrocyte sedimentation rate (ESR) (HR 1.036; 95%CI 1.005-1.067) and soluble intercellular adhesion molecule-1 (sICAM-1) serum levels (HR 1.002; 95%CI 1.000-1.003) significantly contributed to CV events. These results remained significant after adjusting for patients' age. CONCLUSION: We found an incidence of cardiovascular events in women with RA of 7 per 1000 patent-years. This value is similar to that found in other Portuguese cohort of RA patients1 and much higher than the incidence reported for the general Portuguese population. Markers of inflammation and endothelial activation contributed significantly to CV events, but the limited number of events prevents further analysis.

2016 update of the Portuguese recommendations for the use of biological therapies in children and adolescents with Juvenile Idiopathic Arthritis.

OBJECTIVE: To provide evidence-based guidance for the rational and safe prescription of biological therapies in children and adolescents with juvenile idiopathic arthritis (JIAs) considering the latest available evidence and the new licensed biologics. METHODS: Rheumatologists and Pediatricians with expertise in Pediatric Rheumatology updated the recommendations endorsed by the Portuguese Society of Rheumatology and the Portuguese Society of Pediatrics based on published evidence and expert opinion. The level of agreement with final propositions was voted using an online survey. RESULTS: In total, 20 recommendations to guide the use of biological therapy in children and adolescents with JIAs are issued, comprising 4 general principles and 16 specific recommendations. A consensus was achieved regarding the eligibility and response criteria, maintenance of biological therapy, and procedures in case of non-response, for each JIA category. Specific recommendations concerning safety procedures were also updated. CONCLUSIONS: These recommendations take into account the specificities of each JIA category and are intended to continuously improve the management of JIA patients.

Multiplexed immunoassay for detection of rheumatoid factors by FIDISTM technology.

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).

Inflammatory cell infiltrate and RANKL/OPG expression in rheumatoid synovium: comparison with other inflammatory arthropathies and correlation with outcome.

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.

Reinnervation of post-arthritic joints in the rat.

OBJECTIVE: To clarify the role of articular innervation during the acute and post-arthritic phases, we investigated the changes taking place over time in the nerve fibers from joint tissues of adjuvant arthritic rats. METHODS: Nerve densities (i.e., the number of nerve fibers observed per unit area of tissue section) were estimated in periarticular tissues, synovium and epiphysis from ankle joints. Nerves were identified by immunofluorescence microscopy using antibodies against general neuronal markers (Protein Gene Product 9.5, synaptophysin, neurofilaments and Schwann cells), and markers specific for either sensory or sympathetic nerves (Substance P, calcitonin gene related peptide, neuropeptide tyrosine and its C-terminal flanking peptide, and the catecholamine synthesising enzyme tyrosine hydroxilase). RESULTS: In arthritic rats, the density of nerve fibers in the periarticular tissues, epiphysis and synovium was significantly reduced when compared to control animals. This decrease was observed using antibodies for both non releasable neuronal products (Protein Gene Product 9.5, synaptophysin, neurofilaments and Schwann cells) and neuropeptides (Substance P, calcitonin gene related peptide, neuropeptide tyrosine and its C-terminal flanking peptide), thus suggesting the existence of a structural nervous lesion with the parallel depletion of peptides. As the clinical arthritis subsided, there was a progressive reinnervation of all the articular structures analysed, which often exceeded the density of nerves in the control animals. CONCLUSION: This work supports a close relationship between the nervous system and arthritis. We propose that cycles of nerve destruction and regeneration may be related to the characteristic periods of remission and activity of some forms of chronic arthritis.

Dual effects of caspase-1, interleukin-1 beta, tumour necrosis factor-alpha and nerve growth factor receptor in inflammatory myopathies.

OBJECTIVE: To analyse the expression of factors potentially involved in skeletal muscle degeneration and regeneration in dermatomyositis (DM), systemic sclerosis (SSc), polymyositis (PM), systemic lupus erythematosus (SLE) and non-inflammatory myopathies. METHODS: Immunohistochemical staining of skeletal muscle biopsies (10 DM, 10 SSc, 10 PM, 10 SLE, 10 non-inflammatory myopathies) for tumour necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta), activated caspase-1, pan-macrophage marker CD68, inducible nitric oxide synthase (NOS2) and nerve growth factor receptor (NGFR). TechMate staining robot and biotin-streptavidin protocol were used. RESULTS: Expression of TNF-alpha, IL-1 beta, caspase-1 and NOS2 was found in the cytoplasm and sarcolemma of dystrophic skeletal muscle fibres. TNF-alpha and IL-1 beta immunoreactive profiles were faint and few and close to satellite nuclei-containing regenerating muscle fibres both in inflammatory and non-inflammatory myopathies. NGFR expression was found in comparable areas. In non-inflammatory inherited myopathies more nuclei were caspase-1 immunoreactive whereas caspase-1 expression was rarely seen in inflammatory myopathies, implying regeneration of the affected muscle fibres. CONCLUSION: Prominent expression of the proinflammatory factors TNF-alpha, IL-1 beta and NOS2 and caspase-1 is associated with muscle fibre damage, albeit when expressed to a low degree these factors may, like NGFR, contribute to muscle regeneration and healing.

Fibrodysplasia ossificans progressiva: report of two cases.

Fibrodysplasia Ossificans Progressiva (FOP) is a rare hereditary connective tissue disease, genetically inherited as an autosomal dominant trait with complete penetrance but variable expressivity. Onset is typically in childhood and progressive involvement of the spine and proximal extremities leads to immobility and articular dysfunction. We present two cases with the typical features of FOP and a review of the pathogenesis, clinical manifestations and treatment options of this rare disease.

The Portuguese version of the Childhood Health Assessment Questionnaire (CHAQ) and the Child Health Questionnaire (CHQ).

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.