Portuguese multidisciplinary recommendations for non-pharmacological and non-surgical interventions in patients with rheumatoid arthritis.

BACKGROUND: Patients with rheumatoid arthritis (RA) report significant levels of disease impact, which are improved, but not fully abrogated by immunosuppressive therapy, even when remission is achieved. This imposes the need for adjuvant interventions targeting the uncontrolled domains of disease impact. Non-pharmacological interventions are widely used for this purpose, but they have not been the object of professional recommendations or guidelines. OBJECTIVE: To propose multidisciplinary recommendations to inform clinical care providers regarding the employment of non-pharmacological and non-surgical interventions in the management of patients with RA. METHODS: The EULAR standardized operating procedures for the development of recommendations were followed. First, a systematic literature review was performed. Then, a multidisciplinary Technical Expert Panel (TEP) met to develop and discuss the recommendations and research agenda. For each developed recommendation i) the level of evidence and grade of recommendation were determined, and ii) the level of agreement among TEP members was set. A recommendation was adopted if approved by ≥75% of the TEP members, and the level of agreement was considered high when ≥8. All relevant national societies were included in this construction process to attain their endorsement. RESULTS: Based on evidence and expert opinion, the TEP developed and agreed on five overarching principles and 12 recommendations for non-pharmacological and non-surgical interventions in patients with RA. The mean level of agreement between the TEP members ranged between 8.5 and 9.9. The recommendations include a broad spectrum of intervention areas, such as exercise, hydrokinesiotherapy, psychological interventions, orthoses, education, general management of comorbidities, among others; and they set the requirements for their application. CONCLUSIONS: These recommendations are based on the consensus judgment of clinical experts from a wide range of disciplines and patients' representatives from Portugal. Given the evidence for effectiveness, feasibility and safety, non-pharmacological and non-surgical interventions should be an integral part of standard care for people with RA. It is hoped that these recommendations should be widely implemented in clinical practice. The target audience for these recommendations includes all health professionals involved in the care of patients with RA. The target patient population includes adult Portuguese people with RA.

Reuma.pt/vasculitis - the Portuguese vasculitis registry.

BACKGROUND: The vasculitides are a group of rare diseases with different manifestations and outcomes. New therapeutic options have led to the need for long-term registries. The Rheumatic Diseases Portuguese Register, Reuma.pt, is a web-based electronic clinical record, created in 2008, which currently includes specific modules for 12 diseases and > 20,000 patients registered from 79 rheumatology centres. On October 2014, a dedicated module for vasculitis was created as part of the European Vasculitis Society collaborative network, enabling prospective collection and central storage of encrypted data from patients with this condition. All Portuguese rheumatology centres were invited to participate. Data regarding demographics, diagnosis, classification criteria, assessment tools, and treatment were collected. We aim to describe the structure of Reuma.pt/vasculitis and characterize the patients registered since its development. RESULTS: A total of 687 patients, with 1945 visits, from 13 centres were registered; mean age was 53.4 ± 19.3 years at last visit and 68.7% were females. The most common diagnoses were Behçet's disease (BD) (42.5%) and giant cell arteritis (GCA) (17.8%). Patients with BD met the International Study Group criteria and the International Criteria for BD in 85.3 and 97.2% of cases, respectively. Within the most common small- and medium-vessel vasculitides registered, median [interquartile range] Birmingham Vasculitis Activity Score (BVAS) at first visit was highest in patients with ANCA-associated vasculitis (AAV) (17.0 [12.0]); there were no differences in the proportion of patients with AAV or polyarteritis nodosa who relapsed (BVAS≥1) or had a major relapse (≥1 major BVAS item) during prospective assessment (p = 1.00, p = 0.479). Biologic treatment was prescribed in 0.8% of patients with GCA, 26.7% of patients with AAV, and 7.6% of patients with BD. There were 34 (4.9%) deaths reported. CONCLUSIONS: Reuma.pt/vasculitis is a bespoke web-based registry adapted for routine care of patients with this form of rare and complex diseases, allowing an efficient data-repository at a national level with the potential to link with other international databases. It facilitates research, trials recruitment, service planning and benchmarking.

The Portuguese Society of Rheumatology position paper on the use of biosimilars - 2017 update.

Biosimilars are new and more affordable similar versions of previously approved reference biological drugs. Following the approval of the first monoclonal antibody biosimilar in 2013, the Portuguese Society of Rheumatology issued a position paper on the use of biosimilars in rheumatic conditions covering efficacy, safety, extrapolation, interchangeability, substitution and pharmacovigilance. However, as this is a rapidly evolving field, it was felt that the knowledge and evidence gathered since then justified an update of these statements. Literature searches on these issues were performed and the search results were presented and discussed in a national meeting. Portuguese rheumatologists considered that affordability should be taken into consideration when initiating a biological drug, but other factors were equally important. In patients already on reference biological treatment, switch to a more affordable biosimilar is desirable, provided a set of conditions is rigorously met. Automatic substitution is not acceptable and current evidence is insufficient to support interchangeability. Extrapolation of clinical indications is endorsed by Portuguese rheumatologists, and the statements on safety, pharmacovigilance and traceability are in accordance with the previous position paper.

DAS28, CDAI and SDAI cut-offs do not translate the same information: results from the Rheumatic Diseases Portuguese Register Reuma.pt.

OBJECTIVES: . The 28-joint DAS (DAS28), clinical disease activity index (CDAI) and simplified disease activity index (SDAI) are indices frequently used to assess disease activity in RA patients. Cut-off values were defined to classify the states of RA disease activity: remission, low, moderate and high. The aim of this work was to assess disease activity states classified by DAS28, CDAI and SDAI and to analyse their agreement in the Rheumatic Diseases Portuguese Register Reuma.pt. METHODS: . A total of 2795 patients and 14 440 visits were selected from Reuma.pt for analysis. Pearson's correlation coefficients (PCCs) were calculated for the three indices. McNemar's chi-squared tests, PCCs and kappa statistics were performed to analyse and compare the distribution of visits among all disease activity states and indices. RESULTS: A strong correlation was found between the three indices throughout the 14 440 visits: r = 0.874 for DAS28/CDAI, r = 0.877 for DAS28/SDAI and r = 0.984 for CDAI/SDAI (all PCCs with P < 0.0001). However, when categorization in the different disease activity states was analysed, McNemar's chi-squared tests and PCCs revealed significant disagreement between the cut-offs of the three indices. CONCLUSION: DAS28, CDAI and SDAI cut-offs do not translate into the same clinical information in Reuma.pt. Although this might be expected for the original DAS28 cut-offs, when compared with CDAI and SDAI significant disagreement was also found for the DAS28 modified cut-offs. For visits where patients are in CDAI or SDAI remission, we also find disagreement between these two indices, which may contradict previous conclusions that acute phase reactants add little to composite disease activity indices for RA.

A preliminary algorithm introducing immunogenicity assessment in the management of patients with RA receiving tumour necrosis factor inhibitor therapies.

INTRODUCTION: Clinical remission is today the treatment goal for rheumatoid arthritis (RA), which requires fast and assertive therapeutic decisions for a tight control of disease activity. Few objective parameters are available to guide clinical decisions, particularly in switcher patients. We designed a preliminary algorithm introducing immunogenicity assessment in the current approach to patients with RA receiving tumour necrosis factor inhibitors (TNFi). OBJECTIVE: To evaluate the concordance between the new algorithm and current clinical practice, comparing the effectiveness of 'immunogenicity-based' versus 'empirical-based' switches in a cohort of patients with established RA receiving biologics. METHODS: EULAR therapeutic response was evaluated in 105 patients with RA (naive or switchers) over one year, through generalised estimation equation (GEE) analyses. Serum drug trough levels were assessed by ELISA and antidrug antibodies (ADAb) by Bridging ELISA. RESULTS: During follow-up, 48.6% of patients had therapeutic decisions concordant with the proposed algorithm (Group A), and 51.4% had discordant decisions (Group B). One year after the therapeutic decision, patients from Group A had a higher probability of achieving response (OR=7.91, p<0.001, 95% CI 3.27 to 19.13) and low disease activity (OR=9.77, p<0.001, 95% CI 4.69 to 20.37) than patients in Group B. CONCLUSIONS: Immunogenicity assessment might help to optimise therapeutic decisions, leading to a better control of disease activity with significantly better clinical outcomes in patients with RA receiving TNFi.

Interleukin-6 promoter polymorphism -174 G/C is associated with nephritis in Portuguese Caucasian systemic lupus erythematosus patients.

Interleukin-6 (IL-6) is a multifunctional cytokine with an important pathophysiological role in systemic lupus erythematosus (SLE). The polymorphism of the IL-6 gene promoter at position -174, which appears to influence the production of this cytokine, has been associated with susceptibility to some rheumatic diseases. The aim of this study is to investigate whether the IL-6 -174 G/C polymorphism associates with lupus susceptibility or affects disease characteristics in Portuguese patients with SLE. The association between -174 G/C and lupus diagnosis was studied in 115 adult SLE patients (95.7% females) and 152 healthy controls (94.7% females), all Caucasians. There were no significant differences in genotype or allele frequency between patients and controls. The -174 C/C genotype was independently associated with renal disease and the C allele with the presence of irreversible damage. The IL-6 gene promoter polymorphism at position -174 does not contribute to SLE susceptibility in Portuguese Caucasian patients but may predispose to specific manifestations of the disease.

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).

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).

Predictors of damage progression in Portuguese patients with systemic lupus erythematosus.

Patients with systemic lupus erythematosus (SLE) have a longer life expectancy. The occurrence of irreversible damage has become a major concern. The present study assessed damage progression in patients with SLE over a 2-year period and identified baseline features associated with damage accrual. Two hundred and twenty-one patients that fulfilled criteria for SLE and had a follow-up longer than 6 months were enrolled. Demographic, clinical, and immunological data were collected at baseline. Accumulated organ damage was scored using the Systemic Lupus International Collaborating Clinics/American College of Rheumatology damage index (SDI). Patients were prospectively followed and SDI assessment repeated at 2 years. At baseline 72 patients (33%) presented some irreversible damage, and after 2 years 53 had accrued new damage. The mean SDI for the whole cohort increased from 0.582 to 0.980. Damage progression was higher in ocular, cardiovascular, and musculoskeletal systems. Older age [OR = 1.045; 95% confidence interval (CI) 1.021-1.069; P = 0.03], presence of antiphospholipid antibodies (OR = 3.047; 95% CI 1.169-7.941; P = 0.02), steroid use (OR = 6.401; 95% CI 1.601-25.210; P = 0.008), azathioprine use (OR = 3.501; CI 1.224-10.012; P = 0.01), and hypertension (OR = 3.825; 95% CI 1.490-9.820; P = 0.005) were predictors of damage progression in multivariate analysis. Overall SDI increased over time, with some systems being affected more frequently. Demographic and clinical characteristics, co-morbidity, and treatment options may contribute to irreversible damage. It is necessary to determine whether the control of modifiable factors (e.g., hypertension and judicious use of medications) might prevent damage progression in SLE patients.

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.

[Anti-TNF alfa therapy in ankylosing spondylitis]. / Terapêutica anti-TNF alfa na espondilite anquilosante.

Ankylosing spondylitis (AS) is an inflammatory chronic disease that affects young males and in more than 90% of cases is associated with HLA B27 antigen. Therapeutic options for those patients with spondyloarthropathies have been limited during the last decades. Infliximab and etanercept are both approved for the treatment of patients with active disease that does not respond to conventional therapies. Anti-TNF therapy is very effective in AS, and eventually can be more effective than in rheumatoid arthritis. In 2003 Assessments in Ankylosing Spondylitis Group (ASAS) published international recommendations about the use of these agents in AS, which can be used as guidance in taking decisions and elaborating guidelines. To define their utilization it is necessary more studies about efficacy, toxicity and about ways of use.

[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.

[Systemic lupus erythematosus and weakness]. / Lúpus eritematoso sistémico e fraqueza muscular.

We report a case of a 13-year old young girl, with Juvenile Systemic Lupus Erythematosus and recent onset of muscle weakness. Investigations lead to the diagnosis of Myasthenia Gravis. The most important causes of muscle weakness in lupus patients are discussed.