Molecular Profiling of Axial Spondyloarthritis Patients Reveals an Association between Innate and Adaptive Cell Populations and Therapeutic Response to Tumor Necrosis Factor Inhibitors.

This study aims at identifying molecular biomarkers differentiating responders and non-responders to treatment with Tumor Necrosis Factor inhibitors (TNFi) among patients with axial spondyloarthritis (axSpA). Whole blood mRNA and plasma proteins were measured in a cohort of biologic-naïve axSpA patients (n = 35), pre and post (14 weeks) TNFi treatment with adalimumab. Differential expression analysis was used to identify the most enriched pathways and in predictive models to distinguish responses to TNFi. A treatment-associated signature suggests a reduction in inflammatory activity. We found transcripts and proteins robustly differentially expressed between baseline and week 14 in responders. C-reactive protein (CRP) and Haptoglobin (HP) proteins showed strong and early decrease in the plasma of axSpA patients, while a cluster of apolipoproteins (APOD, APOA2, APOA1) showed increased expression at week 14. Responders to TNFi treatment present higher levels of markers of innate immunity at baseline, and lower levels of adaptive immunity markers, particularly B-cells. A logistic regression model incorporating ASDAS-CRP, gender, and AFF3, the top differentially expressed gene at baseline, enabled an accurate prediction of response to adalimumab in our cohort (AUC = 0.97). In conclusion, innate and adaptive immune cell type composition at baseline may be a major contributor to response to adalimumab in axSpA patients. A model including clinical and gene expression variables should also be considered.

Sex and body mass index impact on digit circumference for Leeds Dactylitis Index calculation.

OBJECTIVES: To estimate digit circumference and the impact of sex and body mass index (BMI) for the calculation of the Leeds Dactylitis Index (LDI) in psoriatic arthritis (PsA) patients with bilateral dactylitis. METHODS: Digit circumference of the hands and the foot were measured with a dactylometer and were studied according to sex and BMI (divided in 4 weight categories) in healthy Portuguese subjects, using Student's t-test and One-way ANOVA, respectively. The effect size of sex and BMI were calculated using Cohen's d test and Eta squared, respectively. Multiple linear regression was used to calculate the effect of sex and BMI, as well as their interaction, to create a formula to predict digit circumference. RESULTS: Fifty-nine participants (33 women, 26 men) with a mean BMI of 24.8 were included. Men's mean digit circumferences were statistically higher than those of women (p<0.001), with a large sex effect size in most of the digits. Differences in the mean circumference between the four BMI categories were statistically significant (p<0.05) for all digits, with a large BMI effect size. Sex and BMI were independent variables to predict mean digit circumference (p<0.001). A new tool (based on regression analysis) allowing to estimate the circumference of digits for males and females of different BMIs is presented. CONCLUSIONS: Our data allows the calculation of digit circumference for males and females of different BMIs in the Portuguese population; and shows that BMI influences digital circumference supporting BMI inclusion in LDI references tables.

What is the association of depression with clinical response to therapy in patients with psoriatic arthritis treated with biologic disease-modifying antirheumatic drugs?

INTRODUCTION: Psoriatic arthritis (PsA) is a chronic, progressive inflammatory joint disease that is associated with higher prevalence of depression. There is limited literature about the impact of depression, particularly regarding the response to therapy. METHODS: A retrospective cohort study with PsA patients that started their first biologic disease-modifying antirheumatic drugs (bDMARD) was conducted. In the majority of cases, a cutoff score of ≥ 8 in Hospital Anxiety and Depression Scale (HADS) was used to define cases of depression. In cases where patients did not complete the questionnaire, a previous diagnosis made by a psychiatrist was used to establish the presence of depression. Response to therapy 12 months after the start of bDMARD was evaluated and the switch rate to another bDMARD due to inefficacy was assessed at month 12. RESULTS: A total of 129 patients (66 females, 51.2%; mean age of 47.7 ± 11.0 years and mean disease duration of 10.0 ± 7.7 years) with PsA were included. Thirty-two (24.8%) patients had depression. Patients with depression and peripheral involvement had a significantly lower ACR20/50/70 responses (p = 0.001, p = 0.002, and p = 0.001 respectively) after 12 months of therapy and a significantly worse EULAR response (p = 0.002). Furthermore, patients with depression and axial involvement had a significantly worse response based on ASDAS response criteria (p = 0.031). Switch due to ineffectiveness in the first 12 months was significantly higher in patients with depression (p = 0.002). CONCLUSION: Depression in PsA is a frequent yet often understudied comorbidity. The causal relationship between depression and PsA is difficult to decrypt and further research is needed. Recognition of depressive symptoms is crucial and a multidisciplinary approach should be provided to individuals with this comorbidity. Key Points • Depression in PsA is a frequent yet often understudied comorbidity. In our study, the prevalence of depression was 24.8%. • Depression in PsA seems to be associated to lower response to therapy and higher discontinuation rates of bDMARD. • Recognition of depressive symptoms is crucial and a multidisciplinary approach should be provided to individuals with this comorbidity.

Epilepsy plus blindness in microdeletion of GABRA1 and GABRG2 in mouse and human.

OBJECTIVE: GABAA receptor subunit gene (GABR) mutations are significant causes of epilepsy, including syndromic epilepsy. This report for the first time, describes intractable epilepsy and blindness due to optic atrophy in our patient, who has a microdeletion of the GABRA1 and GABRG2 genes. We then characterized the molecular phenotypes and determined patho-mechanisms underlying the genotype-phenotype correlations in a mouse model who is haploinsufficient for both genes (Gabra1+/-/Gabrg2+/- mouse). METHODS: Electroencephalography was conducted in both human and mice with the same gene loss. GABAA receptor expression was evaluated by biochemical and imaging approaches. Optic nerve atrophy was evaluated with fundus photography in human while electronic microscopy, visual evoked potential and electroretinography recordings were conducted in mice. RESULTS: The patient has bilateral optical nerve atrophy. Mice displayed spontaneous seizures, reduced electroretinography oscillatory potential and reduced GABAA receptor α1, ß2 and γ2 subunit expression in various brain regions. Electronic microscopy showed that mice also had optic nerve degeneration, as indicated by increased G-ratio, the ratio of the inner axonal diameter to the total outer diameter, suggesting impaired myelination of axons. More importantly, we identified that phenobarbital was the most effective anticonvulsant in mice and the patient's seizures were also controlled with phenobarbital after failing multiple anti-seizure drugs. CONCLUSIONS: This study is the first report of haploinsufficiency of two GABR epilepsy genes and visual impairment due to altered axonal myelination and resultant optic nerve atrophy. The study suggests the far-reaching impact of GABR mutations and the translational significance of animal models with the same etiology.

GC-MS Silylation Derivative Method to Characterise Black BIC® Ballpoint 2-Phenoxyethanol Ratio Evaporation Profile-A Contribution to Ink Ageing Estimation.

One of the major challenges in forensic document analysis is estimating the age of ink deposition on a manually written document. The present work aims to develop and optimise a methodology, based on the evaporation of 2-phenoxyethanol (PE) over time, that can contribute to ink age estimation. A black BIC® Crystal Ballpoint Pen was purchased in a commercial area, and ink deposition began in September 2016 over 1095 days. For each ink sample, 20 microdiscs were subjected to n-hexane extraction in the presence of an internal standard (ethyl benzoate) followed by derivatisation with a silylation reagent. A gas chromatography-mass spectrometry (GC/MS) method was optimised for PE-trimethylsilyl (PE-TMS) to characterise the ageing curve. The developed method presented good linearity between 0.5 and 50.0 µg mL-1, as well as limits of detection and quantification of 0.026 and 0.104 µg mL-1, respectively. It was possible to characterise PE-TMS concentration over time, which reveals a two-phase decay behaviour. First, there was a substantial decline between the 1st and the 33rd day of deposition, followed a by a stabilisation of the signal, which allowed to detect the presence of PE-TMS up to 3 years. Two unknown compounds were also present and allowed to identify three dating time frames for the same ink stroke: (i) between time 0 and 33 days, (ii) between time 34 and 109 days, and (iii) more than 109 days. The developed methodology allowed to characterise the behaviour of PE over time and to establish a relative dating of three-time frames.

FRAX 10-year fracture risk in rheumatoid arthritis assessed with and without bone mineral density - are we treating our patients under bDMARDs?

OBJECTIVE: This study aimed to identify the rheumatoid arthritis (RA) patients under biological therapy who have FRAX® scores classified as high fracture risk and to evaluate if they are receiving treatment for osteoporosis (OP). The authors also investigated the intra-individual agreement between FRAX® fracture risk calculated with and without bone mineral density (BMD). METHODS: A single-center retrospective cohort study was performed in a total of 303 patients with RA under biologics. Demographic and clinical data were collected using Rheumatic Diseases Portuguese Register (Reuma.pt), complemented with data from the hospital clinical records. FRAX scores with and without BMD were calculated. The Kendall's Tau coefficient was used to assess the agreement between FRAX risk categories. Correlations were evaluated by the Spearman test. Comparisons of distributions from independent variables used the Mann-Whitney test. RESULTS: When FRAX® score was calculated without BMD (n=303), 25% patients were categorized as high fracture risk. Among them, only 54% were receiving OP treatment. FRAX® assessment with BMD (n=231) identified 33% patients with high fracture risk, 52% in treatment for OP. Thirty patients (21%) previously classified as low fracture risk using FRAX® without BMD were recategorized as high risk (𝜏=0.570, p.

An anti-inflammatory and low fermentable oligo, di, and monosaccharides and polyols diet improved patient reported outcomes in fibromyalgia: A randomized controlled trial.

Background: Fibromyalgia (FM) has been associated with dysbiosis and low-grade inflammation. Studies have reported that diet influences clinical features in FM. Objective: To evaluate the effect of an anti-inflammatory and low fermentable oligo, di, and monosaccharides and polyols (FODMAP) diet on clinical outcomes of patients with FM. Methods: This two arms Randomized Controlled Trial (NCT04007705) included 46 female patients with FM. The intervention group (n = 22) adopted an anti-inflammatory diet for 3 months, excluding gluten, dairy, added sugar, and ultra-processed foods, along with a low FODMAPs diet in the first month. The control group (n = 24) followed general healthy eating recommendations. Both diets were applied by a certified dietitian. Before and after the intervention, participants were assessed regarding pain, fatigue, gastrointestinal symptoms, quality of sleep, and quality of life, through the Revised Fibromyalgia Impact Questionnaire (FIQR), Visual Analogue Pain Scale (VAS), Visual Analog Scale from gastrointestinal symptoms (VAS GI), Brief Pain Inventory (BPI), Pittsburg Sleep Quality Index (PSQI), Fatigue Severity Survey (FSS), and The Short Form Health Survey (SF-36). A blood sample was collected and high-sensitive C-Reactive Protein and Erythrocyte Sedimentation Rate were quantified. Paired Samples t-test/Wilcoxon and independent samples t-test/Mann-Whitney were used to compare variables between groups. Results: After intervention, there was an improvement in intervention group scores of FIQR (p = 0.001), VAS (p = 0.002), BPI (p = 0.011), FSS (p = 0.042), VAS_GI (p = 0.002), PSQI (p = 0.048), and SF36 (p = 0.045) compared to control group. Inflammatory biomarkers (hs-CRP, ESR) did not change in both groups. The intervention was beneficial in the intervention group, regardless of age, disease duration, body mass index variation, and body fat change between baseline and post-intervention. Conclusion: An anti-inflammatory and low-FODMAP diet improved clinical features in patients with FM and may be useful as a complement to pharmacological therapy. Clinical Trial Registration: [https://clinicaltrials.gov/ct2/show/NCT04007705], identifier [NCT04007705].

Pseudotumoral calcinosis of the spine in systemic sclerosis - an atypical location.

Pseudotumoral calcinosis, particularly around the spine, is a rare complication of systemic sclerosis (SSc). The authors report a case of a 60-year-old woman with a limited cutaneous SSc observed for a 4-month history of back pain. Physical examination revealed a left paravertebral mass measuring around 7cm in the longest axis. The computed tomography (CT) showed the presence of calcified mass in the left paravertebral muscle, extending from the 12th dorsal to the 3rd lumbar vertebra. A diagnosis of pseudotumoral calcinosis secondary to SSc was made. Symptomatic treatment with analgesics allowed a significant improvement of clinical symptoms. Subcutaneous calcinosis is a common complication of SSc, however the pseudotumoral form remains extremely rare, particularly around the dorsolumbar spine. Treatment is limited to analgesic therapy or, in more severe cases, to surgical excision. Follow-up should be conducted to rule out complications.

Portuguese recommendations for the use of biological and targeted synthetic disease-modifying antirheumatic drugs in patients with rheumatoid arthritis - 2020 update.

OBJECTIVE: To update the recommendations for the treatment of rheumatoid arthritis (RA) with biological and targeted synthetic disease-modifying antirheumatic drugs (bDMARDs and tsDMARDs), endorsed by the Portuguese Society of Rheumatology (SPR). METHODS: These treatment recommendations were formulated by Portuguese rheumatologists taking into account previous recommendations, new literature evidence and consensus opinion. At a national meeting, in a virtual format, three of the ten previous recommendations were re-addressed and discussed after a more focused literature review. A first draft of the updated recommendations was elaborated by a team of SPR rheumatologists from the SPR rheumatoid arthritis study group, GEAR. The resulting document circulated among all SPR rheumatologists for discussion and input. The level of agreement with each of all the recommendations was anonymously voted online by all SPR rheumatologists. RESULTS: These recommendations cover general aspects such as shared decision, treatment objectives, systematic assessment of disease activity and burden and its registry in Reuma.pt. Consensus was also achieved regarding specific aspects such as initiation of bDMARDs and tsDMARDs, assessment of treatment response, switching and definition of persistent remission. CONCLUSION: These recommendations may be used for guidance of treatment with bDMARDs and tsDMARDs in patients with RA. As more evidence becomes available and more therapies are licensed, these recommendations will be updated.

Atmospheric pollution and mortality in Portugal: Quantitative assessment of the environmental burden of disease using the AirQ+ model.

In Portugal, data on mortality rate attributed to household and ambient air pollution are not reported due to shortness and irregularity of the available data series, and therefore, the disclosure of the national progress in reducing the number of deaths and illnesses from air contamination in exposures to multiple pollutants is incomplete. The present work describes the application of the AirQ+ model developed by the WHO to calculate how much of specific health outcomes is attributable to long-term exposure to atmospheric NO2, PM2.5, and O3 in the population of various municipalities in Portugal, from 2010 to 2019. Linear Mixed Models were used for data analysis and have shown that (i) approximately 5000 deaths per year are attributable to exposure to mixtures of NO2 and PM2.5; (ii) the spatial distribution of the proportion of deaths attributable to NO2, PM2.5 and O3 shows significant differences between locations, and (iii) that AirQ+ is a useful tool for the purpose of effective Public Health policymaking and reporting on the national progress to implement the 2030 Agenda.

A multidisciplinary approach in psoriatic disease: the different models of dermatology-rheumatology collaborations in Portugal.

Psoriatic disease (Psoriasis and Psoriatic Arthritis, PsD) is a condition that affects the skin, the musculoskeletal system, and beyond, impairing patients' quality of life. A multidisciplinary approach of combined dermatology-rheumatology clinics is recommended and valuable to respond to PsD diagnosis, management, and treatment challenges. In Portugal, five Hospitals have implemented a multidisciplinary clinic for PsD assessment. This report aims to describe how these multidisciplinary clinics were developed, their characteristics, and the main obstacles to their implementation. Although the different hospitals adopted distinct functional models, a consensus respecting the minimal core set assessment for PsD in Multidisciplinary Dermatology/Rheumatology Clinics should comprise all disease manifestations and, if possible, quality of life. The main objective of these clinics is to achieve remission/minimal disease activity. Limitations to these multidisciplinary approaches are discussed, namely financial, time management, and human resources obstacles that can be a handicap in their implementation, despite the benefits of PsD integrated care.

A study protocol for a randomized controlled trial of an anti-inflammatory nutritional intervention in patients with fibromyalgia.

BACKGROUND: This study aims to analyze the effects of a potentially anti-inflammatory nutritional intervention in disease assessment parameters, inflammatory markers, and quality of life of fibromyalgia (FM) patients. METHODS: A sample of 100 female patients diagnosed with FM, followed up at Portuguese Institute of Rheumatology (IPR) in Lisbon, is being randomly allocated in two groups. Patients in the intervention group are adopting an anti-inflammatory diet, characterized by the exemption of the intake of foods containing gluten, dairy, sugar, and ultra-processed foods, during 3 months. During the first month, a low fermentable oligo-, di-, and monosaccharides and polyols (FODMAPs) diet is implemented, along with the anti-inflammatory diet, followed by the reintroduction of all fruits and vegetables over a consecutive period of 2 months. Patients in the control group are adopting a diet based on general recommendations for healthy eating. The outcomes are pain, fatigue, quality of sleep, quality of life, gastrointestinal symptoms, and inflammation. Before and after the 3 months intervention, and also 1 month after beginning the intervention, the following questionnaires are applied: Revised Fibromyalgia Impact Questionnaire, visual analog pain scale, Brief Pain Inventory,visual analog scale from a list of common gastrointestinal and extraintestinal symptoms in FM, Short Form 36, Fatigue Severity Survey, and Pittsburg Sleep Quality Index. Ultra-sensitive serum C-reactive protein, eritrocyte sedimentation rate, and interleukin-8 are determined. Age, physical activity, anthropometric parameters, and body composition are being collected. Student's t test will assess the association between the disease evaluation parameters, the inflammatory markers, and the dietary interventions. DISCUSSION: The results of this study are expected to determine whether a change in patient nutrition helps to alleviate symptoms, which would optimize medical intervention. TRIAL REGISTRATION: www.ClinicalTrials.gov NCT04007705 . Registered on July 5, 2019.

Quantitative analysis of air pollution and mortality in Portugal: Current trends and links following proposed biological pathways.

A wealth of studies focusing on the relationships between negative health outcomes and short-term and long-term exposures to environmental risk factors have produced estimates of the burden of disease attributable to air pollution, which have led to the implementation of air pollution control strategies. However, the call to expand those studies, in terms of geographical units of analysis to produce more accurate estimates of the burden of disease in the different countries has been made. Studies of the specific environment-health relationship concerning air pollution in Portugal are scarce and rather descriptive. Therefore, this work assesses the trends both in atmospheric levels of pollutants including particulate matter (PM10), ozone (O3), nitrogen dioxide (NO2) and sulphur dioxide (SO2), and in mortality rates for diabetes, malignant neoplasms and diseases of the respiratory, digestive and circulatory systems, and explores the links between exposure to air pollutants and mortality, following proposed biological pathways and using inferential statistics methods, for the period 2010 to 2017 in Portugal. The following major conclusions were drawn: (i) despite a somewhat initial downward trend in PM10 and a peak in O3 levels, fairly constant air pollution levels were mostly observed; (ii) concomitantly, increases in age-adjusted mortality rates were significant for all diseases except diabetes; (iii) lower atmospheric levels of pollutants were observed in rural areas, when compared to urban areas, except for ozone; (iv) age-adjusted mortality rates were higher in rural regions, for diabetes, and in urban regions, for malignant neoplasms; (v) for a 10 µg/m3 increase in atmospheric levels of PM10, regression analysis estimated an increase of 0.30% in the mortality rate for diseases of the respiratory, digestive and circulatory systems, and malignant neoplasms combined.

GO-DACT: a phase 3b randomised, double-blind, placebo-controlled trial of GOlimumab plus methotrexate (MTX) versus placebo plus MTX in improving DACTylitis in MTX-naive patients with psoriatic arthritis.

OBJECTIVES: To assess the efficacy of golimumab in combination with methotrexate (MTX) versus MTX monotherapy in psoriatic arthritis (PsA) dactylitis. METHODS: Multicentre, investigator-initiated, randomised, double-blind, placebo-controlled, parallel-design phase 3b trial in 11 Portuguese rheumatology centres. Patients with PsA along with active dactylitis and naive to MTX and biologic disease-modifying antirheumatic drugs (bDMARDs) were randomly assigned to golimumab or placebo, both in combination with MTX. The primary endpoint was Dactylitis Severity Score (DSS) change from baseline to week 24. Key secondary endpoints included DSS and Leeds Dactylitis Index (LDI) response, and changes from baseline in the LDI and MRI dactylitis score. Analysis was by intention-to-treat for the primary endpoint. RESULTS: Twenty-one patients received golimumab plus MTX and 23 MTX monotherapy for 24 weeks. One patient from each arm discontinued. Patient inclusion was halted at 50% planned recruitment due to a favourable interim analysis. Median baseline DSS was 6 in both arms. By week 24, patients treated with golimumab plus MTX exhibited significantly greater improvements in DSS relative to MTX monotherapy (median change of 5 vs 2 points, respectively; p=0.026). In the golimumab plus MTX arm, significantly higher proportions of patients achieved at least 50% or 70% improvement in DSS and 20%, 50% or 70% improvement in LDI in comparison to MTX monotherapy. CONCLUSIONS: The combination of golimumab and MTX as first-line bDMARD therapy is superior to MTX monotherapy for the treatment of PsA dactylitis. TRIAL REGISTRATION NUMBER: NCT02065713.

Dietary interventions in fibromyalgia: a systematic review.

Fibromyalgia (FM) is a chronic non-degenerative disease, whose nutritional therapy seems controversial. This systematic review aimed to synthesize the knowledge about the effect of dietary interventions on patient-reported outcomes (PRO) and inflammation in patients with FM. Six electronic databases - PubMed, BioMed Central, Cochrane library, EMBASE, LILACS and ISI - were searched for clinical trials, in which a dietary intervention in patients with FM diagnosed was conducted. Quality of evidence assessment was measured in accordance with GRADE methodology. Seven clinical trials - 3 randomized controlled trials, 1 unrandomized clinical trial and 3 uncontrolled clinical trials were identified. Dietary approaches included gluten-free diet (n = 1), raw vegetarian diet (n = 2), low Fermentable oligo-, di- and monossacharides, alcohols and polyols (FODMAPs) diet (n = 1), hypocaloric diet (n = 2) and monosodium glutamate- and aspartame-free diet interventions (n = 1). The major PRO were pain and functional repercussion, with 5 out of 7 studies reporting an improvement. The progress in secondary outcomes was reported for fatigue (2/5 studies), sleep quality (2/3 studies), depression and anxiety (3/6 studies), quality of life (4/5 studies), gastrointestinal symptoms (1/2 studies) and inflammatory biomarkers (1/1 study). However, according to Cochrane Risk of Bias, these studies had poor statistical quality. Well-designed studies should be performed to investigate the dietary interventions effect on FM. Key messages Fibromyalgia (FM) is a chronic non-degenerative disease, whose nutritional therapy seems controversial but promising. Pain and functional repercussion in FM patients seem to improve with a hypocaloric diet, a raw vegetarian diet or a low FODMAPs diet, as much as quality of life, quality of sleep, anxiety and depression and inflammatory biomarkers. Existing studies in this subject are scarce and low quality, which does not allow conclusions to be drawn.

The GO-DACT protocol: a multicentre, randomized, double-blind, parallel-group study to compare the efficacy of golimumab in combination with methotrexate (MTX) versus MTX monotherapy.

The GO-DACT is an investigator-initiated, national, multicentric randomized placebo-controlled double-blinded trial, that assesses dactylitis as primary endpoint. Psoriatic arthritis patients naïve to methotrexate and biologic disease modifying anti-rheumatic drugs, with at least one active dactylitis, were assigned to golimumab in combination with methotrexate or placebo in combination with methotrexate, for 24 weeks. Both clinical (dactylitis severity score and the Leeds dactylitis index) and imaging (high resolution magnetic resonance imaging), among others, were assessed as outcomes. The main objective of GO-DACT is to provide evidence to improve the treatment algorithm and care of psoriatic arthritis patients with active dactylitis. In this manuscript we describe the GO-DACT protocol and general concepts of the methodology of this trial.