The effect of antimalarials on the safety and persistence of treatment with biologic agents or Janus kinase inhibitors in rheumatoid arthritis.

OBJECTIVES: To test the association of use of antimalarials with the overall safety of treatment in RA patients receiving one or multiple courses of biologic (b)DMARDs or a Janus kinase inhibitor (JAKi). METHODS: BiobadaBrasil is a multicentric registry-based cohort study of Brazilian patients with rheumatic diseases starting their first bDMARD or JAKi. The present analysis includes RA patients recruited from January 2009 to October 2019, followed up over one or multiple (up to six) courses of treatment (latest date, 19 November 2019). The primary outcome was the incidence of serious adverse events (SAEs). Total and system-specific adverse events (AEs) and treatment interruption served as secondary outcomes. Negative binomial regression with generalized estimating equations (to estimate multivariate incidence rate ratios, mIRR) and frailty Cox proportional hazards models were used for statistical analyses. RESULTS: The number of patients enrolled was 1316 (2335 treatment courses, 6711 patient-years [PY]; 1254.5 PY on antimalarials). The overall incidence of SAEs was 9.2/100 PY. Antimalarials were associated with reduced risk of SAEs (mIRR: 0.49; 95% CI: 0.36, 0.68; P < 0.001), total AEs (0.68; 95% CI: 0.56, 0.81; P < 0.001), serious infections (0.53; 95% CI: 0.34, 0.84; P = 0.007) and total hepatic AEs (0.21; 95% CI: 0.05, 0.85; P = 0.028). Antimalarials were also related to better survival of treatment course (P = 0.003). There was no significant increase in the risk of cardiovascular AEs. CONCLUSION: Among RA patients on treatment with bDMARDs or JAKi, concomitant use of antimalarials was associated with reduced the incidence of serious and total AEs and with longer treatment course survival.

Treatment with biological therapy is associated with faster recovery and lower frequency of treatment switch among rheumatic patients with Chikungunya fever.

BACKGROUND/OBJECTIVE: The effects of Chikungunya virus (CHIKV) infection on patients with rheumatic diseases have not been extensively studied. Our aim was to compare the clinical course of patients with rheumatoid arthritis and spondyloarthritis, categorized according to the use or not of biologic disease modifying anti-rheumatic drugs (bDMARDs), during and after infection by CHIKV. METHODS: Patients from a northeastern Brazilian city that suffered an epidemic outbreak of Chikungunya fever (CHIK) between Oct 2015 and Jul 2016, on regular follow-up in a longitudinal registry of rheumatic patients (BiobadaBrasil), were invited to participate. Participants underwent a standardized clinical interview and collection of blood sample for serological tests (IgM/IgG) for CHIKV. A positive IgG was considered evidence of previous CHIKV infection. RESULTS: 105 patients (84 with rheumatoid arthritis, 17 with ankylosing spondylitis, and 4 with psoriatic arthritis) were evaluated. Most patients (58, 55.2%) were on therapy with bDMARDs. The overall prevalence of seropositivity for CHIKV was 47.6% (39.7% in patients on bDMARDs and 57.4% in those exclusively on conventional synthetic (cs-) DMARDs (p = 0.070). Among seropositive patients, asymptomatic disease had similar frequency in those treated and not treated with bDMARDs (39.1% versus 33.3%, respectively; p = 0.670). However, patients exclusively on csDMARDs presented significantly higher prevalence of articular symptoms beyond 3 months and switched treatment more often than patients on bDMARDs (p < 0.05 for both comparisons). CONCLUSIONS: Among rheumatic patients with CHIK, those on bDMARDs had shorter persistence of articular symptoms and switched treatment scheme less often than patients exclusively treated with csDMARDs.

Physical frailty in patients with systemic sclerosis.

INTRODUCTION: Systemic sclerosis (SSc) is a chronic disease characterized by autoimmunity, vasculopathy and fibrosis of several organs, such as skin, lungs, and heart. During the disease course, patients with SSc are prone to accumulating multiple organ damage and increasing their vulnerability to adverse outcomes. This increased vulnerability to adverse outcomes when exposed to a stressor among people of the same age is known as frailty. One of the most used definitions of frailty is the physical frailty phenotype (PFP), including 5 components: unintentional weight loss, exhaustion, muscle weakness, slow walking speed, and low physical activity. There is scarce data about frailty in patients with SSc. OBJECTIVES: To determine the prevalence and clinical profile of PFP in a sample of patients with SSc. To investigate the diagnostic accuracy of the Fatigue, Resistance, Ambulation, Illness and Loss of weight (FRAIL) scale, Edmonton frailty scale (EFS) and Short Physical Performance Battery (SPPB) using the PFP as the reference standard. METHODS: Cross-sectional study including 94 patients with SSc according to the 2013 ACR-EULAR classification criteria or the criteria suggested by Le Roy and Medsger for early disease. Gastrointestinal symptoms were assessed by the UCLA GIT 2.0 questionnaire, malnutrition was defined according to European Society of Clinical Nutrition and Metabolism (ESPEN) recommendations, and physical performance was assessed by SPPB. PFP assessment was according to the original definition, except for physical activity domain, assessed with the International Physical Activity Questionnaire (IPAQ). FRAIL scale and EFS were also applied to the same individuals. For diagnostic assessment of FRAIL, EFS and SPPB, we estimated the area under the receiver operating characteristic curve (AUC), considering PFP as the reference standard and dichotomizing the results in frail vs. non-frail. RESULTS: According to PFP, 33 patients (35.1%) were considered frail and 53 patients (56.4%) pre-frail. According to FRAIL scale, 27 patients (28.7%) were considered frail and 53 patients (56.4%) pre-frail. According to EFS, 28 patients (29.7%) were classified as vulnerable and 15 (15.9%) as frail: mild in 8 (8.5%), moderate in 5 (5.3%) and severe in 2 (2.1%). According to SPPB, 19 patients (20.2%) were considered frail. The AUC against PFP was: 0.829 (95% CI 0.743-0.916) for FRAIL scale, 0.859 (95% CI 0.784-0.934) for EFS and 0.791 (95% CI 0.697-0.885) for SPPB. The PFP was associated with current use of glucocorticoids (p=0.011), UCLA GIT 2.0 score (p=0.001), HAQ (p<0.0001), patient and physician-assigned VAS (p<0.0001, both), malnutrition (p=0.007), hospitalizations in the past year (p=0.008) and dependence on BADL and IADL (p=0.027 and p<0.0001, respectively). The PFP was not associated with gender (p=0.679), age (p=0.303), disease duration (p=0.504), Rodnan skin score (p=0.918), diffuse subtype (p=0.116), polypharmacy (p=845) and sarcopenia (p=0.328). CONCLUSION: Frailty is prevalent in patients with long-standing SSc and is associated with disability, limitations in daily activities and hospitalizations in the past year. Also, malnutrition and more severe gastrointestinal symptoms were more common in frail patients. Both FRAIL scale and EFS showed excellent diagnostic accuracy against PFP as the reference standard, however the FRAIL scale presents a higher sensitivity and seems to be more feasible and practical than EFS and SPPB in clinical practice.

A Simple Double-Spin Closed Method for Preparing Platelet-Rich Plasma.

OBJECTIVE: To describe and analyze a new protocol for the extraction of platelet-rich plasma (PRP) for use in clinical practice and compare this technique with methods that have been previously described in the medical literature. METHODS: Sixteen blood samples from healthy volunteers were collected. PRP was prepared using our new double-spin technique, consisting of successive centrifugation of blood samples with two different spins, without opening the container. Descriptive analysis of cell counts in baseline and PRP samples was undertaken. Comparison between cell and platelet count in baseline and PRP samples, as well as the statistical analysis, were done. RESULTS: The mean platelet concentration ratio was 3.47 (SD: 0.85; 95% CI: 3.01-3.92; range: 2.48-5.71). The baseline whole blood platelet count correlated positively to the PRP platelet count (rP = 0.56; 95% CI: 0.09-0.88; P = 0.023). The PRP was enriched for lymphocytes and monocytes but presented significantly lower counts of neutrophils and eosinophils in comparison to baseline. CONCLUSION:  Results show a safe and easily reproducible method to obtain PRP for use in clinical daily practice.

Effects of a physical self-care support program for patients with fibromyalgia: A randomized controlled trial.

BACKGROUND: The effects of stretching exercises in fibromyalgia (FM) deserves further study. OBJECTIVE: To evaluate the effectiveness of a Physical Self-Care Support Program (PSCSP), with emphasis on stretching exercises, in the treatment of FM. METHODS: Forty-five women with FM were randomized to the PSCSP (n= 23) or to a control group (n= 22). The PSCSP consisted of weekly 90-minute learning sessions over 10 weeks, providing instructions on wellness, postural techniques, and active stretching exercises to be done at home. The control group was monitored through 3 medical appointments over 10 weeks and included in a waiting list. The primary outcomes were the Fibromyalgia Impact Questionnaire (FIQ), the Visual Analogue Scale (VAS) for pain, and the Sit and Reach Test (SRT) at the end of the study. RESULTS: Nineteen and 21 patients completed the trial in PSCSP and control groups, respectively. After 10 weeks, the PSCSP group showed significantly better FIQ (difference between adjusted means, -13.64, 95% CI, -21.78 to -5.49, P= 0.002) and SRT scores (7.24 cm, 3.12 to 11.37, P= 0.001) than the control group, but no significant difference in pain VAS (-1.41, -3.04 to 0.22, P= 0.088). Analysis using multiple imputation (MI) and delta-adjusted MI for missing outcomes rendered similar results. CONCLUSIONS: A PSCSP emphasizing stretching exercises significantly improved FIQ and SRT scores, and may be a helpful therapy for FM.

Personalized multitarget biologic injection in the spine: prospective case series of multitarget platelet-rich plasma for low back pain.

Aim: To evaluate the use of a multitarget platelet-rich plasma (PRP) injection approach for the treatment of chronic low back pain (LBP). Materials & Methods: Forty-six patients with more than 12 weeks of LBP who failed conservative treatments were injected with PRP into the facet joints, intervertebral discs, epidural space and/or paravertebral muscles. Visual analog pain scale and Roland-Morris Disability Questionnaire scores were measured at baseline and predefined intervals. Results: Mean visual analog pain scale was reduced from 8.48 to 5.17 and mean Roland-Morris Disability Questionnaire from 18.0 to 10.98 at 12 weeks (p < 0.001). These statistically significant improvements were sustained over 52 weeks. No adverse effects were observed. Conclusion: Our PRP approach demonstrated clinically favorable results and may be a promising treatment for chronic LBP.

Lay abstract Back pain can be caused by a variety of conditions. Most long-term (chronic) low back pain cases involve one or more parts of the spine causing the pain. This study describes 46 people who received injections of a blood-based substance called platelet-rich plasma into multiple parts of their spine to address chronic low back pain. The patients were followed up at several time points over the course of the following year. The results showed that the patients had improvement in their pain and disability. There was also a reduction in oral pain medication use. No unexpected medical problems were seen with this treatment. This study shows promising results for the treatment of chronic back pain.

Quality of referrals to a rheumatology service before and after implementation of a triage system with telemedicine support.

PURPOSE: To evaluate the quality of referrals for a first Rheumatology consultation at a tertiary care center in a southern Brazilian capital (Porto Alegre, RS), having as background findings from a similar survey performed in 2007/2008. Since then, our state has implemented referral protocols and a triage system with teleconsulting support exclusively for referrals from locations outside the capital, permitting a comparison between patients screened and not screened by the new system. METHODS: Physicians of the Rheumatology Service at Hospital Nossa Senhora da Conceição prospectively collected information regarding first visits over a 6-month period (Oct 2017 to March 2018). We recorded demographic characteristics, diagnostic hypotheses, date of referral, and the municipality of origin (within the state of Rio Grande do Sul). We considered adequate referrals from primary health care when a systemic autoimmune inflammatory disease (SIRD) was suspected at first evaluation by the attending rheumatologist. RESULTS: Three hundred fifty-seven patients/appointments were eligible for analysis (193 from the capital and 164 from small and medium towns). In 2007/2008, suspected SIRD occurred in 76/260 (29.2%) and 73/222 (32.9%) among patients from the capital and outside counties, respectively (P = 0.387). In 2017/2018, suspected SIRD occurred in 75/193 (38.9%) and 111/164 (67.7%) in patients from the capital and outside counties, respectively (difference: 28.8, 95% CI: 19.0 to 38.9, P < 0.001), indicating a marked improvement in referrals submitted to the new triage system. CONCLUSION: The quality of Rheumatology referrals in our state improved over the 10-year interval under study, particularly among patients from locations submitted to referral protocols and teleconsulting support.

Safety of the Methotrexate-leflunomide Combination in Rheumatoid Arthritis: Results of a Multicentric, Registry-based, Cohort Study (BiobadaBrasil).

OBJECTIVE: To evaluate the safety of the methotrexate (MTX)-leflunomide (LEF) combination in rheumatoid arthritis (RA), comparing it with other therapeutic schemes involving conventional synthetic (cs-) and biologic (b-) disease-modifying antirheumatic drugs (DMARDs) or Janus kinase inhibitors (JAKi). METHODS: Patients with RA starting a treatment course with a csDMARD (without previous use of bDMARD or JAKi) or their first bDMARD/JAKi were followed up in a registry-based, multicentric cohort study in Brazil (BiobadaBrasil). The primary outcome was the incidence of serious adverse events (SAEs); secondary outcomes included serious infections. Multivariate Cox proportional hazards models and propensity score matching analysis (PSMA) were used for statistical comparisons. RESULTS: In total, 1671 patients (5349 patient-years [PY]) were enrolled; 452 patients (1537 PY) received MTX + LEF. The overall incidence of SAEs was 5.6 per 100 PY. The hazard of SAEs for MTX + LEF was not higher than for MTX or LEF (adjusted HR [aHR] 1.00, 95% CI 0.76-1.31, P = 0.98). MTX + LEF presented a lower hazard of SAEs (aHR 0.56, 95% CI 0.36-0.88, P = 0.01) and infectious SAEs (aHR 0.48, 95% CI 0.25-0.94, P = 0.03) than bDMARDs/JAKi with MTX or LEF. MTX + LEF presented lower hazard of SAEs than MTX + sulfasalazine (SSZ; aHR 0.33, 95% CI 0.16-0.65, P = 0.002). Analysis using PSMA confirmed the results obtained with traditional multivariate Cox analysis. CONCLUSION: In our study, MTX + LEF presented a relatively good overall safety profile in comparison to MTX + SSZ and schemes involving advanced therapies in RA.

Practical screening tools for sarcopenia in patients with systemic sclerosis.

INTRODUCTION: In view of the method of diagnosing sarcopenia being complex and considered to be difficult to introduce into routine practice, the European Working Group on Sarcopenia in Older People (EWGSOP) recommends the use of the SARC-F questionnaire as a way to introduce assessment and treatment of sarcopenia into clinical practice. Only recently, some studies have turned their attention to the presence of sarcopenia in systemic sclerosis (SSc).There is no data about performance of SARC-F and other screening tests for sarcopenia in this population. OBJECTIVE: To compare the accuracy of SARC-F, SARC-CalF, SARC-F+EBM, and Ishii test as screening tools for sarcopenia in patients with SSc. METHODS: Cross-sectional study of 94 patients with SSc assessed by clinical and physical evaluation. Sarcopenia was defined according to the revised 2019 EWGSOP diagnostic criteria (EWGSOP2) with assessments of dual-energy X-ray absorptiometry, handgrip strength, and short physical performance battery (SPPB). As case finding tools, SARC-F, SARC-CalF, SARC-F+EBM and Ishii test were applied, including data on calf circumference, body mass index, limitations in strength, walking ability, rising from a chair, stair climbing, and self reported number of falls in the last year. The screening tests were evaluated through receiver operating characteristic (ROC) curves. Standard measures of diagnostic accuracy were computed using the EWGSOP2 criteria as the gold standard for diagnosis of sarcopenia. RESULTS: Sarcopenia was identified in 15 (15.9%) patients with SSc by the EWGSOP2 criteria. Area under the ROC curve of SARC-F screening for sarcopenia was 0.588 (95% confidence interval (CI) 0.420-0.756, p = 0.283). The results of sensitivity, specificity, positive likelihood ratio (+LR), negative likelihood ratio (-LR) and diagnostic Odds Ratio (DOR) with the EWGSOP2 criteria as the gold standard were 40.0% (95% CI, 19.8-64.2), 81.0% (95% CI, 71.0-88.1), 2.11 (95% CI, 0.98-4.55), 0.74 (95% CI, 0.48-1.13) and 2.84 (95% CI, 0.88-9.22), respectively. SARC-CalF and SARC-F+EBM showed better sensitivity (53.3%, 95% CI 30.1-75.2 and 60.0%, 95% CI 35.7-80.2, respectively) and specificity (84.8%, 95% CI 75.3-91.1 and 86.1%, 95% CI 76.8-92.0, respectively) compared with SARC-F. The best sensitivity was obtained with the Ishii test (86.7%, 95% CI 62.1-96.3), at the expense of a small loss of specificity (73.4%, 95% CI 62.7-81.9). Comparing the ROC curves, SARC-F performed worse than SARC-CalF, SARC-F+EBM and Ishii test as a sarcopenia screening tool in this population (AUCs 0.588 vs. 0.718, 0.832, and 0.862, respectively). Direct comparisons between tests revealed differences only between SARC-F and Ishii test for sensitivity (p = 0.013) and AUC (p = 0.031). CONCLUSION: SARC-CalF, SARC-F+EBM, and Ishii test performed better than SARC-F alone as screening tools for sarcopenia in patients with SSc. Considering diagnostic accuracy and feasibility aspects, SARC-F+EBM seems to be the most suitable screening tool to be adopted in routine care of patients with SSc.

Quality of referrals to a rheumatology service before and after implementation of a triage system with telemedicine support

Abstract Purpose: To evaluate the quality of referrals for a first Rheumatology consultation at a tertiary care center in a southern Brazilian capital (Porto Alegre, RS), having as background findings from a similar survey performed in 2007/2008. Since then, our state has implemented referral protocols and a triage system with teleconsulting support exclusively for referrals from locations outside the capital, permitting a comparison between patients screened and not screened by the new system. Methods: Physicians of the Rheumatology Service at Hospital Nossa Senhora da Conceição prospectively collected information regarding first visits over a 6-month period (Oct 2017 to March 2018). We recorded demographic characteristics, diagnostic hypotheses, date of referral, and the municipality of origin (within the state of Rio Grande do Sul). We considered adequate referrals from primary health care when a systemic autoimmune inflammatory disease (SIRD) was suspected at first evaluation by the attending rheumatologist. Results: Three hundred fifty-seven patients/appointments were eligible for analysis (193 from the capital and 164 from small and medium towns). In 2007/2008, suspected SIRD occurred in 76/260 (29.2%) and 73/222 (32.9%) among patients from the capital and outside counties, respectively (P = 0.387). In 2017/2018, suspected SIRD occurred in 75/193 (38.9%) and 111/164 (67.7%) in patients from the capital and outside counties, respectively (difference: 28.8, 95% CI: 19.0 to 38.9, P < 0.001), indicating a marked improvement in referrals submitted to the new triage system. Conclusion: The quality of Rheumatology referrals in our state improved over the 10-year interval under study, particularly among patients from locations submitted to referral protocols and teleconsulting support.

Cross-cultural validation and psychometric properties of the Brazilian Portuguese version of the Psoriasis Epidemiology Screening Tool (PEST-bp).

Although the Psoriasis Epidemiology Screening Tool (PEST) questionnaire is a useful tool for screening patients for psoriatic arthritis (PsA), it has not been validated in Portuguese. Our aim was to perform a cross-cultural validation of the PEST for Brazilian Portuguese, as well as to analyse its psychometric properties and to test the association of PEST scores with patient clinical characteristics. The first step was the translation and cross-cultural adaptation of the PEST questionnaire into Brazilian Portuguese, which included forward translation, synthesis, back translation, consolidation with an expert panel and cognitive debriefing with pilot testing. The second step was validation and psychometric testing, in which 124 dermatology patients with no previous PsA diagnosis completed the new adapted questionnaire (PEST-bp). Patients were initially assessed by a dermatologist for clinical characteristics, then they answered the Dermatology Life Quality Index (DLQI) and PEST-bp questionnaires. Afterwards, a rheumatologist, blind to former tests, evaluated the presence of PsA according to CASPAR criteria. The PEST-bp proved to be 0.81 accurate (95% CI: 0.73-0.88) in the ROC curve, indicating a cutoff score ≥ 3 as suggestive of PsA (sensitivity = 84.6%, specificity = 63.3%). The assessment of internal consistency, via the Cronbach test, presented a coefficient of 0.72 (acceptable). A higher PEST-bp score was positively associated with lower quality of life scores and with male patients. In conclusion, the PEST-bp questionnaire proved to be suitable as a screening tool for PsA in patients with psoriasis. Elevated PEST-bp scores are associated with decreased patient quality of life.

Turn down - turn up: a simple and low-cost protocol for preparing platelet-rich plasma.

OBJECTIVE: To describe and analyze a new protocol for the extraction of platelet-rich plasma (PRP) for use in clinical practice and compare this technique with methods that have been previously described in the medical literature. METHODS: We extracted PRP from 20 volunteers using four different protocols (single spin at 1600 ×g, single spin at 600 ×g, double spin at 300 and 700 ×g, and double spin at 600 and 900 ×g). In another group of 12 individuals, we extracted PRP with our new technique (named 'turn down-turn up') consisting of a double spin (200 ×g and 1600 ×g) closed system using standard laboratory equipment (including an ordinary benchtop centrifuge), where the blood remained in the same tube during all processes, reducing the risk of contamination. Platelet counts adjusted to baseline values were compared using analysis of covariance (ANCOVA). RESULTS: Using the four previously described protocols (mentioned above), we obtained concentrations of platelets that were 1.15-, 2.07-, 2.18-, and 3.19-fold greater than the baseline concentration, respectively. With the turn down-turn up technique, we obtained a platelet count that was 4.17-fold (95% confidence interval (CI): 3.09 to 5.25) greater than the baseline platelet count (p=0.063 compared with the double spin at 600 and 900 ×g method). The total cost of the disposable materials used in the extraction process was less than US$10.00 per individual. CONCLUSION: In the present study, we described a simple and safe method for obtaining PRP using low-cost devices.

Ultrasound inflammatory parameters and Treg/Th17 cell profiles in established rheumatoid arthritis.

BACKGROUND: Imbalance and disfuntion in regulatory T-cells (Tregs) and IL-17 producer lymphocytes (Th17) have been implicated in the pathogenesis of rheumatoid arthritis (RA). Gray scale synovial proliferation (GS), power Doppler signal (pD) and bone erosions seen on high resolution muskuloskeletal ultrasound (MSUS) are hallmarks of destructive articular disease. OBJECTIVE: To evaluate the association of peripheral Tregs and Th17 with MSUS findings in RA. METHODS: RA patients (1987 ACR criteria) treated with disease-modifying antirheumatic drugs (DMARDs) were included. Lymphocytes were isolated and immunophenotyped by flow cytometry to investigate regulatory FoxP3+ T cells and IL-17+ cells. MSUS (MyLab 60, Esaote, Genova, Italy, linear probe 6-18 MHz) was performed on hand joints, and a 10-joint US score was calculated for each patient. RESULTS: Data on lymphocytes subsets were avaiable for 90 patients. The majority of patients were Caucasian women with a median disease duration of 6 years (interquartile range: 2-13 years). Mean DAS28 was 4.28 (SD ± 1.64) and mean HAQ score was 1.11 (SD ± 0.83). There was no significant correlation of 10-joint GS score (rS = 0.122, 95% CI: - 0.124 to 0.336, P = 0.254) and 10-joint pD score (rS = 0.056, 95% CI: - 0.180 to 0.273, P = 0.602) with the mean percentage of peripheral Treg cells. Also, 10-joint GS score (rS = 0.083, 95% CI: - 0.125 to 0.302, P = 0.438) and 10-joint pD score 10 (rS = - 0.060, 95% CI: - 0.271 to 0.150, P = 0.575); did not correlate to Th17 profile. No association of bone erosions on MSUS with Treg and Th17 profiles (P = 0.831 and P = 0.632, respectively) was observed. CONCLUSION: In this first study addressing MSUS features and lymphocytes subtypes in established RA, data did not support an association of circulating Tregs and Th17 lymphocytes with inflammatory and structural damage findings on MSUS.