Markus Bredemeier

Low‐ Versus High‐Dose Rituximab for Rheumatoid Arthritis: A Systematic Review and Meta‐Analysis

The approved dose of rituximab (RTX) for rheumatoid arthritis (RA) is 2 × 1,000 mg infusions given 2 weeks apart. There is contradictory evidence regarding the effectiveness of a lower‐dose regimen (2 × 500 mg) of RTX. Our aim was to compare the efficacy and safety of low‐ and high‐dose RTX and to test the noninferiority of the low‐dose regimen.

Evaluation of cytokines, oxidative stress markers and brain-derived neurotrophic factor in patients with fibromyalgia - A controlled cross-sectional study.

OBJECTIVESnPrevious studies measuring serum levels of biomarkers of inflammation/oxidative stress and neurotrophins levels in fibromyalgia (FM) have rendered inconsistent results. In the present study, our aim was to explore the levels of interleukins, oxidative stress markers and brain-derived neurotrophic factor (BDNF) in patients with FM in relation to depression and severity of disease.nnnMETHODSnIn a prospective controlled cross-sectional study, serum concentrations of IL-6, IL-8, IL-10, TNF-α, thiobarbituric acid reactive substances (TBARS), protein carbonyl and BDNF were measured in 69 FM patients and 61 healthy controls (all women). In the FM group, the Fibromyalgia Impact Questionnaire (FIQ), the Beck Depression Inventory (BDI) and the Hamilton Depression Rating Scale (HDRS) were applied. Mann Whitneys and Spearman correlation tests were used for statistical analysis.nnnRESULTSnThe FM patients demonstrated a significant impact of the disease on quality of life (FIQ 70.2±17.8) and most of them had depression at some level (82.6% and 87.0% as assessed by BDI and HDRS, respectively). Most biomarkers (IL-6, IL-8, TNF-α, TBARS and protein carbonyl) and BDNF did not differ significantly between patients and controls, but the IL-10 levels were higher in FM patients (adjusted p=0.041). Among FM patients, there was no correlation of HDRS, FIQ, and BDI scores with any biomarker tested here.nnnCONCLUSIONnWe observed no significant differences in biomarkers between FM patients and controls, except for higher levels of IL-10 (an anti-inflammatory cytokine) in patients. The levels of biomarkers were not correlated with parameters of disease and depression severity.

Updated systematic review and meta-analysis of randomized controlled trials comparing low- versus high-dose rituximab for rheumatoid arthritis

Thexa0purpose of this study is to update a systematic review and meta-analysis comparing low- (2u2009×u2009500 or 1u2009×u20091000xa0mg) and high-dose (2u2009×u20091000xa0mg) rituximab (RTX) for the treatment of rheumatoid arthritis (RA), considering the recent emergence of new evidence. The systematic literature review searching for randomized controlled trials (RCTs) was updated to November 6, 2014 using the PubMed, EMBASE, Cochrane Library, Web of Science databases, and hand searching. The primary outcomes were the American College of Rheumatology (ACR) criteria for 20xa0% improvement (ACR20), ACR50, and ACR70 responses and the Disease Activity Score in 28 joints (DAS28) at 24 and 48/52xa0weeks. The secondary outcomes were change in Health Assessment Questionnaire (HAQ) score, change in the radiographic modified Total Sharp Score (mTSS), levels of immunoglobulin G (IgG), and adverse events. In total, seven RCTs were identified, including two new full publication versions and one abstract of RCTs. There were no significant differences in the primary outcomes and change in HAQ, although the mean change in mTSS was 0.25 units (95xa0% CI, 0.01 to 0.49; Pu2009=u20090.04) higher in low-dose group at week 52. Two RCTs did not demonstrate difference between the RTX regimens for maintaining clinical response (obtained initially using high-dose RTX) in anti-TNF-experienced patients. IgG levels were significantly higher (Pu2009≤u20090.02), and first infusion reactions were less frequent in the low-dose group (Pu2009=u20090.02). Our updated results further support the similar efficacy of both RTX regimens in different subsets of RA patients, demonstrating a better clinical and laboratory safety profile of the low-dose scheme.

Xanthine oxidase inhibitors for prevention of cardiovascular events: a systematic review and meta-analysis of randomized controlled trials

BackgroundXanthine oxidase inhibitors (XOI), classified as purine-like (allopurinol and oxypurinol) and non-purine (febuxostat and topiroxostat) XOI, present antioxidant properties by reducing the production of reactive oxygen species derived from purine metabolism. Oxidative stress is an important factor related to endothelial dysfunction and ischemia-reperfusion injury, and may be implicated in the pathogenesis of heart failure, hypertension, and ischemic heart disease. However, there is contradictory evidence regarding the possible cardiovascular (CV) protective effect exerted by XOI. Our objective is to compare the incidence of major adverse cardiovascular events (MACE), mortality, total (TCE) and specific CV events in randomized controlled trials (RCTs) testing XOI against placebo or no treatment.MethodsPubMed, EMBASE, Web of Science, Cochrane Central, Lilacs databases were searched from inception to Dec 30 2016, along with hand searching. RCTs including exclusively adult individuals, lasting ≥u20094xa0weeks, with no language restriction, were eligible. Independent paired researchers selected studies and extracted data. Considering the expected rarity of events, Peto and DerSimonian/Laird odds ratios (OR), the latter in case of heterogeneity, were used for analysis. Random-effects meta-regression was used to explore heterogeneity.ResultsThe analysis of MACE included 81 articles (10,684 patients, 6434 patient-years). XOI did not significantly reduce risk of MACE (ORPxa0=u20090.71, 95% CI 0.46–1.09) and death (0.89, 0.59–1.33), but reduced risk of TCE (0.60, 0.44–0.82; serious TCE: 0.64, 0.46 to 0.89), and hypertension (0.54, 0.37 to 0.80). There was protection for MACE in patients with previous ischemic events (0.42, 0.23–0.76). Allopurinol protected for myocardial infarction (0.38, 0.17–0.83), hypertension (0.32, 0.18–0.58), TCE (0.48, 0.31 to 0.75, I2xa0=u200955%) and serious TCE (0.56, 0.36 to 0.86, I2xa0=u200944%). Meta-regression associated increasing dose of allopurinol with higher risk of TCE and serious TCE (Pu2009<u20090.05). Accordingly, lower doses (≤u2009300xa0mg/day) of allopurinol reduced the risk of TCE, unlike higher doses. Non-purine-like XOI did not significantly reduce or increase the risk of adverse CV events, but confidence intervals were wide. Quality of evidence was generally low to moderate.ConclusionsPurine-like XOI may reduce the incidence of adverse CV outcomes. However, higher doses of allopurinol (>u2009300xa0mg/day) may be associated with loss of CV protection.

Ultrasound power Doppler synovitis is associated with plasma IL-6 in established rheumatoid arthritis.

BACKGROUND AND OBJECTIVEnCytokines have an important role in the pathogenesis of rheumatoid arthritis (RA). Although plasma levels of IL-6 have been related to musculoskeletal ultrasound (MSUS) synovitis in early DMARD-naïve RA, there are no similar studies in established disease.nnnMETHODSn64 RA patients treated with non-biological DMARDs and 30 healthy controls were included in this prospective cross-sectional study. A blood sample was taken before evaluation of disease activity (DAS28) and ultrasonography (all tests performed in a blinded fashion). MSUS was performed by one of two ultrasound-trained rheumatologists on 10 joints of both hands. Gray scale (GS) and pD (power Doppler) synovitis were evaluated using a semi-quantitative scale (0-3) in individual joints, and their sum (score 10) was calculated. Plasma cytokines (IL-2, IL-4, IL-6, IL-10, IL-17, TNF, IFN-γ, and VEGF) were quantified by flow cytometry.nnnRESULTSnLevels of all cytokines, excepting VEGF, were significantly higher in RA patients than in controls (P⩽0.05). In RA patients, IL-6, but not other cytokines, correlated positively with DAS28 and swollen joint count (P⩽0.01), as well as with 10-joint pD score, and GS and pD of both wrists (P<0.01 for all tests). In multiple linear regression, the association of IL-6 with 10-joint pD score was maintained even after adjustment for DAS28. However, there was no correlation of IL-6 with tender joint count, 10-joint GS score, or presence of erosions.nnnCONCLUSIONnWe demonstrated an association of inflammatory findings on MSUS and plasma IL-6 independently of DAS28 in established RA.

Capillary loss on nailfold capillary microscopy is associated with mortality in systemic sclerosis

The objective of this study is to test the association of the severity of nailfold capillaroscopy (NFC) abnormalities with mortality in systemic sclerosis (SSc). One hundred and seventy SSc patients underwent an extensive evaluation (including high-resolution computed tomography, pulmonary function tests, and Doppler echocardiography) at baseline following a standard protocol. Capillary loss on NFC was evaluated using the avascular score (AS, ranging from 0 to 3), and the mean number of ectasias, megacapillaries, and hemorrhages per finger was also recorded. After a mean period of 10.1xa0±xa04.9xa0years, the life status of the patients was ascertained. Univariate and multivariate Cox proportional hazards models were used for statistical analysis. Overall, 73 patients died. By univariate Cox analysis, the AS was significantly associated with mortality (hazard ratio [HR]xa0=xa01.64, 95% CI 1.22 to 2.19, pxa0=xa00.001). In our study, this association was stronger than that of race, gender, anticentromere antibodies, anti-topoisomerase I antibodies, and form of disease and had similar strength to that of skin score in univariate analyses. However, after controlling for a combination of variables (age, skin score, gender, race, signs of peripheral ischemia, and extent of interstitial lung disease, all independently associated with mortality), the association of AS with mortality was blunted (HRxa0=xa01.15, 95% CI 0.80 to 1.65, pxa0=xa00.445). Other NFC variables were not related to mortality. AS was associated with higher risk of death and, despite not having an independent association with mortality after controlling for a set of demographic and clinical variables, may be a useful tool in prognostic evaluation of SSc.

Clinical Algorithms for the Diagnosis and Prognosis of Interstitial Lung Disease in Systemic Sclerosis

INTRODUCTIONnInterstitial lung disease (ILD) is currently the primary cause of death in systemic sclerosis (SSc). Thoracic high-resolution computed tomography (HRCT) is considered the gold standard for diagnosis. Recent studies have proposed several clinical algorithms to predict the diagnosis and prognosis of SSc-ILD.nnnOBJECTIVEnTo test the clinical algorithms to predict the presence and prognosis of SSc-ILD and to evaluate the association of extent of ILD with mortality in a cohort of SSc patients.nnnMETHODSnRetrospective cohort study, including 177 SSc patients assessed by clinical evaluation, laboratory tests, pulmonary function tests, and HRCT. Three clinical algorithms, combining lung auscultation, chest radiography, and percentage predicted forced vital capacity (FVC), were applied for the diagnosis of different extents of ILD on HRCT. Univariate and multivariate Cox proportional models were used to analyze the association of algorithms and the extent of ILD on HRCT with the risk of death using hazard ratios (HR).nnnRESULTSnThe prevalence of ILD on HRCT was 57.1% and 79 patients died (44.6%) in a median follow-up of 11.1 years. For identification of ILD with extent ≥10% and ≥20% on HRCT, all algorithms presented a high sensitivity (>89%) and a very low negative likelihood ratio (<0.16). For prognosis, survival was decreased for all algorithms, especially the algorithm C (HR = 3.47, 95% CI: 1.62-7.42), which identified the presence of ILD based on crackles on lung auscultation, findings on chest X-ray, or FVC <80%. Extensive disease as proposed by Goh et al. (extent of ILD > 20% on HRCT or, in indeterminate cases, FVC < 70%) had a significantly higher risk of death (HR = 3.42, 95% CI: 2.12-5.52). Survival was not different between patients with extent of 10% or 20% of ILD on HRCT, and analysis of 10-year mortality suggested that a threshold of 10% may also have a good predictive value for mortality. However, there is no clear cutoff above which mortality is sharply increased.nnnCONCLUSIONnClinical algorithms had a good diagnostic performance for extents of SSc-ILD on HRCT with clinical and prognostic relevance (≥10% and ≥20%), and were also strongly related to mortality. Non-HRCT-based algorithms could be useful when HRCT is not available. This is the first study to replicate the prognostic algorithm proposed by Goh et al. in a developing country.

Characteristics of NK cell activity in patients with systemic sclerosis

INTRODUCTIONnPrevious studies have shown an increased expression of natural killer (NK) cells in the peripheral blood of patients with systemic sclerosis (SSc). NK cells are part of innate immunity, recognizing infected cells through killer immunoglobulin-like receptors (KIR), which show marked polymorphism. A novel model has been proposed predicting the activity of NK cells, evaluating whether there is excessive activation (EA), excessive inhibition (EI) or balance (B) (neutral).nnnOBJECTIVEnTo evaluate the activity of NK cells in patients with SSc and compare it with that of a control group.nnnMETHODnThis study comprised 110 patients with SSc and 115 healthy controls. A novel model that predicts the activity of NK cells was used. For that, cells with their respective KIR/HLA-C and Bw4 ligands were considered. The activity of NK cells was defined as EA, EI, or B.nnnRESULTSnOur results showed that 63.5% of healthy controls had the KIR phenotype characterized by EI, as compared with 39.1% of the patients with SSc (P = 0.001). Considering only KIR2DL2-positive individuals, 34.7% of EI was found in healthy controls and 10.9% in patients with SSc (P < 0.001).nnnCONCLUSIONnIn our study, the model that predicts the action of NK cells showed that healthy controls have higher frequency of EI as compared with SSc patients, suggesting a protective effect of the EI profile against the development of SSc. These results suggest a potential role of NK cells in the pathogenesis of SSc, but further studies should be conducted to confirm our data.

Comments on Mignot et al.: bisphosphonate drug holidays in postmenopausal osteoporosis: effect on clinical fracture risk

Dear Editor, We read with interest the study by Mignot et al. [1], which observed a significant association of drug holiday with higher incidence of clinical fractures in the treatment of osteoporosis. Although the results are interesting, we have some concerns about problems in the analysis of data. The authors reported that 5 of 31 patients on drug holiday sustained fragility fractures, in comparison to 16 of 135 still on osteoporosis medications. The duration of follow-up in both groups is not clearly informed, but if they are similar (as would be expected), the hazard ratio (HR) should provide values similar to those observed using relative risk (RR). If we calculate the RR, we obtain a value of 1.36 (95% confidence interval [CI] 0.54 to 3.43; Fisher’s exact test, two-tailed P = 0.551), similar to the adjusted HR reported by the authors (1.40, 95% CI 1.12 to 1.60; P = 0.0095), but still far from statistical significance. It may be argued that, after adjustment for 5 confounding factors in Cox proportional hazards model, a statistically significant association emerged, but such analysis may be subject to overfitting considering the small number of events (21) in the entire cohort [2]. Therefore, it seems that the P values presented by the authors in univariate (log-rank test) and multivariate analyses are overly optimistic. Other evidence of problems comes from the Kaplan-Meier curves (Fig. 4). In the Bdrug holiday^ curve, all patients seem to have presented events (i.e., fragility fractures), given that at each point there was a reduction in the prevalence of eventfree individuals. So, it seems that individuals that should have been only censored (due to absence of events during followup) were statistically treated as having fragility fractures. With these comments, our objective is to help to clarify some issues that may compromise the interpretation and validity of the results. Problems in data bank management and statistical analysis are not infrequent in medical articles, but clarification of possible concerns goes in the best interest of scientific progress.

Ultrasound resistive index, power Doppler, and clinical parameters in established rheumatoid arthritis

Ultrasonography (US) is a useful tool for the evaluation of sinovial vascularization and proliferation in rheumatoid arthritis (RA). Accordingly, resistive index (RI) on spectral Doppler (sD) US provides a quantitative analysis of vascular inflammation, but its utility in the evaluation of RA activity has not been established. Our objective was to determine the association of RI with other US parameters of synovitis and with clinical disease activity in established RA. Patients with positive power Doppler (pD) were included in a prospective cross-sectional study. Disease activity and disability were evaluated using the Disease Activity Score in 28-joints (DAS28) and Health Assessment Questionnaire (HAQ), respectively. Gray scale (GS) synovitis, pD, and sD analyses were performed by one of two examiners in wrists and the second and third metacarpophalangeal and proximal interphalangeal joints. The 10-joint GS and 10-joint pD scores and mean RI were then calculated. Weighted kappa (WK) values were employed to assess interobserver reability, and correlations were tested using the Spearman coefficient. Ninety-five RA patients (median duration of disease of 7xa0years and mean DAS28 of 4.32xa0±xa01.66) were included. WK values in real-time US were 0.77 for synovitis, 0.87 for pD, and 0.68 for RI. There were no significant correlations of RI with 10-joint GS, 10-joint pD, DAS28, joint counts, or HAQ (Pxa0>xa00.10 for all tests). Patients in remission had a mean RI similar to those with high disease activity (0.62xa0±xa00.10, nxa0=xa015 versus 0.63xa0±xa00.13, nxa0=xa034, respectively). The addition of the RI score did not seem to improve US performance in patients with established RA.