Rituximab versus azathioprine for maintenance of remission for patients with ANCA-associated vasculitis and relapsing disease: an international randomised controlled trial.

OBJECTIVE: Following induction of remission with rituximab in anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) relapse rates are high, especially in patients with history of relapse. Relapses are associated with increased exposure to immunosuppressive medications, the accrual of damage and increased morbidity and mortality. The RITAZAREM trial compared the efficacy of repeat-dose rituximab to daily oral azathioprine for prevention of relapse in patients with relapsing AAV in whom remission was reinduced with rituximab. METHODS: RITAZAREM was an international randomised controlled, open-label, superiority trial that recruited 188 patients at the time of an AAV relapse from 29 centres in seven countries between April 2013 and November 2016. All patients received rituximab and glucocorticoids to reinduce remission. Patients achieving remission by 4 months were randomised to receive rituximab intravenously (1000 mg every 4 months, through month 20) (85 patients) or azathioprine (2 mg/kg/day, tapered after month 24) (85 patients) and followed for a minimum of 36 months. The primary outcome was time to disease relapse (either major or minor relapse). RESULTS: Rituximab was superior to azathioprine in preventing relapse: HR 0.41; 95% CI 0.27 to 0.61, p<0.001. 19/85 (22%) patients in the rituximab group and 31/85 (36%) in the azathioprine group experienced at least one serious adverse event during the treatment period. There were no differences in rates of hypogammaglobulinaemia or infection between groups. CONCLUSIONS: Following induction of remission with rituximab, fixed-interval, repeat-dose rituximab was superior to azathioprine for preventing disease relapse in patients with AAV with a prior history of relapse. TRIAL REGISTRATION NUMBER: NCT01697267; ClinicalTrials.gov identifier.

Physical activity, sedentary behaviour and well-being: experiences of people with knee and hip osteoarthritis.

Living with knee and hip osteoarthritis (OA) means living with pain and difficulty in movement. Given the beneficial effects of physical activity (PA) and reduction of sedentary behaviour (SB), these behaviours need to be understood in the context of individuals' daily lives and sense of well-being. Twelve individuals (age: 43-79 years; 67% female) with knee and/or hip OA purposively selected (e.g., age, OA duration, OA severity) participated in semi-structured interviews. Data was analysed using inductive thematic analysis. PA and SB were narrated as multifaceted experiences with two overarching themes, PA negotiations (valuing mobility, the burden of osteoarthritis, keep going, the feel-good factor), SB negotiations (the joy of sitting, a lot is too bad, the osteoarthritis confines), and two overlapping themes (the life context, finding a balance). Physical and psychological aspects of PA and SB experiences were interwoven. Participants valued mobility and were proactively trying to preserve it by keeping active. A constant negotiation among the OA burden, the need to enjoy life and life circumstances was underlying PA behaviour. Prescription and encouragement of a physically active lifestyle in this population should be linked to mobility-related personal values and sense of well-being, while addressing concerns around OA-safety and normalizing PA trade-offs.

Assessing moderate-to-vigorous physical activity in hip and knee osteoarthritis using accelerometers: Implications of different patterns and cut-points for health and well-being.

OBJECTIVE: This cross-sectional study explored how using age-specific and non-age-specific cut-points to assess moderate-to-vigorous physical activity (MVPA) measured by GT3X accelerometers affected bouted and total volume MVPA associations with health and well-being. METHODS: MVPA correlations with physical function, BMI, joint pain, quality of life, anxiety and depression were tested. Steiger's z compared the strength of these correlations for each pair of cut-points. RESULTS: A total of 109 adults with hip/knee osteoarthritis [M= 63.8 years (±10.58), 63.3% women] participated. Applying age-specific cut-points resulted in significantly more time classified as MVPA (76/9.5min total volume/bouted) compared to non-age-specific (38.8/7min total volume/bouted). Only total volume MVPA correlations differed significantly as a function of cut-points for self-reported function, quality of life, anxiety and depression (p ≤ .05). For age-specific cut-points, more time spent in MVPA was associated with a worse psychological profile. DISCUSSION: Applying age-specific cut-points for MVPA assessment in older adults with lower limb OA had implications for MVPA associations with health and well-being when total volume, but not bouted, MVPA was considered. Age-specific total volume MVPA needs further understanding regarding patterns and affective responses it comprises. Bouted MVPA is an important pattern for MVPA accrual, but probably not an applicable PA target for many patients.

Rituximab as therapy to induce remission after relapse in ANCA-associated vasculitis.

OBJECTIVES: Evaluation of rituximab and glucocorticoids as therapy to induce remission after relapse in ANCA-associated vasculitis (AAV) in a prospective observational cohort of patients enrolled into the induction phase of the RITAZAREM trial. METHODS: Patients relapsing with granulomatosis with polyangiitis or microscopic polyangiitis were prospectively enrolled and received remission-induction therapy with rituximab (4×375 mg/m2) and a higher or lower dose glucocorticoid regimen, depending on physician choice: reducing from either 1 mg/kg/day or 0.5 mg/kg/day to 10 mg/day by 4 months. Patients in this cohort achieving remission were subsequently randomised to receive one of two regimens to prevent relapse. RESULTS: 188 patients were studied: 95/188 (51%) men, median age 59 years (range 19-89), prior disease duration 5.0 years (range 0.4-34.5). 149/188 (79%) had previously received cyclophosphamide and 67/188 (36%) rituximab. 119/188 (63%) of relapses had at least one major disease activity item, and 54/188 (29%) received the higher dose glucocorticoid regimen. 171/188 (90%) patients achieved remission by 4 months. Only six patients (3.2% of the study population) did not achieve disease control at month 4. Four patients died in the induction phase due to pneumonia (2), cerebrovascular accident (1), and active vasculitis (1). 41 severe adverse events occurred in 27 patients, including 13 severe infections. CONCLUSIONS: This large prospective cohort of patients with relapsing AAV treated with rituximab in conjunction with glucocorticoids demonstrated a high level of efficacy for the reinduction of remission in patients with AAV who have relapsed, with a similar safety profile to previous studies.

Cartilage turnover and intra-articular corticosteroid injections in knee osteoarthritis.

Intra-articular corticosteroid injections (IACI) are commonly used interventions for pain relief in patients with knee osteoarthritis (OA). Biomarkers may be helpful in further elucidating how IACI exert their effect. The aim of this study is to look at the response of biomarkers of cartilage and bone metabolism after IACI in knee OA. Eighty subjects with symptomatic knee OA [45% male, mean age (SD) 64 (11) years] underwent routine knee joint injection with 40 mg triamcinolone acetonide and 4 ml 1% lignocaine. Knee pain (as pain subscale of WOMAC VAS) and biomarkers [C-telopeptides of type-II collagen (uCTX-II), and N-telopeptides of type-I collagen in urine; cartilage oligomeric matrix protein (COMP), hyaluronic acid, N-terminal propeptide of type-IIA collagen, and human cartilage glycoprotein-39 (YKL-40) in serum] were measured at baseline and 3 weeks after IACI. Radiographic severity of disease was evaluated using knee radiographs. Median uCTX-II, a cartilage degradation marker, was lower at 3 weeks post IACI compared with baseline: 306.3 and 349.9 ng/mmol, respectively (p < 0.01), which remained significant after Bonferroni correction. Apart from a weak trend of lower sCOMP post IACI (p = 0.089), other biomarkers showed no change after IACI. Both baseline uCTX-II values and the change in uCTX-II from baseline to 3 weeks post injection correlated with radiographic severity of joint space narrowing, but not osteophyte grade. No association between uCTX-II and pain was observed. This observational study suggests that IACI in knee OA may reduce cartilage degradation in the short term.

Barriers and facilitators of physical activity in knee and hip osteoarthritis: a systematic review of qualitative evidence.

Physical activity (PA), including engagement in structured exercise, has a key role in the management of hip and knee osteoarthritis (OA). However, maintaining a physically active lifestyle is a challenge for people with OA. PA determinants in this population need to be understood better so that they can be optimised by public health or healthcare interventions and social policy changes. OBJECTIVES: The primary aim of this study is to conduct a systematic review of the existing qualitative evidence on barriers and facilitators of PA for patients with hip or knee OA. Secondary objective is to explore differences in barriers and facilitators between (1) lifestyle PA and exercise and (2) PA uptake and maintenance. METHODS: Medline, Embase, Web of Science, Cumulative Index to Nursing and Allied Health Literature, SPORTDiscus, Scopus, Grey literature and qualitative journals were searched. Critical Appraisal Skills Programme-Qualitative checklist and Lincoln and Guba's criteria were used for quality appraisal. Thematic synthesis was applied. FINDINGS: Ten studies were included, seven focusing on exercise regimes, three on overall PA. The findings showed a good fit with the biopsychosocial model of health. Aiming at symptom relief and mobility, positive exercise experiences and beliefs, knowledge, a 'keep going' attitude, adjusting and prioritising PA, having healthcare professionals' and social support emerged as PA facilitators. Pain and physical limitations; non-positive PA experiences, beliefs and information; OA-related distress; a resigned attitude; lack of motivation, behavioural regulation, professional support and negative social comparison with coexercisers were PA barriers. All themes were supported by high and medium quality studies. Paucity of data did not allow for the secondary objectives to be explored. CONCLUSION: Our findings reveal a complex interplay among physical, personal including psychological and social-environmental factors corresponding to the facilitation and hindrance of PA, particularly exercise, engagement. Further research on the efficacy of individualised patient education, psychological interventions or social policy change to promote exercise engagement and lifestyle PA in individuals with lower limb OA is required. TRIAL REGISTRATION NUMBER: CRD42016030024.

Biologic drugs as analgesics for the management of osteoarthritis.

BACKGROUND: Biologic drugs are novel therapeutic agents with demonstrated effectiveness in the management of a variety of chronic inflammatory disorders. Unmet needs in the treatment of chronic pain have led physicians to utilize a similar approach to patients suffering from conditions not characterized by systemic inflammation such as osteoarthritis (OA). The aim of this review is to discuss the current knowledge on the use of commonly used biologic agents [i.e., anti-tumor necrosis factor alpha (anti-TNF alpha) and anti-nerve growth factor (anti-NGF)] for the management of OA. METHODS: A narrative literature review of studies investigating the use of biologic agents for the management of osteoarthritis was conducted. We searched MEDLINE and EMBASE for English language publications. A hand-search of reference lists of relevant studies was also performed. RESULTS: Current evidence does not support TNF-alpha inhibition for the management of OA, although a selected subgroup of these patients with a marked inflammatory profile may benefit from this therapy. Anti-NGF therapy has been shown to reduce pain and improve function compared to placebo and non-steroidal anti-inflammatory drugs in OA but concerns remain regarding the safety of such treatment. The discrepant results observed in RCTs of biologic agents may be related to heterogeneity, small sample sizes, and differences in the mode of administration of these drugs. CONCLUSION: Anti-NGF therapy is efficacious for pain in patients with hip and knee OA. Despite the fact that current data suggests that anti-cytokine treatments have limited efficacy in patients with chronic osteoarthritic pain, larger and better designed studies in more selected populations are justified to determine whether such therapeutic approaches can improve outcomes in this disabling condition where our medical treatment armamentarium is relatively poor.

Barriers and facilitators to physical activity in people with hip or knee osteoarthritis: protocol for a systematic review of qualitative evidence.

INTRODUCTION: This protocol aims to describe the objective and methods to be followed in a systematic review of qualitative studies on barriers and facilitators to physical activity (PA) in people with hip or knee osteoarthritis (OA). METHODS AND ANALYSIS: MEDLINE, EMBASE, PhychINFO, Web of Science, CINAHL, SPORTDiscus, Scopus and grey literature sources will be electronically searched. Hand search of qualitative research-centred journals, reference screening of relevant reviews and inquiries to researchers active in the field will complement the search. Studies will be selected if they apply qualitative or mixed-methods designs to directly explore factors that correspond to engagement in PA/exercise or, the perceptions regarding PA/exercise in people with hip or knee OA. The Critical Appraisal Skills Programme Qualitative Checklist and the evaluative criteria of credibility, transferability, dependability and confirmability will be applied for the study appraisal. 2 independent reviewers will perform the search, study selection and study appraisal. Thematic synthesis will be used for synthesising the findings of the primary studies and the process and product of the synthesis will be checked by a second researcher. ConQual approach will be used for assessing the confidence in the qualitative findings. ETHICS AND DISSEMINATION: This systematic review will inform our understanding of the PA determinants and how to optimise behaviour change in people living with hip or knee OA. The review findings will be reported in a peer-reviewed journal and presented at national or international conferences. The study raises no ethical issues. TRIAL REGISTRATION NUMBER: CRD42016030024.

Systemic inflammatory disease resolution following cosmetic silicone breast implant removal.

A 37-year-old Caucasian woman presented with subacute, symmetrical inflammatory arthralgia, which was affecting her work. Apart from fatigue, she had no other constitutional symptoms. She had undergone cosmetic bilateral silicone breast implant surgery in 2008. Blood tests revealed erythrocyte sedimentation rate 53 mm/h, weakly positive antinuclear antibodies and IgG cardiolipin antibody, while breast ultrasound revealed a ruptured left silicone implant. The working diagnosis was systemic inflammatory disease of uncertain origin. She decided to have replacement, rather than removal, of her silicone breast implants privately, but her symptoms persisted postoperatively with a new erythema multiforme-like rash despite treatment with methotrexate and moderate dose prednisolone. Following further consultation with a National Health Service breast surgeon, her silicone implants were removed. Within 10 weeks of surgery, all immunomodulatory treatment was discontinued with complete symptom and inflammatory response resolution. This case illustrates that implant silicone can induce clinically significant systemic inflammatory disease and implant removal is essential for disease resolution.

Activity of daily living is associated with circulating CD34+/KDR+ cells and granulocyte colony-stimulating factor levels in patients after myocardial infarction.

The study aimed to investigate whether the extent of activities of daily living (ADL) of patients after myocardial infarction affect numbers of circulating CD34(+)/KDR(+) and CD45(+)/CD34(+) cells, which are supposed to protect structural and functional endothelial integrity. In a cross-sectional study, 34 male coronary artery disease patients with a history of myocardial infarction were assessed for times spent per week for specific physical ADL, including basic activities (instrumental ADL), leisure time activities, and sport activities, using a validated questionnaire. Individual specific activity times were multiplied with respective specific metabolic equivalent scores to obtain levels of specific activities. Numbers of circulating CD34(+)/KDR(+) and CD45(+)/CD34(+) cells were analyzed by flow cytometry. Furthermore, the colony-forming capacity of CD34(+) cells and the level of granulocyte colony-stimulating factor (G-CSF) in serum were measured. Analysis revealed that the extent of total activities and basic activities, as well as total activity time, were positively correlated with numbers of circulating CD34(+)/KDR(+) cells (r = 0.60, 0.56, and 0.55, P < 0.05). Higher levels of total activity were also associated with increased colony-forming capacity of CD34(+) cells (r = 0.54, P < 0.05) and with higher systemic levels of G-CSF (r = 0.44, P < 0.05). These findings indicate that even ADL-related activities of coronary artery disease patients after myocardial infarction exert stimulating effects on CD34(+)/KDR(+) cell mobilization, potentially mediated by increased G-CSF levels. This, in turn, potentially contributes to the beneficial effects of exercise on the diseased cardiovascular system.

Generation of functional endothelial-like cells from adult mouse germline-derived pluripotent stem cells.

Functional endothelial cells and their progenitors are required for vascular development, adequate vascular function, vascular repair and for cell-based therapies of ischemic diseases. Currently, cell therapy is limited by the low abundance of patient-derived cells and by the functional impairment of autologous endothelial progenitor cells (EPCs). In the present study, murine germline-derived pluripotent stem (gPS) cells were evaluated as a potential source for functional endothelial-like cells. Cells displaying an endothelial cell-like morphology were obtained from gPS cell-derived embryoid bodies using a combination of fluorescence-activated cell sorting (FACS)-based selection of CD31-positive cells and their subsequent cultivation on OP9 stromal cells in the presence of VEGF-A. Real-time reverse transcriptase polymerase chain reaction, FACS analysis and immunofluorescence staining showed that the gPS cell-derived endothelial-like cells (gPS-ECs) expressed endothelial cell-specific markers including von Willebrand Factor, Tie2, VEGFR2/Flk1, intercellular adhesion molecule 2 and vascular endothelial-cadherin. The high expression of ephrin B2, as compared to Eph B4 and VEGFR3, suggests an arterial rather than a venous or lymphatic differentiation. Their capability to take up Dil-conjugated acetylated low-density lipoprotein and to form capillary-like networks on matrigel confirmed their functionality. We conclude that gPS cells could be a novel source of endothelial cells potentially suitable for regenerative cell-based therapies for ischemic diseases.

Clinical outcome of ultrasound-guided steroid injections for chronic shoulder pain.

AIM: To investigate the short- to medium-term effectiveness of ultrasound (US)-guided steroid injections for shoulder pain in patients who previously failed to respond to unguided steroid injections. METHODS: We examined 60 consecutive patients who had undergone US examination and US-guided steroid injection. Patients were categorised into having had a good response (i.e., good pain relief at time of follow-up), some response (improvement for 2-4 weeks) or no response, as documented by their usual rheumatologist in their subsequent routine out-patient review appointments. RESULTS: Average age was 64.4 ± 11.5 years and 42 were female. Median interval between US-guided injection and follow-up was four (interquartile range 2-5) months. Thirty-four (56.6%) patients reported a good response, 13 (21.7%) some response and another 13 (21.7%) no response. CONCLUSIONS: US guidance of steroid injections may achieve good short- to medium-term benefit in the majority of patients with chronic shoulder pain due to a variety of clinical syndromes.

Intra-articular corticosteroid injection in osteoarthritis of the knee and hip: factors predicting pain relief--a systematic review.

OBJECTIVES: Variations in the degree of pain relief reported by patients with osteoarthritis following intra-articular corticosteroid injections are well recognized but the reasons for this are not widely understood and factors which might predict variations in response have not been subjected to systematic review. We set out to review systematically the literature relating to predictors of pain reduction following intra-articular corticosteroid injections in patients with knee and hip osteoarthritis. METHODS: Searches were performed using Medline, EMBASE, Web of Knowledge and MeSH search of Pubmed, the last search being performed in August 2012. Search terms included knee osteoarthritis, hip osteoarthritis, corticosteroid and related terms, and intra-articular injection. Papers were selected and reviewed by 2 reviewers. For inclusion, papers were required to describe studies in which patients with osteoarthritis of the knee or hip received intra-articular corticosteroid injection as an intervention, contain clearly defined outcome measures relating to pain and contain analysis relating to predictors of clinical response to treatment. RESULTS: Twenty-one studies met criteria for inclusion from a total of 54 papers reviewed in full. Eight of these related to hip OA and 13 related to knee OA. No factors that were investigated as potential predictors of response, including radiographic grade and clinical or sonographic evidence of inflammation or synovial hypertrophy were supported by strong evidence. The review also identified that several plausible potential predictors had not been studied to date. CONCLUSIONS: Previous research has not identified reliable predictors of response to IA corticosteroid injections, a widely practised intervention in knee and hip OA. Further studies are required if this question is to be answered.

Exercise delays neutrophil apoptosis by a G-CSF-dependent mechanism.

The aim of the study was to determine whether exercise affects neutrophil apoptosis and to characterize the underlying mechanisms. Using annexin V labeling, neutrophil apoptosis was measured using flow cytometry after various bouts of exercise (marathon run, concentric/eccentric treadmill exercise, moderate/intensive resistance training) and in vitro conditions. Similarly, apoptosis-related markers as death receptors/ligands and mitochondrial membrane potential were detected. Furthermore, concentrations of intracellular free calcium and glutathione were measured using spectrofluorometry. After both marathon run and intensive laboratory exercise tests, neutrophil apoptosis was delayed. Furthermore, neutrophils mitochondrial membrane potential and death receptor/ligand expression were not affected by exercise. Apoptosis delay was accompanied under some exercise conditions by enhanced intracellular calcium transients and decreased glutathione levels. A delay of spontaneous apoptosis in vitro could be induced by incubation of neutrophils in postexercise serum. Heating of postexercise serum abolished the apoptosis delaying effect. In vitro stimulation of resting neutrophils with granulocyte-colony-stimulating factor (G-CSF) and C-reactive protein resulted in apoptosis delay too. Addition of anti-G-CSF antibody to postexercise serum was also effective in reversing its apoptosis-delaying effect. Exercise-induced mobilization of neutrophils is associated with a delay of apoptosis. This fundamental process seems to maintain exercise-induced neutrophilia and to contribute to the alerting and activation of the nonadaptive immune system known from other inflammatory conditions. An important extracellular trigger of apoptosis delay during exercise conditions seems to be G-CSF; intracellular processes may include calcium and redox signaling.

Acute inhibition of the Na(+)/Ca(2+) exchanger reduces proarrhythmia in an experimental model of chronic heart failure.

BACKGROUND: Molecular remodeling in heart failure includes slowing of repolarization, leading to proarrhythmia. OBJECTIVE: To evaluate the effects of Na(+)/Ca(2+) exchanger (NCX) inhibition on repolarization as a novel antiarrhythmic concept in chronic heart failure (CHF). METHODS AND RESULTS: CHF was induced by rapid ventricular pacing in rabbits. Left ventricular function was assessed by echocardiography. Monophasic action potentials (MAPs) showed a prolongation of repolarization in CHF after atrioventricular block and stimulation at different cycle lengths. Sotalol (100 µM, n = 13) or veratridine (0.5 µM; n = 15) resulted in a further significant increase in the MAP duration. CHF was associated with an increased dispersion of repolarization, as compared with sotalol-treated (+22 ± 7 ms; P < .05) and veratridine-treated (+20 ± 6 ms; P < .05) sham hearts. In the presence of a low potassium concentration, sotalol and veratridine reproducibly induced early afterdepolarizations (EADs) and polymorphic ventricular tachyarrhythmias (VTs). SEA0400 (1 µM), a pharmacological inhibitor of NCX, significantly shortened the MAP duration (P < .01) and reduced dispersion (P < .05). It suppressed EAD in 6 of 13 sotalol-treated failing hearts and in 9 of 10 veratridine-treated failing hearts, leading to a reduction in VT (60% in sotalol-treated failing hearts and 83% in veratridine-treated failing hearts). Simulations using a mathematical model showed a reduction in the action potential duration and the number of EADs by the NCX block in all subgroups. CONCLUSIONS: In an experimental model of CHF, the acute inhibition of NCX (1) reduces the MAP duration, (2) decreases dispersion of repolarization, and (3) suppresses EAD and VT. Our observations indicate for the first time that pharmacological NCX inhibition increases repolarization reserve and protects against VTs in heart failure.

G-CSF therapy reduces myocardial repolarization reserve in the presence of increased arteriogenesis, angiogenesis and connexin 43 expression in an experimental model of pacing-induced heart failure.

G-CSF (granulocyte colony-stimulating factor) treatment has been shown to cause beneficial effects including a reduction of inducible arrhythmias in rodent models of ischemic cardiomyopathy. The aim of the present study was to test whether these effects do also apply to pacing-induced non-ischemic heart failure. In 24 female rabbits, heart failure was induced by rapid ventricular pacing. 24 rabbits were sham operated. The paced rabbits developed a significant decrease of ejection fraction. 11 heart failure rabbits (CHF) and 11 sham-operated (S) rabbits served as controls, whereas 13 sham (S-G-CSF) and 13 heart failure rabbits (CHF-G-CSF) were treated with 10 µg/kg G-CSF s.c. over 17 ± 4 days. G-CSF treatment caused a ~25% increased arterial and capillary density and a ~60% increased connexin 43 expression in failing hearts. In isolated, Langendorff-perfused rabbit hearts eight monophasic action potential recordings showed prolongation of repolarization in CHF as compared with controls in the presence of the QT prolonging agent erythromycin (+33 ± 12 ms; p < 0.01). Moreover, a significant increase in dispersion of repolarization contributed to a significantly higher rate of ventricular tachyarrhythmias in CHF. G-CSF-pre-treated hearts showed a further increase in prolongation of repolarization as compared with S and CHF. The further increase in dispersion of repolarization [S-G-CSF: +23 ± 9 ms (spatial), +13 ± 7 ms (temporal); CHF-G-CSF: +38 ± 14 ms (spatial), +10 ± 4 ms (temporal); p < 0.05 as compared with S and CHF], increased the incidence of ventricular tachyarrhythmias. In summary, chronic G-CSF treatment has moderate beneficial effects on parameters potentially related to hemodynamic function in the non-ischemic rabbit CHF model. However, a significant reduction of repolarization reserve might seriously challenge its suitability as a therapeutic agent for chronic CHF therapy.