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Concept: Cyclophosphamide

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There is increased interest in using microRNAs (miRNAs) as biomarkers in different diseases. Present in body fluids, it is controversial whether or not they are mainly enclosed in exosomes, thus we studied if urinary miRNAs are concentrated inside exosomes and if the presence of systemic lupus erythematosus with or without lupus nephritis modifies their distribution pattern. We quantified specific miRNAs in urine of patients with systemic lupus erythematosus (n = 38) and healthy controls (n = 12) by quantitative reverse-transcription PCR in cell-free urine, exosome-depleted supernatant and exosome pellet obtained by ultracentrifugation. In control group, miR-335* and miR-302d were consistently higher in exosomes than in exosome-depleted supernatant, and miR-200c and miR-146a were higher in cell-free fraction. In lupus patients, all urinary miRNAs tested were mainly in exosomes with lower levels outside them (p<0.05 and p<0.01, respectively). This pattern is especially relevant in patients with active lupus nephritis compared to the control group or to the SLE patients in absence of lupus nephritis, with miR-146a being the most augmented (100-fold change, p<0.001). Among the exosomal miRNAs tested, only the miR-146a discriminates the presence of active lupus nephritis. In conclusion, urinary miRNAs are contained primarily in exosomes in systemic lupus erythematosus, and the main increment was found in the presence of active lupus nephritis. These findings underscore the attractiveness of exosomal miRNAs in urine, a non-invasive method, as potential renal disease markers.

Concepts: Cyclophosphamide, Lupus erythematosus, Rheumatology, Lupus nephritis, Glomerulonephritis, Systemic lupus erythematosus

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Non-adherence to disease-modifying antirheumatic drugs (DMARDs) hampers the targets of rheumatoid arthritis (RA) treatment, obtaining low disease activity and decreasing radiological progression. This study investigates if, and to what extent, non-adherence to treatment would lead to a higher 28-joint count disease activity score (DAS28) in the first year after diagnosis.

Concepts: Uranium, Cyclophosphamide, Sulfasalazine, Methotrexate, Rheumatology, Hydroxychloroquine, Disease-modifying antirheumatic drug, Rheumatoid arthritis

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OBJECTIVES: To evaluate the efficacy and safety of subcutaneous golimumab as add-on therapy in patients with active rheumatoid arthritis (RA) despite disease-modifying antirheumatic drug (DMARD) treatment. To evaluate an intravenous plus subcutaneous (IV+SC) golimumab strategy in patients who had not attained remission. METHODS: GO-MORE was an open-label, multinational, prospective study in patients with active RA in typical clinical practice settings. In part 1, patients received add-on monthly 50-mg subcutaneous golimumab for 6 months. The percentage of patients with good/moderate European League Against Rheumatism (EULAR) 28-joint disease activity score (DAS28)-erythrocyte sedimentation rate (ESR) response was compared in patient subgroups with various concurrent or previous DMARD treatments. In part 2, patients with EULAR responses but not remission were randomly assigned to receive IV+SC or subcutaneous golimumab to month 12; DAS28-ESR remission was measured. RESULTS: 3366 patients were enrolled. At baseline of part 1, 3280 efficacy-evaluable patients had mean disease duration of 7.6 years and mean DAS28-ESR of 5.97 (SD=1.095). At month 6, 82.1% achieved good/moderate EULAR responses and 23.9% attained remission. When EULAR responses were analysed by the number of previously failed DMARD or the concomitant methotrexate dose, DMARD type, or corticosteroid use, no statistically significant differences were observed. Part 2 patients (N=490) who received IV+SC or subcutaneous golimumab achieved similar remission rates (∼25%). Adverse events were consistent with previous reports of golimumab and other tumour necrosis antagonists in this population. CONCLUSIONS: Add-on monthly subcutaneous golimumab resulted in good/moderate EULAR response in most patients; 25% achieved remission after 6 more months of golimumab, but an IV+SC regimen provided no additional efficacy over the subcutaneous regimen.

Concepts: Statistical significance, Cyclophosphamide, Sulfasalazine, Hydroxychloroquine, Rheumatology, Methotrexate, Disease-modifying antirheumatic drug, Rheumatoid arthritis

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To compare the risk of lupus-like events (LLEs) and vasculitis-like events (VLEs) in tumour necrosis factor-α inhibitor (TNFi)-treated patients with rheumatoid arthritis (RA) to those receiving non-biological disease-modifying antirheumatic drugs (nbDMARDs).

Concepts: Arthritis, Cyclophosphamide, Hydroxychloroquine, Rheumatology, Disease-modifying antirheumatic drug, Rheumatoid arthritis

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Lupus nephritis (LN) is one of the most severe manifestations of systemic lupus erythematosus (SLE), affecting ∼50% of patients, and both renal disease and treatment-related toxicity contribute to significant morbidity and mortality. Although our understanding of the aetiopathogenesis of LN is improving, treatment still remains a challenge, with the achievement of complete remission at 1 year in <50% of patients treated with current standard of care immunosuppressive therapy; this is associated with considerable short- and long-term side effects, some of which further contribute to non-adherence. Calcineurin inhibitors (CNIs) have been successfully used in organ transplantation and there is increasing evidence that cyclosporin A (CSA), and especially tacrolimus (TAC), are also effective in the treatment of LN. Randomised controlled trials showed similar efficacy for TAC when compared with mycophenolate mofetil (MMF) and multitarget therapy, including TAC and low-dose MMF, and resulted in significantly more complete remissions and overall responses compared with intravenous cyclophosphamide (CYC). Flares are observed in up to 45% of patients with LN, and an increase in relapse rate following induction with CNIs may be an issue. Most studies on this matter have been restricted to patients from Asia, and studies in more balanced cohorts are desirable. Moreover, there is a need to understand and determine the long-term effects of CNIs on renal function, proteinuria and comorbidities, with a special focus on cardiovascular risk. In this 'Pros and Cons' debate, the potential benefits and disadvantages of CNIs in the treatment of LN will be critically highlighted.

Concepts: Nephrotic syndrome, Lupus nephritis, Cyclophosphamide, Rheumatoid arthritis, Mycophenolic acid, Immunosuppressive drug, Glomerulonephritis, Systemic lupus erythematosus

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Staphylococcus aureus (SA) is a commensal bacterium representing one of the most important components of the skin microbiome, mostly isolated in the anterior nares. A higher rate of SA nasal colonization in patients affected by Wegener’s granulomatosis and rheumatoid arthritis compared with healthy subjects (HS) has been described. No studies focusing on systemic lupus erythematosus (SLE) are available. We aimed at analyzing the prevalence of SA nasal carriers in an SLE cohort and evaluating correlation between nasal colonization and clinical, laboratory and therapeutic features.

Concepts: Osteoporosis, Lupus erythematosus, Corticosteroid, Arthritis, Cyclophosphamide, Systemic lupus erythematosus, Rheumatoid arthritis, Rheumatology

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In acute myeloid leukemia, the prognosis for patients with primary treatment failure remains very poor. In order to improve their outcome, we conducted a phase 2, prospective, multicenter trial to test the feasibility of a new sequential regimen combining a short course of intensive chemotherapy and a reduced intensity-conditioning regimen, before allogeneic stem-cell transplantation. Twenty-four patients (median age, 47 years) with acute myeloid leukemia in primary treatment failure have been included. Cytogenetics was poor in 15 patients (62%) and intermediate in 9 (38%). The sequential regimen consisted of clofarabine (30 mg/m2/d) and cytosine arabinoside (1 g/m2/d) for 5 days, followed, after 3 day-rest, by a RIC allo-SCT combining cyclophosphamide (60 mg/kg), intra-venous busulfan (3.2 mg/kg/d) for 2 days and anti-thymocyte globulins (2.5 mg/kg/d) for 2 days. Patients in complete remission at day + 120 received prophylactic donor lymphocyte infusion . Eighteen patients (75%) achieved complete remission. With a median follow-up of 24.6 months, the Kaplan-Meier estimate of overall survival was 54% (95% CI, 33-71) at one year, and 38% (95% CI, 18-46) at 2-years. The Kaplan-Meier estimate of leukemia-free survival was 46% (95% CI, 26-64) at one year and 29% (95% CI, 13-48) at 2-years. The cumulative incidence of non-relapse mortality was 8% (95% CI, 1-24) at one year and 12% (95% CI, 3-19) at 2-years. Results from this phase 2 prospective multicenter trial endorsed the safety and efficacy of a clofarabine-based sequential reduced-toxicity conditioning regimen, warranting further investigations. This study was registered at www.clinicaltrials.gov, identifier number: NCT01188174.

Concepts: Cytarabine, Cyclophosphamide, Blood disorders, Organ transplant, Chemotherapy, Hematopoietic stem cell transplantation, Leukemia, Acute myeloid leukemia

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To assess trends and predictors of mechanical device/aid use by rheumatoid arthritis (RA) patients since the introduction of biologic disease-modifying antirheumatic drugs (DMARDs).

Concepts: Cyclophosphamide, Illness, Sulfasalazine, Rheumatology, Methotrexate, Hydroxychloroquine, Disease-modifying antirheumatic drug, Rheumatoid arthritis

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A highly distressing side-effect of cancer chemotherapy is chemotherapy-induced alopecia (CIA). Scalp cooling remains the only treatment for CIA, yet there is no experimental evidence to support the cytoprotective capacity of cooling. We have established a series of in vitro models for the culture of human keratinocytes under conditions where they adopt a basal, highly-proliferative phenotype thus resembling the rapidly-dividing sub-population of native hair-matrix keratinocytes. Using a panel of chemotherapy drugs routinely used clinically (docetaxel, doxorubicin and the active metabolite of cyclophosphamide 4-OH-CP), we demonstrate that although these drugs are highly-cytotoxic, cooling can markedly reduce or completely inhibit drug cytotoxicity, in agreement with clinical observations. By contrast, we show that cytotoxicity caused by specific combinatorial drug treatments cannot be adequately attenuated by cooling, supporting data showing that such treatments do not always respond well to cooling clinically. Importantly, we provide evidence that the choice of temperature may be critical in determining the efficacy of cooling in rescuing cells from drug-mediated toxicity. Therefore, despite their reductive nature, these in vitro models have provided experimental evidence for the clinically-reported cytoprotective role of cooling and represent useful tools for future studies on the molecular mechanisms of cooling-mediated cytoprotection.

Concepts: Recreational drug use, Drug addiction, Drugs, Drug, Cyclophosphamide, Alopecia, Pharmacology, Chemotherapy