Drugs associated with incident fragility fractures in kidney transplant recipients.

Background: The risk of fragility fractures is high in kidney transplant recipients, and steroids are reportedly a major cause. Other drugs known to induce fragility fractures have been studied in the general population but not in kidney transplant recipients. Here, we investigated the association between exposure over time to drugs that can injure bone (namely vitamin K antagonists, insulin, loop diuretics, proton pump inhibitors, opioids, selective serotonin reuptake inhibitors, antiepileptics and benzodiazepines) and incident fractures and changes over time in T-scores in this population. Methods: A total of 613 consecutive kidney transplant recipients were included between 2006 and 2019. Drug exposures and incident fractures during the study period were comprehensively documented, and dual-energy X-ray absorptiometry was performed regularly. The data were analyzed using Cox proportional hazards models with time-dependent covariates and linear mixed models. Results: Incident fractures occurred in 63 patients, giving a fracture incidence of 16.9 per 1000 person-years. Exposures to loop diuretics [hazard ratio (95% confidence interval) 2.11 (1.17-3.79)] and opioids [5.94 (2.14-16.52)] were associated with incident fractures. Exposure to loop diuretics was associated with a decrease over time in the T-score for the lumbar spine (P = .022) and for the wrist (P = .028). Conclusions: This study suggests that the exposure to loop diuretics and opioids increases the risk of fracture in kidney transplant recipients.

Associations between dysbiosis-inducing drugs, overall survival and tumor response in patients treated with immune checkpoint inhibitors.

BACKGROUND: There are conflicting data on the effects of dysbiosis-inducing drugs, and especially antibiotics (ATBs), on clinical outcomes in patients treated with immune checkpoint inhibitors (ICIs). There is a particular lack of data for patients with melanoma. METHODS: We performed a single-center retrospective study of the associations between ATBs and other drugs known to modify the gut microbiota (proton pump inhibitors, nonsteroidal anti-inflammatory drugs, statins, opioids, anti-vitamin K, levothyroxine, vitamin D3, antiarrhythmics, metformin and phloroglucinol), overall survival (OS) and tumor response in consecutive cancer patients (particularly those with melanoma) treated with an ICI (ipilimumab, nivolumab or pembrolizumab) over a 9-year period. RESULTS: A total of 372 patients were included. The mean ± standard deviation age was 64.0 ± 12.1 years. The most frequently prescribed ICI was nivolumab (in 58.3% of patients) and the most frequent indications were lung cancer (44.6%) and melanoma (29.6%). Overall, 112 patients (30.1%) had received ATBs. ATB use was associated with (1) shorter OS in the study population as a whole [adjusted hazard ratio [95% confidence interval (CI)]: 1.38 (1.00-1.90), p = 0.048] and in patients with melanoma [adjusted hazard ratio (95% CI): 2.60 (1.06-6.39), p = 0.037], and (2) a lower response rate in the study population as a whole [8.1%, versus 31.1% in patients not treated with ATBs; adjusted odds ratio (95% CI): 6.06 (2.80-14.53), p < 0.001] and in patients with melanoma [adjusted odds ratio (95% CI): 4.41 (1.04-22.80), p = 0.045]. Sensitivity analyses that minimized the indication bias did not reveal an association between OS and the presence of an infection requiring ATBs (quantified as the severity of infection, hospitalization for an infection, or ICI discontinuation). Other dysbiosis-inducing drugs were not associated with a difference in OS. CONCLUSION: Unlike other dysbiosis-inducing drugs, ATBs were associated with poorer clinical outcomes in ICI-treated patients overall and in the subset of patients with melanoma.

Impact of the corticosteroid indication and administration route on overall survival and the tumor response after immune checkpoint inhibitor initiation.

BACKGROUND: Based on their indications, systemic corticosteroids appear to negatively affect clinical outcomes in immune checkpoint inhibitor (ICI)-treated patients. There are few data on the influence of topical and inhaled corticosteroids on the ICIs' effectiveness. METHODS: In a single-center study, we retrospectively investigated the impact of systemic corticosteroids according to their indication [an immune-related adverse event (irAE) or another indication] on overall survival (OS) and the tumor response in all consecutive patients after initiation of ipilimumab, nivolumab or pembrolizumab over a 9-year period. The impacts of topical and inhaled corticosteroids were also examined. RESULTS: Three hundred and seventy-two patients were included. The mean ± standard deviation age was 64.0 ± 12.1 years. The most frequently prescribed ICI was nivolumab (in 58.3% of the patients) and the most frequent indications were lung cancer (44.6%) and melanoma (29.6%). Systemic corticosteroid use for an irAE did not have a negative impact on OS [adjusted hazard ratio (HR) [95% confidence interval (CI)] 1.04 (0.56-1.95), p = 0.902] or the best overall tumor response [adjusted odds ratio (OR) (95% CI) 1.69 (0.52-6.56), p = 0.413], while systemic corticosteroid use for another indication was associated with shorter OS [adjusted HR (95% CI) 1.34 (1.05-2.03), p = 0.046] and a poor best overall tumor response [adjusted OR (95% CI) 2.04 (1.07-5.80), p = 0.039] with a cumulative dose cut-off of 3215 mg prednisolone equivalent (specificity 71.4%; sensitivity 65.3%) and a time cut-off of 132 days (specificity 71.4%; sensitivity 89.8%). The use of topical corticosteroids was associated with a longer OS; this was probably due to dermatological irAEs. Inhaled corticosteroid use did not influence OS. CONCLUSION: Systemic corticosteroid use for an irAE does not impact OS or the tumor response, whereas use for other indications (themselves often associated with a worse prognosis) does. Topical and inhaled steroids do not have a negative impact on OS.

Rheumatic and musculoskeletal disorders induced by immune checkpoint inhibitors: Consequences on overall survival.

OBJECTIVES: Immune checkpoint inhibitors (ICIs) frequently induce immune related adverse events (irAEs) that may be associated with more favorable clinical outcomes. We aimed to evaluate the impact of all types of rheumatic adverse events (AEs) on overall survival (OS) and tumor response in patients treated with ICIs. METHODS: We performed a single-center retrospective observational study to analyze the OS and tumor response in patients receiving ICIs who experienced a rheumatic AE compared to those who did not experience any AE. RESULTS: From December 2010 to September 2018, 264 patients with any cancer type were included. Forty-three patients (16.3%) presented with at least one rheumatic AE. The median OS of patients with rheumatic AEs was significantly higher than that of patients without AEs, with 132 weeks (95% CI [69.3-not reached]) and 42.7 weeks (95% CI [25.6-not reached]), respectively (P<0.01). This result remained significant after multivariate analysis (HR 0.54, 95% CI [0.30-0.97], P<0.05). Also, tumor response was better in patients with rheumatic AEs. CONCLUSION: The occurrence of rheumatic AEs in patients treated with ICIs is associated with better survival and tumor response. Therefore, it seems essential to detect rheumatic AEs as early as possible to allow rapid and optimal management, given the long-term response potential of these patients.

Mobile Phone Text Messages and Effect on Treatment Adherence in Patients Taking Methotrexate for Rheumatoid Arthritis: A Randomized Pilot Study.

OBJECTIVE: To assess the impact of weekly text messages on adherence in patients taking methotrexate (MTX) for rheumatoid arthritis (RA). METHODS: This prospective, randomized pilot, single-site study included patients with RA stabilized using MTX alone or combined with biologics. Participants were randomized to 3 interventions: a standard consultation (controls), a 15-minute pharmacist-led counseling session, or the receipt of text message reminders. The change over time in the Compliance Questionnaire Rheumatology (CQR-19) score between baseline and 6 months was defined as the primary outcome for adherence. Multivariable analyses and final adherence (as a composite outcome of the CQR-19 score, the Girerd score, and the medication possession ratio) were probed in sensitivity tests. Rheumatologic scales, inflammation, and patient satisfaction were also analyzed. RESULTS: A total of 96 patients (mean ± SD Disease Activity Score in 28 joints 2.42 ± 1.03) were monitored. The change over time in the CQR-19 score was significantly higher in the text message group (mean ± SD 3.32 ± 5.66; P = 0.02) than in the control group (mean ± SD 0.22 ± 6.56) and the pharmacist-led counseling group (mean ± SD -0.14 ± 7.56). Multivariable logistic regression showed that text messages remained associated with an increase in the CQR-19 score, independently of the baseline CQR-19 score (odds ratio 3.63 [95% confidence interval 1.26-10.49]; P = 0.017). In the text message group, the increase in the CQR-19 score was correlated with the Health Assessment Questionnaire score (r = -0.405, P = 0.021), and patient satisfaction was significantly higher (P < 0.01) than in the control group. CONCLUSION: Our results showed evidence of a positive impact of text messages on adherence to MTX treatment for RA. The clinical benefit and the ideal target patient remain to be determined.

Expression of the calcium-sensing receptor in monocytes from synovial fluid is increased in osteoarthritis.

OBJECTIVES: We assessed calcium-sensing receptor (CaSR) expression in monocytes isolated from synovial fluid of patients with different types of rheumatisms and explored whether CaSR expression was related to the inflammatory nature of synovial fluid. METHODS: Forty-one patients were included: osteoarthritis (n=10), microcristallin rheumatisms (n=10), rheumatoid arthritis (n=12) and other inflammatory rheumatisms (n=9). Surface and total CaSR expressions in monocytes isolated from synovial fluid and blood were assessed by flow cytometry analysis. U937 cells were cultured during 24hours in presence of cell-free synovial fluids. RESULTS: Every monocyte population tested express the CaSR intra- and extracellularly. Whereas similar pattern of CaSR expression exist in monocyte isolated from blood or synovial fluids, our results indicate that higher CaSR expression levels can be observed in monocytes from synovial fluids than in circulating monocytes. In both populations of monocytes, surface and total CaSR expressions were found to be significantly increased in patients with osteoarthritis compared to rheumatoid arthritis. Similar data were obtained when U937 cells were incubated with cell-free synovial fluids from osteoarthritis patients. Still present, this effect was significantly lowered when "inflammatory" synovial fluids were introduced in culture. CONCLUSIONS: Our results indicate that CaSR expression in synovial derived monocytes is higher in osteoarthritis than in inflammatory rheumatisms and that CaSR expression is modulated by the nature of the synovial fluid. Given the role played by monocytes in the pathogenesis of chronic rheumatisms, monocytes could be interesting therapeutic targets via the CaSR.

Osteoporosis: Is milk a kindness or a curse?

Cow's milk is often severely criticized as a cause of multiple health problems, including an increased risk of fractures. A close look at the scientific literature shows a striking contradiction. On the one hand, experimental studies of surrogate markers (e.g., bone turnover markers and bone mineral density [BMD]) usually indicate benefits from drinking cow's milk. On the other, the findings from epidemiological studies are conflicting and disconcerting. In all age groups, including children and postmenopausal women, consuming cow's milk, powdered milk supplements, or whey protein is associated with a slower bone turnover and unchanged or higher BMD values. These benefits are particularly marked in populations where calcium deficiency is prevalent, for instance in Asian countries. No interventional studies have addressed the fracture risk potentially associated with drinking cow's milk. The only available data come from epidemiological observational studies, whose results are conflicting, with a lower fracture risk in some cases and no difference or a higher risk in others. Several hypotheses have been offered to explain these findings, such as a deleterious effect of D-galactose, lactose intolerance, and acid overload. Epidemiological studies face many obstacles when seeking to detect effects of a single food, particularly the multiplicity of interactions among foods. Furthermore, reliable dietary intake data must be collected over prolonged periods, often long before the occurrence of a fracture, and defective recall may therefore introduce a major yet often unrecognized bias, particularly in populations where calcium deficiency is uncommon. To date, there is no conclusive evidence that we should modify our currently high level of consumption of cow's milk.

Morbimortality in adult patients with septic arthritis: a three-year hospital-based study.

BACKGROUND: The objective of this ambispective study was to determine outcomes and associated factors for adult patients with confirmed septic arthritis (SA). METHODS: All adult patients admitted to Amiens University Hospital between November 2010 and December 2013 with confirmed SA were included in the study. Patients with prosthetic joint infections were excluded. A statistical analysis was performed in order to identify risk factors associated with a poor outcome (including mortality directly attributable to SA). RESULTS: A total of 109 patients (mean ± SD age: 60.1 ± 20.1; 74 male/35 females) were diagnosed with SA during the study period. The most commonly involved sites were the small joints (n = 34, 31.2 %) and the knee (n = 25, 22.9 %). The most frequent concomitant conditions were cardiovascular disease (n = 45, 41.3 %) and rheumatic disease (n = 39, 35.8 %). One hundred patients (91.7 %) had a positive microbiological culture test, with Staphylococcus aureus as the most commonly detected pathogen (n = 59, 54.1 %). Mortality directly attributable to SA was relatively infrequent (n = 6, 5.6 %) and occurred soon after the onset of SA (median [range]: 24 days [1-42]). Major risk factors associated with death directly attributable to SA were older age (p = 0.023), high C-reactive protein levels (p = 0.002), diabetes mellitus (p = 0.028), rheumatoid arthritis and other inflammatory rheumatic diseases (p = 0.021), confusion on admission (p = 0.012), bacteraemia (p = 0.015), a low creatinine clearance rate (p = 0.009) and the presence of leg ulcers/eschars (p = 0.003). The median duration of follow-up (in patients who survived for more than 6 months) was 17 months [6-43]. The proportion of poor functional outcomes was high (31.8 %). Major risk factors associated with a poor functional outcome were older age (0.049), hip joint involvement (p = 0.003), the presence of leg ulcers/eschars (p = 0.012), longer time to presentation (0.034) and a low creatinine clearance rate (p = 0.013). CONCLUSIONS: In a university hospital setting, SA is still associated with high morbidity and mortality rates.

Two cases of fatal encephalopathy related to Ifosfamide: an adverse role of aprepitant?

Ifosfamide is used in the treatment of sarcomas and other tumors. It sometimes provokes encephalopathy, which is a serious complication even if it is usually reversible within 48-72 h after drug cessation. Ifosfamide is required to be activated by hepatic cytochrome P450 (CYP), especially the 3A4 subtype, leading to 4-hydroxy-ifosfamide. Ifosfamide is also converted by CYP3A4 to inactive but neurotoxic metabolites. Aprepitant is a neurokinin-1 receptor antagonist that is a potent antiemetic used in combination with 5-HT3 antagonists and corticosteroids. Aprepitant has an inhibitory effect, as well as a possible inductive effect, on CYP3A4. Since ifosfamide and aprepitant are both substrates of CYP3A4, a pharmacokinetic interaction could result in secondary effects such as the potentialization of neurological side effects. In this report, we describe 2 cases of fatal encephalopathy in patients who have received both ifosfamide and aprepitant, and we discuss the mechanisms that could be involved. Our observations draw attention to the fact that aprepitant must be avoided, or at least used with caution, in patients who are receiving ifosfamide due to the risk of severe neurological side effects.

Bone remodelling markers in rheumatoid arthritis.

Bone loss in rheumatoid arthritis (RA) patients results from chronic inflammation and can lead to osteoporosis and fractures. A few bone remodeling markers have been studied in RA witnessing bone formation (osteocalcin), serum aminoterminal propeptide of type I collagen (PINP), serum carboxyterminal propeptide of type I collagen (ICTP), bone alkaline phosphatase (BAP), osteocalcin (OC), and bone resorption: C-terminal telopeptide of type 1 collagen (I-CTX), N-terminal telopeptide of type 1 collagen (I-NTX), pyridinolines (DPD and PYD), and tartrate-resistant acid phosphatase (TRAP). Bone resorption can be seen either in periarticular bone (demineralization and erosion) or in the total skeleton (osteoporosis). Whatever the location, bone resorption results from activation of osteoclasts when the ratio between osteoprotegerin and receptor activator of nuclear factor kappa-B ligand (OPG/RANKL) is decreased under influence of various proinflammatory cytokines. Bone remodeling markers also allow physicians to evaluate the effect of drugs used in RA like biologic agents, which reduce inflammation and exert a protecting effect on bone. We will discuss in this review changes in bone markers remodeling in patients with RA treated with biologics.