Rheumatic disorders associated with immune checkpoint inhibitors in patients with cancer-clinical aspects and relationship with tumour response: a single-centre prospective cohort study.

OBJECTIVES: To evaluate the prevalence and type of rheumatic immune-related adverse events (irAEs) in patients receiving immune checkpoint inhibitors (ICIs), as well as the correlation with tumour response. METHODS: This was a single-centre prospective observational study including all cancer patients receiving ICIs. The occurrence of irAEs and tumour response was assessed on a regular basis. Patients who experienced musculoskeletal symptoms were referred to the department of rheumatology for clinical evaluation and management. RESULTS: From September 2015 to May 2017, 524 patients received ICIs and 35 were referred to the department of rheumatology (6.6%). All but one of the rheumatic irAEs occurred with anti-programmed cell death protein 1(PD-1)/PD-1 ligand 1(PD-L1) antibodies, with a median exposure time of 70 days. There were two distinct clinical presentations: (1) inflammatory arthritis (3.8%) mimicking either rheumatoid arthritis (n=7), polymyalgia rheumatica (n=11) or psoriatic arthritis (n=2) and (2) non-inflammatory musculoskeletal conditions (2.8%; n=15). One patient with rheumatoid arthritis was anti-cyclic citrullinated peptide (anti-CCP) positive. Nineteen patients required glucocorticoids, and methotrexate was started in two patients. Non-inflammatory disorders were managed with non-steroidal anti-inflammatory drugs, analgesics and/or physiotherapy. ICI treatment was pursued in all but one patient. Patients with rheumatic irAEs had a higher tumour response rate compared with patients without irAEs (85.7% vs 35.3%; P<0.0001). CONCLUSION: Since ICIs are used with increasing frequency, knowledge of rheumatic irAEs and their management is of major interest. All patients were responsive either to low-to-moderate doses of prednisone or symptomatic therapies and did not require ICI discontinuation. Furthermore, tumour response was significantly higher in patients who experienced rheumatic irAEs.

Increased risk of abnormal proximal renal tubular function with HIV infection and antiretroviral therapy.

Abnormal kidney function is common in the course of human immunodeficiency virus (HIV) infection. Here, we performed a cross-sectional analysis using 399 patients within the Aquitaine cohort (a hospital-based cohort of HIV-1-infected patients receiving routine clinical management) to estimate the prevalence of proximal renal tubular dysfunction (PRTD) associated with HIV infection. These patients did not differ statistically by sociodemographics, median age, years since HIV diagnosis, AIDS stage, or median CD4 cell count from the entire 3080 patient cohort. Antiretroviral therapy was received by 352 patients, with 256 given tenofovir (TDF); 325 had undetectable HIV plasma viral load, and 26 were diagnosed with PRTD. In multivariate analysis, significant independent associations were found between PRTD and age (odds ratio (OR) 1.28 per 5-year increase), atazanavir (OR 1.28 per year of exposure), and TDF (OR 1.23 per year) treatment. Among patients having received TDF-containing regimens over a 5-year period, PRTD remained significantly associated with TDF exposure when treatment was ongoing (OR 5.22) or had been discontinued (OR 11.49). Thus, cumulative exposure to TDF and/or atazanavir was associated with an increased risk of PRTD, with concern about its reversibility in patients with HIV.

Evaluation of the potential use of trabecular bone score to complement bone mineral density in the diagnosis of osteoporosis: a preliminary spine BMD-matched, case-control study.

The trabecular bone score (TBS) is a new parameter that is determined from gray-level analysis of dual-energy X-ray absorptiometry (DXA) images. It relies on the mean thickness and volume fraction of trabecular bone microarchitecture. This was a preliminary case-control study to evaluate the potential diagnostic value of TBS as a complement to bone mineral density (BMD), by comparing postmenopausal women with and without fractures. The sample consisted of 45 women with osteoporotic fractures (5 hip fractures, 20 vertebral fractures, and 20 other types of fracture) and 155 women without a fracture. Stratification was performed, taking into account each type of fracture (except hip), and women with and without fractures were matched for age and spine BMD. BMD and TBS were measured at the total spine. TBS measured at the total spine revealed a significant difference between the fracture and age- and spine BMD-matched nonfracture group, when considering all types of fractures and vertebral fractures. In these cases, the diagnostic value of the combination of BMD and TBS likely will be higher compared with that of BMD alone. TBS, as evaluated from standard DXA scans directly, potentially complements BMD in the detection of osteoporotic fractures. Prospective studies are necessary to fully evaluate the potential role of TBS as a complementary risk factor for fracture.

Chronic viral hepatitis is associated with low bone mineral density in HIV-infected patients, ANRS CO 3 Aquitaine Cohort.

BACKGROUND: High prevalence rates of low bone mineral density (BMD) have been reported in people living with HIV infection. We aimed to investigate the association of chronic viral hepatitis with low BMD in HIV-infected patients. METHODS: A hospital-based cohort of HIV-infected patients was screened for hepatitis B and C coinfection. BMD was measured by dual energy x-ray absorptiometry. T-score was used to define bone status according to the World Health Organization's classification; moreover, each observed BMD value was compared with reference to an average person of the same age and gender as a Z-score <-2.0 allow the diagnosis of patients having less bone mass and/or losing bone material more rapidly than expected. A polytomial logistic regression was performed by gender to investigate the association between chronic viral hepatitis and low BMD (osteopenia and osteoporosis) in HIV-infected patients. RESULTS: A total of 626 patients (166 females of whom 52 postmenopausal) were recruited: 357 HIV monoinfected, and 269 HIV-coinfected with chronic viral hepatitis, among whom 61 with a diagnosis of cirrhosis. Osteopenia was present in 320 patients (51.1%) and osteoporosis in 187 (29.9%). After adjustment, osteoporosis was associated with older age and low body mass index in both genders. The association between chronic viral hepatitis B or C and osteoporosis was found in women only (odds ratio: 19.0; P value: 0.047). CONCLUSIONS: We found a high prevalence of low BMD overall, but chronic viral hepatitis was independently associated with osteoporosis only in female participants. Our data confirm the need of BMD evaluations for patients living with HIV.

Severity of osteoporosis: what is the impact of co-morbidities?

The co-morbidity profile varies widely across postmenopausal women with osteoporosis, and comorbidities often adversely affect the management of osteoporosis. There is a need for detailed information on the co-morbidities that may affect the course of osteoporosis by increasing the risk of subsequent fractures or inducing multiple fractures. We consequently reviewed the literature on the most common co-morbidities in adults older than 50 years of age, with special attention to published meta-analyses. We found that osteoporosis severity was increased not only by conventional risk factors, but also by a number of conditions including inflammatory bowel and joint diseases with or without glucocorticoid therapy, breast cancer and prostate cancer treated with chemotherapy or hormone therapy, diabetes (chiefly type 1), and celiac disease. Studies suggest an adverse impact of moderate renal failure and depression, although their methodological weaknesses preclude definitive conclusions. In practice, these co-morbidities should be taken into account when evaluating the fracture risk and making treatment decisions.

Osteoporosis and mortality.

Osteoporosis is classified as a public health problem by healthcare authorities because it is associated with an increased risk of potentially serious fractures. Osteoporotic fractures are known to generate a heavy burden of morbidity and financial cost [1]. However, recent data indicate that some osteoporotic fractures are also associated with excess mortality. These data have led to public health measures such as the addition by the World Health Organization of fracture prevention to the list of public health priorities [2] and the update on hip fractures issued recently by the statistics department of the French ministry of health (DREES [3]). Hip fractures constitute the most severe complication of osteoporosis because they can induce permanent physical disability, loss of self-sufficiency, institutionalization and, above all, an increased risk of death. Interestingly, two recent publications support the hypothesis that optimal osteoporosis management may affect the risk of death. Here, we will review the main data linking osteoporotic fractures overall (as opposed to hip fractures only) and mortality.

Severe osteoporosis: does structural monitoring help?

Vertebral fractures, the most common osteoporotic fractures, are associated with excess mortality even in the absence of symptoms. Presence of at least one radiological or clinical prevalent vertebral fracture increases the risk of incident vertebral fractures not only in untreated patients, but also in treated patients, as established by studies involving routine radiological monitoring. Therefore, whether structural monitoring is indicated on a routine basis deserves discussion. Height measurement is a basic monitoring tool for detecting new vertebral fractures. However, loss of height is nonspecific. Radiography involves radiation exposure levels and financial costs that are not consistent with use for routine monitoring. Vertebral fracture assessment based on dual-energy X-ray absorptiometry (VFA), in contrast, is an inexpensive method that delivers only low radiation levels. VFA used in conjunction with absorptiometry may be well suited to the monitoring of women with severe osteoporosis.

Stabilized severe osteoporosis: should the treatment be stopped?

Several medications have been proven to decrease the risk of postmenopausal osteoporotic fractures of the spine, hip, or peripheral skeleton. However, the optimal duration of treatment with these medications has not been determined. The efficacy data come chiefly from controlled trials conducted over 3 to 5 years in elderly women at high risk for fractures. Some of these trials were followed by open-label extension phases that showed sustained bone mineral density gains over 7 to 10 years. The data pointing to a sustained decrease in the fracture rate beyond 4-5 years of treatment vary across studies and drugs but are generally scant and open to criticism. The published evidence does not suggest a need for stopping osteoporosis medications after the first 4-5 years out of concern about bisphosphonate-induced osteonecrosis of the jaw or alendronate-induced atypical fractures. Given that pharmacotherapy targets patients with severe osteoporosis, continued treatment beyond the first 5 years is probably warranted in most cases.

Defining treatment failure in severe osteoporosis.

The management of postmenopausal osteoporosis has benefited from the recent introduction of several new drug classes and is now well standardized. However, none of the available osteoporosis drugs completely abolishes the occurrence of fractures. Therefore, criteria are needed to determine when the occurrence of a fracture during treatment indicates failure to respond to the drug. Such criteria would improve patient management. A panel of national osteoporosis experts was convened to discuss data from a literature review on severe osteoporosis (Osteoporosis DIagnosis and Surveillance of SEvErity, ODISSEE). The experts reached a consensus that "an inadequate response to treatment for postmenopausal osteoporosis is the occurrence, in a patient with severe osteoporosis, adequate calcium and vitamin D intakes, and good treatment adherence, of any of the following: incident major fracture within the first treatment year, more than one minor insufficiency fracture, or a bone mineral density decrease by at least the smallest significant amount (0.03 g/cm(2)) after 5 years or earlier in the event of a minor fracture".

Management of patients with incident fractures during osteoporosis treatment.

Official recommendations are available for detecting osteoporosis and initiating osteoporosis medications in postmenopausal women. However, there are no recommendations about the management of patients with incident fractures despite osteoporosis therapy. Second-line osteoporosis treatments have been evaluated only based on laboratory and absorptiometry criteria. Nevertheless, we will try to answer the following questions: (1) What criteria should be used to determine whether a fracture during osteoporosis treatment indicates treatment failure (low-energy fracture, fracture not due to an intercurrent health condition, fracture of the type targeted by the osteoporosis treatment, sufficient treatment duration at occurrence of the fracture, and good adherence to the treatment and to vitamin D supplementation)? (2) In patients with treatment failure or an inadequate clinical response, defined as a fracture despite adherence to osteoporosis therapy for at least 1 year, what are the best treatment strategies?

Severe osteoporosis: diagnosis and follow-up. Lessons for clinical practice.

The management of osteoporosis has improved considerably, leading to the development of new goals. A major concern today is the management of patients with severe osteoporosis, in whom the need for pharmacotherapy is clear [1]. Epidemiological data have established that osteoporosis is associated with severe complications [2,3]. Furthermore, osteoporosis is now recognized as a complication of several chronic diseases, whose presence adversely affects the management of osteoporosis. The ODISSEE task force (Osteoporosis DIagnosis and Surveillance of SEvErity) was established to answer practical questions regarding the management of severe osteoporosis, based on evidence in the literature. Several groups conducted an exhaustive literature review, and advice was obtained from a panel of French rheumatologists. The ODISSEE scientific committee then developed the first consensus statement on the diagnosis, follow-up and management of severe osteoporosis. This statement was validated by a panel of 70 French rheumatologists at the first national ODISSEE meeting held on November 13-14, 2009.

Coagulopathies frequency in aseptic osteonecrosis patients.

Many risk factors of aseptic osteonecrosis (AO) are well-known, even if 40% of events are idiopathic. Intravascular thrombosis is one of the physiopathological mechanisms of AO. The aim of this study is to determine the influence of coagulopathies on AO set-up. We performed a prospective case-control study, with 39 cases and 39 controls matched on age and sex. Cases are defined according to radiological criteria, and controls as non-affected by renal or hepatic insuffiency, and without inflammatory syndrome. Well-known AO risk factors were studied. Assessment of thrombosis was based on anti-phospholipid, anti beta2 Glycoprotein I, antiprothrombin, anti-cardiolipin, antithrombin, protein S and C, factor V Leiden, prothrombin gene and MTHFR mutations. 71% of cases presented a classical AO risk factor, vs. 38% of the controls. A significant association was also found between smoking and risk of AO. No significant difference in coagulopathy frequency was shown between cases and controls (56.4% vs. 48.7% respectively, p>0.05). Only abusive consumption of alcohol and tobacco is associated with risk of AO. Our study did not demonstrate any implication of coagulopathies in AO susceptibility. Further studies are needed to investigate more precisely these features.

Reduced bone mineral density in HIV-infected patients: prevalence and associated factors.

BACKGROUND: There is a high prevalence of bone demineralization among HIV-infected patients but mechanisms of alteration of bone turnover are still unclear and it is thought to be multifactorial. METHODS: A cross-sectional survey of 492 HIV-infected patients within the Aquitaine cohort estimated the prevalence of osteoporosis/osteopenia and investigated associated factors. Bone mineral density of total body, lumbar spine and femoral neck was measured by dual-energy X-ray absorptiometry. Multivariable analyses of the association with HIV disease status, treatment and anthropometric parameters were stratified according to gender. RESULTS: Median age was 43 years (interquartile range, 38-50); 73% were male; 19.7% patients had reached AIDS, 93.1% were treated with HAART; and 28.5% had lipodystrophy. Based on World Health Organization criteria, osteopenia was diagnosed in 54.6% of men [95% confidence interval (CI), 49.4-59.7) and 51.1% of women (95% CI, 42.6-59.6) and osteoporosis in 33.7% of men (95% CI, 28.8-38.6) and 8.3% of women (95% CI, 3.6-13.9). Using a polytomous logistic regression, older age, homosexual transmission group, low body mass index and low HIV plasma viral load were associated with the diagnosis of bone abnormalities in men, whereas older age and low CD4 lymphocyte count nadir were independently associated with osteoporosis/osteopenia in women. The use of HAART was not related to osteoporosis after adjustment (P = 0.58). CONCLUSIONS: This cohort-based survey showed a high prevalence of osteopenia and osteoporosis of multifactorial origin. Mechanisms and consequences of these bone disorders need to be investigated.