Thierry Schaeverbeke

Immune related adverse events associated with anti-CTLA-4 antibodies: systematic review and meta-analysis

BackgroundTargeting CTLA-4 is a recent strategic approach in cancer control: blocking CTLA-4 enhances an antitumor immunity by promoting T-cell activation and cytotoxic T-lymphocyte proliferation. This induction of a tolerance break against the tumor may be responsible for immune-related adverse events (irAEs). Our objective was to assess the incidence and nature of irAEs in oncologic patients receiving anti-CTLA-4 antibodies (ipilimumab and tremelimumab).MethodsA systematic search of literature up to February 2014 was performed in MEDLINE, EMBASE, and Cochrane databases to identify relevant articles. Paired reviewers independently selected articles for inclusion and extracted data. Pooled incidence was calculated using R©, package meta.ResultsOverall, 81 articles were included in the study, with a total of 1265 patients from 22 clinical trials included in the meta-analysis. Described irAEs consisted of skin lesions (rash, pruritus, and vitiligo), colitis, and less frequently hepatitis, hypophysitis, thyroiditis, and some rare events such as sarcoidosis, uveitis, Guillain-Barré syndrome, immune-mediated cytopenia and polymyalgia rheumatic/Horton. The overall incidence of all-grade irAEs was 72 % (95 % CI, 65–79 %). The overall incidence of high-grade irAEs was 24 % (95 % CI, 18–30 %). The risk of developing irAEs was dependent of dosage, with incidence of all-grade irAEs being evaluated to 61 % (95 % CI, 56–66 %) for ipilimumab 3 mg/kg and 79 % (95 % CI, 69–89 %) for ipilimumab 10 mg/kg. Death due to irAEs occurred in 0.86 % of patients.The median time of onset of irAEs was about 10 weeks (IQR, 6–12) after the onset of treatment, corresponding with the first three cycles but varied according to the organ system involved. Such immune activation could also be indicative for tumor-specific T-cell activation and irAE occurrence was associated with clinical response to CTLA-4 blocking in 60 % of patients.ConclusionThe price of potential long-term survival to metastatic tumors is an atypical immune toxicity, reflecting the mechanism of action of anti-CTLA-4 antibodies. A better knowledge of these irAEs and its management in a multidisciplinary approach will help to reduce morbidity and therapy interruptions.

Clinical Pharmacokinetics of Low-Dose Pulse Methotrexate in Rheumatoid Arthritis

SummaryLow-dose pulse methotrexate has emerged as one of the most frequently used slow-acting, symptom-modifying antirheumatic drugs in patients with rheumatoid arthritis (RA) because of its favourable risk-benefit profile.Methotrexate is a weak bicarboxylic acid structurally related to folic acid. The most widely used methods for the analysis of methotrexate are immunoassays, particularly fluorescence polarisation immunoassay. After oral administration, the drug is rapidly but incompletely absorbed. Since food does not significantly affect the bioavailability of oral methotrexate in adult patients, the drug may be taken regardless of meals. There is a marked interindividual variability in the extent of absorption of oral methotrexate. Conversely, the intraindividual variability is moderate even over a long time period. Intramuscular and subcutaneous injections of methotrexate result in comparable pharmacokinetics, suggesting that these routes of administration are interchangeable.A mean protein binding to serum albumin of 42 to 57% is usually reported. Again, the unbound fraction exhibits a large interindividual variability. The steady-state volume of distribution is approximately 1 L/kg. Methotrexate distributes to extravascular compartments, including synovial fluid, and to different tissues, especially kidney, liver and joint tissues. Finally, the drug is transported into cells, mainly by a carrier-mediated active transport process.Methotrexate is partly oxidised by hepatic aldehyde oxidase to 7-hydroxy-methotrexate. This main, circulating metabolite is over 90% bound to serum albumin. Both methotrexate and 7-hydroxy-methotrexate may be converted to polyglutamyl derivatives which are selectively retained in cells. Methotrexate is mainly excreted by the kidney as intact drug regardless of the route of administration. The drug is filtered by the glomeruli, and then undergoes both secretion and reabsorption processes within the tubule. These processes are differentially saturable, resulting in possible nonlinear elimination pharmacokinetics. The usually reported mean values for the elimination half-life and the total body clearance of methotrexate are 5 to 8 hours and 4.8 to 7.8 L/h, respectively. A positive correlation between methotrexate clearance and creatinine clearance has been found by some authors.Finally, the pharmacokinetics of low-dose methotrexate appears to be highly variable and largely unpredictable even in patients with normal renal and hepatic function. Furthermore, studies in patients with juvenile rheumatoid arthritis provide evidence of age-dependent pharmacokinetics of the drug. These features must be considered when judging the individual clinical response to methotrexate therapy.Various drugs currently used in RA may interact with methotrexate. Aspirin might affect methotrexate disposition to a greater extent than other nonsteroidal anti-inflammatory drugs without causing greater toxicity. Corticosteroids do not interfere with the pharmacokinetics of methotrexate, whereas chloroquine may reduce the gastrointestinal absorption of the drug. Folates, especially folic acid, have been shown to reduce the adverse effects of methotrexate without compromising its efficacy in RA. Finally, both trimethoprim-sulfamethoxazole (cotrimoxazole) and probenecid lead to increased toxicity of methotrexate, and hence should be avoided in patients receiving these drugs.A relationship between oral dosage and efficacy has been found in the range 5 to 20mg methotrexate weekly. The plateau of efficacy is attained at approximately 10 mg/m2/week in most patients. No clear relationship between pharmacokinetic parameters and clinical response has been demonstrated. Overall, the dosage must be individualised because of interindividual variability in the dose-response curve. This variability is probably related, at least in part, to the wide interindividual variability in the disposition of the drug.

Lymphoma in patients treated with anti-TNF. Results of the 3-year prospective French RATIO registry.

Objective: To describe cases of lymphoma associated with anti-TNF therapy, identify risk factors, estimate the incidence and compare the risks for different anti-TNF agents. Methods: A national prospective registry was designed (Research Axed on Tolerance of bIOtherapies; RATIO) to collect all cases of lymphoma in French patients receiving anti-TNF therapy from 2004 to 2006, whatever the indication. A case–control analysis was conducted including two controls treated with anti-TNF per case and an incidence study of lymphoma with the French population was used as the reference. Results: 38 cases of lymphoma, 31 non-Hodgkin’s lymphoma (NHL) (26 B cell and five T cell), five Hodgkin’s lymphoma (HL) and two Hodgkin’s-like lymphoma were collected. Epstein–Barr virus was detected in both of two Hodgkin’s-like lymphoma, three of five HL and one NHL. Patients receiving adalimumab or infliximab had a higher risk than those treated with etanercept: standardised incidence ratio (SIR) 4.1 (2.3–7.1) and 3.6 (2.3–5.6) versus 0.9 (0.4–1.8). The exposure to adalimumab or infliximab versus etanercept was an independent risk factor for lymphoma in the case–control study: odds ratio 4.7 (1.3–17.7) and 4.1 (1.4–12.5), respectively. The sex and age-adjusted incidence rate of lymphoma was 42.1 per 100 000 patient-years. The SIR was 2.4 (95% CI 1.7 to 3.2). Conclusion: The two to threefold increased risk of lymphoma in patients receiving anti-TNF therapy is similar to that expected for such patients with severe inflammatory diseases. Some lymphomas associated with immunosuppression may occur, and the risk of lymphoma is higher with monoclonal-antibody therapy than with soluble-receptor therapy.

Central analgesic effects of aspirin-like drugs

Summary— Aspirin‐like drugs mainly include paracetamol, salicylates and other non‐steroidal anti‐inflammatory drugs, and metamizole. Their analgesic effect is classically ascribed to a peripheral site of action, within the pain‐processing site. There is, however, convincing evidence that a central component contributes to the overall analgesia provided by these agents. Experimental and clinical studies referring to this challenging proposal are reviewed here. The exact site and mode of action of aspirin‐like drugs within the central nervous system remains controversial. It is likely that supraspinal mechanisms play an important role. Some experiments lend support to the involvement of monoaminergic control systems. Other data indicate that these drugs act centrally through the inhibition of cyclo‐oxygenase activity. The interactions between prostaglandins and various neurotransmitters suggest that both mechanisms may be linked.

Comparison of the long-term outcome for patients with rheumatoid arthritis with persistent moderate disease activity or disease remission during the first year after diagnosis: data from the ESPOIR cohort

Objective To investigate if patients with early RA with persistent moderate disease activity during the first year after diagnosis have a worse 3–5u2005year outcome than those who achieve sustained clinical remission within the first year, in a daily life setting. Methods The ESPOIR cohort included patients with early arthritis of <6u2005months’ duration. Treatment was the standard of care. We had 5-year follow-up data for 573 patients. This study compared patients who had persistent moderate disease activity (Disease Activity Score in 28 joints (DAS28)>3.2 and ≤5.1) at both the 6- and 12-month visits, with those who were in sustained DAS28 remission. The primary outcome was radiographic progression at the 36-month visit. Secondary endpoints were clinical remission (DAS28 score, Simplified Disease Activity Index, ACR/EULAR criteria), Health Assessment Questionnaire-Disability Index (HAQ-DI) and number of missed workdays at months 36 and 60. A Fisher exact test was used to compare categorical variables, and the Kruskal–Wallis test for quantitative variables. Logistic regression analysis was used to determine predictors of outcome. Results Patients were aged 48.1±12.5u2005years and their duration of symptoms was 103.2±52.1u2005days. Mean baseline DAS28 was 5.1±1.3. Persistent moderate disease activity (107 patients) rather than sustained remission (155 patients) during the first year was associated with increased radiographic disease progression at 3u2005years (OR=1.99 (95% CI 1.01 to 3.79)), increased HAQ-DI at 3 and 5u2005years (5.23 (2.81 to 9.73) and 4.10 (2.16 to 7.80), respectively), a 7–11 times smaller chance of achieving clinical remission and a five times greater number of missed workdays. Conclusions Patients with early RA with persistent moderate disease activity during the first year had a worse outcome than patients who achieved sustained clinical remission. Persistent moderate disease activity affects long-term structure, remission rate and functional and work disability. Such patients may benefit from intensive treatment.

Association of Anti–Porphyromonas gingivalis Antibody Titers With Nonsmoking Status in Early Rheumatoid Arthritis: Results From the Prospective French Cohort of Patients With Early Rheumatoid Arthritis

To investigate the possible link between Porphyromonas gingivalis infection and rheumatoid arthritis (RA), according to antibody profile, genetic and environmental factors, and RA severity.

Anti‐Porphyromonas gingivalis antibodies titres are associated with non‐smoking status in early rheumatoid arthritis: Results from the ESPOIR cohort

To investigate the possible link between Porphyromonas gingivalis infection and rheumatoid arthritis (RA), according to antibody profile, genetic and environmental factors, and RA severity.

Where are peripheral analgesics acting

Most chronic rheumatic diseases result in pain, deformities, and decreased functional ability. Interestingly, a substantial number of patients, including rheumatoid patients, rank pain relief as the most desirable objective of treatment. In this respect, the non-narcotic analgesics are usually considered as the best drugs.2 These agents mainly include paracetamol, salicylates, and other non-steroidal antiinflammatory drugs (NSAIDs), and non-acidic pyrazolone derivatives-for example, dipyrone (metamizole) and phenazone (antipyrine); aminophenazone (aminopyrine) has been withdrawn from the market.5 As a group, they share analgesic, antipyretic, and, to a greater or lesser extent, antiinflammatory properties.2 Conversely, these compounds show marked differences in their therapeutic action and side effects.5 Their common denominator was thus believed to be their site of action within the damaged tissues,6 and hence they were termed peripheral analgesics. This assumption was mainly based on the following findings. Firstly, the classic cross-circulation experiment performed in the dog by Lim et alP indicated that the analgesic effect of aspirin-like drugs occurred in the pain producing site itself rather than in the central nervous system. Secondly, injections of minute amounts of acetylsalicylic acid, indomethacin, or paracetamol into the inflamed paws of rats were shown to attenuate the nociceptive responses.8 Moreover, NSAIDs may alter perceived pain intensity in rodents when applied locally to the injured sites.9 1 In humans too, locally applied aspirin and paracetamol appeared to be effective for controlling pain in the early postoperative period after third molar surgery.1 Thirdly, pharmacokinetic data are consistent with the peripheral activity of these drugs.5 12 Systemically administered NSAIDs were found to achieve particularly high concentrations in their target tissues in animals5 as well as in humans. 13 4 Finally, the analgesic property of aspirin-like drugs might be ascribed to their ability to inhibit prostaglandin biosynthesis.6 15 Indeed any tissue damage related to trauma, ischaemia, hyperthermia, or inflammation results in the release of various chemical substances, including prostaglandins, which may sensitise the primary afferent nociceptors to pain mediators, such as bradykinin. 16 However, this mechanism ofaction has been questioned. 17 18 Furthermore, experimental and clinical studies support the possibility of an additional central component in the analgesic action of aspirin-like drugs. This paper aims at reviewing these challenging findings.

Gut metagenome and spondyloarthritis

Joint Bone Spine - In Press.Proof corrected by the author Available online since mardi 25 juin 2013

Shared genetic predisposition in rheumatoid arthritis-interstitial lung disease and familial pulmonary fibrosis

Despite its high prevalence and mortality, little is known about the pathogenesis of rheumatoid arthritis-associated interstitial lung disease (RA-ILD). Given that familial pulmonary fibrosis (FPF) and RA-ILD frequently share the usual pattern of interstitial pneumonia and common environmental risk factors, we hypothesised that the two diseases might share additional risk factors, including FPF-linked genes. Our aim was to identify coding mutations of FPF-risk genes associated with RA-ILD. We used whole exome sequencing (WES), followed by restricted analysis of a discrete number of FPF-linked genes and performed a burden test to assess the excess number of mutations in RA-ILD patients compared to controls. Among the 101 RA-ILD patients included, 12 (11.9%) had 13 WES-identified heterozygous mutations in the TERT, RTEL1, PARN or SFTPC coding regions. The burden test, based on 81 RA-ILD patients and 1010 controls of European ancestry, revealed an excess of TERT, RTEL1, PARN or SFTPC mutations in RA-ILD patients (OR 3.17, 95% CI 1.53–6.12; p=9.45×10−4). Telomeres were shorter in RA-ILD patients with a TERT, RTEL1 or PARN mutation than in controls (p=2.87×10−2). Our results support the contribution of FPF-linked genes to RA-ILD susceptibility. Contribution of TERT, RTEL1, PARN and SFTPC mutations to rheumatoid interstitial lung disease susceptibility http://ow.ly/SXEm30a98Ic