The risk of malignancy in patients with secukinumab-treated psoriasis, psoriatic arthritis and ankylosing spondylitis: analysis of clinical trial and postmarketing surveillance data with up to five years of follow-up.

BACKGROUND: Data on the use of biologic therapy and malignancy risk are inconsistent due to limited long-term robust studies. OBJECTIVES: To assess the malignancy risk in patients with secukinumab-treated psoriasis, psoriatic arthritis (PsA) and ankylosing spondylitis (AS). METHODS: This integrated safety analysis from both the secukinumab clinical trial programme and postmarketing safety surveillance data included any patient receiving at least one approved dose of secukinumab with a maximum of 5 years of follow-up. Safety analyses evaluated the rate of malignancy using exposure-adjusted incidence rates [EAIR; incidence rates per 100 patient treatment-years (PTY)]. Standardized incidence ratios (SIRs) were reported using the Surveillance, Epidemiology, and End Results Program (SEER) database as a reference population. Crude incidence of malignancy was also reported using postmarketing surveillance data. RESULTS: Safety data from 49 clinical trials with secukinumab-treated patients were included: 10 685 patients with psoriasis, 2523 with PsA and 1311 with AS. Across indications over a 5-year period, the EAIR of malignancy was 0·85 per 100 PTY [95% confidence interval (CI) 0·74-0·98] in secukinumab-treated patients, corresponding to 204 patients per 23 908 PTY. Overall, the observed vs. expected number of malignancies from secukinumab clinical trial data were comparable, as indicated by an SIR of 0·99 (95% CI 0·82-1·19) across indications. The estimated crude cumulative incidence reporting rate per 100 PTY for malignancy was 0·27 in the postmarketing surveillance data across indications with a cumulative exposure of 285 811 PTY. CONCLUSIONS: In this large safety analysis, the risk of malignancy was low for up to 5 years of secukinumab treatment. These data support the long-term use of secukinumab in these indications.

Effect of fibrosis on adverse events in patients with hepatitis C treated with telaprevir.

BACKGROUND: Data about adverse events are needed to optimise telaprevir-based therapy in a broad spectrum of patients. AIM: To investigate adverse events of telaprevir-based therapy in patients with and without advanced fibrosis or cirrhosis in a real-world setting. METHODS: Data on 174 hepatitis C-infected patients initiating telaprevir-based therapy at Mount Sinai and Montefiore medical centres were collected. Biopsy data and FIB-4 scores identified patients with advanced fibrosis. Multivariable fully adjusted models were built to assess the effect of advanced fibrosis on specific adverse events and discontinuation of treatment due to an adverse event. RESULTS: Patients with (n = 71) and without (n = 103) advanced fibrosis were similar in BMI, ribavirin exposure, gender, prior treatment history, haemoglobin and creatinine, but differed in race. Overall, 47% of patients completed treatment and 40% of patients achieved SVR. Treated patients with and without advanced fibrosis or cirrhosis had similar rates of adverse events; advanced fibrosis, however, was independently associated with ano-rectal discomfort (P = 0.03). Three patients decompensated and had advanced fibrosis. The discontinuation of all treatment medications due to an adverse event was significantly associated with older age (P = 0.01), female gender (P = 0.01) and lower platelets (P = 0.03). CONCLUSIONS: Adverse events were common, but were not significantly related to the presence of advanced fibrosis or cirrhosis. More critical monitoring in older and female patients with low platelets throughout treatment may reduce adverse event-related discontinuations.

Fludrocortisone therapy in renal transplant recipients with persistent hyperkalemia.

Hyperkalemia after kidney transplantation is a common electrolyte disturbance and the risk factors are multifactorial. Pharmacotherapeutic agents for chronic management of hyperkalemia in kidney transplant patients may be relatively contraindicated or provide suboptimal efficacy. Fludrocortisone, an endogenous mineralocorticoid mimics the actions of aldosterone, hence hyperkalemia reversal. We describe three- case series of persistent hyperkalemia with demonstrated benefit from fludrocortisone therapy. Our three renal transplant recipients with multiple emergency room visits for elevated serum potassium levels despite treatment with diuretics, sodium bicarbonate, and sodium polystyrene sulfonate responded well to fludrocortisones therapy. Upon fludrocortisone initiation and maintenance therapy, all three patients experienced a decline in serum potassium levels to normal reference range.

Postexposure prophylaxis of H1N1 with oseltamivir in a newly transplanted kidney recipient receiving intense immunosuppressive therapy.

Solid organ transplant recipients undergoing immunosuppressive therapy are considered to be at high risk for serious infectious complications. Recently in the United States, a pandemic of H1N1 flu infection has been reported with serious complications. We describe H1N1 infection in a living kidney donor and the 42-year-old kidney transplant recipient exposed to this kidney donor and undergoing intense immunosuppressive therapy. Postexposure prophylaxis with oseltamivir was effective to prevent H1N1 influenza A virus in a donor and a recipient.

Antiretroviral and immunosuppressive drug-drug interactions in human immunodeficiency virus-infected liver and kidney transplant recipients.

Highly active antiretroviral therapy (HAART) has significantly reduced mortality, and prolonged life expectancy of human immunodeficiency virus (HIV)-positive patients. Such improvements have led to increasing numbers of HIV-infected patients with end-stage organ disease as potential candidates for transplantation. A HAART regimen usually consists of a combination of nucleoside reverse transcriptase inhibitors (NRTI), non-nucleoside reverse transcriptase inhibitors (NNRTI), and/or protease inhibitors (PI). PI are known to strongly inhibit the cytochrome P450 3A (CYP3A) enzyme system that is responsible for the metabolism of immunosuppressive drugs, such as tacrolimus, sirolimus, and cyclosporine. Besides these pharmacokinetic drug-drug interactions, potential pharmacodynamic drug-drug interactions may also occur with concomitant HAART and antimetabolites, such as mycophenolate mofetil. An approach to immunosuppressive management in HIV-infected organ transplant recipients requires attention to such complexities as unique drug-drug interactions and increased drug-related toxicities.

Use of Tris-hydroxymethyl aminomethane in severe lactic acidosis due to highly active antiretroviral therapy: a case report.

BACKGROUND: Lactic acidosis is a rare, yet life-threatening adverse drug effect of highly active antiretroviral therapy (HAART), specifically stavudine and lamivudine. These nucleoside analogue reverse transcriptase inhibitors (NRTIs) are commonly used to treat patients infected with the human immunodeficiency virus (HIV). CASE: We report the use of Tris-hydroxymethyl aminomethane (THAM) to treat severe lactic acidosis due to HAART in a 50-year-old African-American woman. NRTIs can cause hyperlactinaemia by interfering with mitochondrial oxidative phosphorylation function, which normally removes H(+) generated by the hydrolysis of adenosine triphosphate. This side-effect is associated with a high mortality in patients infected with HIV. One explanation for this high mortality is that lactic acidosis is typically refractory to treatment with commonly used buffering agents. CONCLUSION: THAM generates serum bicarbonate, and reduces the level of carbon dioxide in arterial blood. Both of these qualities appear to make THAM an ideal agent for treating lactic acidosis caused by HAART.

Correlates of maternal directiveness with children who are developmentally delayed.

Interactions between 25 mothers and their children with developmental delays were correlated to determine the relationships between maternal directiveness and a) maternal behavior regarded as developmentally facilitative, b) maternal intrusiveness, and c) child developmental competence and behavioral engagement. The findings, many of which challenge common conceptions about the nature and role of maternal directiveness, are discussed in relation to these conceptions and to the potential role of directiveness in the development of children with handicaps.

Maternal directiveness in interactions with mentally handicapped children: an analytical commentary.

Maternal directiveness is portrayed as a negative interactional phenomenon in the mental retardation literature. Based on the speculation that a directive interactional style is causally related to poor developmental outcomes, the reduction of maternal directive behaviour is becoming a major thrust in early intervention work. This paper questions the characterization of directiveness as an inherently negative interactional phenomenon and highlights limitations in our current understanding of directiveness. Critical issues requiring attention in future research are identified and early interventionists cautioned that management of maternal directive behaviour must be founded on sound, empirically validated principles.