Comparative usability study for a certolizumab pegol autoinjection device in patients with rheumatoid arthritis

Objectives: To compare the usability of a new certolizumab pegol (CZP) autoinjector with the adalimumab, etanercept, and golimumab devices in patients with rheumatoid arthritis.

Methods: Two identical studies were performed in 2013 and 2016; patients performed a simulated self-injection with the CZP autoinjector and the most up-to-date device versions at the time in a randomized, consecutive sequence. The primary end point was the ranking of the four autoinjectors in order of preference. Device usability and intuitiveness were assessed across a range of secondary and exploratory end points.

Results: The 2013 and 2016 study populations included 76 patients each; a significant majority (2013: 67%; 2016: 59%) ranked the CZP autoinjector as their most preferred device (p < 0.001). Most patients agreed that the CZP autoinjector was easier to use, start, and manipulate, and were more willing to use it than the comparator devices (p < 0.001 for all pairwise comparisons with CZP). Likert score differences also favored the CZP autoinjector regarding how easy it was to determine injection completion. The CZP autoinjector was associated with a low rate of use error.

Conclusions: In both studies, the CZP autoinjector was the preferred choice compared to the alternative devices and was associated with a high level of patient satisfaction.     

Outcomes of Recipients With Pancreas Transplant Alone Who Develop End‐Stage Renal Disease

Recipients of pancreas transplant alone (PTA) may be at increased risk for developing end‐stage renal disease (ESRD). The survival experience of PTA recipients developing ESRD has not been described. Furthermore, the relative survival of these patients as compared to diabetics on chronic dialysis is unknown. We studied all adult PTA recipients from January 1, 1990 to September 1, 2008 using the Scientific Registry of Transplant Recipients. Each PTA recipient developing ESRD was matched to 10 diabetics on chronic dialysis from the United States Renal Data System. Cox proportional hazards models were fitted to determine the relation between ESRD and mortality among PTA recipients, and the relation between PTA and mortality among diabetics on chronic dialysis. There were 1597 PTA recipients in the study, of which 207 developed ESRD. Those with ESRD had a threefold increase in mortality versus those without (adjusted hazard ratio 3.28 [95% confidence interval: 2.27, 4.76]). There was no significant difference in the risk of death among PTA recipients with ESRD versus diabetics on dialysis. PTA recipients developing ESRD are three times more likely to die than PTA recipients without ESRD; however, the risk of death in these patients was similar to diabetics on chronic dialysis without PTA.     

Cortical fibrosis and blood-vessels damage in human ovaries exposed to chemotherapy. Potential mechanisms of ovarian injury

BACKGROUND: Chemotherapy destroys primordial follicles and can lead to ovarian atrophy. Although reports indicate that apoptosis is the mechanism responsible for follicle loss, additional pathways can be involved. This study investigates the damage in human ovaries after administration of non-sterilizing doses of chemotherapy. METHODS: In a blind study, pathological changes in ovarian tissue harvested for cryopreservation were evaluated. The study group comprised young non-sterile cancer patients, previously exposed to chemotherapy who were (mean +/- SD), when compared with non-exposed patients. RESULTS: Thirty-five cancer patients aged 28.7 +/- 6.74; 17 were previously exposed to non-sterilizing chemotherapy and 18 were not. In all samples, primordial follicles were present. In previously exposed patients, damage to cortical blood vessel and proliferation of small vessels was observed. The cortex showed focal areas of fibrosis with disappearance of follicles (sensitivity 76%, positive predictive value 75% for <37 years old patients). Older patients, not exposed to chemotherapy (5/7) showed similar pathological changes. CONCLUSIONS: Injury to blood vessels and focal ovarian cortical fibrosis are aspects of ovarian damage caused by chemotherapy. These findings indicate a potential additional mechanism of damage to the direct apoptotic effect of chemotherapy on follicles. The possibility that these changes are involved in ageing ovaries should be further investigated.     

Response to sirolimus in capillary lymphatic venous malformations and associated syndromes: Impact on symptomatology,quality of life,and radiographic response

Background

Capillary lymphatic venous malformations (CLVM) and associated syndromes, including Klippel–Trenaunay syndrome (KTS) and congenital lipomatous overgrowth, vascular malformation, epidermal nevi, skeletal, and spinal syndrome (CLOVES), are underrecognized disorders associated with high morbidity from chronic pain, recurrent infections, bleeding, and clotting complications. The rarity of these disorders and heterogeneity of clinical presentations make large-scale randomized clinical drug trials challenging. Identification of PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha [gene]) mutations in CLVM has made targeted medications, such as sirolimus, attractive treatment options. The aim of this study was to investigate the safety and efficacy of sirolimus therapy in CLVM.

Procedure

A combined prospective and retrospective cohort of pediatric and young adult patients with CLVM treated with sirolimus was evaluated for disease response, including symptom improvement, quality of life (QOL), and radiologic response. Sirolimus dosing regimens and toxicities were also assessed.

Results

Twenty-nine patients with CLVM, including KTS and CLOVES, were included. Ninety-three percent of patients reported improved QOL, and 86% had improvement in at least one symptom. Most significantly, improvement was noted in 100% of patients with bleeding and 89% with thrombotic complications with corresponding decreases in mean D-dimer (p = .008) and increases in mean fibrinogen (p = .016). No patients had progressive disease on sirolimus. Most common side effects included neutropenia, lymphopenia, infection, and aphthous ulcers/stomatitis. No toxicities were life-threatening, and none required long-term discontinuation of sirolimus.

Conclusion

Sirolimus appears to be effective at reducing complications and improving QOL in patients with CLVM and associated syndromes. In this patient cohort, sirolimus was well tolerated and resulted in few treatment-related toxicities.     

Almost a tragedy: severe methotrexate toxicity in a hemodialysis patient treated for ectopic pregnancy

Background

Methotrexate (MTX), an antimetabolite of folic acid, is the drug of choice for the nonsurgical management of ectopic pregnancy. MTX-related toxicity may include leukopenia, thrombocytopenia, pancytopenia, nausea, vomiting, stomatitis, mucositis, and liver and lung toxicity, depending primarily on the dosage of the drug and patients' renal function. Currently, the use of MTX in hemodialysis patients, even at a low dosage, is controversial, and no clear-cut guidelines are available.

Case report

We report here a rare case of a life-threatening complication characterized by severe pancytopenia and skin and mucosal injury, which developed in a young patient on hemodialysis after oral treatment with MTX for ectopic pregnancy.

Conclusion

We conclude that even low-dose MTX administration is not to be used in patients with renal insufficiency, and when no other therapeutic options are available we suggest taking several clinical measures to prevent or treat myelosuppression.     

Efficacy of tacrolimus in rheumatoid arthritis patients who have been treated unsuccessfully with methotrexate: a six-month,double-blind,randomized, dose-ranging study

OBJECTIVE: To assess the efficacy, safety, and optimal dose of tacrolimus monotherapy in patients with rheumatoid arthritis (RA). METHODS: This phase II, randomized, double-blind, placebo-controlled monotherapy study was set in 12 community sites and 9 university-based sites. Two hundred sixty-eight patients with RA who were resistant to or intolerant of methotrexate (mean dose 15.2 mg/week) and had active disease for at least 6 months (mean tender joint count 28.2, mean erythrocyte sedimentation rate 46.5 mm/hour) were randomized to receive treatment after discontinuation of methotrexate. Those who received at least 1 dose of tacrolimus were analyzed; 141 completed the study. Stable dosages of nonsteroidal antiinflammatory drugs and low-dose prednisone were allowed during treatment. All patients were given 1, 3, or 5 mg of tacrolimus or placebo once daily for 24 weeks. The American College of Rheumatology definition of 20% improvement (ACR20) and the tender and swollen joint counts at the end of treatment were the primary outcomes. RESULTS: ACR20 response rates demonstrated a clear dose response. The ACR20 response was observed in 15.5% of patients receiving placebo (95% confidence interval [95% CI] 7.1-23.9%), 29% of the 1 mg tacrolimus group (95% CI 18.3-39.7%) (P < 0.058); 34.4% of the 3 mg group (95% CI 22.7-46.0%) (P < 0.013), and 50% of the 5 mg group (95% CI 37.8-62.3%) (P < or = 0.001). The tender joint count improved statistically significantly in all tacrolimus groups. The swollen joint count, physical function, and patient-assessed pain improved statistically significantly in the 3 mg and 5 mg groups. The incidence of creatinine elevation > or =40% above baseline levels increased in a dose-dependent manner. Dropout rates were high (41-59%) and were more common for inefficacy in the placebo patients (71.4%), whereas they were more common for toxicity in the high-dose tacrolimus groups (31-33%). Discontinuation for creatinine elevation occurred in the 3 mg (3.1%) and 5 mg (10.9%) tacrolimus groups. CONCLUSION: Tacrolimus improved disease activity in methotrexate-resistant or -intolerant patients with RA. A dose response was observed when efficacy and toxicity were assessed at different doses. The optimal dose of tacrolimus appears to be >1 mg but < or=3 mg daily.     

Hepatitis B virus reactivation after cytotoxic chemotherapy: the disease and its prevention.

Reactivation of hepatitis B virus (HBV) is a well-recognized complication in patients with chronic HBV infection who receive cytotoxic or immunosuppressive therapy. In most cases, reactivations occur in patients who are carriers of HBV infection showing positive hepatitis B surface antigen (HBsAg). Reactivation also may occur in patients with resolved infection who are HBsAg negative, anti-HBs positive, and anti-hepatitis B core positive. HBV reactivations can lead to severe flares that may be life-threatening unless recognized and treated promptly. Physician awareness is essential because prophylactic antiviral treatment can diminish the occurrence and improve the outcome of such episodes. Patients undergoing cytotoxic therapy should be checked routinely for HBV serologic markers and serum HBV DNA levels. Patients who are HBV carriers or anti-hepatitis B core positive should be monitored closely during and after the administration of cytotoxic chemotherapy. Prophylactic treatment with a nucleoside or nucleotide analogue should be considered strongly to prevent HBV reactivation in these patients.