Donnie P. Funch

Ganciclovir and acyclovir reduce the risk of post-transplant lymphoproliferative disorder in renal transplant recipients.

Given its association with Epstein‐Barr virus (EBV), there is considerable interest in assessing the impact of prophylactic anti‐viral therapy on post‐transplant lymphoproliferative disorder (PTLD). A recently completed multi center case–control study assessed the impact of immunosuppressive therapy on PTLD risk among renal transplant patients and collected information on the use of anti‐viral therapy. Biopsy‐confirmed PTLD cases (n = 100) were matched to 375 controls by center, date of transplant, and age. Data were collected on immunosuppression and rejection therapies, demographics, pre‐transplant viral status, number of rejections, and anti‐viral use. With adjustment for known risk factors, prophylactic anti‐viral use was associated with up to 83% reduction in the risk of PTLD, depending on the anti‐viral agent. These results were stronger for the first year post‐transplant. For every 30 days of ganciclovir treatment, risk of PTLD during the first year was lower by 38% (Odds Ratio [OR]= 0.62; 95% confidence interval [CI]= 0.38–1.0); acyclovir effects were less striking (OR = 0.83; 95% CI = 0.59–1.16). Anti‐viral therapy appears to play a role in reducing the risk of PTLD in renal transplant patients. Ganciclovir may be more potent than acyclovir.

Topical Treatments with Pimecrolimus, Tacrolimus and Medium- to High-Potency Corticosteroids, and Risk of Lymphoma

Background/Aims: A potential risk of lymphoma associated with the use of topical calcineurin inhibitors is debated. We assessed the risk of lymphoma among patients treated with topical pimecrolimus, tacrolimus or corticosteroids. Methods: We conducted a cohort study using health insurance claims data. Cohorts of initiators of topical pimecrolimus, tacrolimus and corticosteroids, along with cohorts of persons with untreated dermatitis and randomly sampled enrollees were identified from January 2002 to June 2006. Lymphomas were identified using insurance claims and adjudicated by medical records review. We adjusted for confounders by propensity score matching. Results: Among 92,585 pimecrolimus initiators contributing 121,289 person-years of follow-up, we identified 26 lymphomas yielding an incidence of 21/100,000 person-years. This incidence of lymphoma was similar to that among tacrolimus users (rate ratio, RR = 1.16; 95% confidence interval, CI = 0.74–1.82) as well as corticosteroid users (RR = 1.15; 95% CI = 0.49–2.72). All three topical treatments were associated with an increased risk of lymphoma compared with the general population (RRPim = 2.89; RRTac = 2.82; RRCort = 2.10) suggesting increased detection of preexisting lymphomas. Conclusion: This study did not find an increased risk of lymphoma among initiators of topical pimecrolimus relative to other topical agents during an average follow-up of 1.3 years. Longer-term studies may be needed.

Posttransplant lymphoproliferative disorder among renal transplant patients in relation to the use of mycophenolate mofetil

Background. The introduction of increasingly effective immunosuppressants has raised the question of whether posttransplant lymphoproliferative disorder (PTLD), a complication of immunosuppression, would become more frequent. This study assessed the risk of PTLD in relation to immunosuppression during a period that saw the introduction and eventual market dominance of mycophenolate mofetil (MMF). Methods. A case-control study was conducted at 23 U.S. transplant centers. All participants received a renal-only transplant on or after July 1, 1995. PTLD cases were reported by centers and confirmed by central review. The United Network for Organ Sharing (UNOS) supplemented case ascertainment and identified controls matched on center, transplant date, and age. Center personnel abstracted risk factor and therapy data for cases and up to four controls per case. Cases and controls were compared, using a matched multivariate analysis, to assess the impact of MMF as one component of triple-therapy adjusted for other drug therapies and known risk factors. Results. Data were collected for 108 PTLD cases and 404 controls. PTLD risk for individuals on triple therapy with MMF was similar to the risk experienced by individuals on triple therapy with no MMF (adjusted odds ratio = 1.19; 95% CI 0.55–2.55). There was no dose response relationship between MMF and PTLD risk. Conclusions. Use of MMF was not associated with an increase in PTLD among patients who received triple immunosuppressive therapy, but an excess in risk as large as 155% or a reduction in risk by as much as 45% cannot be ruled out.

Risk of Guillain-Barré syndrome after meningococcal conjugate vaccination.

A new meningococcal conjugate vaccine (MCV4) was introduced in 2005. Shortly after, case reports of Guillain–Barré syndrome (GBS), a serious demyelinating disease, began to be reported to the Vaccine Adverse Event Reporting System. In 2006, the Centers for Disease Control and Prevention and the Food and Drug Administration requested the evaluation of GBS risk after MCV4 vaccination. We conducted a study to assess the risk of GBS after MCV4 vaccination using health plan administrative and claims data together with the review of primary medical records of potential cases.

Methods and Objectives of a Large US Multicenter Case-Control Study of Post-Transplant Lymphoproliferative Disorder in Renal Transplant Patients

A large multicenter case-control study is in progress in the United States, the primary goal of which is to provide information about the effects of specific immunosuppressants and other risk factors on posttransplant lymphoproliferative disorder (PTLD) in renal transplant patients. It will also provide incidence data and case characterization on PTLDs arising in a large contemporary population. Medical record data are being collected on up to 120 PTLD cases and up to four controls per case transplanted at 20 large US centers. Participants all received transplants on or after July 1, 1995 and PTLD cases will be identified through December 31, 2001. All cases undergo central clinical and pathologic review. Abstracted information includes detailed data (dosages, duration) on all immunosuppressants (induction, maintenance, anti-rejection) as well as antiviral treatment. Other data include demographics, transplant history, HLA matching and viral status (e.g., Epstein-Barr virus, cytomegalovirus). Information associated with the PTLD diagnosis and initial therapy for PTLD is also collected. To date, 86 potential cases have been reported. Twenty (24%) are pediatric patients (< or =18 years). Median time between transplant and PTLD is 268 days; 53 (62%) were diagnosed within the first year. Cumulative incidence through 1998 is 0.7% for adults and 4.5% for children. The most common single site for PTLD is the allograft. Common treatments included either a reduction or discontinuation of immunosuppression (90%) and antiviral treatment (66%). Overall, the allograft appears to be an important site of PTLD recurrence. Also, the incidence of renal PTLD since the introduction of new immunosuppressive therapies is similar to that reported earlier.

A combination study design to examine mycophenolate mofetil (MMF) and PTLD in renal transplant patients.

Renal transplant recipients who are chronically immunosuppressed by drugs are at a higher risk of developing malignancies. Commonly observed malignancies are several forms of posttransplant lymphoproliferative disorders (PTLD), skin, lip and gynaecological cancers. The risk is associated with many risk factors including the extent of immunosuppression. Mycophenolate mofetil (MMF) is an immunosuppressant, indicated for the prophylaxis of organ rejection in patients receiving allogenic renal and heart transplants. During the European approval of MMF for renal transplantation, the question was raised as to whether the use of MMF was associated with an increased risk of PTLD in comparison with alternate immunosuppressive regimens. In response, F. Hoffman‐La Roche Ltd set up a prospective observational cohort study with a companion case–control study. This paper describes the objectives and the methods of these studies along with the rationale of the methodology. Copyright

Adherence to recommended dosing and monitoring for mitoxantrone in patients with multiple sclerosis: a healthcare claims database study supplemented with medical records—the RETRO study†

Mitoxantrone was approved for treatment of multiple sclerosis (MS) in October 2000. Monitoring and dosing guidelines in the product labeling accompanying this indication include blood counts, liver function, and pregnancy tests at each administration. Due to potential cardiotoxicity, left ventricular ejection fraction (LVEF) testing prior to initial infusion and all infusions at a cumulative dose ≥100 mg/m2 was recommended until April 2005 when LVEF testing before all infusions was recommended in the approved labeling. We sought to estimate provider adherence to dosing and monitoring guidelines and the effect of changes in LVEF monitoring guidelines.

Performance of claims-based algorithms for identifying incident thyroid cancer in commercial health plan enrollees receiving antidiabetic drug therapies

BackgroundThyroid cancer incidence is increasing in the United States (US) and many other countries. The objective of this study was to develop and evaluate algorithms using administrative medical claims data for identification of incident thyroid cancer.MethodsThis effort was part of a prospective cohort study of adults initiating therapy on antidiabetic drugs and used administrative data from a large commercial health insurer in the US. Patients had at least 6 months of continuous enrollment prior to initiation during 2009–2013, with follow-up through March, 2014 or until disenrollment. Potential incident thyroid cancers were identified using International Classification of Diseases, 9th Revision (ICD-9) diagnosis code 193 (malignant neoplasm of the thyroid gland). Medical records were adjudicated by a thyroid cancer specialist. Several clinical variables (e.g., hospitalization, treatments) were considered as predictors of case status. Positive predictive values (PPVs) and 95% confidence intervals (CIs) were calculated to evaluate the performance of two primary algorithms.ResultsCharts were requested for 170 patients, 150 (88%) were received and 141 (80%) had sufficient information to adjudicate. Of the 141 potential cases identified using ≥1 ICD-9 diagnosis code 193, 72 were confirmed as incident thyroid cancer (PPV of 51% (95% CI 43–60%)). Adding the requirement for thyroid surgery increased the PPV to 68% (95% CI 58-77%); including the presence of other therapies (chemotherapy, radio-iodine therapy) had no impact. When cases were required to have thyroid surgery during follow-up and ≥2 ICD-9 193 codes within 90 days of this surgery, the PPV was 91% (95% CI 81-96%); 62 (82%) of the true cases were identified and 63 (91%) of the non-cases were removed from consideration by the algorithm as potential cases.ConclusionsThese findings suggest a significant degree of misclassification results from relying only on ICD-9 diagnosis codes to detect thyroid cancer. An administrative claims-based algorithm was developed that performed well to identify true incident thyroid cancer cases.