Agreement between results of meta-analyses from case reports and clinical studies, regarding efficacy and safety of idursulfase therapy in patients with mucopolysaccharidosis type II (MPS-II). A new tool for evidence-based medicine in rare diseases.

BACKGROUND: A preliminary exploratory study shows solid agreement between the results of case reports and clinical study meta-analyses in mucopolysaccharidosis Type I (MPS-I) adult patients. The aim of the present study is to confirm previous results in another patient population, suffering from mucopolysaccharidosis Type II (MPS-II). METHODS: A systematic review and meta-analysis of case reports published by April 2018 was conducted for MPS-II patients treated with enzyme replacement therapy (ERT). The study is reported in accordance with PRISMA and MOOSE guidelines (PROSPERO database code CRD42018093408). The assessed population and outcomes were the same as previously analyzed in a meta-analysis of MPS-II clinical studies. The primary endpoint was the percent of clinical cases showing improvement in efficacy outcome, or no harm in safety outcome after ERT initiation. A restrictive procedure to aggregate case reports, by selecting standardized and well-defined outcomes, was proposed. Different sensitivity analyses were able to evaluate the robustness of results. RESULTS: Every outcome classified as "acceptable evidence group" in our case report meta-analysis had been graded as "moderate strength of evidence" in the aforementioned meta-analysis of clinical studies. Sensitivity, specificity, and positive-negative predictive values for results of both meta-analyses reached 100%, and were deemed equivalent. CONCLUSIONS: Aggregating case reports quantitatively, rather than analyzing them qualitatively, may improve conclusions in rare diseases and personalized medicine. Additionally, we propose some methods to evaluate publication bias and heterogeneity of the included studies in a meta-analysis of case reports.

Agreement between the results of meta-analyses from case reports and from clinical studies regarding the efficacy of laronidase therapy in patients with mucopolysaccharidosis type I who initiated enzyme replacement therapy in adult age: An example of case reports meta-analyses as an useful tool for evidence-based medicine in rare diseases.

BACKGROUND: Case reports might have a prominent role in the rare diseases field, due to the small number of patients affected by one such disease. A previous systematic review regarding the efficacy of laronidase therapy in patients with mucopolysaccharidosis type I (MPS-I) who initiated enzyme replacement therapy (ERT) in adult age has been published. The review included a meta-analysis of 19 clinical studies and the description of eleven case reports. It was of interest to perform a meta-analysis of those case reports to explore the role of such meta-analyses as a tool for evidence-based medicine in rare diseases. METHODS: The study included all case reports with standard treatment regimen. Primary analysis was the percentage of case reports showing an improvement in a specific outcome. Only when that percentage was statistically higher than 5%, the improvement was confirmed as such. The outcomes that accomplished this criterion were ranked and compared to the GRADE criteria obtained by those same outcomes in the previous meta-analysis of clinical studies. RESULTS: There were three outcomes that had a significant improvement: Urine glycosaminoglycans, liver volume and 6-minute walking test. Positive and negative predictive values, sensitivity and specificity for the results of the meta-analysis of case reports as compared to that of clinical studies were 100%, 88.9%, 75% and 100%, respectively. Accordingly, absolute (Rho=0.82, 95%CI: 0.47 to 0.95) and relative agreement (Kappa=0.79, 95%CI: 0.593 to 0.99) between the number of case reports with improvement in a specific outcome and the GRADE evidence score for that outcome were good. Sensitivity analysis showed that agreement between the meta-analysis of case reports and that of the clinical studies were good only when using a strong confirmatory strategy for outcome improvement in case reports. CONCLUSIONS: We found an agreement between the results of meta-analyses from case reports and from clinical studies in the efficacy of laronidase therapy in patients with MPS-I who initiated ERT in adult age. This agreement suggests that combining case reports quantitatively, rather than analyzing them separately or qualitatively, may improve conclusions in the field of rare diseases.

Adenovirus IVa2 protein plays an important role in transcription from the major late promoter in vivo.

Adenovirus IVa2 protein is essential and multifunctional, with roles in encapsidation and transcriptional activation of the Major Late Promoter (MLP), but the importance of the transcriptional function to viability has not been assessed. To address this question, viral genomes with multiple nonbinding mutations in the MLP downstream elements DE1 and DE2, alone or in combination with nonbinding mutations in the UPE (USF0), were constructed. The results show that DE1/2 and the UPE are functionally redundant, suggesting an important role of IVa2 protein in the activation of the MLP in vivo. Previously, a virus (vIVa2) expressing a 40-kDa IVa2 isoform was created. Neither the DE1/2 mutations nor the USF0 mutations could be recovered in this genetic background. These results suggest that this 40-kDa isoform can play a role in transcription.

A 40 kDa isoform of the type 5 adenovirus IVa2 protein is sufficient for virus viability.

The multifunctional IVa2 protein is essential for adenovirus replication [J. Virol. 77 (2003) 3586], but the relative importance of the transcriptional and encapsidation functions is unknown. As part of a study of IVa2 function, we created a set of mutations in the IVa2 gene in the correct location in the viral genome. Unexpectedly, an opal stop codon at position 6 was recovered in virus twice. Isolate #2 showed defective viral replication, but produced late proteins at almost wild-type levels. Analysis of IVa2 mRNA showed an additional species, larger and more abundant than the equivalent wild-type species. It was a hybrid of the 5' UTR of L3 23 kDa attached to the IVa2 second exon, so that M75 is the 5' proximal methionine. This mRNA arises from a corresponding hybrid DNA, present in the virus stock. A protein of approximately 40 kDa, consistent with translation from the hybrid mRNA, was detected. It is able to bind to the packaging sequence and to the MLP downstream elements (DE1/2). Isolate #8 was more defective in replication than #2. No hybrid mRNA or DNA was detected, but it also produces a 40 kDa isoform, which is present in wild-type-infected cells. Mutational analysis of M75 and M101 revealed that the 40 kDa isoform is produced by initiation at Met75. This might be the origin of the previously unidentified 40 kDa factor present in the heterodimer DEF-A, which binds to DE1 and DE2a.