CAPÍTULO 3. CUMPLIMIENTO DE REQUISITOS PARA OBTENER LA
3.2 APROBACIÓN OPERACIONAL
Safety assessment of therapies in inflammatory bowel disease
Although randomized controlled trails (RCTs) are the golden standards for studying efficacy, in studying safety aspects of medical treatment their use is limited by strict inclusion criteria and relatively short follow-up periods.7 The ongoing long-term
follow-up via registries is important in this respect.8 Recently, the European League
Against Rheumatism reported on elements to consider when establishing, analyzing and reporting safety data of biologics registers in rheumatology.9 Most of these
points also apply for safety analysis in patients with IBD. First of all, sample size is of major importance. Safety assessment requires large cohorts due to the relatively low background rates of serious adverse events. Furthermore, there should be clear reporting of study design and methodological techniques in order to be able to compare the results of these registries. A meaningful comparator (i.e. an unexposed cohort) must be included, which should be as similar as possible to the exposed group and potential biases should be noticed. Potential bias includes the higher rate of co-morbidity observed in referral centers together with the fact that clinical decisions will influence which patients receive more extensive treatment, potentially introducing ‘channeling bias’.
The Dutch ‘Parelsnoer’ project, a biobank project in which all eight medical university centers in the Netherlands participate, might function as a template for a large clinical practice registry which enables to study long term safety of various treatments given in IBD. In this biobank project, standardized clinical data of IBD patients is obtained prospectively and integrated with standard molecular data from biomaterials taken.
This approach will enable us to collect a large dataset on patients with distinct clinical characteristics.
Predictors of effects and adverse events
The treatment of patients with IBD can be very challenging. First of all, although the natural history of IBD progressively leads to the development of complications in approximately two-thirds of Crohn’s disease patients and less than one-third of ulcerative colitis patients, the clinical course of the disease varies greatly among patients.10 Therefore, sensitive and specific markers to predict disease course and to
identify those patients with an aggressive and progressive disease course that would benefit from early use of biologics to prevent future complication and surgery are necessary. Some clinical factors have been associated with a disabling course of disease including disease location (terminal ileum), disease behavior (structuring and penetrating behavior), age at diagnosis (< 40 years), the presence of perianal disease and the initial requirements for steroids.11,12 Furthermore, several predictive
factors for successful response to anti TNF therapy in Crohn’s disease have been identified. Early luminal Crohn’s disease, a high CRP, and high trough concentrations of infliximab have been associated with more durable maintenance of clinical response.13 On the other hand, the presence of antibodies to infliximab (ATI) as a
marker of immunogenicity, have been associated with an increased risk of infusion reactions and a reduced duration of response.14-16 These observations however, have
been challenged in a systematic review stating that a more relevant measure than ATIs is likely to be measurement of circulating drug concentration since measurement of ATIs is so dependent on analytical technique, timing of sampling, dosing regimen, circulating drug, concomitant therapy, and the individual patient.17 Additionally,
advanced age appears to be an independent risk factor for severe infections and mortality in patients given anti-tumor necrosis factor therapy for IBD.18
The use of a large clinical registry as mentioned before, would be of major importance to identify risk factors for serious outcomes in drug treatment. Since biological therapies are indicated for various auto inflammatory disorders, this identification process will require a multidisciplinary approach. Currently, the ‘Parelsnoer’ project includes a registry on IBD as well on rheumatoid arthritis. Since biomaterials are also obtained in this project, efforts should be made to unravel genetic susceptibility factors for efficacy and/ or side effects of biological treatment for various indications. In the future, this might enable clinicians to select the appropriate therapy for patients and to predict responses to these therapies.
Genetic susceptibility and IBD
In our studies we used a mechanistic approach, in which known functional polymorphisms were tested in IBD patients. However, in the era of genome wide association studies (GWAS), many new genomic regions containing IBD risk factors have been identified with much more statistical power. Knowledge on the functional Summary and future perspectives | 121
consequences of these genetic variants however is scarce. Additional studies are therefore needed to investigate the biological and cellular pathways involved.
Most of the alleles identified by GWAS are relatively common (allele frequencies >5%) and all these loci together explain less than 25% of the overall predicted genetic heritability in Crohn’s disease.19 Polymorphisms that have a stronger effect
on disease development might be maintained at a lower frequency in the population (uncommon alleles) through negative selection, because they reduce reproductive fitness. The identification of these uncommon alleles might be greatly facilitated by new techniques as whole-exome and whole-genome sequencing. Recently, successful clinical application of whole-exome sequencing was shown in a child with intractable IBD, having a hemizygous missense mutation in the X-linked inhibitor of apoptosis gene.20 These new sequencing technologies can also be used to catalogue the resident
microflora at distinct body sites, and studying correlations between specific diseases and the composition of the microbiome.21
Furthermore, a full understanding of IBD requires capturing much of the genetic variation across the human population (i.e. genetic studies on IBD should also include non Caucasian populations), which will increase the power of GWAS. Also, the annotation and correlation of genomic information with high-quality phenotypic data is of major importance.22 In the (near) future, this might lead to personalized
medicine, tailored to individual patients.
Finally, to study the links between biological and environmental factors in complex diseases, such as IBD, it will be necessary to conduct suitably large (several hundred thousand people) prospective cohort studies with GWA genotyping, and reproducible reliable exposure measures at baseline.22,23 Although the costs are high, several
prospective cohorts for studying complex diseases have been established,24-26 which
will definitely enhance our understanding of the gene-environmental interplay.
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