Strategies for overcoming anti-tumor necrosis factor drug antibodies in inflammatory bowel disease:Case series and review of literature

Anti-tumor necrosis factor(TNF) biologics are currentlyamongst the most widely used and efficacious therapies for inflammatory bowel disease(IBD). The development of therapeutic drug monitoring for infliximab and ada-limumab has allowed for measurement of drug levels and antidrug antibodies. This information can allow for manipulation of drug therapy and prediction of response. It has been shown that therapeutic anti-TNF drug levels are associated with maintenance of remission, and development of antidrug antibodies is predictive of loss of response. Studies suggest that a low level of drug antibodies, however, can at times be overcome by dose escalation of anti-TNF therapy or addition of an immunomodulator. We describe a retrospective case series of twelve IBD patients treated at the University of California-Irvine, who were on infliximab or adalimumab therapy and were found to have detectable but low-level antidrug antibodies. These patients underwent dose escalation of the drug or addition of an immunomodulator, with subsequent follow-up drug levels obtained. Eight of the twelve patients(75%) demonstrated resolution of antidrug antibodies, and were noted to have improvement in disease activity. Though data regarding overcoming low-level anti-TNF drug antibodies remains somewhat limited, cases described in the literature as well as our own experience suggest that this may be a viable strategy for preserving the use of an anti-TNF drug. Low-level anti-TNF drug antibodies may be overcome by dose escalation and/or addition of an immunomodulator, and can allow for clinical improvement in disease status. Therapeutic drug monitoring is an important tool to guide this strategy.

Genetic polymorphisms predict response to anti-tumor necrosis factor treatment in Crohn's disease

To investigate genetic factors that might help define which Crohn’s disease (CD) patients are likely to benefit from anti-tumor necrosis factor (TNF) therapy. METHODSThis was a prospective cohort study. Patients were recruited from a university digestive disease practice database. We included CD patients who received anti-TNF therapy, had available medical records (with information on treatment duration and efficacy) and who consented to participation. Patients with allergic reactions were excluded. Patients were grouped as ever-responders or non-responders. Genomic DNA was extracted from peripheral blood, and 7 single nucleotide polymorphisms (SNPs) were assessed. The main outcome measure (following exposure to the drug) was response to therapy. The patient genotypes were assessed as the predictors of outcome. Possible confounders and effect modifiers included age, gender, race, and socioeconomic status disease, as well as disease characteristics (such as Montreal criteria). RESULTS121 patients were included. Twenty-one were non-responders, and 100 were ever-responders. Fas ligand SNP (rs763110) genotype frequencies, TNF gene -308 SNP (rs1800629) genotype frequencies, and their combination, were significantly different between groups on multivariable analysis controlling for Montreal disease behavior and perianal disease. The odds of a patient with a Fas ligand CC genotype being a non-responder were four-fold higher as compared to a TC or TT genotype (P = 0.009, OR = 4.30, 95%CI: 1.45-12.80). The presence of the A (minor) TNF gene -308 allele correlated with three-fold higher odds of being a non-responder (P = 0.049, OR = 2.88, 95%CI: 1.01-8.22). Patients with the combination of the Fas ligand CC genotype and the TNF -308 A allele had nearly five-fold higher odds of being a non-responder (P = 0.015, OR = 4.76, 95%CI: 1.35-16.77). No difference was seen for the remaining SNPs. CONCLUSIONThe Fas-ligand SNP and TNF gene -308 SNP are associated with anti-TNF treatment response in CD and may help select patients likely to benefit from therapy.

Seronegative spondyloarthropathy-associated inflammatory bowel disease

Seronegative spondyloarthropathy(SpA)usually starts in the third decade of life with negative rheumatoid factor,human leukocyte antigen-B27 genetic marker and clinical features of spinal and peripheral arthritis,dactylitis,enthesitis and extra-articular manifestations(EAMs).Cases can be classified as ankylosing spondylitis,psoriatic arthritis,reactive arthritis,enteropathic arthritis,or juvenileonset spondyloarthritis.Joint and gut inflammation is intricately linked in SpA and inflammatory bowel disease(IBD),with shared genetic and immunopathogenic mechanisms.IBD is a common EAM in SpA patients,while extraintestinal manifestations in IBD patients mostly affect the joints.Although individual protocols are available for the management of each disease,the standard therapeutic guidelines of SpA-associated IBD patients remain to be established.Nonsteroidal anti-inflammatory drugs are recommended as initial therapy of peripheral and axial SpA,whereas their use is controversial in IBD due to associated disease flares.Conventional disease-modifying anti-rheumatic drugs are beneficial for peripheral arthritis but ineffective for axial SpA or IBD therapy.Anti-tumor necrosis factor monoclonal antibodies are effective medications with indicated use in SpA and IBD,and a drug of choice for treating SpA-associated IBD.Janus kinase inhibitors,approved for treating SpA and ulcerative colitis,are promising therapeutics in SpA coexistent with ulcerative colitis.A tight collaboration between gastroenterologists and rheumatologists with mutual referral from early accurate diagnosis to appropriately prompt therapy is required in this complex clinical scenario.

Controversies in the treatment of Crohn’s disease: The case for an accelerated step-up treatment approach

The ideal treatment strategy for Crohn’s disease (CD) remains uncertain, as does the optimal endpoint of therapy. Top-down versus step-up describes two different approaches: early use of immunomodulators and biological agents in the former versus initial treatment with steroids in the latter, with escalation to immunomodulators or biological drugs in patients proven to be steroid refractory or steroid dependent. Top-down therapy has been associated with higher rates of mucosal healing. If mucosal healing proves to be associated with better long-term outcomes, such as a decreased need for hospitalization and surgery, top-down therapy may be the better approach for many patients. The main concern with the top-down approach is the toxicity of the immunomodulators and biological agents, which have been linked with infectious complications as well as an increased risk of lymphoma. It is unlikely that one strategy will be best for all patients given the underlying heterogeneity of CD presentation and severity. Ultimately, we must weigh the safety and efficacy of the therapies with the risks of the disease itself. Unfortunately our ability to risk stratify patients at diagnosis remains rudimentary. The purpose of this paper is to review the data that supports or refutes the differing treatment paradigms in CD, and to provide a rationale for an approach, termed the "accelerated step-up" approach, which attempts to balance the risks and benefits of our currently available therapies with the risk of disease related complications as we understand them in 2008.

Therapeutic drug monitoring in patients with inflammatory bowel disease

Thiopurine analogs and anti-tumor necrosis factor (TNF) agents have dramatically changed the therapeutics of inflammatory bowel diseases (IBD), improving short and long-term outcomes. Unfortunately some patients do not respond to therapy and others lose response over time. The pharmacokinetic properties of these drugs are complex, with high inter-patient variability. Thiopurine analogs are metabolized through a series of pathways, which vary according to the patients’ pharmacogenetic profile. This profile largely determines the ratios of metabolites, which are in turn associated with likelihoods of clinical efficacy and/or toxicity. Understanding these mechanisms allows for manipulation of drug dose, aiming to reduce the development of toxicity while improving the efficacy of treatment. The efficacy of anti-TNF drugs is influenced by many pharmacodynamic variables. Several factors may alter drug clearance, including the concomitant use of immunomodulators (thiopurine analogs and methotrexate), systemic inflammation, the presence of anti-drug antibodies, and body mass. The treatment of IBD has evolved with the understanding of the pharmacologic profiles of immunomodulating and TNF-inhibiting medications, with good evidence for improvement in patient outcomes observed when measuring metabolic pathway indices. The role of routine measurement of metabolite/drug levels and antibodies warrants further prospective studies as we enter the era of personalized IBD care.