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In Search of Better Algorithms for Treatment of Crohn Disease


Wide variation in treatment patterns for Crohn disease is attributable to failures to translate evidence uniformly and cost barriers. Authors of a new report have formulated algorithms to help reduce heterogeneity in treatment of patients.

The authors of a new clinical review article combined evidence-based guidelines and clinical experience to create algorithms to guide decision making on the use of biosimilar anti—tumor necrosis factor (TNF) agents for moderate to severe Crohn disease (CD).

The authors, who see their work as a step toward standardizing care, noted that anti-TNF biologics, infliximab and adalimumab in particular, “constituted a quantum leap in efficacy” in CD treatment, and that access to these drugs “began to improve with the introduction of biosimilars for infliximab in 2013 and adalimumab in 2018.” However, standard procedures for initiating, monitoring, and managing anti-TNF therapy in CD have not yet been established.

The authors have presented their decision-making algorithm visually as a series of flowcharts, beginning with determining which patients are appropriate for anti-TNF therapy, followed by criteria favoring infliximab vs adalimumab and dosing regimens for each. A final set of flowcharts represents real-world scenarios physicians may encounter when monitoring a patient during treatment with infliximab or adalimumab biosimilars, along with recommendations for adjustment of therapy in those scenarios.

Identifying Patients Indicated for Anti-TNF Therapy

The authors started by providing criteria for establishing an indication for anti-TNF therapy, which includes assessment of disease activity scores, inflammatory biomarkers, and imaging.

Although disease activity scoring with the CD Activity Index (CDAI) has been used in clinical studies of anti-TNF agents in patients with CD, it is impractical for routine clinical practice because it must be calculated over a period of 7 days. The authors recommend an alternative assessment, the Harvey-Bradshaw Index (HBI), which they say correlates well with CDAI. An HBI of at least 8, they say, corresponds to moderate to severe disease.

Because HBI does not correlate well with inflammatory burden, the authors recommend measuring inflammatory markers and assessing the presence of mucosal lesions to corroborate the HBI score. Although there are no established cutoffs for C-reactive protein and fecal calprotectin, or established endoscopic criteria, the authors made recommendations supported by published research and clinical experience.

Before initiating therapy, they added, safety checks should be performed according to local and international guidelines and contraindications for anti-TNF therapy. They also advised setting patient-specific treatment goals.

Choosing Between Infliximab and Adalimumab Biosimilars

The authors note that although direct comparisons of infliximab and adalimumab in CD have not been published, the available evidence from observational studies suggests “no major differences in efficacy and safety between infliximab and adalimumab but a higher immunogenicity of the former.” They recommend weighing the preferred route and schedule of administration, dosing, combination therapy, and the patient’s inflammatory load.

Infliximab requires intravenous administration, whereas adalimumab is administered subcutaneously, allowing for self-administration by the patient at home. Subcutaneous infliximab is approved in Europe and is under review by the FDA. However, in the United States it will “ follow the [approval] pathway for novel products rather than biosimilars,” the authors state. Infliximab dosing is more easily tailored to the patient, whereas adalimumab dosing is limited by fixed-dose injections.

Because of the greater potential immunogenicity of infliximab, the authors say combination therapy with azathioprine should be considered, as it “has been shown to be superior to either treatment alone in patients with CD.” In contrast, combining immunomodulators with adalimumab is “potentially only marginally more effective” compared with adalimumab monotherapy.

The authors recommended infliximab in cases of perianal fistulizing disease, a requirement for flexible dosing, high systemic inflammatory load, or severe CD. They recommended adalimumab in cases of low inflammatory load or a preference for self-administration or monotherapy as opposed to combination therapy.

As of yet, most trials involving biosimilars in inflammatory bowel disease have been on infliximab. The first infliximab biosimilars were approved in 2013; adalimumab biosimilars became available in Europe in 2018, but these are not yet available in the United States owing to patent issues.

The authors cautioned that initiating biosimilars “may require a tailored approach beyond that used for reference biologics.” They advised using positive framing to avoid encouraging the nocebo effect when addressing patients’ concerns regarding biosimilars.

Monitoring and Adjustment of Therapy

Once treatment is initiated, monitoring and adjusting therapy may improve outcomes for patients with CD treated with anti-TNF agents, the authors suggested, because a large proportion of patients experience loss of response within 1 year of treatment initiation.

Recommendations for clinical monitoring, biomarker analysis, imaging, and therapeutic drug monitoring and options for adjustment of therapy were provided for different clinical scenarios: primary remission, primary response without remission, primary nonresponse, and loss of remission/response. As a whole, the authors’ algorithm aims to standardize anti-TNF therapy for CD while also personalizing therapy to the individual patient.


Reinisch W, Gecse K, Halfvarson J, et al. Clinical practice of adalimumab and infliximab biosimilar treatment in adult patients with Crohn's disease.Inflamm Bowel Dis. Published online July 7, 2020. doi:10.1093/ibd/izaa078

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