Appeal type: Experimental/Investigational
Decision: Upheld

Diagnosis: Crohn's disease.
Treatment: Adalimumab testing.

The insurer denied Adalimumab testing.  The determination is upheld.

The patient was diagnosed with Crohn's disease. The patient has been on adalimumab and was having a flare of the Crohn's disease, and the testing was needed to see if the adalimumab was working for him. The provider stated that the testing will allow implementing dose changing or different therapy. A complete blood count (CBC) was normal and a metabolic panel was stable. Based on low levels of adalimumab, he began weekly therapy. He is also on methotrexate and Lialda. A colonoscopy showed a deformed ileocecal valve, normal ileum, some areas of congestion in the colonic mucosa, all compatible with Crohn's disease. The pathology showed mild inflammatory activity, no dysplasia. The testing showed no detectable adalimumab antibodies. The drug level was 9.4 micrograms per milliliter (g/mL). A progress note stated the patient was feeling much better with weekly Humira, no abdominal pain, occasional rectal bleeding, 4 bowel movements per day. The final impression stated the patient was doing better with weekly Humira and continues on methotrexate and Lialda. The plan was to check antibody and serum levels of adalimumab. His body mass index (BMI) was 27.66. A progress note described that the patient had been changed to weekly injections, with no symptoms, no abdominal pain, and no bleeding. At issue is whether the proposed health service or treatment Adalimumab testing is likely to be more beneficial than any standard treatment or treatments for the insured's life threatening or disabling condition or disease.

The proposed health service or treatment Adalimumab testing is not likely to be more beneficial than any standard treatment or treatments for the insured's life threatening or disabling condition or disease.

The clinical follow-up and management of the patient would determine a dose changes or switching medications and not the antibody/serum testing. Since the progress note described that the patient was doing better, and the patient had already been dose escalated to every week adalimumab, further testing with antibody and serum levels would not change management. A staging colonoscopy was performed a week later and showed only mild activity in the colonic mucosa. There was no described flare but rather a patient that was doing better with dose escalated adalimumab. There are no randomized controlled studies or well-designed cohort studies that show an improvement in health outcomes with antibody/serum testing in patients with Crohn's disease that are described as "doing better", maintaining hemoglobin, maintaining weight.

Although antibodies to Adalimumab can occur and lead to resistance to therapy, routine assay of antibody levels to Adalimumab has not been proven to improve health outcomes. The decision to continue, or increase the dose of Adalimumab, are based upon the clinical response of the patient. Whether to continue or discontinue Adalimumab is determined by the patient's clinical status and not based on antibody assays to Adalimumab. A diminished or suboptimal response to Adalimumab can be managed in several ways: shortening the interval between doses, increasing the dose, switching to a different anti-tumor necrosis factor (TNF) agent, or switching to a non-anti-TNF agent.

Data regarding the clinical utility of Adalimumab serum/antibody testing is still emerging. There is no clear evidence at this time that these tests improve health outcomes over standard clinical management. It is also unclear what, if any, different decisions physicians would make for their patients based on anti-drug antibody levels as opposed to their current approach of managing the drug based on the patient's clinical response. Some studies have shown changes to management after antibody measurement. However, no controls were used and there is no comparison to changes made when management is based on clinical findings alone. Measurement of antibodies to Adalimumab in a patient receiving treatment with Adalimumab, either alone or as a combination test which includes the measurement of serum Adalimumab levels, is unproven. Studies evaluating the validation of the results between different assays are lacking, making interstudy comparisons difficult. Antibodies to Adalimumab are present in a substantial number of patients treated with Adalimumab, and there may be a correlation between the level of these antibodies and clinical response. However, the clinical utility of measuring anti-Adalimumab antibody concentrations has not been established, as it is not known how patient management would change based on test results. Limited evidence describes changes in management after measurement of antibody but does not compare these management changes to those made in the absence of antibody measurement. In addition, there are technical factors relating to the use of different assay methods across studies, it has not yet been established whether the use of threshold levels aids in the discrimination of response to Adalimumab, nor has the optimal timing of when to measure antibody levels been established. Therefore, the measurement of antibodies to Adalimumab in a patient receiving treatment with Adalimumab is considered investigational. There is no consensus on the clinical significance of the presence of antidrug antibodies.

Yarur et al. in a study showed that satisfactory serum anti-tumor necrosis factor (TNF) levels do not necessarily correlate to tissue concentrations and clinical response. It is postulated that some patients with high serum anti-TNF levels have insufficient tissue levels of anti-TNF to neutralize local TNF production. Hence, there is a questionable relationship between the correlation of serum anti- TNF levels and their relationship to endoscopic disease activity.

D'Haens described data from a randomized controlled trial comparing symptom-based dosing with symptom, biomarker, drug level, based dosing in Crohn's disease. The study suggests that proactive trough level based dose intensification was not superior compared with dosing based on symptoms alone. In other words, clinical symptoms dictated management as well as antibody testing.

Chaparro in a study with limitations of drug monitoring: "OBJECTIVES: (a)To evaluate the diagnostic accuracy of anti-TNF trough levels to predict mucosal healing in inflammatory bowel disease (IBD); (b) to determine the best cut-off point to predict mucosal healing in IBD patients treated with anti-TNF. There was an association between anti-TNF trough levels and mucosal healing in IBD patients; however, the accuracy of the determination of infliximab and adalimumab concentrations able to predict mucosal healing was suboptimal."

Wright et al. in a study with limitations of drug monitoring: "Anti-TNF prevents postoperative Crohn's disease recurrence in most patients but not all. This study aimed to define the relationship between adalimumab pharmacokinetics, maintenance of remission and recurrence. Adalimumab concentration in patients treated with adalimumab to prevent symptomatic endoscopic recurrence postoperatively is, for most patients, well within the therapeutic window, and is not significantly lower in patients who develop recurrence compared with in those who remain in remission. Mechanisms of anti-TNF failure to prevent postoperative recurrence remain to be determined in these patients."

Papamichael summarized limitations of drug monitoring: "Anti-tumour necrosis factor (TNF) therapies, such as infliximab, adalimumab, certolizumab pegol and golimumab, have been proven to be effective for the treatment of patients with Crohn's disease and ulcerative colitis. However, 10%-30% of patients with inflammatory bowel disease (IBD) show no initial clinical benefit to anti-TNF therapy (primary non-response), and over 50% after an initial favourable outcome will lose response over time (secondary loss of response (SLR)). Numerous recent studies in inflammatory bowel disease (IBD) have revealed an exposure-response relationship suggesting a positive correlation between high serum anti-TNF concentrations and favourable therapeutic outcomes including clinical, biomarker and endoscopic remission, whereas antidrug antibodies have been associated with SLR and infusion reactions. Currently, therapeutic drug monitoring (TDM) is typically performed when treatment failure occurs either for SLR, drug intolerance (potential immune-mediated reaction) or infusion reaction (reactive TDM). Nevertheless, recent data demonstrate that proactive TDM and a treat-to-target (trough) therapeutic approach may more effectively optimise anti-TNF therapy efficacy, safety and cost. However, implementing TDM in real-life clinical practice is currently limited by the diversity in study design, therapeutic outcomes and assays used, which have hindered the identification of robust clinically relevant concentration thresholds." There was no treatment failure, drug intolerance (potential immune-mediated reaction) or infusion reaction documented in this case that would warrant dose escalation for Humira.