Appeal type: Medical necessity
Decision: Overturned

Diagnosis: Crohn's disease
Treatment: Stelara 90 milligrams (mg) every 4 weeks
The insurer denied Stelara 90 milligrams (mg) every 4 weeks.
The determination is overturned.


The patient has severe ileal Crohn's disease (CD) and psoriasis. He has previously tried and failed steroids. He was started on Stelara but did not achieve remission and had worsening symptoms following a steroid taper. Therefore, the attending gastroenterologist would like to escalate the dose of Stelara to 90 milligrams (mg) every 4 weeks to treat his severe Crohn's disease.
At issue is the medical necessity of the requested Stelara.
The requested health service/treatment of Stelara 90 mg/ml every 4 weeks is medically necessary for this patient.
Since this patient was not responding to standard dosing of Stelara, it is reasonable to increase the dose of Stelara to 90 mg every 4 weeks. Dose escalation in biologic therapy used in inflammatory bowel disease can be done either based on clinical symptoms or laboratory markers or endoscopic or radiological features with or without therapeutic drug monitoring. Dose escalation is done either by increasing the dose of the medication or shortening the interval between doses or sometimes a combination of both. There are only a finite number of biological agents used to treat inflammatory bowel disease and the standard of care is to optimize dose of the biological agent before switching to another agent. Therefore, it is medically necessary to use Stelara 90 mg subcutaneous (SC) every 4 weeks to treat this patient's severe Crohn's disease.
While therapeutic levels of infliximab and adalimumab are well-established in the medical literature, there are less data on appropriate therapeutic levels of ustekinumab since this medication and therapeutic drug monitoring of ustekinumab have been available for only a few years as opposed to over a decade for the anti tumor necrosis factor (TNF) agents. Current guidelines for therapeutic drug monitoring for patients with inflammatory bowel disease (IBD) address only the anti TNF agents and not vedolizumab or ustekinumab. The current evidence supporting the role of therapeutic drug monitoring (TDM) regarding ustekinumab is based on two exposure-response relationship studies showing that higher ustekinumab concentrations correlate to better therapeutic outcomes. At this time, there are still no studies comparing either proactive or reactive therapeutic drug monitoring (TDM) with empiric ustekinumab optimization. Therefore, although there are emerging data that may show an association between drug concentrations and outcomes, they are not sufficient to guide specific induction and maintenance drug concentrations for vedolizumab and ustekinumab other than confirming that there is detectable drug.
Crohn's disease results from a pathological immune response to luminal antigens in genetically predisposed individuals. Since the causes of Crohn's disease are complex and only partially understood, treatment is based on the empiric use of anti-inflammatory drugs. Although multiple therapies for Crohn's disease currently exist, a substantial proportion of patients are unresponsive to conventional agents. Approximately a third of patients fail treatment with TNF antagonists, and up to 40% of patients who initially benefit subsequently lose response. Ustekinumab, a fully human immunoglobulin (Ig) G1-kappa monoclonal antibody to the p40 subunit shared by interleukin (IL)-12 and IL-23, has emerged as a promising new treatment for both psoriasis and Crohn's disease. Clinical efficacy of ustekinumab in Crohn's disease was evaluated for the treatment of moderate to severe Crohn's disease in a randomized, placebo-controlled trial that included 104 patients. In this study, ustekinumab was given subcutaneously (90 mg) or intravenously (IV) (4 or 5 milligrams per kilogram [mg/kg]). There were 2 Crohn's disease populations: the first comprised patients who had previously received conventional or biologic therapy (population 1), and the second comprised patients who did not respond to infliximab (population 2). In the first population, patients were randomized to receive SC placebo at weeks 0, 1, 2, and 3, followed by ustekinumab 90 mg at weeks 8, 9, 10, and 11; or SC ustekinumab at weeks 0, 1, 2, and 3 followed by placebo at weeks 8, 9, 10, and 11; or IV placebo at week 0 followed by ustekinumab 4.5 mg/kg at week 8; or IV ustekinumab 4.5 mg/kg at week 0 followed by placebo at week 8. In this first population, compared with placebo, ustekinumab groups showed a higher rate of clinical response at week 4 as evaluated by the Crohn's Disease Activity Index (ustekinumab versus placebo: 52.9% versus 30.2%, respectively; P = 0.02). However, at week 8, the percentage of responders was similar in the ustekinumab and placebo groups (49% versus 39.6%; probablility [P] = 0.34). In a subgroup analysis of 49 patients from population 1 who had previously received infliximab, clinical response at weeks 2, 4, 6, and 8 was higher in ustekinumab-treated patients than in placebo-treated patients. On the other hand, clinical response was obtained by 43% (SC ustekinumab) and 54% (IV ustekinumab) of patients in the open-label study (population 2), which was similar to those observed in the first population. The authors concluded that the ustekinumab response was more evident in patients who had previously received infliximab.
Another trial evaluated the clinical efficacy of ustekinumab in patients with Crohn's Disease resistant to TNF-alpha inhibitors. In an induction phase, patients were randomized to receive IV ustekinumab at a dose of 1, 3, or 6 mg/kg or placebo at week 0. In the maintenance phase, patients responding to ustekinumab at week 8 underwent second randomization to receive SC ustekinumab 90 mg or placebo at weeks 8 and 16. The clinical response as evaluated by the Crohn's Disease Activity Index was better in the ustekinumab group (1, 3, and 6 mg/kg) compared with placebo: 36.6%, 34.1%, and 39.7% versus 23.5%, but results were only significant at the 6 mg/kg dose (P equals [=] 0.005). Maintenance therapy resulted in a significantly increased rate of clinical remission and response in the ustekinumab group compared with placebo. These results demonstrated the clinical efficacy of ustekinumab as induction therapy in Crohn's disease resistant to TNF-alpha inhibitors. Furthermore, patients who initially responded to ustekinumab also had significantly increased rates of response to this treatment when given as maintenance therapy.
Ustekinumab offers a treatment option to Crohn's disease patients who have never responded to infliximab, primary non-responders, as well as patients who have attenuated anti-TNF response or become intolerant to anti-TNF therapy. One third of anti-TNF naive patients are primary non-responders. Approximately one third of initial anti-TNF responders lose response or become intolerant over time, secondary non-responders, requiring dose escalation or switching to another anti-TNF agent. Typically, response rates among anti-TNF naive patients are higher than response rates among secondary nonresponders who switch within the anti-TNF class. Anti-IL-12 and anti-IL-23 is therapeutic option for both anti-TNF primary and secondary nonresponders. In a study by Kopylov and colleagues 38 patients (18 males, median age 35.5 years) with Crohn's disease resistant to anti-TNF agents at 3, 6, 12 months and at last follow up were enrolled. The most frequent loading schedule (73.7%) was 90 mg at weeks 0, 1 and 2, while 73.7% were treated with maintenance regimen of 90 mg every 8 weeks. The majority of patients (73.7%) had an initial clinical response, of whom 80% had sustained response at 6 months. Among the patients who showed a response at 6 months, 88.9% continued to maintain a clinical response at 12 months. At their last follow up (7.9 plus or minus () 5.2 months); 71% maintained response while 73.3% were in corticosteroid-free remission. There was a need for dose escalation (number [n] = 18) (mostly by interval reduction in 17 out of 18 patients) in 47.7% and this was successful in a majority (61.1%) of them. This would suggest that further dose optimization of ustekinumab may be needed in Crohn's disease.
In a multi-center study, Fumery and colleagues found that two-thirds of patients recaptured response following treatment intensification with ustekinumab 90 mg every 4 weeks.
Similarly, Ollech and colleagues showed that shortening the ustekinumab 90 mg dose interval to 4 weeks for patients with CD who did not respond to doses every 8 weeks improved clinical and biological indices of disease activity. Patients who lose response to the standard dose of ustekinumab might benefit from dose interval shortening, which was effective and safe. Meserve and colleagues showed that in real world settings, ustekinumab dose escalation was effective in achieving response in patients with CD with inadequate response, or loss of response to standard dose induction and/or maintenance therapy.
Based on the clinical data provided, the use of Stelara at the escalated dose of 90 mg every 4 weeks, as requested by the attending gastroenterologist, is medically necessary.