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Combination therapy with immunomodulators added to the newer biologics ustekinumab (Stelara) or vedolizumab (Entyvio) did not improve rates of clinical remission or response, endoscopic remission, or persistence of therapy at 1 year in patients with Crohn's disease (CD) or ulcerative colitis (UC), an international study found.

Similar proportions of patients remained on treatment or showed endoscopic response at 12 months with either monotherapy with one of these newer non-anti-tumor necrosis factor (TNF) biologics or combination therapy with a biologic plus methotrexate or a thiopurine, according to Ashwin N. Ananthakrishnan, MD, MPH, of the Crohn's and Colitis Center at Massachusetts General Hospital in Boston, and colleagues.

For vedolizumab recipients, adding a thiopurine or methotrexate resulted in no difference in clinical remission or response versus monotherapy at the following time points:

• Week 14 (68.2% vs 74.1%; P=0.22)
• Week 30 (74.3% vs 75.6%; P=0.78)
• Week 54 (78.3% vs 72.9%; P=0.33)

Similarly, with ustekinumab, no difference emerged in clinical remission or response with combination therapy at:

• Week 14 (54.6% vs 65.8%; P=0.08)
• Week 30 (71.6% vs 77.4%; P=0.33)
• Week 54 (62.1% vs 67.0%; P=0.52)

During the first year of follow-up, 48.9% of patients on combination therapy and 45% on monotherapy experienced therapy failure (P=0.44).

"Patients with CD or UC receiving treatment with ustekinumab or vedolizumab do not require combination therapy with a immunomodulator," the authors wrote online in .

They noted that for each class of the older biologics there was a loss of response occurring at a rate of 10% to 25% annually, mainly through the mechanism of anti-drug antibodies causing suboptimal trough concentrations. Consequently, treatment for inflammatory bowel disease (IBD) has evolved to combine biologics with a when initiating anti-TNF therapy, particularly infliximab. The impact of combination therapy with newer non-anti-TNF drugs has been unclear.

The study, conducted at three tertiary care centers in the U.S., Canada, and France, looked at UC (n=263) and CD patients (n=286) receiving either ustekinumab or vedolizumab maintenance therapy from January 1, 2012 to July 1, 2019. The primary outcome was clinical remission or response at week 14, based on the Harvey Bradshaw index for CD or simple clinical colitis index or partial Mayo score for UC. Mean disease duration ranged from 13 to 15 years.

Of 131 patients receiving vedolizumab, 78 were also receiving a thiopurine and 53 were receiving methotrexate. Of 120 patients receiving ustekinumab, 57 were also receiving a thiopurine and 63 were receiving methotrexate. The mean age at diagnosis was about 30 in both treatment groups, and more than 50% of participants were women.

On multivariable analysis, adjusting for disease duration, prior anti-TNF exposure, study site, use of steroids at baseline, and subcutaneous induction dosing, baseline immunomodulator use was not a predictor of clinical remission or response at any of the time points. In addition, none of these other clinical parameters independently predicted clinical remission or response.

Subgroup analysis by IBD type, naive or experienced biologic status, and type of immunomodulator showed no benefit of combination therapy in both treatment groups.

These results echo those of previous studies. A subanalysis of the , for example, found no difference in clinical outcome between patients treated with vedolizumab monotherapy and combination therapy, while for ustekinumab, and showed no improvement with the addition of an immunomodulator.

One possible explanation, the authors noted, is that these newer biologics have a reduced rate of anti-drug compared with older drugs such as TNF inhibitors, and therefore have higher serum drug concentrations and rates of response.

Sharing her perspective on the findings, Maia Kayal, MD, of the Susan and Leonard Feinstein IBD Center at the Icahn School of Medicine at Mount Sinai in New York City, said, "The results of this excellent multicenter study provide further evidence that the routine use of an immunomodulator with ustekinumab or vedolizumab is not associated with improved clinical or endoscopic remission."

Furthermore, the risk of immunogenicity with ustekinumab and vedolizumab was low, and hence the addition of an immunomodulator to minimize immunogenicity may not be necessary, added Kayal, who was not involved in the research. "Avoiding immunomodulators when medically appropriate is paramount given their associated risks of infection and malignancy. Of course, prospective studies are needed before definitive guidance can be provided, but these data are encouraging."

The researchers, too, called for prospective studies with adequate power and with minimal potential confounders to assess the benefit of combination therapy during the treatment course and to optimize their use in newer biologic therapies.

They cited several limitations to the study, including its retrospective nature and the heterogeneity in treatment strategies between centers.

They also noted an inherent selection bias even within the centers themselves, with combination therapy recipients perhaps having a more severe disease phenotype.

In addition, the majority of study patients were biologic-experienced, which could impact the results' generalizability to the biologic-naive. Another limitation was that objective measures such as fecal calprotectin, C-reactive protein, and drug levels could not be analyzed, since not all centers performed these tests during the 1-year follow-up. Therefore, the study could not determine if concurrent immunomodulator use impacted the pharmacokinetics of vedolizumab or ustekinumab.

Moreover, absent data on immunomodulator-naive status, the analysis couldn't address whether the benefit was greater in immunomodulator-naive patients at initiation of combination therapy.

Finally, the study sites did not systematically collect data on treatment-related safety endpoints such as serious infections.

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