Triple therapy with adalimumab, ustekinumab and methotrexate for induction of remission in moderate to severe ileocolonic Crohn’s disease with upper gastrointestinal involvement in a biologic-experienced individual

Abstract

Induction of remission in biologic-experienced individuals with moderate to severe Crohn’s disease (CD) can be a challenge. We hereby present a case of CD with secondary non-response to infliximab. Adding methotrexate and switching to ustekinumab plus methotrexate did not stop the inflammatory process. Therefore, combination therapy with two classes of biologics consisting of ustekinumab and adalimumab plus methotrexate was initiated. He achieved clinical remission in 4 weeks and remained on triple therapy for 6 months which was subsequently tailored to adalimumab/methotrexate combination therapy due to insurance restriction on ustekinumab. He remained in remission for the duration of follow-up, 14 months after initiation of triple therapy and 8 months after switching to methotrexate/adalimumab biologic monotherapy. Triple therapy with anti-TNF, IL-12/23 inhibitor and methotrexate could potentially be an option for induction of remission in biologic-experienced individuals with good initial clinical response to anti-TNF agents.

Background

Crohn’s disease (CD) is a chronic inflammatory disorder of the gastrointestinal (GI) tract with episodes of remission and relapse with long-term consequences such as bowel stricture, perforation and fistula formation. FDA-approved biologic therapy for CD is limited to five medications (infliximab, adalimumab, certolizumab, ustekinumab and vedolizumab) with or without immunomodulators (azathioprine and methotrexate).

Induction of remission in CD can be challenging owing to the declining response rate to biologic agents for induction of remission once patients fail the first biologic agent.¹ Primary response to biologic agents may be absent in as many as 40% of patients.² Furthermore, among primary responders, there is a risk of secondary non-response. An analysis of adalimumab therapy for CD identified an annual risk of losing response amounting to 20.3% per patient-year, and the annual risk of needing dose escalation to maintain response was 24.4% per patient-year.³

Control of inflammation is the cornerstone of achieving mucosal healing, often necessitating the need for combined regimens of immunomodulators and biologics. However, remission may not be achieved despite such combinations.

Patients with CD who have failed to respond to biologic therapy or a combination of biologic therapy and an immunomodulator such as methotrexate or azathioprine are often left with no other alternative outside the domain of clinical trials. However, there is growing evidence in the form of case reports and case series,^4–13 suggesting that dual biologic therapy with or without immunomodulators, although not the current standard of care, may enhance induction and maintenance of remission in biologic-experienced individuals. This may be a viable option in managing active small-bowel CD in patients who have otherwise failed all three classes of biologic agents used individually.

Case presentation

We present a 41-year-old man with stricturing, penetrating and fistulising ileocolonic CD involving the duodenum, ileum and right colon, diagnosed at age 29. He established care at the multidisciplinary inflammatory bowel disease clinic at our institution when he was having frequent episodes of abdominal pain and post-prandial nausea and vomiting despite recent gastrojejunostomy for management of duodenal stricture. The course of the disease since the time of diagnosis is summarised in table 1.

Table 1.

Treatment and disease progress timeline

Date	Events and complications	Endoscopy and imaging	Therapeutic interventions
2008	Diagnosis of ileal CD		5-ASA and 6-MP
Early 2013	Enterocutaneous (EC) fistula		Ileocecectomy with take-down of EC fistula
Late 2013	Episode of pancreatitis		6-MP discontinued IFX initiated
2016			Cholecystectomy
2017	Low-titre antibodies against IFX with good drug level		MTX added to IFX regimen
Mar 2018	Symptoms of upper GI obstruction	OGD: severe luminal narrowing at duodenal sweep
Sep–Oct 2018 (figures 1 and 2)	Continued obstructive symptoms necessitating surgery	OGD and CT scan: duodenal inflammation and luminal narrowing	Pyloric exclusion and gastrojejunostomy
Mar 2019		Follow-up OGD: persistent duodenal narrowing and deformity without inflammation on biopsies
Sep–Nov 2019	Episodic abdominal pain Development of small ventral abdominal wall incisional hernia containing bowel without obstruction	CT scan: slight increase in mural inflammation in duodenal wall	IFX switched to UST plus MTX due to inflammation and stricture while on IFX Incisional hernia repair
Dec 2019–Jan 2020	Intermittent abdominal pain	CT scan: acute duodenal wall inflammation on a background of fibrosis
Feb 2020 (figures 3 and 4)	Admission to hospital with intractable abdominal pain	OGD: erythema and oedema at juncture of first and second portion of the duodenum with stricture which was not traversed CT scan: increase in inflammation of the first and second portions of the duodenum, minimal retroperitoneal fat stranding adjacent to pancreatic head in the setting of normal lipase ruled out pancreatitis	Started on ADA every 2 weeks in addition to UST every 8 weeks plus methotrexate
Mar 2020	Asymptomatic
Jun 2020 (figure 5)	Continued to do well clinically	OGD: mild stricture at duodenal sweep which could be traversed Biopsies free of inflammation	UST refill denied by insurance Patient remained on weekly ADA injection with MTX
Oct 2020 (figure 6)		MRE: improving inflammation of proximal duodenum with mild residual active inflammation and stricture
Feb 2021	Asymptomatic
April 2021	Asymptomatic	OGD: complete resolution of inflammation and obstruction

5-ASA, 5-aminosalicylic acid; CD, Crohn’s disease; EC, enterocutaneous; IFX, infliximab; 6-MP, 6-mercaptopurine; MRE, magnetic resonance enterography; MTX, methotrexate; OGD, oesophagogastroduodenoscopy; UST, ustekinumab.

He did clinically well for 5 years on infliximab before experiencing frequent episodes of obstructive symptoms due to duodenal stricture. This was managed by creating a gastrojejunal anastomosis. However, while there was an initial improvement in radiologic and endoscopic appearance of duodenal inflammation after the gastrojejunostomy, this did not last beyond 1 year. Despite surgical intervention, addition of methotrexate and adjustment of the infliximab dosage, clinical remission was not achieved. Switching the biologic agent from infliximab to ustekinumab 1 year after the surgery only resulted in worsening of inflammation, based on clinical symptoms and endoscopic and radiologic findings. Therefore, the decision was made to add an anti-TNF agent to current therapy. Adalimumab was chosen in his case.

Figure 1.

Sep 2018: mucosal erythema and oedema with luminal narrowing at the junction of the first and second portions of the duodenum, traversed with adult upper endoscope.

Figure 2.

Sep 2018: coronal CT scan with intravenous and oral contrast showing mild inflammatory oedema surrounding the second portion of the duodenum while on infliximab.

Figure 3.

Feb 2020: unchanged duodenal inflammation despite therapy with ustekinumab, with progression of luminal narrowing in the same region that could no longer be traversed with adult upper endoscope due to stricture.

Figure 4.

Feb 2020: coronal CT scan with intravenous and oral contrast showing mild inflammatory oedema surrounding the second portion of the duodenum, now spreading to the fat adjacent to the pancreatic head while off infliximab and after 4 months of ustekinumab exposure.

Figure 5.

Jun 2020: complete mucosal healing in the examined portion of duodenum after 4 months of triple therapy with adalimumab, ustekinumab and methotrexate; previous stricture in duodenum could now be traversed with adult upper endoscope without difficulty.

Figure 6.

Oct 2020: MRE, axial section, T2-weighted fat-saturation image showing resolution of previously reported inflammation around the second portion of the duodenum and pancreatic head.

Outcome and follow-up

Four weeks after initiation of triple therapy with weekly adalimumab, ustekinumab every 8 weeks (subsequently every 4 weeks to achieve therapeutic level) and oral methotrexate 15 mg weekly, there has been complete resolution of abdominal pain. The clinical remission lasted for the duration of follow-up. The adalimumab level was 15.5 µg/mL in August 2020 and the ustekinumab level was 5.1 µg/mL in September 2020. Unfortunately, 6 months after initiation of triple therapy, ustekinumab refill was denied by his insurance and several attempts to obtain prior authorisation were unsuccessful. He continued to do well clinically and the follow-up magnetic resonance enterography (MRE) 3 months after discontinuation of the third agent, ustekinumab, showed no inflammation while he remained in clinical remission. Follow-up endoscopy in April 2021 showed no inflammatory or obstructive findings.

Discussion

Achieving and maintaining remission in CD can be challenging.¹⁴ Up to one-third of patients develop stricturing or penetrating disease at 5 years after diagnosis.¹⁵ Biologic agents have improved disease remission rates in moderate to severe CD. However, treatment failure after trying successive biologics often leaves no other alternatives as per current clinical guidelines. Concomitant use of biologic agents, with or without immunomodulators, can theoretically be an intervention to achieve remission. Dual biologic therapy has shown promising results in several reports.

In a cohort of 22 patients with refractory CD who had failed a median of four prior trials of biologic monotherapy, 41% achieved clinical remission with the use of dual biologic therapy.⁴ Another study of 16 patients with active disease despite treatment with biologics showed clinical responses with dual biologic therapy in all patients with no serious adverse events reported.⁵

In a study on the use of anti-TNF agents with vedolizumab, 8 of 10 patients achieved clinical remission and could stop the anti-TNF agent, with almost no adverse events during combination therapy.⁶

Two case reports noted the absence of any side effects even after 21 months⁷ and 37 months⁸ of continued dual biologic therapy, and another noted improved control of intestinal and extra-intestinal disease with dual biologic therapy compared with either agent alone.⁹ These findings are corroborated by other investigators as well.¹⁰

The anti-IL-12/23 agent, ustekinumab, has also been successfully used as dual biologic therapy with infliximab¹¹ and vedolizumab^{12 13} in maintaining remission in refractory CD.

In this case, there was disease progression to duodenal stricture due to ongoing duodenal inflammation on IFX therapy. However, stopping IFX and switching to ustekinumab and methotrexate only resulted in rapid deterioration of his symptoms. This switch is the standard of care and current practice based on national guidelines.¹⁶ Restarting an anti-TNF agent in addition to this therapy then resulted in rapid induction of remission which lasted over a year. The sequence of events in this case suggests the importance of adding a second agent and not withdrawing the primary biologic agent in case of secondary non-response. This approach is well accepted in other fields such as endocrinology and cardiology where, in case of uncontrolled diabetes or hypertension, one or more agents with different mechanisms of action will be added to the existing agent(s) rather than discontinuing the initial therapy which had some initial response.

This case report highlights the safety and efficacy of combination biologic therapy with adalimumab and ustekinumab in achieving remission in a patient with active CD.

Patient’s perspective.

Infliximab kept my disease under control for several years, but I was told that there was inflammation and narrowing in the small bowel despite taking infliximab for so long. When my medication was changed to ustekinumab, my abdominal pain, nausea, and vomiting worsened and I ended up in the hospital a few times. It was then that I was offered a new approach to control hard-to-treat Crohn’s disease using two biologic medications. I was told that this approach was not part of the national guidelines at the time and was not widely used, but my doctors shared with me reports about patients similar to me who had had good results with dual biologic therapy. I accepted this new treatment and adalimumab was added to my medication regimen. Together with my older medication, my disease came to be well under control. Months later, my insurance decided to not pay for ustekinumab, but I continued to take the adalimumab. I had another upper endoscopy in 2021 where my doctor noticed that my small bowel was free of inflammation compared with my previous tests. For me, the two biologic therapy was the right decision when my disease was very active, and I noticed a substantial improvement in my symptoms pretty soon after starting this new treatment.

Learning points.

• There may be a role for dual biologic therapy in conjunction with methotrexate in biologic-experienced patients with moderate to severe Crohn’s disease who failed to respond to monotherapy with one or more biologics.

• Triple therapy with adalimumab, ustekinumab and methotrexate for 6 months was effective and well tolerated in this case, resulting in rapid induction of clinical remission which lasted beyond a year on dual therapy with adalimumab and methotrexate.

• Adding a second biologic agent, rather than switching the primary biologic agent, which resulted in partial response, may promote induction and maintenance of clinical and endoscopic remission in those experiencing relapse despite biologic monotherapy.

Ethics statements

Patient consent for publication

Obtained.