Safety of Dual Biological Therapy in Crohn's Disease
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Case report BMJ Open Gastroenterol: first published as 10.1136/bmjgast-2018-000243 on 9 November 2018. Downloaded from Safety of dual biological therapy in Crohn’s disease: a case series of vedolizumab in combination with other biologics Eric J Mao,1 Sara Lewin,2 Jonathan P Terdiman,2 Kendall Beck2 To cite: Mao EJ, Lewin S, ABSTRACT with mesalamine preparations, 6-mercapto- Terdiman JP, et al. Safety Uncertainty exists regarding safety and efficacy of dual purine (6-MP) monotherapy, subcutaneous of dual biological therapy biological therapy (DBT) in inflammatory bowel disease. methotrexate monotherapy and infliximab. in Crohn’s disease: a case We present four cases of DBT in Crohn’s disease. series of vedolizumab in He remained steroid dependent despite these Three patients had refractory disease non-responsive combination with other therapies. He was able to achieve a steroid-free to biological monotherapy or combination therapy biologics. BMJ Open Gastro clinical remission in his CD with adalimumab with immunomodulators. One patient had concomitant 2018;5:e000243. doi:10.1136/ monotherapy. His AS was quiescent with adal- bmjgast-2018-000243 ankylosing spondylitis. DBT was implemented by combining vedolizumab with an anti tumour necrosis imumab as well. Unfortunately, he had several lapses in adalimumab therapy leading to drug Received 3 September 2018 antibody or with ustekinumab. DBT was well-tolerated, Revised 3 October 2018 though two patients did experience self-limited infections. antibody formation and secondary loss of Protected by copyright. Accepted 16 October 2018 The efficacy of DBT remains unproven but it appears response. He was subsequently started on vedol- promising as three of the four patients achieved clinical izumab 300 mg every 8 weeks and azathioprine remission. Our case series contributes insight into the 50 mg daily with clinical response. A repeat safety of DBT that incorporates vedolizumab for future colonoscopy and endoscopy showed persistent efficacy studies. terminal ileitis, prompting escalation of vedol- izumab dosing to every 4 weeks. On transition from adalimumab to vedolizumab, the patient noted worsening of AS symptoms of back and INTRODUCTION hip pain. He was hospitalised for a flare of his Biologics are the mainstay of therapy in inflam- AS 1 year after transitioning to vedolizumab. matory bowel disease (IBD), rheumatolog- MRI revealed severe hip inflammatory arthrop- ical disease and dermatological disease. The athy bilaterally with sacroiliac joint fusion. safety profile of biological monotherapy or http://bmjopengastro.bmj.com/ Given the prior clinical response of his AS to in combination with immunomodulators has 1 antitumour necrosis factor therapy (anti-TNF), been well-characterised. There have been etanercept 50 mg weekly was added to vedol- a few prior reports of the use of dual biolog- izumab and azathioprine. The azathioprine © Author(s) (or their ical therapy (DBT) for refractory IBD and in was discontinued 3 months afterwards due to employer(s)) 2018. Re-use patients with a dual diagnosis of IBD and other permitted under CC BY-NC. No immune-mediated inflammatory disease.2–9 concern for excessive immunosuppression. commercial re-use. See rights DBT has also been explored in both the rheu- Within 3 months of initiation of etanercept, and permissions. Published his joint pains were well controlled. After 20 by BMJ. matological and dermatological literature, but months on DBT without severe adverse events 1Department of Internal the biologics used differ from those used in 10 or infectious complications (table 1), his AS Medicine, Division of IBD. To contribute further understanding on on September 26, 2021 by guest. Gastroenterology and DBT in IBD, we present a case series of four remained quiescent, but his CD flared despite Hepatology, University of vedolizumab and prednisone 60 mg daily. His California, Davis, Sacramento, patients with Crohn’s disease (CD) treated with DBT. laboratory tests demonstrated elevated C reac- California, USA tive protein (CRP) of 20.5 mg/L, erythrocyte 2Department of Medicine, Division of Gastroenterology, sedimentation rate (ESR) of 77 of mm/hour, University of California, San CASE REPORTS albumin of 3.3 g/dL and vedolizumab trough Francisco, San Francisco, The first case is a young man diagnosed with drug level of 12 µg/mL without antibodies. A California, USA ileocolonic CD and ankylosing spondylitis limited colonoscopy revealed multiple deep, Correspondence to (AS) at age 13. His index upper endoscopy serpiginous ulcers in the sigmoid colon with Dr Eric J Mao; and colonoscopy revealed esophagitis and histology confirming chronic active colitis. In ejmao@ ucdavis. edu ileitis. His CD had been treated unsuccessfully collaboration with rheumatology, etanercept Mao EJ, et al. BMJ Open Gastro 2018;5:e000243. doi:10.1136/bmjgast-2018-000243 1 Open access BMJ Open Gastroenterol: first published as 10.1136/bmjgast-2018-000243 on 9 November 2018. Downloaded from Table 1 Safety experience of dual biological therapy in Crohn’s disease Duration of dual biological Crohn’s disease Case Disease Dual biological regimen therapy Adverse events status 1 Ileocolonic Crohn’s disease, ankylosing Etanercept and vedolizumab 20 months None Active spondylitis Etanercept and ustekinumab 2 months None 2 Colonic and perianal Crohn’s disease Vedolizumab and ustekinumab 5 months Two Clostridium Clinical remission difficile infections 3 Ileocolonic and perianal Crohn’s Vedolizumab and golimumab 8 months None Clinical remission disease 4 Ileocolonic and perianal Crohn’s Vedolizumab, golimumab and 37 months Hand-foot-mouth Clinical remission disease 6-mercaptopurine disease and influenza was continued to maintain AS remission and vedolizumab difficile infection (CDI) that resolved with 2 week courses was switched to ustekinumab with the addition of metho- of vancomycin. trexate. He remains symptomatic from a CD perspective Comment: In a patient with severely active disease and after receiving ustekinumab induction, though with good limited alternative biological therapies, this case demon- control of joint pains. strates the efficacy of DBT to achieve clinical remission. Comment: This case illustrates a situation where Although he developed CDI shortly after DBT initiation, combining rather than switching biologics is the most prac- he possessed many CDI risk factors including high-dose tical approach to effectively treat both diseases. Unfortu- steroids and severe IBD. Ultimately, the possibility of nately, DBT did not maintain remission for both conditions achieving clinical remission outweighed potential adverse and he required another biological switch in an attempt effects of DBT, especially with the favourable safety profiles Protected by copyright. to effectively manage his CD. The efficacy of DBT remains of vedolizumab and ustekinumab. unproven but combination of anti-TNF and vedolizumab The third case is a young man with stricturing ileoco- appeared to be safe and well-tolerated in this case. lonic and perianal CD diagnosed at age 6. He was initially The second case is a young man diagnosed with colonic treated with mesalamine, azathioprine and budesonide. At and perianal CD at age 12. He had been treated unsuc- age 12, he started infliximab and azathioprine combina- cessfully with 4.8 g of mesalamine, requiring intermittent tion therapy. Despite combination therapy, at age 14, he courses of prednisone 40 mg daily with taper. He achieved developed multiple small and large bowel obstructions, clinical remission for 5 years with infliximab 5 mg/kg requiring ileal resection and right hemicolectomy with administered every 8 weeks and subcutaneous metho- primary ileocolonic anastomosis. Postoperatively, he was trexate 25 mg weekly. But, he experienced a secondary loss not on therapy. He developed disease recurrence at age 18 of response due to mechanistic failure despite increasing and failed to respond to adalimumab, certolizumab and the infliximab dose to 10 mg/kg administered every 8 ustekinumab. He did not tolerate methotrexate or tofaci- weeks. At this time, his faecal calprotectin was 1362 µg/g, tinib. At age 23, he required another ileocolonic resection http://bmjopengastro.bmj.com/ and colonoscopy demonstrated colitis to the hepatic flexure with end-ileostomy. Postoperatively, vedolizumab 300 mg with biopsies confirming active colitis throughout. He had every 8 weeks was started but he experienced disease recur- an infliximab drug trough level of 31.2 µg/mL without rence 1 year after initiation. Magnetic resonance enterog- antibodies. Biologics was switched to ustekinumab 90 mg raphy demonstrated inflammatory changes and narrowing subcutaneous every 8 weeks and subcutaneous weekly in two segments of small bowel. At age 26, the patient was methotrexate was continued. Initially, the patient demon- admitted to the hospital with a partial small bowel obstruc- strated a clinical response to ustekinumab, but persistent tion requiring intravenous corticosteroids, despite vedol- symptoms led to escalation of ustekinumab administration izumab dose intensification to every 4 weeks. Laboratory to every 4 weeks. Unfortunately, he continued to experi- studies during this hospitalisation demonstrated a serum ence bloody diarrhoea and nocturnal symptoms, requiring albumin 3.3 g/dL, ESR 15 mm/h, CRP 41.2 mg/L and on September 26, 2021 by guest. concurrent high-dose prednisone taper. His laboratories an elevated faecal calprotectin 1407.5 mcg/g. CT of the demonstrated a CRP