"Medical Journeys" is a set of clinical resources reviewed by doctors, meant for physicians and other healthcare professionals as well as the patients they serve. Each episode of this 12-part journey through a disease state contains both a physician guide and a downloadable/printable patient resource. "Medical Journeys" chart a path each step of the way for physicians and patients and provide continual resources and support, as the caregiver team navigates the course of a disease.
This month: A noteworthy case study.
A 13-year-old girl with severe ulcerative colitis (UC) presented for assessment due to worsening symptoms. Two years earlier she had been diagnosed with severe steroid-refractory UC; the only treatment that produced a response was induction with infliximab (10 mg/kg). She weighed 40 kg and had a body mass index (BMI) of 17.3; her pediatric UC activity index (PUCAI) was 80 points (score range is 0 to 85).
The patient's medical history showed an initial response to combination therapy with infliximab at 10 mg/kg every 8 weeks and azathioprine at 2.5 mg/kg, which was maintained without steroid treatment for about 6 months. Her PUCAI score dropped to 0, and her BMI increased to 19.3.
However, 6 months after starting infliximab, her symptoms flared and she had to be re-admitted to the hospital. Clinicians performed an infectious disease work-up, which returned negative findings for infectious organisms, including clostridium difficile and cytomegalovirus colitis. She then underwent a flexible sigmoidoscopy, which identified severe extensive colitis (Mayo 3).
Tests showed that the patient had an undetectable serum level of infliximab and very high levels of antibodies against the medication, at 30 AU/ml (normal is <5 AU/ml), thus confirming that her loss of response was due to immunogenicity.
At that point, her BMI had dropped again to 17.3, and her PUCAI score was 80. Clinicians started her on a tapering course of prednisone 40 mg and she went into clinical remission. Her treatment was then changed to adalimumab 40 mg every 2 weeks subcutaneously with azathioprine 2.5 mg/kg for maintenance.
She stayed in clinical and biochemical remission for the next 9 months, and then had another relapse. Another infectious diseases work-up returned negative findings. Sigmoidoscopy confirmed severe extensive colitis (Mayo 3) with multiple pseudopolyps.
Because she continued to show a suboptimal 5 μg/ml level of adalimumab (therapeutic level is >7.5 μg/ml) and adalimumab antibodies of 5 (normal range <10 AU/ml), clinicians increased her adalimumab dose – initially to 40 mg weekly and later, based on findings of therapeutic drug monitoring, to 80 mg weekly.
She was started on another tapering course of prednisone at 40 mg. However, when the tapering dose of steroids reached 15 mg/day, the patient's symptoms rapidly returned; at symptomatic recurrence, she had a therapeutic adalimumab level of 12 µg/ml, but adalimumab antibodies of 20 (normal range <10 AU/ml).
Test Results
Laboratory results were as follows:
- White blood cell count: 4.6×109 (reference range 3.9-10×109 cells/L)
- Hemoglobin: 81 g/L (reference range 120-150 g/L)
- Mean corpuscular volume: 71.6 fL (reference range 83-101 fL)
- Platelets: 362,000 mcL (reference range 130,000-430,000 mcL)
- Albumin: 28 g/L (reference range 35-50 g/L)
- C-reactive protein (CRP): 110 mg/L (reference range 0-10 mg/L)
- Erythrocyte sedimentation rate: 74 mm/hr (reference range 0-20 mm/hr)
Next Steps
The patient was assessed by a dietitian, and underwent a trial of total exclusive enteral nutrition diet, which was unsuccessful. Consultation with the colorectal surgical team led to consideration of a proctocolectomy, but the patient's parents declined that option. She continued to maintain a BMI of 17.3 and PUCAI score of 80.
Clinicians then discussed off-label use of other medication options, including vedolizumab and ustekinumab. However, because these agents are not approved for pediatric ulcerative colitis, the medical insurance company refused to provide coverage. After consultation with the patient and her family, clinicians proposed tofacitinib as a potential salvage therapy, explaining that while the medication is not licensed yet for children with UC, it is approved for adults with UC and children with juvenile idiopathic arthritis.
After being advised of the benefits, risks, potential complications, and side effects, the patient and her parents provided informed consent to try tofacitinib. She was approved to receive it on compassionate grounds, and the treatment was paid for by a patient funding organization.
She began treatment with tofacitinib at 5 mg orally twice daily. "Remarkably," the medical team noted, the patient had a complete clinical response, and achieved complete remission. She was weaned off steroids without having any symptoms such as bloody diarrhea or abdominal pain.
At her follow-up assessment 9 months later, she was in complete clinical, biochemical, and endoscopic remission. Lab tests showed decreased levels of both CRP (to 5 mg/L), and fecal calprotectin, from over 1,000 to 10 μg/g. A repeat colonoscopy showed complete healing of the mucosa in the whole colon (Mayo 0) with mild loss of erythema in the sigmoid colon (Mayo 1). Her colonic biopsies showed inactive chronic colitis in the rectum, her PUCAI score was 0, and her BMI had increased to 21.2.
Discussion
Clinicians reporting this case of a 13-year-old girl with treatment-refractory UC noted that her clinical and endoscopic response "highlights the safety and efficacy of tofacitinib in pediatric patients with severe refractory UC, potentially avoiding proctocolectomy in this young patient population."
As a chronic, inflammatory, and potentially progressive disorder with no known cure, UC generally requires long-term treatment to maintain remission, the authors said. The condition is usually diagnosed at ages 15-30.
Childhood UC takes a heavy toll on many of these young patients. "The contemporary management of ambulatory UC continues to be challenging with ∼20% of children needing a colectomy within childhood years," according to the guidelines of the European Crohn's and Colitis Organization and the Paediatric IBD Porto group of the European Society of Paediatric Gastroenterology, Hepatology and Nutrition.
Tofacitinib, a Janus kinase inhibitor, is recommended by the American College of Gastroenterology practice guidelines in adults as second- or third-line therapy following a lack of response to at least one class of biologic therapy. It has not been licensed for use in pediatric patients with UC, and there is limited research about its use for induction of remission/maintenance in this population. The case authors noted that they used tofacitinib in their patient after all therapeutic options had been exhausted, and after surgery had been declined by the patient and her parents.
In addition, the case authors wrote, since tofacitinib is licensed for use in patients with other autoimmune diseases such as rheumatoid arthritis, psoriasis, and juvenile idiopathic arthritis, the safety in pediatric patients is "well-established" in these diseases. It is also known that pediatric steroid-dependent UC patients may be managed with thiopurines and biologics such as infliximab, adalimumab, golimumab, and vedolizumab.
The team also pointed to a recent commentary about a small study involving dual biologic and small molecule therapy for refractory UC that stated that "clinical disease remission is achieved in only 40%–60% of patients on anti-TNF medications, and patients who fail to improve after induction with anti-TNF are 27% less likely to respond to second-line biologics such as ustekinumab."
Despite the limited evidence on the use of tofacitinib in children with UC, there are some case series that reported similar outcomes. In one, the authors of a letter in Alimentary Pharmacology and Therapeutics described use of high-dose tofacitinib (10 mg twice daily) in five children with severe refractory UC receiving the agent over a mean duration of 9.7 weeks, and reported that the regimen produced clinical and/or steroid-free remission in all the patients.
Another study evaluated tofacitinib in a dual therapy regimen with vedolizumab in eight refractory UC patients under age 18, all of whom had been unresponsive to treatment with at least two biologics, and had never achieved steroid-free remission. The primary outcome – achievement of steroid-free remission at 6 months (i.e., a partial Mayo score <2 and a steroid-free response for at least 4 weeks) – was observed in four of five UC patients on vedolizumab/tofacitinib. Additionally, two of the three UC patients treated with ustekinumab/tofacitinib achieved steroid-free remission at 6 months.
A phase III placebo-controlled clinical trial found that tofacitinib significantly reduced the rate of disease exacerbations compared with placebo, the case authors noted, and July 2021 saw the launch of an open-label phase III trial for pediatric patients with moderately to severely active UC, with an expected primary completion date in August 2026. The efficacy of tofacitinib in both induction and maintenance phases will be evaluated, and the hope is that the research will "provide strong evidence for the use of tofacitinib in pediatric patients with UC," the case authors noted.
They cautioned that physicians treating patients with tofacitinib should be aware of adverse effects including headache, nausea, arthralgia, increased low-density lipoprotein levels, infections (especially varicella zoster), and thrombosis.
Conclusion
The case study authors concluded that tofacitinib is an important and relatively new drug in the management of refractory UC, that it can be considered for off-label use as salvage therapy for refractory UC in pediatric patients if biological therapy has been unsuccessful, and that randomized controlled trials are needed to better establish efficacy and safety in this population.
In addition, the authors said, "our case provides some evidence to support that low-dose tofacitinib monotherapy may be sufficient to achieve clinical response and remission, hence avoiding the need for high-dose tofacitinib and/or combining it with other biological therapies that may increase the risk of adverse events in young patients with no other comorbidities."
Read previous installments in this Medical Journeys series:
Part 1: UC: Understanding the Epidemiology and Pathophysiology
Part 2: UC: Symptoms, Exams, Diagnosis
Part 3: UC: How and Why Does It Arise?
Disclosures
The case study authors reported no conflicts of interest.
Primary Source
American Journal of Case Reports
Source Reference: Alajmi R, et al "Tofacitinib for a child with refractory steroid-dependent ulcerative colitis: a case report and review of the literature" Am J Case Rep 2021; 22: e934460.