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06 November 2023: Articles  Kuwait

Upadacitinib as a Rescue Therapy in Acute Severe Ulcerative Colitis: A Case Report and Review of the Literature

Unusual or unexpected effect of treatment

Nargess Mahmoud Ali1DEF, Mohammad Abdullah Shehab1ABDE*

DOI: 10.12659/AJCR.940966

Am J Case Rep 2023; 24:e940966

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Abstract

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BACKGROUND: Ulcerative colitis (UC) is a chronic immune-mediated disease of the colon. The mainstay of treatment to achieve and maintain remission is 5-aminosalicylic acid (5-ASA). At least 20% of patients with UC experience an acute severe ulcerative colitis (ASUC) flare, requiring aggressive early intervention to prevent complications. The first-line treatment of ASUC is intravenous steroids followed by infliximab or cyclosporin in patients for whom steroids fail. Refractory disease failing medical therapy and warranting surgery is common. Lately, Janus kinase (JAK) inhibitors, such as tofacitinib, filgotinib, and upadacitinib, have been licensed for moderate-to-severe UC in adults. Nevertheless, the safety and efficacy of upadacitinib in ASUC has not yet been established.

CASE REPORT: We report a case of an 18-year-old woman with 4-year history of severe UC. Both infliximab and adalimumab treatments failed, despite the concurrent use of azathioprine, and she was reliant on steroids. Moreover, tofacitinib failed after 1 year of therapy. She was admitted as a case of ASUC. Flexible sigmoidoscopy confirmed severe pancolitis. Finally, she was treated effectively with oral upadacitinib 45 mg given once daily. She went into full clinical, biochemical, and steroid-free remission in 60 days and endoscopic remission at 180 days.

CONCLUSIONS: This case report features the potential safety and efficacy of upadacitinib in adults with ASUC. Larger trials are required to confirm the efficacy and safety in patients admitted with ASUC.

Keywords: Colitis, Colitis, Ulcerative, Upadacitinib

Background

Ulcerative colitis (UC) is a chronic immune-mediated disorder of the colon and rectum with no definite cure. It is believed to be the result of an interface between the immune system, environment, and intestinal microbiome in genetically predis-posed individuals. Abdominal pain, rectal bleeding, and diarrhea are the most common symptoms of the disease. Early adulthood, ranging between 15 and 30 years of age, displays the highest incidence of UC. Prolonged treatment is usually required to maintain the disease in remission; however, choosing the appropriate therapy depends on the severity of the disease [1]. For mild-to-moderate disease, 5-aminosalicylic acid (5-ASA) and azathioprine are advised. Acute exacerbations of the disease, up to this time, are mainly treated with steroids. Regarding moderate-to-severe UC in adults, biologics, for example tumor necrosis factor inhibitor (anti-TNF), specifically vedolizumab, and ustekinumab, are used [2]. At least 20% of patients with UC will develop acute severe ulcerative colitis (ASUC), a life-threatening medical emergency, in the course of their illness, requiring early and aggressive intervention and hospitalization to prevent complications [3]. According to the Truelove and Witts criteria, ASUC is defined as a combination of ≥6 bloody stools with at least 1 of the following; pulse rate >90 beats per min, temperature >37.8°C, hemoglobin level of 30 mm/h, erythrocyte sedimentation rate (ESR) >30 mm/h, or C-reactive protein (CRP) level >30 mg/L [4]. The therapeutic options for ASUC are more limited, with corticosteroids remaining the cornerstone of therapy for such flares, followed by infliximab or cyclosporine when corticosteroid treatment fails [3]. Additionally, tofacitinib, a Janus kinase (JAK) inhibitor, demonstrated promising results as a rescue therapy for adults with ASUC in whom the usual therapy with either infliximab or cyclosporin failed [5]. Upadacitinb, another JAK inhibitor, has been licensed for treating adults with moderate-to-severe UC; however, its safety and efficacy in ASUC has not yet been well established. In this paper, we present an 18-year-old woman, dependent on steroid treatment, who responded clinically, biochemically, and endoscopically to oral upadacitinib 45 mg once daily. She went into steroid-free remission and avoided proctocolectomy, which was offered for her as a salvage therapy. This case features the potential safety and efficacy of upadacitinib for treating ASUC.

Case Report

A 18-year-old woman with a known case of severe UC with a 4-year duration was admitted for a flare. At the time of diagnosis in December 2019, at the age of 15 years, she presented with severe UC that was steroid-resistant. She started induction therapy with infliximab (10 mg/kg) and showed a resolution of her symptoms. For about 6 months, she was maintained in remission using both infliximab 10 mg/kg every 8 weeks and azathioprine 2.5 mg/kg. She was steroid free, and her body mass index (BMI) improved from 17.3 kg/m2 at the time of diagnosis to 19.3 kg/m2 on therapy. However, in June 2020, she was readmitted for an exacerbation of her disease, with a BMI of 17.3 kg/m2 once again. As per protocol, infectious workup was conducted and came back negative for Clostridium difficile and cytomegalovirus colitis. The diagnosis of severe pancolitis (Mayo 3, involvement of the entire colon) was confirmed by flexible sigmoidoscopy. Further workup assessing her infliximab drug level and antibodies was performed. Results came back as an undetectable infliximab drug level and a high level of antibodies against infliximab (30 AU/mL, normal reference range <5 AU/mL), presenting a picture of secondary non-response because of immunogenicity. Clinical remission was achieved after starting her on a tapering course of prednisone 40 mg. To maintain remission, which was achieved for 9 months, infliximab was substituted for adalimumab 40 mg every 2 weeks subcutaneously with azathioprine (2.5 mg/kg). Unfortunately, in March 2021, at the age of 17 years, the patient presented with another relapse. The diagnosis of severe pancolitis, involvement of the entire colon, was established by flexible sigmoidoscopy. Once more, her infectious workup was negative. Based on therapeutic drug monitoring, her dose of adalimumab was boosted to 40 mg weekly and ultimately to 80 mg weekly, given her drug level was sub-standard (5 ug/mL) and owing to the presence of antibodies (5 AU/mL). Another prednisone 40 mg tapering course was offered, although complete wean off was not possible, as the patient developed rapid relapse once the prednisone dose reached 15 mg/day. Her adalimumab level at the time was therapeutic (12 ug/mL); however, adalimumab antibodies reached 20 (reference range <10 AU/ mL). Her laboratory test results revealed the following: white blood cell count 4.6 (reference range 3.9-10×109/L), microcytic anemia (hemoglobin 81 g/L and mean corpuscular volume 71.6 fL), platelet count of 362 000 mcL, and hypoalbuminemia (albumin 28 g/L). Her inflammatory markers were as follows: CRP level of 110 mg/L and ESR of 74 mm/hr. A trial of a total exclusive enteral nutrition diet was offered to the patient by our dietician, with no success. At this stage, our colorectal surgeons advised for proctocolectomy; however, it was refused by the patient’s parents (BMI was still at 17.3 kg/m2).

Other medical alternatives on an off-label use were discussed with the patient’s parents, owing to the complexity of her case. Since both vedolizumab and ustekinumab are not approved for pediatrics with UC, her medical insurance company declined them. Tofacitinib, a pan-JAK inhibitor approved for adults with UC and pediatric patients with juvenile idiopathic arthritis, was offered as a possible salvage therapy. It was explained to the patient and her family that it is not yet licensed for pediatrics with UC, but they agreed to give it a trial. Informed consent explaining its benefits, risks, adverse effects, and complications

was obtained from the patient and her parents, since she was under 18, and the drug was funded to the patient by a patient funding organization. Her lipid profile and cardiopulmo-nary status were both assessed and were normal, confirming the presence of no contraindications to try tofacitinib. More importantly, regarding her varicella zoster status, it was confirmed that she had varicella zoster infection when she was 5 years old and she was vaccinated fully up to her age. Oral tofacitinib 5 mg given twice daily was started and clinical remission was accomplished. She was able to taper off steroids with no recurrence of her symptoms. Clinical, biochemical, and endoscopic remission was achieved at 9 months. Her follow-up CRP level was 5 mg/L, and fecal calprotectin level declined from >1000 ug/g to 110 ug/g. Her BMI improved to 21.2 kg/m2. Remarkably, clinical and endoscopic remissions were sustained for 12 months.

A year later, at the age of 18 years, in November 2022, she was admitted to the hospital with ASUC. She presented with abdominal pain associated with 9 episodes of bloody diarrhea per day. Her laboratory test results on admission showed a hemoglobin level of 95 g/L and CRP level of 75 mg/L, and all infectious and stool workups were negative. She underwent sigmoidoscopy to confirm the diagnosis, which revealed severe pancolitis (Mayo 3, involvement of the entire colon) with numerous pseudopolyps (Figure 1A, 1B). Intravenous methylprednisolone was started and the tofacitinib dose was increased in an attempt to control the flare (10 mg 3 times daily).

Three days after admission and treatment, the patient was still passing 9 bloody diarrhea per day and her CRP level remained elevated, at 55 mg/L. The patient did not want to receive cyclosporine owing to its adverse effects and her previous azathioprine failure history. Once more, the patient and her parents were advised to do colectomy, but refused surgery. Other salvage medical options were searched for as per the request of the patient and the patient’s parents. Upadacitinib 45 mg orally once daily was started after a thorough informed consent, discussing the risks, benefits, adverse effects, and off-label use. As early as 3 days after the start of treatment with upadacitinib, her bowel movement improved to 3 bloody diarrhea per day, and she was switched to oral prednisone. Seven days after therapy, she was passing 2 watery, non-bloody bowel movements per day, and her CRP level improved to 25 mg/L. On discharge, she was given upadacitinib 45 mg orally once daily and a prednisone 40-mg tapering course. On her 60-day follow-up appointment, she was remarkably doing well, with normal bowel movements, a BMI of 22.2 kg/m2, CRP level of 5 mg/L, and fecal calprotectin level of 181 ug/g. To maintain the patient in remission, the upadacitinib dose was reduced to 30 mg orally once daily. Six months later, she underwent colonoscopy to confirm endoscopic remission, which revealed restored healthy mucosa throughout the colon (Mayo 0), with mild loss of erythema in the sigmoid colon (Mayo 1). Biopsies obtained from the colon revealed dormant chronic colitis in the rectum (Figure 1C, 1D).

Discussion

In this case, we used upadacitinib, a once-daily oral selective JAK1 inhibitor, for an 18-year-old woman with ASUC flare with a loss of response history to tofacitinib, a pan-JAK inhibitor, after 1 year of therapy. No studies up to this time have thoroughly elucidated the use of upadacitinib in ASUC; however, given its established effectiveness in tofacitinib-experienced adult patients with moderate-to-severe UC, we decided to offer it to our patient after exhausting all therapeutic options [6–8]. Clinical improvement was evident as early as 1 week after starting treatment, and clinical/biochemical remission was seen at week 8, avoiding proctocolectomy.

With regards to the treatment of ASUC, which is considered a life-threatening medical emergency requiring hospitalization, it is worth mentioning the current management recommendations among the adult population, which includes the use of steroids as the first-line therapy, followed by rescue therapy with either cyclosporin or infliximab in patients for whom steroid treatment failed after a period of 3 to 5 days [3]. The choice of using either cyclosporin or infliximab depends solely on physician preference and their availability, as there is no difference in efficacy between the 2 agents, according to the CySIF and CONSTRUCT trials [9,10]. It is imperative to not forget the importance of starting patients on thromboprophylaxis, as inflammatory bowel disease is considered an independent risk factor for thromboembolism [11]. Surgery conducted in a 3-step approach, starting with subtotal colectomy and loop ileostomy, followed by ileal pouch anal anastomosis, and finally ileostomy reversal, remains the last resort when medical therapy fails, as the failure rate remains high, reaching 20% to 40%, demonstrating the important role of colorectal surgeons and the importance of involving them in the management of ASUC early in the course [12,13].

In contrast to the use of upadacitinib to treat ASUC, its effective and safe use in treating moderate-to-severe UC has been well established in several studies. The comprehensible phase 2b U-ACHIEVE induction (UC1) trial established great evidence about upadacitinib efficacy in treating adults with moderate-to-severe UC who developed insufficient response, loss of response, or intolerance to steroids, immunosuppressive agents, and/or biologics. The aforementioned study has shown a positive dose-response relationship between multiple upadacitinib doses, 7.5 mg, 15 mg, 30 mg, and 45 mg once daily, at inducing remission, the primary outcome, compared with placebo at 8 weeks [6]. Studies showed that the symptomatic relief from UC symptoms was evident as early as 1 to 3 days after starting treatment with upadacitinib [14]. Similarly, our patient reported improvement in her symptoms 3 days after starting on upadacitinib 45 mg orally once daily, avoiding colectomy once again, which was excluded according to her wishes.

Upadacitinib is licensed as a therapy for adults with rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, and non-radiographic axial spondyloarthritis, with its efficacy and safety being well elaborated in these disease entities [15,16]. Despite the dose of upadacitinib, 45 mg once daily, being higher than the induction dose indicated for diseases other than inflammatory bowel disease, it established the secondary outcome of endoscopic improvement and remission, displaying a prime benefit-risk profile, high efficacy, and no significant increase in clinically related safety events in comparison with lower doses, which was confirmed in the U-ACCOMPLISH (UC2) phase 3 trial, promoting its selection as the optimal induction dose. A total of 451 patients from the previous trials who attained clinical remission after an 8-week induction therapy with upadacitinib 45 mg once daily were randomly assigned to obtain a maintenance dose of upadacitinib of either 15 mg, 30 mg, or placebo once daily for a duration of 52 weeks in the U-ACHIEVE maintenance (UC3) trial. The principal outcome of the UC3 study, clinical remission, clinical response, and endoscopic and histological improvement at 52 weeks, was achieved by 63 (42%) of 149 patients receiving upadacitinib 15 mg once daily, 80 (52%) of 154 receiving upadacitinib 30 mg once daily, and 18 (12%) of 149 receiving placebo (adjusted treatment difference of 30.7% [95% CI 21.7–39.8] for upadacitinib 15 mg vs placebo, P<0.0001; and 39.0% [29.7–48.2] for upadacitinib 30 mg vs placebo, P<0.0001) [17]. After these thorough trials, the Food and Drug Administration (FDA) and European Medicines Agency licensed the drug for the treatment of adults with moderate-to-severe UC.

In addition to the previous major trials, a prospective real-world single-center analysis of 18 patients with UC in whom treatment with tofacitinib and at least 2 biologics had failed concluded that upadacitinib is an effective treatment for moderate-to-severe UC. The study established this after close follow-up of those patients after starting upadacitinib, confirming clinical, steroid-free, and biochemical remission at 8 weeks [8]. In our case, we accomplished clinical, steroid-free, and biochemical remission at 8 weeks after starting the patient on upadacitinib 45 mg orally once daily and endoscopic remission at 180 days after the start of treatment.

As the rates of colectomy in adults with ASUC remain high, there is an ongoing need to evaluate novel medical therapies that could delay surgical intervention and increase survival without the need for surgery [18]. A systemic review including 148 adult patients assessing tofacitinib, a JAK inhibitor, as a rescue therapy for treating adults with ASUC in whom steroid, infliximab, or cyclosporin treatment failed and who were deemed to require colectomy, demonstrated high short-term colectomy-free survival among such patients. The study displayed a promising outcome for tofacitinib as a rescue therapy for adults with ASUC [5]. Similarly, the results were confirmed by another systemic review published in June 2023 that incorporated 2 observational studies, 7 case series, and 5 case reports, with a total of 134 adult patients with ASUC who were treated with tofacitinib. The study reported a colectomy-free rate of 79.9% (95% CI 73.1–86.7) at 90 days and a colectomy-free rate of 71.6% (95% CI 64–79.2) at 6 months. Once again, the study established the effectiveness of tofacitinib in ASUC [23].

Due to the complexity of JAK signaling, healthcare providers should consider the detrimental effects related to the use of JAK inhibitors, as they are quite common. These include headache, nausea, arthralgia, increased low-density lipoprotein levels, infections, mainly varicella zoster, thrombosis, creatine phosphokinase elevation, neutropenia/lymphopenia, and acne [17,19,20]. Our patient had her vaccination against shingles, her lipid profile was normal during her regular checkups, and she showed no adverse effects specific to the drug throughout treatment.

In 2021, after the results of a randomized control trial studying adults with rheumatoid arthritis on methotrexate, comparing tofacitinib with an TNF inhibitor, the FDA updated the record of adverse effects linked to the use of tofacitinib, adding to it the elevated risk of cardiovascular events, malignancy, thrombosis, and death. This was done after revealing a higher risk of acquiring the aforementioned risks in patients receiving tofacitinib. Therefore, physicians should educate patients thoroughly about these detrimental events and advise them to carefully outweigh the risks and benefits when considering tofacitinib. Upadacitinib safety concerns were not studied in depth compared with those of tofacitinib; however, since upadacitinib descends from the same drug class as tofacitinib and shares the same mechanism of action, it was deemed necessary for the FDA to include upadacitinib in this update with the presumption of it having the same adverse effects. The inclusion criteria of the above-mentioned trial was age 50 years or older and a minimum of 1 cardiovascular risk factor, including smoking, hypertension, diabetes mellitus, and previous heart attack [21,22]. Since our patient was younger than 50 years and had no cardiovascular risk factors, the above-mentioned adverse effects were less feared. Based on our case, upadacitinib 45 mg orally once daily monotherapy, similar to tofacitinib, revealed promising results to support the role of upadacitinib in achieving clinical response and remission in adults with ASUC, avoiding the need for the ultimate cure, proctocolectomy, and its sequelae.

Conclusions

Upadacitinib, showing promising outcomes in ASUC, can be considered as a salvage therapy on an off-label use for adults with ASUC for whom biologic treatment failed. Therefore, randomized controlled trials are required to determine its efficacy and safety.

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American Journal of Case Reports eISSN: 1941-5923
American Journal of Case Reports eISSN: 1941-5923