A patient with ulcerative colitis treated with a combination of vedolizumab and tofacitinib

Abstract

Ulcerative colitis (UC) is an inflammatory bowel disease of autoimmune origin with an estimated prevalence in Spain of 0.39%. Current treatments for UC do not achieve high long-term efficacy. Treatment recommendations in moderate and severe disease involve drugs, but when these options fail, the alternatives are scarce, and surgery is intended to be reserved for the last option. We present the case of a 48-year-old male patient with UC for 23 years, who had failed several lines of treatment. The patient started combined therapy with tofacitinib and vedolizumab. These drugs have different mechanisms of action, achieving an immune response and reducing gastrointestinal inflammation. The patient’s disease symptoms improved 11 months after starting this treatment, and he is now entirely asymptomatic. Analytical parameters related to the disease have also shown improvement, and the patient has so far avoided the need for surgical intervention.

Background

Ulcerative colitis (UC) is an inflammatory bowel disease (IBD) of autoimmune origin that affects the large intestine’s deeper lining (the colon) and the rectum. UC usually starts between 15 and 30 years of age. It is a disease in which stages of flare-up alternate with phases of remission of inflammation.¹ The latest data published in Spain estimates a prevalence of 0.39%.²

The goal of IBD treatment, which includes UC and Crohn’s disease (CD), is to achieve remission of the outbreak and complete healing of the mucosa. Current guidelines for treatment and consensus recommendations for moderate and severe stages of the disease indicate the use of combination therapies based on tumour necrosis factor α (TNFα) antagonists and immunosuppressive drugs since they yield better responses without increasing adverse effects.^{1 3–5}

However, the best remission results obtained using available treatment options, including biological therapy, are estimated at around 40%.⁶ Primary non-response and secondary loss of response deserve much room for improvement for the treatment of IBD.⁷ Colectomy rates are high (33%) when the response to medical treatment is incomplete, despite the evolution of second-line therapies for acute severe UC.^{8 9}

New biologicals targeting different inflammatory pathways, such as ustekinumab or vedolizumab, are now available. Vedolizumab binds specifically to the α4β7 integrin, which is preferentially expressed on T cells of the gut mucosa. The drug inhibits adhesion of these cells to the mucosal addressin cell adhesion molecule-1 (MAdCAM-1). This molecule plays a critical role in the homing of T cells to tissues within the gut. Vedolizumab is indicated in patients who do not respond to a TNFα antagonist.¹⁰

Janus kinase (JAK) inhibitors are a family of small oral drugs showing promising activity in IBD treatment. These drugs block one or more of the intracellular tyrosine kinases that have a critical role in intracellular cytokine signalling involved in colitis perpetuation. Recently the European Medicines Agency (EMA) approved tofacitinib to treat adult patients with moderate to severe UC who have had an inadequate response to either conventional therapy or a biological agent.¹¹

Case presentation

A 48-year-old man affected by IBD came to our facility with a new flare-up of UC despite being on treatment with vedolizumab and tacrolimus. The combination was initiated 8 months before, after the last flare-up. The doses used were those recommended: 300 mg loading dose at week 0, 2 and 6 followed by 300 mg every 8 weeks.¹⁰ The patient received the loading dose and continued with an intensified maintenance dose (monthly administration). The tacrolimus dose was 4 mg per day, which achieved adequate plasma levels (therapeutic margin 5–10 ng/mL),¹² although this treatment was not well tolerated as the patient said he had symptoms of joint pain since starting the drug.

Before, during the first 6 years following his diagnosis, the patient received only salicylates. In 2017 he presented with a corticosteroid-dependent flare and azathioprine was initiated as a maintenance treatment. The inflammatory activity persisted despite the corticosteroid and azathioprine combination. The patient received a ciclosporin induction course with clinical and analytical remission. However, only 2 months later he presented with a new attack, and was started on adalimumab, which produced only a partial response. The patient stopped ciclosporin, as he did not tolerate it, and was maintained on azathioprine in combination with adalimumab. This combination was deemed insufficient, and adalimumab was switched to infliximab. The combination of infliximab and azathioprine only achieved a partial clinical remission. The infliximab treatment was intensified to obtain a better response, although this approach was also ineffective. At this point, the attending physicians performed a swap to vedolizumab. Persistent symptoms motivated changing azathioprine to tacrolimus, given the good previous response to calcineurin inhibitors.

Investigations

At the time of the last flare-up, the patient presented abnormal analytical values of calprotectin (5641 mg/kg of stool) and C-reactive protein (CRP) (7.9 mg/L). The Mayo endoscopic activity score was 2 for the final section of colon (20 cm from the anal margin) and 1 for a 20–60 cm upper section. At this point, the patient had only two options: either surgery or starting treatment with tofacitinib. Given that this was a young patient for whom surgery was the last resort, the physicians decided to add tofacitinib to the ongoing treatment with vedolizumab.

Treatment

The proposed new treatment was sent to the hospital Institutional Review Board (IRB) that reviews off-label drug use. As is the usual procedure when reviewing these treatments, the physician presented the case to the IRB and justified the request for the medication. The IRB approved the discontinuation of tacrolimus and the addition of tofacitinib at a dose of 10 mg twice daily to the ongoing vedolizumab treatment. Although the IRB approved this combination as an induction regimen, it also recommended tapering vedolizumab administration every 8 weeks and tofacitinib doses to 5 mg every 12 hours, once the patient had achieved remission.

The combination of vedolizumab and tofacitinib yielded a favourable outcome in our patient.

Outcome and follow-up

The patient showed clinical improvement with the disappearance of blood from his stools and a reduction in depositions. Figure 1 depicts the evolution of faecal calprotectin and CRP values after the beginning of the new treatment. One year after, these values remained at normal levels. The patient did not report adverse effects over this time.

Figure 1.

Evolution of faecal calprotectin and C-reactive protein (CRP) values after the beginning of the new treatment.

Vedolizumab treatment was de-intensified 3 months after the introduction of tofacitinib. The tofacitinib doses were tapered to 5 mg every 12 hours 1 year later when the EMA issued a warning asking that tofacitinib—at any dose—be used with caution ‘in all patients at high risk of blood clots’.¹³

Discussion

The combination of anti-TNFα with an immunosuppressant is the preferred approach to treat IBD in patients with an aggressive/severe disease course, although the supporting evidence is of very low quality.^{4 14} Most patients exhibit drug resistance during the disease, defined as the reduction of effectiveness to cure IBD.¹⁵ Our patient presented a secondary failure to adalimumab, which caused the change to infliximab, which also failed. Thus the anti-TNFα family was discarded for future treatments. Regarding the immunosuppressant, the patient presented a lack of response to azathioprine and intolerance to tacrolimus, so they were also ruled out.

In pivotal clinical trials of tofacitinib for UC, some concomitant medications were allowed such as oral aminosalicylates and oral glucocorticoids.¹⁶ Prohibited concomitant therapies included TNFα antagonists, azathioprine, methotrexate, and mercaptopurine. Our patient had shown steroid resistance in a previous flare-up. In this context, and given the patient’s characteristics (young man, aggressive disease, drug resistance), the attending physician proposed a combined therapy of vedolizumab and tofacitinib. This combination would be equivalent to that of a biological with an immunosuppressant.

In IBD medical treatment, the rationale supporting the combination of biological therapies with different targets comes from combining drugs that may produce complementary effects.⁶ These combinations could include two biologicals with different mechanisms of action but also one biological and a small inhibitory molecule from the JAK family. However, available data on the clinical use of such combinations are scant. As described by Hirten et al, they are limited to case series, and precisely three studies in the case of patients affected only by IBD⁶: Sands et al described 79 patients with CD treated with infliximab and natalizumab or placebo; Hirten et al treated one patient with CD with infliximab and vedolizumab; and Yzet et al used treatment with ustekinumab and infliximab in two CD patients. None of the patients included in these studies had UC or received a combination of vedolizumab and tofacitinib.

There are no previous reports on the combined use of vedolizumab and tofacitinib for the treatment of UC to the best of our knowledge. In 2019 Le Berre et al published a case report in which they applied this combination in a patient with simultaneous digestive and rheumatic pathology. The patient achieved remission of both pathologies at 3 months without presenting adverse effects.¹⁷

As mucosal healing correlates with reduced hospitalisation and surgery, endoscopic mucosal inflammation assessment is needed, even if symptom control is maintained.¹⁴ In the present case report, the absence of an endoscopic examination 1 year after initiating the vedolizumab and tofacitinib combination is a limitation.

Learning points.

• The combination of vedolizumab with tofacitinib could help ulcerative colitis treatment when the standard of care options fail. However, it is mandatory to test the efficacy and safety of such a combination in randomised clinical trials.

• Pharmacists have a relevant role to play in hospital Institutional Review Boards to improve the efficacy and safety of ‘off-label’ treatments.

Data availability statement

All data relevant to the study are included in the article.

Ethics statements

Patient consent for publication

Not required.