Immunomodulators

Introduction

The goal of ulcerative colitis (UC) treatment is to achieve and maintain remission by controlling ongoing intestinal inflammation. Immunomodulators function by weakening or modifying the activity of the immune system, which in turn impairs the inflammatory response. Immunomodulators are commonly used to prevent organ rejection following transplantation, but they are also used in autoimmune diseases such as rheumatoid arthritis (RA). They have also been used in the treatment of inflammatory bowel disease (IBD) since the 1960s, although they are not Food and Drug Administration (FDA) approved for this indication. Specific immunomodulators include azathioprine and 6-mercaptopurine. The immunomodulator methotrexate has a slow onset of action and has been used to prevent immunogenicity in patients with UC and Crohn’s disease (CD). Methotrexate has demonstrated efficacy as a steroid sparing agent for primary therapy in CD but not UC. Immunomodulators (specifically 6-mercaptopurine and azathioprine) are used in several treatment situations for patients with UC, such as for patients who do not respond to or are intolerant of aminosalicylates or corticosteroids, patients with steroid-dependent disease, to enhance the effect of biologics, to prevent development of immunogenicity to biologics and others.

Immunomodulators typically have a slow onset of action, often requiring 3 to 6 months to see symptom improvement. For this reason, they may be initiated with corticosteroids to produce a faster response. However, a lower dose of steroids may be used, and they may be withdrawn more rapidly when used in combination with an immunomodulator. A primary benefit of immunomodulators is their steroid-sparing effect, as they decrease the long-term need of steroids for recurring flares.

Since immunomodulators reduce the activity of the immune system, they decrease the body’s ability to combat infection and certain types of cancer (e.g., lymphoma, skin cancer). As such, immunomodulators can be associated with an elevated risk of infection and malignancy. Live vaccines should be avoided in patients while they are taking immunomodulators. Routine hematologic monitoring to evaluate the effect of medical therapy on the bone marrow, liver, and kidney are also required; specifically, complete blood count and comprehensive metabolic panel assessment.

There are newer immunomodulators, including tacrolimus and cyclosporine, which have been shown to have a rapid onset of action, within a few days of their administration. The most recently introduced agents include tofacitinib, upadacitinib, ozanimod, and etrasimod.

The immunomodulators with FDA approval to be used in the treatment of UC include:

• Tofacitinib
• Upadacitinib
• Ozanimod
• Etrasimod
• Thiopurines (azathioprine and 6-mercaptopurine; not FDA-approved for UC)
• Cyclosporine A (not FDA-approved for UC)
• Tacrolimus (not FDA-approved for UC)
• Methotrexate (MTX; not FDA-approved for UC); MTX is only used to prevent immunogenicity.

Of these medicinal products, tofacitinib, Upadacitinib, ozanimod and etrasimod have an FDA-approved indication for the treatment of UC (Table 10-1). The safety and efficacy of these treatments are discussed below.

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Tofacitinib (Xeljanz/Xeljanz XR)

Tofacitinib was initially approved in 2012 for the treatment of adult patients with moderately to severely active RA who have had an inadequate response or intolerance to methotrexate (MTX). Therapeutic use was extended to the treatment of active psoriatic arthritis (PsA) and UC in 2017 and 2018, respectively. Tofacitinib is indicated for the treatment of adult patients with moderately to severely active UC, who have had an inadequate response or who are intolerant to tumor necrosis factor (TNF) blockers.

Tofacitinib is a Janus kinase (JAK) inhibitor. JAKs are intracellular enzymes that transmit signals arising from cytokine- or growth factor-receptor interactions on the cellular membrane to influence hematopoiesis and immune cell function. Upon cytokine binding, JAKs form heterodimers with other JAKs (e.g., JAK1/JAK3), then phosphorylate and activate signal transducers and activators of transcription (STATs), which modulate intracellular activity, including gene expression (Figure 10-1). The JAK/STAT pathway is therefore an important mechanism by which many cytokines (e.g., IL-2, IL-7, IFN-g) exert their effect on biological processes, including those involved in the pathogenesis of UC. Tofacitinib modulates the signaling pathway at the point of JAKs, preventing the phosphorylation and activation of STATs.

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Efficacy

The efficacy of tofacitinib was evaluated in three phase 3 trials as induction (OCTAVE Induction 1 and 2) and maintenance (OCTAVE Sustain) therapy for UC. Patients were initially enrolled into the OCTAVE induction trials. Eligible patients were ≥18 years of age, had a confirmed diagnosis of UC for at least 4 months and moderately to severely active disease. Patients were also required to have had treatment failure with, or been intolerant to, oral or intravenous glucocorticoids, azathioprine, mercaptopurine, infliximab, or adalimumab. Permitted concomitant medications for UC included oral aminosalicylates and oral glucocorticoids (maximum 25 mg per day of prednisone or a prednisone equivalent) if medications were administered at stable doses throughout the induction trials. Tapering of glucocorticoids was mandatory during the maintenance trial. Concomitant treatment with TNF antagonists, azathioprine, MTX, or mercaptopurine was prohibited.

In OCTAVE Induction 1 and 2 trials, 1,161 patients were randomized 4:1 to receive induction therapy with either 10 mg tofacitinib BID or placebo for 8 weeks. The primary efficacy endpoint of these trials was remission (defined as a total Mayo score of ≤2, with no subscore >1 and a rectal bleeding subscore of 0) at 8 weeks. The key secondary endpoint was mucosal healing (a Mayo endoscopic subscore of ≤1), also at 8 weeks.

A significantly greater proportion of patients in the tofacitinib groups of OCTAVE Induction 1 and 2 met the remission criteria at 8 weeks compared to those in the placebo groups (OCTAVE Induction 1: 18.5% vs 8.2% [P = 0.007]; OCTAVE Induction 2: 16.6% vs 3.6% [P <0.001]; Figure 10-2). In both trials, treatment effects were similar between groups irrespective of prior treatment with a TNF antagonist. Mucosal healing at 8 weeks also occurred in significantly more patients in the tofacitinib groups than in the placebo groups and was similar irrespective of prior TNF antagonist treatment (Figure 10-3). Improvements in the partial Mayo score were significantly greater in the tofacitinib groups of OCTAVE Induction 1 and 2 than in the placebo groups at all scheduled visits and as early as the first assessment at Week 2.

Upon completion of OCTAVE Induction 1 and 2, patients who had a clinical response during the induction trials were eligible to participate in the OCTAVE Sustain trial. Clinical response was defined as a decrease from baseline in the total Mayo score of ≥3 points and at least 30%, with an accompanying decrease in the rectal bleeding subscore of ≥1 point or an absolute rectal bleeding subscore of 0 or 1. The 593 enrolled patients were randomized 1:1:1 to receive maintenance therapy with either 5 mg tofacitinib BID, 10 mg tofacitinib BID, or placebo for 52 weeks. Most patients (88%) enrolled in OCTAVE Sustain had received tofacitinib during the induction trial. The primary endpoint was remission at 52 weeks. Key secondary endpoints included mucosal healing at 52 weeks and sustained remission among patients who were in remission at maintenance-trial entry, defined as remission occurring at both 24 and 52 weeks and occurring without the administration of glucocorticoids for ≥4 weeks before the assessment.

In OCTAVE Sustain, significantly more patients in the 5-mg (34.3%) and 10-mg (40.6%) tofacitinib groups met the criteria for remission compared to placebo (11.1%) at 52 weeks (P <0.001 for both comparisons; Figure 10-2). Mucosal healing also occurred in significantly more patients in the 5-mg (37.4%) and 10-mg (45.7%) tofacitinib groups compared to those in the placebo group (13.1%) at 52 weeks (Figure 10-3). Among patients in remission at trial entry, sustained and glucocorticoid-free remission occurred in 35.4% and 47.3% of patients in the 5-mg and 10-mg tofacitinib groups, respectively, compared to 5.1% in the placebo group. Significant improvements in partial Mayo score were observed at all study visits in both tofacitinib groups compared to placebo.

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Safety

Selected safety outcomes for the three OCTAVE trials are shown in Table 10-2. In OCTAVE Induction 1, adverse events (AEs) were experienced by 56.5% and 59.8% of patients in the 10-mg tofacitinib and placebo groups, respectively. In OCTAVE Induction 2, corresponding rates were 54.1% and 52.7%, respectively. In OCTAVE Sustain, adverse events (AEs) occurred in 72.2%, 79.6% and 75.3% of patients in the 5-mg tofacitinib, 10-mg tofacitinib, and placebo groups, respectively. Similar proportions of patients discontinued treatment due to AEs in the tofacitinib and placebo groups in OCTAVE Induction 1 and 2. In OCTAVE Sustain, a greater proportion of patients in the placebo group discontinued treatment due to AEs.

Infections of any severity were higher in the 10-mg tofacitinib groups of OCTAVE Induction 1 and 2 (23.3% and 18.2%, respectively) compared to placebo (15.6% and 15.2%, respectively). Serious infections occurred in 1.3% and 0.2% of patients in the OCTAVE Induction 1 and 2 trials, respectively, compared to no patients in the placebo groups. In OCTAVE Sustain, infections occurred in 35.9% of patients in the 5-mg tofacitinib group, 39.8% in the 10-mg tofacitinib group, and 24.2% in the placebo group, whereas serious infections occurred in 1.0%, 0.5% and 1.0% of patients in these treatment groups, respectively. Some cases of herpes zoster were reported in all studies, but none were serious or resulted in treatment discontinuation.

One randomized, open-label, noninferiority, post-authorization trial assessed the safety of two tofacitinib doses (5 mg and 10 mg) compared to a TNF inhibitor (adalimumab 40 mg every two weeks or etanercept 50 mg once weekly) in a population of patients 50 years of age or older with active rheumatoid arthritis (RA) despite methotrexate treatment and with at least one cardiovascular risk factor. In this trial, tofacitinib noninferiority was defined as an upper boundary value of less than 1.8 for the two-sided 95% confidence interval (CI) of the hazard ratio (HR) for the combined tofacitinib doses and the TNF inhibitors. Cancers (excluding non-melanoma skin cancers) were shown to occur more frequently with tofacitinib (HR 1.48 [95% CI, 1.04 to 2.09]); lung cancer was the most common cancer in the tofacitinib group. The incidence of major adverse cardiovascular events (MACE; death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke) was also higher with tofacitinib (HR 1.33 (95% [CI, 0.91 to 1.94]). These findings are restricted to patients with RA aged 50 and older; a tofacitinib-related increase in cancer or MACE incidence has not to date been observed in patients with UC. Nevertheless, healthcare providers should remain vigilant as more post-authorization safety data emerges.

Warnings and Precautions

The prescribing information for tofacitinib contains a boxed warning for serious infections, mortality, malignancy and thrombosis. The risk of thrombosis (including deep vein thrombosis and pulmonary embolism) is mostly seen in patients with RA aged 50 years or older who are takin the 10 mg twice daily dose. Serious and sometimes fatal infections due to bacterial, mycobacterial, invasive fungal, viral, or other opportunistic pathogens have been reported in patients receiving tofacitinib. The most common serious infections reported with tofacitinib included pneumonia, cellulitis, herpes zoster, urinary tract infection, diverticulitis and appendicitis. Patients with infections were often taking concomitant immunomodulating agents such as MTX or corticosteroids. Use of tofacitinib should be avoided in patients with an active, serious infection, including localized infections.

The risks and benefits of treatment with tofacitinib should be considered prior to initiation in patients with chronic or recurrent infection, who have been exposed to tuberculosis, with a history of a serious or an opportunistic infection, who have resided or traveled in areas of endemic tuberculosis or endemic mycoses, or with underlying conditions that may predispose them to infection. Patients should be evaluated and tested for latent or active tuberculosis infection prior to and during treatment with tofacitinib. Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with tofacitinib, and treatment should be interrupted if a patient develops a serious infection, an opportunistic infection, or sepsis. 

Viral reactivation, including cases of herpes virus reactivation, have been observed in clinical studies with tofacitinib. Screening for viral hepatitis should be performed before starting treatment with tofacitinib. Use of live vaccines concurrently with tofacitinib should be avoided.

Malignancies have been observed in clinical trials with tofacitinib. The risks and benefits of tofacitinib treatment should be considered prior to initiating therapy in patients with a known malignancy other than a successfully treated nonmelanoma skin cancer or when continuing treatment in patients who develop a malignancy. Other malignancies (e.g., lung cancer, breast cancer, melanoma, prostate cancer) have been observed in clinical studies of tofacitinib and the post-marketing setting.

Rheumatoid arthritis patients 50 years of age and older with at least one CV risk factor treated with tofacitinib 10 mg twice a day had a higher rate of all-cause mortality, including sudden CV death, compared to those treated with tofacitinib 5 mg given twice daily or TNF blockers in a large, ongoing, post-marketing safety study.

Thrombosis, including pulmonary embolism, deep venous thrombosis and arterial thrombosis, has been observed at an increased incidence in rheumatoid arthritis patients who were 50 years of age and older with at least one CV risk factor treated with tofacitinib 10 mg twice daily compared to tofacitinib 5 mg twice daily or TNF blockers in a large, ongoing post-marketing safety study. Many of these events were serious and some resulted in death. Avoid tofacitinib in patients at risk. Discontinue tofacitinib and promptly evaluate patients with symptoms of thrombosis. In patients with UC, tofacitinib should be used at the lowest effective dose and for the shortest duration needed to achieve/maintain therapeutic response.

Dosage and Administration

Tofacitinib is provided as 5-mg and 10-mg immediate-release tablets and 11-mg extended-release tablets. Tofacitinib can be taken with or without food, but tablets should be swallowed whole and intact.

The recommended induction dose of tofacitinib in adult patients with UC is 10 mg twice daily for 8 weeks; evaluate patients and transition to maintenance therapy depending on therapeutic response. If needed, continue 10 mg twice daily for a maximum of 16 weeks. Discontinue 10 mg twice daily after 16 weeks if adequate therapeutic response is not achieved. As maintenance therapy, the recommended dose of tofacitinib is 5 mg twice daily. Use of 10 mg twice daily beyond induction should be limited to those with loss of response and used for the shortest duration, with careful consideration of the benefits and risks for the individual patient. Use the lowest effective dose needed to maintain response.

In patients receiving a strong CYP3A4 inhibitor or a moderate CYP3A4 inhibitor with a strong CYP2C19 inhibitor, the dose of tofacitinib should be reduced by half (i.e., if taking 10 mg twice daily, reduce to 5 mg twice daily; if taking 5 mg twice daily, reduce to 5 mg once daily). Dose should be similarly reduced in patients with moderate or severe renal impairment or moderate hepatic impairment. Use in patients with severe hepatic impairment is not recommended. For patients undergoing hemodialysis, dose should be administered after the dialysis session on dialysis days.

Additional dose modifications are recommended in patients with low lymphocyte count, low absolute neutrophil count, or low hemoglobin count.

Upadacitinib (Rinvoq)

The FDA initially authorized upadacitinib in 2019 for the treatment of adult patients with moderate to severe rheumatoid arthritis. Similar to tofacitinib, the indications for the use of upadacitinib were gradually expanded to include the management of other inflammatory diseases, including psoriatic arthritis, atopic dermatitis, ankylosing spondylitis, and, in March 2022, UC. Upadacitinib is indicated for the treatment of patients with moderately to severely active UC, who have had an inadequate response or intolerance to one or more TNF blockers.

As a JAK inhibitor, upadacitinib is in the same class of medications as tofacitinib and affects the JAK/STAT signaling pathway (see Figure 10-1). Upadacitinib had a more potent inhibitory action on JAK1 and JAK2 (compared to JAK3 and TYK2) in a cell-free isolated enzyme assay; in human leukocytes, upadacitinib was a more potent inhibitor of JAK1 and JAK1/JAK3 (compare to JAK2/JAK2). The relevance of differential inhibitory potencies to therapeutic efficacy is unknown.

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Efficacy

The efficacy of upadacitinib was assessed in three phase 3 studies - two replicate induction studies (U-ACHIEVE induction [UC1] and U-ACCOMPLISH [UC2]) and one maintenance study (U-ACHIEVE maintenance [UC3]). Eligible participants were between the ages of 16 and 75, had active UC and had a confirmed diagnosis for at least 90 days. Additionally, patients must have previously had an inadequate response, a loss of response, or an intolerance to at least one oral aminosalicylate, corticosteroid, immunosuppressant, or biologic agent (infliximab, adalimumab, golimumab, vedolizumab, or ustekinumab). Patients who had previously used vedolizumab or anti-tumor necrosis factor (TNF) medications were required to undergo an 8-week washout period (or 12 weeks if they had used ustekinumab). Important exclusion criteria included: Crohn’s disease, indeterminate colitis, fulminant colitis, toxic megacolon, illness restricted to the rectum, current infection and prior exposure to JAK inhibitors.

Patients were initially enrolled in two induction trials. In both UC1 (474 patients) and UC2 (522 patients), participants were randomized (2:1) to receive upadacitinib (45 mg orally once a day) or a placebo for eight weeks. The primary endpoint was clinical remission (defined as an Adapted Mayo score of ≤2, with a Mayo stool frequency subscore of ≤1 and not greater than baseline, rectal bleeding score [RBS] of 0, and endoscopic subscore ≤1 without friability) at week 8. The key secondary endpoints (also assessed at week 8) were endoscopic remission (endoscopic score of 0), clinical response (a decrease in the Adapted Mayo score of ≥2 points and ≥30% from baseline, and a decrease in the RBS of ≥1 point or an absolute RBS of ≤1; a decrease in the Partial Adapted Mayo score of ≥1 point and ≥30% from baseline, and a decrease in RBS of ≥1 point or an absolute RBS of ≤1 at week 2), and histological-endoscopic mucosal improvement (HEMI; endoscopic score ≤1 without friability and Geboes score ≤3.1).

In the induction trials, significantly more patients achieved clinical remission with upadacitinib 45 mg than with placebo (UC1: 26% vs 5%; UC2: 33% vs 4%; P <0.0001 for both; see Figure 10-4). In both trials, treatment effects were consistent across all groups. Comparing the upadacitinib 45 mg once daily group to the placebo group, all secondary endpoints in both induction trials were achieved (Figure 10-4). At week 8, disease activity and symptoms were statistically significantly improved as shown by the achievement of clinical response, no abdominal pain and no bowel urgency. Additionally, endoscopic and histological improvements, as well as improvements in quality of life (QOL) were made. In both UC1 and UC2, the proportion of patients achieving clinical response at week 2 with upadacitinib was statistically significantly greater than with placebo.

Following the 8-week induction period, the first 451 patients who achieved clinical response (defined as a decrease from baseline in the Adapted Mayo score ≥2 points and ≥30% from baseline, plus a decrease in the RBS of ≥1 or an absolute RBS ≤1) in UC1 and UC2 were randomly assigned (1:1:1) to receive upadacitinib 15 mg, upadacitinib 30 mg, or placebo once daily for 52 weeks in the UC3 maintenance study. The primary endpoint was clinical remission per the Adapted Mayo score at week 52. Secondary endpoints at week 52 were endoscopic improvement, maintenance of clinical remission, corticosteroid-free clinical remission, maintenance of endoscopic improvement, endoscopic remission, maintenance of clinical response per Adapted Mayo score, HEMI, change from baseline in IBDQ (Inflammatory Bowel Disease Questionnaire) score, mucosal healing, no bowel urgency, no abdominal pain and a change from baseline in FACIT-F (Functional Assessment of Chronic Illness Therapy-Fatigue) score.

In UC3, significantly more patients in the 15 mg (42%) and 30 mg (52%) upadacitinib groups met the criteria for remission compared those in the placebo group (12%) at 52 weeks (P <0.0001 for both comparisons; see Figure 10-5). Both upadacitinib 15 mg and 30 mg once daily groups showed a sustained treatment effect compared to placebo, with more patients achieving the endpoints of maintenance of clinical remission, endoscopic remission, maintenance of clinical response, and HEMI (Figure 10-5). Compared to patients in the placebo group, significantly higher proportions of patients in both upadacitinib groups achieved all other secondary endpoints (P <0.0001 for all comparisons to placebo), including endoscopic improvement (placebo: 14%, upadacitinib 15 mg: 49%, upadacitinib 30 mg: 62%), corticosteroid-free clinical remission (placebo: 22%, upadacitinib 15 mg: 57%, upadacitinib 30 mg: 68%), maintenance of endoscopic improvement (placebo: 19%, upadacitinib 15 mg: 62%, upadacitinib 30 mg: 70%), no bowel urgency (placebo: 17%, upadacitinib 15 mg: 56%, upadacitinib 30 mg: 64%), and no abdominal pain (placebo: 21%, upadacitinib 15 mg: 46%, upadacitinib 30 mg: 55%). Mucosal healing was achieved by 5% of patients in the placebo group, compared to 18% in the upadacitinib 15 mg (P = 0.0003) and 19% in the upadacitinib 30 mg group (P <0.0001). A significantly greater QOL improvement (IBDQ and FACIT-F) was achieved with upadacitinib 15 mg or 30 mg compared to the placebo (all P <0.0001).

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Safety

In UC1, AEs were experienced by 56% and 62% of patients in the 45-mg upadacitinib and placebo groups, respectively. In UC2, corresponding rates were 53% and 40%, respectively. In the UC3 maintenance study, AEs occurred in 78%, 79%, and 76% of patients in the 15-mg upadacitinib, 30-mg upadacitinib and placebo groups, respectively. More patients discontinued treatment due to AEs in the placebo groups than in treated groups in both UC1 and UC2, as well as in UC3.

In UC1, the most commonly reported adverse events were nasopharyngitis, creatine phosphokinase elevation and acne. In UC2, the most frequently reported adverse event was acne. In both induction studies, similar proportions of patients reported serious infections across treatment groups and placebo groups (UC1: 1% vs 2%; UC2: 1% vs 1%). In the maintenance study, the rate of serious infections was slightly higher in the placebo group than in the upadacitinib groups (3% for 15-mg upadacitinib and 3% for 30-mg upadacitinib vs 4% for placebo). Overall, upadacitinib was well tolerated in UC1-3, with a safety profile consistent with prior studies in other indications. See Table 10-3 and Table 10-4 for a summary of safety outcomes in UC1/2 and UC3, respectively.

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Warnings and Precautions

Upadacitinib’s prescribing information includes a boxed warning for serious infections, mortality, malignancy, major adverse cardiovascular events and thrombosis.

The risks and benefits of treatment with upadacitinib should be carefully considered prior to initiating therapy in patients with chronic or recurrent infection. Patients treated with upadacitinib are also more likely to acquire severe infections that can lead to hospitalization or death. The majority of individuals who had these infections were also on immunosuppressants such as methotrexate or corticosteroids. The most common serious infections associated with upadacitinib were pneumonia and cellulitis. Upadacitinib was also associated with tuberculosis, multi-dermatomal herpes zoster, oral/esophageal candidiasis and cryptococcosis among opportunistic illnesses. Active tuberculosis can manifest as pulmonary or extrapulmonary illness. Prior to using upadacitinib, patients should be screened and treated if exhibiting signs of any latent infections. If a serious infection develops during the treatment, upadacitinib should be interrupted until the infection is controlled. Patients should also be closely monitored for the development of signs and symptoms of infection after treatment, including the possible development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy.

Viral reactivation, including cases of herpes virus reactivation (e.g., herpes zoster) and hepatitis B virus reactivation, were reported in clinical trials with upadacitinib. If a patient develops herpes zoster, stopping upadacitinib treatment temporarily should be considered until the infection is managed. Before and throughout upadacitinib treatment, patients should be screened for viral hepatitis and monitored for reactivation in accordance with clinical guidelines.

Mortality was observed in a large, randomized, post-marketing safety study of rheumatoid arthritis patients 50 years of age and older with at least one cardiovascular risk factor comparing another JAK inhibitor to TNF blockers. A higher rate of all-cause mortality, including sudden cardiovascular death, was observed with the JAK inhibitor. Prior to initiating or maintaining upadacitinib treatment, the potential advantages and disadvantages for the specific patient should be taken into account.

Lymphoma and other malignancies have been observed in patients treated with upadacitinib. When compared to TNF blockers, rheumatoid arthritis patients treated with another JAK inhibitor experienced a greater prevalence of malignancies (excluding non-melanoma skin cancer [NMSC]). Current and past smokers are at a greater risk. Prior to starting or continuing upadacitinib therapy, take into account the benefits and risks for the specific patient, especially in those who have a known malignancy (other than successfully treated NMSC), those who develop a malignancy while receiving treatment, and those who are current or previous smokers.

When compared to TNF blockers, a higher rate of major adverse cardiovascular events (MACE), defined as cardiovascular death, myocardial infarction, and stroke, was observed in rheumatoid arthritis patients 50 years of age or older with at least one cardiovascular risk factor who were treated with another JAK inhibitor. Patients who are current or past smokers are at additional increased risk. Prior to initiating or maintaining upadacitinib use, the advantages and disadvantages for the specific patient should be considered, especially in patients who are current or former smokers and patients with additional cardiovascular risk factors. Patients who have had a myocardial infarction or stroke should discontinue the use of upadacitinib.

Cases of thrombosis have occurred in patients using JAK inhibitors for inflammatory diseases; these have included deep vein thrombosis (DVT), pulmonary embolism (PE) and arterial thrombosis. Many of these negative side effects were severe, and some even had fatal outcomes. When compared to TNF blockers, a greater rate of thrombosis was seen in rheumatoid arthritis patients 50 years of age and older with at least one cardiovascular risk factor who were treated with another JAK inhibitor. Patients who show signs of thrombosis should stop taking upadacitinib and be promptly evaluated and appropriately treated. The use of upadacitinib should be avoided in patients that may be at an increased risk of thrombosis.

Dosage and Administration

Upadacitinib is provided as 15-mg (purple), 30-mg (red) and 45-mg (yellow) extended-release tablets that should be taken orally, with or without food. Upadacitinib tablets should be swallowed whole.

For patients with UC, the recommended induction dose of upadacitinib in adults is 45 mg once a day for 8 weeks, and 15 mg once a day for the maintenance treatment. A maintenance dosage of 30 mg once daily may be considered for patients with refractory, severe, or extensive disease. Upadacitinib should be discontinued if an adequate therapeutic response is not achieved with the 30 mg dosage. The lowest effective dosage needed to maintain response should be used in treatment.

For patients with severe renal impairment and for patients with mild to moderate hepatic impairment, the recommended dosage for induction treatment is 30 mg once daily for 8 weeks, followed by 15 mg once daily for maintenance. Upadacitinib is not recommended for use in patients with end-stage renal disease or with severe hepatic impairment. Dosage should be similarly reduced in patients receiving strong CYP3A4 inhibitors.

Interruption of dosing may be needed for management of laboratory abnormalities such as low neutrophil count, low lymphocyte count and low hemoglobin, or if drug-induced liver injury is suspected.

Ozanimod (Zeposia)

Ozanimod is a sphingosine 1-phosphate (S1P) receptor modulator first approved by the FDA in March 2020 for the treatment of relapsing forms of multiple sclerosis. In April 2022, ozanimod received FDA approval for the treatment of UC as a first-in-class drug. Ozanimod is indicated for the treatment of moderately to severely active UC in adults.

Ozanimod is a small molecule which binds to S1P receptor subtypes 1 (S1P₁) and 5 (S1P₅). The S1P receptors regulate various cellular functions, including differentiation, proliferation and migration, with each of the five subtypes involved in different processes. Although the exact mechanism of action of ozanimod is unknown, it is believed to exert its anti-inflammatory action by binding to S1P₁ on lymphocytes; this leads to the internalization of the receptor, preventing the migration of lymphocytes into sites of inflammation in the intestine.

Efficacy

The efficacy of ozanimod was assessed in the True North study, a multicenter, randomized, double-blind, placebo-controlled trial which included an indication period and a maintenance period. Eligibility criteria included: 18-75 years of age; moderately to severely active UC (total Mayo score of 6-12, endoscopy subscore of ≥2, rectal bleeding subscore of ≥1, and stool frequency subscore of ≥1); receiving stable doses of oral aminosalicylates or glucocorticoids (or both) at least 2 weeks before screening; documented presence of varicella-zoster virus antibodies or vaccination at least 30 days before randomization; response to induction therapy with ≥2 biologics approved for UC therapy; and lack of a clinically relevant cardiac condition or history of uveitis or macular edema).

Two cohorts of patients were enrolled in the True North study. During the 10-week induction period, patients in cohort 1 (N = 645) were randomized (2:1) to receive 0.92 mg ozanimod or placebo once daily, while patients in cohort 2 (N = 367) received open-label ozanimod at the same dose as in cohort 1. In the 52-week maintenance period, patients from either cohort who had a clinical response were randomized (1:1) to either ozanimod 0.92 mg or placebo once daily. Clinical response was defined as total Mayo score decrease of ≥3 points and ≥30% from baseline or a reduction in the three-component Mayo score of ≥2 points and ≥35% from baseline, and a decrease in the rectal-bleeding subscore of ≥1 point or an absolute rectal-bleeding subscore of ≤1 point). Patients continued receiving aminosalicylates or glucocorticoids throughout the induction period; in the maintenance period, glucocorticoid tapering was mandatory.

The primary efficacy endpoint in both periods was the percentage of patients with clinical remission, defined as: rectal-bleeding subscore of 0; stool-frequency subscore of ≤1, with a decrease from baseline of at least 1 point; and endoscopy subscore of ≤1. In the induction period, the key secondary endpoints were the proportion of patients with a clinical response, endoscopic improvement, and mucosal healing. Key secondary endpoints were assessed hierarchically. In the maintenance period, the key secondary endpoints were the proportion of patients with a clinical response, endoscopic improvement, maintenance of clinical remission (remission at week 52 in patients with remission at week 10), glucocorticoid-free remission (remission without glucocorticoid use for ≥12 weeks), mucosal healing, and durable clinical remission (remission at weeks 10 and 52, evaluated in all patients in the maintenance period).

At the end of the induction period, a significantly greater proportion of patients treated with ozanimod (18.4%) achieved the primary endpoint of clinical remission compared to patients who received placebo (6.0%; P <0.001; see Figure 10-6A). Ozanimod treatment also resulted in a significantly greater proportion of patients who achieved the key secondary endpoints of clinical response (47.8%, compared to 25.9% with placebo; P <0.001), endoscopic improvement (27.3% vs 11.6% with placebo; P <0.001), and mucosal healing (12.6% vs 3.7% with placebo; P <0.001); see Figure 10-6A.

A total of 457 patients from both cohorts achieved a clinical response during the induction period and were randomized or re-randomized in the maintenance period. Ozanimod demonstrated superiority to placebo in the maintenance period as well. Clinical remission at week 52 was achieved by 38.0% of ozanimod-treated patients compared to 18.0% of patients who received the placebo (P <0.001; see Figure 10-6B). Ozanimod was also superior to the placebo with respect to the proportion of patients achieving the key secondary endpoints, including clinical response (60.0% vs 41.0%; P <0.001), endoscopic improvement (45.7% vs 26.4%; P <0.001), maintenance of remission (52% vs 26.4%; P = 0.001), glucocorticoid-free remission (31.7% vs 16.7%; P <0.001), mucosal healing (29.6% vs 14.1%; P <0.001), and durable remission (17.8% vs 9.7%; P = 0.003); see Figure 10-6B.

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Safety

Safety assessments in True North included AEs (with bradycardia, cardiac conduction abnormalities, macular edema, cancer, serious or opportunistic infection, pulmonary effects and hepatic effects assessed as AEs of special interest), clinical laboratory assessments, vital signs, pulmonary function tests, ophthalmologic examination and electrocardiography. Selected safety outcomes from the two cohorts and periods of True North are shown in Table 10-5. While the incidence of AEs was comparable among treatment groups and cohorts in the induction period (38.0% with placebo and 40.1% with ozanimod in cohort 1; 39.8% with ozanimod in cohort 2), more patients who received ozanimod experienced an AE (49.1%) during the maintenance period, compared to patients who received placebo (36.6%).

Serious infections occurred in less than 2% of patients in each group in both periods. Bradycardia was more frequent in the ozanimod-treated group during the induction period, but not in the maintenance period. No cases of serious cardiac conduction abnormalities were reported. Macular edema occurred in 3 patients taking ozanimod and was resolved in all 3 cases after discontinuation. Cancer was diagnosed in 1 patient taking ozanimod in the induction period, and 2 patients on ozanimod and 2 patients on placebo in the maintenance period. Alanine aminotransferase elevation were more common in the ozanimod group, but liver AEs were predominantly mild or moderate. Overall, the safety profile of ozanimod in True North was consistent with that of earlier ozanimod trials.

Warnings and Precautions

The prescribing information for ozanimod contains warnings and precautions concerning infection risk, progressive multifocal leukoencephalopathy (PML), liver injury, fetal risk, increased blood pressure, respiratory effects, macular edema, posterior reversible encephalopathy syndrome (PRES), additive immunosuppressive effects with other immunosuppressive or immune-modulating medications, and the effects on the immune system when ozanimod is discontinued.

Because ozanimod causes a reduction in the peripheral blood lymphocyte count, its use may increase infection susceptibility. Increased infection risk was observed with ozanimod treatment during the maintenance period of the True North Trial. Before starting ozanimod, a recent (<3 months) complete blood count (including lymphocyte count) should be obtained. Ozanimod should only be started in patients with an active infection after the infection has resolved. Patients should also be monitored for signs and symptoms of PML, a serious condition that can lead to death or severe disability; if PML is diagnosed, ozanimod should be discontinued.

Sphingosine 1-phosphate signaling is involved in cardiovascular function, including regulation of heart rate. Treatment with ozanimod may therefore cause transient bradycardia and atrioventricular conduction delays. Because of this, ozanimod should be up-titrated to the final maintenance dose, as discussed in the Dosage and Administration section below. Advice from a cardiologist should be sought when ozanimod treatment is considered for individuals with significant QT prolongation, arrhythmias requiring treatment with Class Ia or Class III anti-arrhythmic drugs, ischemic heart disease, heart failure, history of cardiac arrest or myocardial infarction, cerebrovascular disease, uncontrolled hypertension, history of second-degree Mobitz type II or higher AV block, sick-sinus syndrome, or sinoatrial heart block. Ozanimod may also cause hypertension, and blood pressure should be carefully monitored during the course of treatment with ozanimod. Foods that contain more than 150 mg of tyramine may interact with ozanimod to cause severe hypertension, and should be avoided while taking ozanimod.

Liver enzyme elevations and hepatic dysfunction may occur in patients receiving ozanimod. Before starting ozanimod, recent (<6 months) transaminase and bilirubin levels should be obtained. Liver enzymes should be assessed in patients who develop symptoms of hepatic dysfunction, including unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, jaundice, or dark-colored urine. If significant liver injury is diagnosed, ozanimod should be discontinued.

Preclinical studies suggest that ozanimod may cause fetal harm. Therefore, although there are no adequate studies of ozanimod in pregnant women, women of childbearing potential should avoid pregnancy while taking ozanimod and for a minimum of 3 months after discontinuing treatment.

Data from True North and other studies of ozanimod suggest that its use may be associated with changes in respiratory function, including reductions in absolute forced expiratory volume over 1 second (FEV₁) and in forced vital capacity (FVC). The reversibility of these changes is currently unknown. If clinically indicated, spirometric evaluation of respiratory function should be performed in patients taking ozanimod.

Like other S1P receptor modulators, ozanimod is associated with increased risk of macular edema; although rare, cases of macular edema have been reported in patients treated with ozanimod in True North. An ophthalmic assessment of the ocular fundus, including the macula, is recommended in patients taking ozanimod who experience any change in vision. Data are currently lacking on the continuation of ozanimod treatment in patients who develop macular edema; the decision on whether to discontinue treatment should be based on an individualized risk-benefit profile.

Although rare, cases of posterior reversible encephalopathy syndrome (PRES) have been reported in patients taking S1P receptor modulators, including a single case of PRES in a trial of ozanimod for multiple sclerosis. If unexpected neurological or psychiatric signs or symptoms develop in a patient on ozanimod, a complete physical and neurological examination is indicated (and an MRI should be considered). Ozanimod should be discontinued is PRES is suspected.

Because it takes approximately 30 days after discontinuing ozanimod for peripheral blood lymphocyte levels to return to the normal range, the use of other immunosuppressive medications within this period may lead to unwanted additive immunosuppressive effects. Conversely, when initiating ozanimod after discontinuation of other medications with prolonged immune effects, caution should be taken to examine the half-life and mode of action of the other drugs to minimize additive immunosuppressive effects. Starting ozanimod after treatment with alemtuzumab is not recommended.

Dosage and Administration

Ozanimod capsules are provided in three dosage forms: 0.23 mg, 0.46 mg and 0.92 mg. The capsules should be swallowed whole, and can be taken either with or without food.

Ozanimod should be initiated with a 7-day titration, starting with a 0.23 mg once-daily dose on days 1-4 and escalating to 0.46 mg once daily on days 5-7. Starting at day 8 and every day thereafter, the recommended dose of ozanimod is 0.92 mg once daily. If a dose of ozanimod is missed within the first two weeks of treatment, ozanimod should be reinitialized using the titration regimen. A missed dose after more than two weeks of treatment is simply skipped and the treatment is continued as planned.

Prior to initiating ozanimod treatment, the following must be assessed: complete blood count (including lymphocyte count); ECG (to assess for conduction abnormalities); liver function (transaminase and bilirubin levels); evaluation of the ocular fundus including the macula (in patients with a history of uveitis or macular edema); current or prior anti-neoplastic, non-corticosteroid immunosuppressive, or immune-modulating therapies; and current use of medications that could slow heart rate or atrioventricular conduction. Patients lacking a documented history of chickenpox or vaccination against the varicella zoster virus (VZV) should be tested for VZV antibodies before initiating treatment with ozanimod; patients without VZV antibodies should be vaccinated before starting ozanimod, and live attenuated vaccines should be administered at least one month before initiating treatment with ozanimod.

Etrasimod (Velsipity)

In October 2023, etrasimod became the second S1P receptor modulator to be approved by the FDA for the treatment of UC.¹³ Etrasimod is indicated for the treatment of moderately to severely active UC in adult patients.

Etrasimod has a high affinity for the same two receptors as ozanimod, S1P₁ and S1P_5, and additionally also binds S1P₄.¹³ By contrast, it has minimal binding activity on S1P₃ and no activity on S1P₂. Etrasimod acts by partially and reversibly impeding lymphocyte movement from lymphoid organs, thereby decreasing their presence in the bloodstream. Although the precise mechanism by which etrasimod acts in the treatment of UC remains unclear, it likely involves limiting lymphocyte migration into the intestine. Recent data has suggested that S1P modulators may work by alteration of gut angiogenesis.¹⁴

Efficacy

The efficacy of etrasimod was assessed in ELEVATE UC 52 and ELEVATE UC 12 - two randomized, multicenter, double-blind, placebo-controlled phase 3 trials. In both trials, eligibility criteria included age 16–80 years, moderately to severely active UC (modified Mayo score [MMS] of 4-9 with an endoscopy subscore of ≥2 and a rectal bleeding subscore of ≥1), and history of inadequate response, loss of response, or intolerance to at least one approved UC therapy. Patients with isolated proctitis (<10 cm rectal involvement) at baseline who met other eligibility criteria could enroll in both trials. Concomitant treatment with stable doses of oral aminosalicylates or corticosteroids was allowed, provided that the dose was stable 2 weeks or 4 weeks before trial screening, respectively. In ELEVATE UC 52, corticosteroid use was tapered at week 12.

In both trials, patients were randomly assigned (2:1) to etrasimod 2 mg or placebo once a day. This assignment was stratified based on several factors including previous exposure to biologicals or JAK inhibitor therapy (yes vs no), baseline corticosteroid use (yes vs no), and baseline disease activity (MMS 4-6 vs MMS 7-9). ELEVATE UC 52 enrolled 433 patients, and consisted of a 12-week induction period followed by a 40-week maintenance period and a 4-week follow-up period. ELEVATE UC 12 enrolled 354 patients and comprised only a 12-week induction period and a 4-week follow-up period. By the end of week 12, patients from both trials experiencing worsened symptoms (defined as rectal bleeding subscore ≥2 and/or rectal bleeding plus stool frequency subscores ≥4 at two timepoints ≥7 and ≤14 days apart) had the option to enroll in an ongoing open-label extension study. Those who chose not to participate in the open-label extension study underwent a 4-week follow-up period, with scheduled visits at week 2 and week 4.

In ELEVATE UC 52, the coprimary endpoints were the proportion of patients achieving clinical remission at week 12 (end of the induction period) and week 52 (end of the maintenance period).¹⁵ The primary endpoint for ELEVATE UC 12 was the proportion of patients in clinical remission at the end of the 12-week induction period. Clinical remission was defined as a composite of stool frequency subscore of 0 (or stool frequency subscore of 1 with a ≥1-point decrease from baseline), rectal bleeding subscore of 0, and endoscopic subscore of ≤1. Key secondary endpoints for both ELEVATE UC 12 and ELEVATE UC 52 included endoscopic improvement at week 12, symptomatic remission at week 12, and histologic-endoscopic mucosal improvement (Geboes Index score <2.0) at week 52. Additional key secondary endpoints in ELEVATE UC 52 were corticosteroid-free clinical remission (clinical remission at week 52 and corticosteroid free for ≥12 weeks prior to week 52) and maintenance of clinical remission (clinical remission at both weeks 12 and 52).

In ELEVATE UC 52 at week 12, 27% of patients treated with etrasimod achieved clinical remission, compared to 7% of those treated with placebo (P<0.0001; see Figure 10-7A). At week 52, 32% and 7% of patients achieved clinical remission with etrasimod and placebo, respectively (P<0.0001; Figure 10-7A). Significant improvements with etrasimod over placebo were observed in the three key secondary endpoints at week 12: endoscopic improvement (35% vs 14%; P<0.0001), symptomatic remission (46% vs 21%; P<0.0001), and histologic-endoscopic mucosal improvement (21% vs 4%; P<0.0001). All key secondary efficacy endpoints were met by week 52, including the corticosteroid-free clinical remission (etrasimod: 32%, placebo: 7%; P<0.0001) and the maintenance of clinical remission (etrasimod: 18%, placebo: 2%; P<0.0001).

In ELEVATE UC 12, clinical remission was achieved by 25% of patients in the etrasimod group and 15% of patients in the placebo group at the conclusion of the 12-week induction period (P=0.026; Figure 10-7B). Additionally, the key secondary endpoints were achieved by a higher portion of patients treated with etrasimod than those who received the placebo (endoscopic improvement, 31% vs 19% [P=0.0092]; symptomatic remission, 47% vs 29% [P=0.0013]; histologic-endoscopic mucosal improvement, 16% vs 9% [P=0.036]).

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Safety

Safety assessments in both ELEVATE UC 52 and ELEVATE UC 12 encompassed monitoring of AEs, clinical laboratory results, physical exams, pulmonary function tests, and ophthalmological examinations. The safety outcomes are summarized in Table 10.6. Adverse events reported in ≥3% of patients treated with etrasimod included anemia, headache, and worsening of UC or UC flare. The incidence of serious AEs was low and comparable between etrasimod and placebo groups in both trials (ELEVATE UC 52: 7% of patients in the etrasimod group vs 6% of patients in the placebo group; ELEVATE UC 12: 3% of patients in the etrasimod group vs 2% of patients in the placebo group).

Across both studies, the incidence of overall infections, serious infections, and opportunistic infections (such as tuberculosis and cytomegalovirus infection) did not significantly differ between the treatment groups. Four patients experienced herpes zoster infections: 2 in the etrasimod group in ELEVATE UC 52 and 2 in the placebo group in ELEVATE UC 12. Additionally, 4 (ELEVATE UC 52) and 5 (ELEVATE UC 12) instances of bradycardia were documented among patients receiving etrasimod, with no occurrences reported among those on placebo. There were no serious events of bradycardia or atrioventricular block. Elevated liver enzyme levels were observed in both trials, with a higher frequency noted in the etrasimod treatment cohorts.¹³ Specifically, in ELEVATE UC 52, alanine aminotransferase elevations exceeding 3 times the upper limit of normal occurred in 4.5% of etrasimod-treated patients and 2.1% of placebo-treated patients. In ELEVATE UC 12, such elevations were seen in 2.5% of etrasimod-treated patients and 0.5% of placebo-treated patients. Finally, no cases of malignancy were reported in either trial.

Warnings and Precautions

The prescribing information for etrasimod lists warnings and precautions concerning infections, bradyarrhythmia and AV conduction delays, liver injury, macular edema, increased blood pressure, fetal risk, malignancies, PRES, respiratory effects, additive immunosuppressive effects from prior treatment with immunosuppressive or immune-modulating medications, and effects on the immune system when etrasimod is discontinued.

Etrasimod causes reversible sequestration of lymphocytes in lymphoid tissues leading to a decrease in peripheral blood lymphocyte count. The number of lymphocytes drops to approximately 45% of baseline values by week 52, therefore increasing the susceptibility to infections. In ELEVATE UC 52 and ELEVATE UC 12, infection rate was slightly increased with etrasimod treatment compared to placebo. Therefore, when initiating etrasimod, a complete blood count with lymphocyte count should be obtained. If there is an ongoing infection, etrasimod treatment should not be started until the infection has resolved. Furthermore, patients should be monitored for signs and symptoms of PML, and if PML is diagnosed, etrasimod should be discontinued.

Commencing etrasimod therapy may lead to a temporary reduction in heart rate and delays in AV conduction. Following the initial dose of etrasimod 2 mg, patients with UC experienced the most significant mean decrease from baseline in heart rate, reaching 7.2 beats per minute (bpm) at hour 3 in the ELEVATE UC 52 study and hour 2 in the ELEVATE UC 12 study. A cardiologist should be consulted before starting etrasimod treatment in patients with QT prolongation (QTcF ≥450 msec in males, ≥470 msec in females), arrhythmias necessitating treatment with Class Ia or Class III anti-arrhythmic drugs or QT prolonging drugs, unstable ischemic heart disease, Class I or II heart failure, history of cardiac arrest, cerebrovascular disease, uncontrolled hypertension, resting heart rate below 50 bpm, and history of symptomatic bradycardia, recurrent cardiogenic syncope, severe untreated sleep apnea, or Mobitz type I second-degree AV block (unless the patient has a functioning pacemaker).

Elevated aminotransferase levels have been observed in patients using etrasimod in the ELEVATE UC 52 and ELEVATE UC 12 trials. Therefore, transaminase and bilirubin levels should be assessed before initiating etrasimod, as well as during treatment in patients who develop symptoms suggestive of hepatic dysfunction (unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice and/or dark urine). If significant liver injury is confirmed, etrasimod treatment should be discontinued.

Etrasimod has been associated with an increased risk of macular edema. A baseline assessment of the fundus, including the macula, should be conducted at the beginning of etrasimod treatment. Furthermore, periodic evaluations of the fundus, including the macula, should be performed during therapy and whenever changes in vision occur. Patients taking etrasimod who notice any changes in their vision should undergo an ophthalmic assessment of the ocular fundus, including the macula. Additionally, discontinuation of the drug should be considered if macular edema develops.

Animal studies indicate that etrasimod may pose a risk for fetal harm if administered to pregnant women. It is crucial to inform pregnant women and patients of reproductive potential about the potential hazards to a developing fetus. Additionally, women of reproductive potential should be advised to use effective contraception methods to prevent pregnancy both during etrasimod treatment and for one week after discontinuation.

Even though PRES is not common with S1P receptor modulators, a complete physical and neurological examination is recommended if symptoms develop, and an MRI should also be considered. If PRES is suspected, etrasimod should be discontinued.

Etrasimod use may prompt alterations in respiratory function, potentially leading to reductions in FEV₁. Therefore, spirometric assessment of respiratory function should be undertaken during etrasimod therapy if deemed clinically necessary.

When transitioning to etrasimod from medications with prolonged immune effects, careful consideration should be given to the half-life and mechanism of action of these drugs to prevent unintended cumulative immunosuppressive effects. Following cessation of etrasimod, lymphocyte counts typically return to the normal range within 4 to 5 weeks for 90% of individuals. However, the use of immunosuppressants during this period may heighten the risk of additive immunosuppression. Consequently, patients receiving concomitant immunosuppressants should be closely monitored for infectious complications for up to 5 weeks following the final dose of etrasimod.

Dosage and Administration

Etrasimod is available in the form of 2-mg tablets. The capsules should be swallowed whole, and can be taken either with or without food.

Before starting etrasimod treatment, several assessments are necessary. These include: complete blood count (including lymphocyte count), ECG (to assess for conduction abnormalities), liver function tests (transaminase and bilirubin levels), evaluation of the ocular fundus including the macula, current use of medications that could slow heart rate or atrioventricular conduction, current or prior anti-neoplastic, non-corticosteroid immunosuppressive, or immune-modulating therapies, and varicella and VZV antibody assessment. A skin examination should also be conducted before or shortly after the start of etrasimod treatment. Furthermore, any suspicious skin lesions should be promptly evaluated.

Thiopurines (Azathioprine and 6-Mercaptopurine)

The thiopurines azathioprine and 6-mercaptopurine are purine antimetabolites that act as immunosuppressants by incorporating into the ribonucleotides of proliferating lymphocytes to block DNA replication, preventing proliferation. The thiopurines were first used in IBD based on their efficacy in the treatment of other autoimmune disorders, including systemic lupus erythematous (SLE) and RA. For decades, thiopurines have been used off-label in the induction and maintenance treatment of glucocorticoid-dependent or glucocorticoid-refractory IBD. However, more recent publications have challenged the perceived efficacy of these compounds.

In a meta-analysis of seven studies, induction therapy with thiopurines was found to offer no significant benefit to patients with UC. These results are in line with current guidelines, which do not recommend the use of monotherapy with thiopurines as therapy to induce remission for patients with UC; given it slow onset of action. Thiopurines have more recently been evaluated in combination with TNF antagonists for induction therapy, with promising results. In UC SUCCESS, which enrolled 239 patients with moderate to severe UC, corticosteroid-free remission was achieved at week 16 by 39.7% of patients receiving infliximab and azathioprine compared to 22.1% (P = 0.017) and 23.7% (P = 0.032) of patients receiving infliximab alone or azathioprine alone, respectively. Rates of mucosal healing were also improved in the combination group.

A Cochrane review analyzed the efficacy and safety of thiopurines in maintaining remission in UC. Randomized controlled trials (RCTs) of ≥12 months duration that compared azathioprine or 6-mercaptopurine with placebo or standard maintenance therapy were included. Seven studies enrolling a total of 302 patients were included. The study found that azathioprine was better than placebo for maintenance treatment. However, given the established safety and efficacy of the aminosalicylates for remission maintenance in UC, the authors were unable to recommend thiopurines as first-line treatment in this setting. However, the authors did conclude that azathioprine or 6-mercaptopurine could be effective as maintenance therapy for patients who have failed or cannot tolerate mesalamine or sulfasalazine and for patients who require repeated courses of steroids. In another previously described meta-analysis, maintenance of clinical remission in UC was significantly higher in patients treated with azathioprine or mercaptopurine compared to placebo, but not compared to 5-aminosalicylates.

As CD and UC patient are increasingly treated with immunomodulators and biologics, therapeutic drug monitoring (TDM) in being employed to help guide therapy towards optimization. TDM can be performed proactively or reactively. Drug failure can be related to many possible etiologies, including genetic variations, disease process and inflammatory mediators, rapid drug clearance and anti-drug antibodies. Thiopurine methyltransferase (TPMT) enzyme activity should be checked prior to initiation of therapy, since 1 in 300 individuals has no enzyme activity and another 11% have low enzyme level leading to the potential for more significant toxicity. Furthermore, thiopurine metabolite monitoring has been recommended by some, but not all, to potentially help guide monotherapy, with a target of 6-thioguanine (6-TG) between 230 and 450 pmol/8x10 red blood cells, with less certainty when combination therapy is used.

Recently, the utility assessing the NUDT15 genotype has been highlighted as well. Azathioprine is a prodrug that must first be activated to form thioguanine nucleotides (TGNs), the major active metabolites. The active metabolites are metabolized and inactivated by TPMT and the enzyme nudix hydrolase 15 (NUDT15). Thus, individuals with reduced activity of either enzyme are exposed to higher levels of thioguanine and have a higher risk of toxicity side effects, including severe bone marrow suppression (myelosuppression).

Dose-related bone marrow suppression is common, so CBC monitoring should also occur during therapy. Drug-induced pancreatitis can be anticipated in 3% to 15% of patients and resolves when the drug is discontinued. This is an idiosyncratic side effect that typically occurs in therapy, usually within the first 3 to 4 weeks of therapy. Thiopurines are also associated with rare cases of serious AEs, such as an elevated risk of lymphoma and nonmelanoma skin cancer, fever, rash and hepatitis.

Overall, evidence for the use of thiopurines in the treatment of UC comes primarily from studies performed several decades ago, many of which had shortcoming, such as a lack of sufficient power, concomitant steroid use and high dropout rates. Large scale RCTs are required to update current guidelines on thiopurine use in UC.

Additionally, thiopurines have been used to lessen the immunogenicity potential when using biologic therapy, particularly when using anti-TNF therapy (infliximab, adalimumab and golimumab) for the treatment of UC. Giving biologic therapies in combination with concomitant immunosuppressive agents has been shown in several studies to reduce the development of ADAbs. It is now well recognized that immunogenicity contributes to increased formation of antibodies to anti-TNF, leading to lower trough levels, and eventual loss of response. An ad hoc analysis of the ACCENT I trial showed that receiving concomitant immunomodulators resulted in improved remission and response rates at week 52. These findings were the first to suggest that combination therapy was more effective than monotherapy, which could be due to immunomodulators decreasing the antibody response to infliximab. Out of the 1,601 patients with CD in the PANTS 3-year observational cohort, 751 patients received infliximab while the rest received adalimumab. The immunogenicity rates were 26% for Remicade and 28% for biosimilar infliximab (Inflectra/Remsima). The use of immunomodulators reduced the infliximab therapy-associated risk of immunogenicity significantly (HR = 0.37, P <0.0001). In the UC SUCCESS trial, 19% of patients receiving infliximab monotherapy developed antibodies vs 3% in patients receiving combination therapy. In a post-hoc analysis of the SONIC trial, it was demonstrated that among patients with CD and similar serum concentrations of infliximab, combination therapy with azathioprine was not significantly more effective than infliximab monotherapy. Combination therapy with azathioprine appears to improve efficacy by increasing pharmacokinetic features of infliximab. This represents post-hoc data. It is uncertain if immunomodulators are needed when therapeutic drug monitoring is prospectively performed to attain high therapeutic serum trough levels of anti-TNF therapy. The high TNF trough levels may be protective against immunogenicity development. This has been suggested in the post-hoc analysis of the SONIC trial.

Cyclosporine A

Cyclosporine A is an immunosuppressive drug that acts primarily by reversibly inhibiting T-lymphocyte function, which is essential for the propagation of inflammation in patients with UC. T-helper cells are the main target, although T-suppressor cells may also be suppressed. Cyclosporine has been shown to inhibit the production and release of lymphocyte-produced cytokines, including IL-2.

Cyclosporine A is approved by the FDA for the prevention of organ rejection in kidney, liver and heart allogeneic transplants, as well as for the treatment of severe active RA and severe recalcitrant plaque psoriasis. Due to its rapid onset of action, cyclosporine A may be used as rescue therapy in patients with severe UC who do not respond to the first-line therapy of intravenous corticosteroids, as an alternative to emergent colectomy, which is associated with elevated mortality and morbidity. In this setting, it is used as a bridge to the slower-acting thiopurines in corticosteroid-refractory UC. Additional options for maintenance therapy after induction of remission with cyclosporine would include subsequent use of anti-TNF therapy (e.g., infliximab, adalimumab, or golimumab), tofacitinib, ustekinumab, vedolizumab, mirikizumab, upadacitinib, ozanimod, and etrasimod. In a retrospective study of UC patients between 1991 and 1995, treatment with cyclosporine A allowed most severe steroid-resistant UC patients to retain their colons and provided time for elective colectomy in others, especially if azathioprine or mercaptopurine were also given. However, more recent data have shown the benefit of newer biologic agents, such as infliximab, as rescue therapy in patients with more severe UC, with perhaps a relatively better safety profile.

A 2005 Cochrane review, later updated in 2010, sought to evaluate the effectiveness of cyclosporine A in patients with severe UC. The review identified two small RCTs: the first randomized patients to receive either intravenous cyclosporine or placebo and the second randomized patients to either intravenous cyclosporine or intravenous methylprednisolone. The Cochrane review concluded that there was little evidence to support cyclosporine A being more effective than standard of care and that although its rapid onset of action made it an attractive option, too little was known about its long-term efficacy and safety. More recently, a meta-analysis of six trials found the efficacy of cyclosporine as a rescue therapy in severe steroid-refractory UC comparable to that of the TNF antagonist infliximab. A large 14-year (1989-2013) retrospective cohort study found that treatment with cyclosporine A showed similar efficacy and lower rate of severe AEs compared with infliximab in patients with steroid-refractory acute severe UC. Infection were the most common severe AEs in both groups of this study.

In contrast to many other immunosuppressants, cyclosporine does not suppress bone marrow or affect hematopoietic stem cells. Since cyclosporine A is used off-label in patients with UC, comprehensive safety data from large RCTs is lacking However, well-described side effects may include hypertrichosis, tremor, seizures in patients with low cholesterol levels, nausea, vomiting, hyperglycemia, infectious complications and renal insufficiency.

Tacrolimus

Tacrolimus is a calcineurin inhibitor, a type of nonsteroidal immunomodulator, that inhibits the expression and/or production of several cytokines (e.g., IL-2, IL-4, IL-8, TNFa). Tacrolimus also has several other effects, the net result of which is inhibition of T-lymphocyte activation/proliferation and the T helper cell–dependent B-cell response. Tacrolimus is indicated as a treatment to help prevent organ rejection in people who have had a kidney, liver, or heart transplant. It is also indicated, as a topical ointment, for the short-term treatment of moderate-to-severe atopic dermatitis. It does not have an FDA-approved indication for the treatment of UC; it has been used off-label for the induction of remission in patients with steroid-dependent or steroid-refractory UC, as an alternative to cyclosporine A.

Few RCTs have examined the safety and efficacy of tacrolimus in the treatment of UC. One 2016 systemic review and meta-analysis identified two RCTs, two prospective, and 21 retrospective studies to include in their analysis. The included RCTs compared tacrolimus with placebo therapy in moderate-to-severe steroid-dependent or steroid-refractory UC, and the meta-analysis found tacrolimus to be more effective than placebo in inducing short-term clinical response at 2 weeks. A meta-analysis of the observational studies supported this finding, showing high response rates with tacrolimus at 1 and 3 months. One issue when treating severe UC is the long-term risk of colectomy, which can be necessary in close to 50% of patients treated with cyclosporine A within 1 to 2 years. The meta-analysis found that colectomy-free rates in the observation studies were between 70% and 90% during a follow-up of up to 12 months with tacrolimus. A 2017 systemic review and meta-analysis came to similar conclusions.

In terms of safety, tacrolimus is associated with nephrotoxicity, tremor and infections, among other AEs. A 2008 Cochrane review found that most AEs associated with tacrolimus were mild and included finger tremor, sleepiness, hot flashes, headache, queasiness, abdominal discomfort, hypomagnesemia and kidney problems. In the 2016 meta-analysis, the rate of serious AEs was not higher with tacrolimus compared to placebo. Of the patients who did experience serious AEs, all of them improved upon discontinuation or reduction of tacrolimus. Although AE rates in the observational studies support the long-term safety of tacrolimus, additional long-term RCTs are required to determine the long-term safety of the drug in the treatment of UC.

Methotrexate (MTX)

MTX is an antimetabolite that antagonizes the actions of folic acid. At high doses, MTX has antineoplastic activities through the inhibition of dihydrofolate reductase (DHFR), which deprives rapidly diving cells of DNA and RNA. At lower doses, MTX is used to treat autoimmune disease and is thought to exert its effect through multiple additional mechanisms, including the inhibition of T cell activation, downregulation of B cells, inhibition of methyltransferase activity important to immune system function, among other functions. MTX does not have an FDA-approved indication for UC but can be used for reducing immunogenicity in patients receiving biologic agents.

A 2014 Cochrane review of two studies assessed the efficacy and safety of MTX for induction of remission in patients with UC. One study compared oral MTX (12.5 mg/week) to placebo and the other compared oral MTX (15 mg/week) to 6-mercaptopurine (1.5 mg/kg/day) and 5-aminosalicylic acid (3 g/day). No significant differences were observed in clinical remission rates between the MTX and comparator groups in either study. In addition, no difference was observed in the proportion of patients who withdrew from steroids in the study comparing oral MTX to 6-mercaptopurine and 5-aminosalicylic acid. The overall quality of evidence of these studies was low due to small trial size (101 patients in total) and risk of bias. The authors concluded that there was no evidence to support the use of MTX for induction of remission in UC.

The efficacy and safety of MTX for maintenance of remission in patients with UC was assessed in a 2015 Cochrane review. Three trials enrolling a total of 165 patients were included in their analysis. One study compared oral MTX (12.5 mg/week) to placebo, another compared oral MTX (15 mg/week) to 6-mercaptopurine (1.5 mg/kg/day) or 5-aminosalicylic acid (3 g/day) and the other compared MTX (15 mg/week) in combination with sulfasalazine (3 g/day) to sulfasalazine. No significant differences were observed in clinical remission rates between the MTX and comparator groups in any study. The quality of evidence of the studies was low due to low sample size and risk of bias. The authors concluded that there was no evidence to support the use of MTX for maintenance or remission in UC.

MTX can be administered orally, intramuscularly, or subcutaneously. As such, there was considerable interest in assessing whether parenteral administration would demonstrate improved efficacy in UC, since the previously described clinical trials used oral MTX. Two large RCTs, METEOR and MERIT-UC, were therefore performed to assess the safety and efficacy of intramuscular or subcutaneous MTX in patients with active UC. Results from METEOR, which randomized patients to receive placebo or MTX (intramuscularly or subcutaneously, 25 mg/week) for 24 weeks, were published in 2016. The trial found that parenteral MTX was not superior to placebo for induction of steroid-free remission in patients with UC (31.7% MTX vs 19.6% placebo; P = 0.15). However, the proportion of patients in steroid-free clinical remission at week 16 was greater in the MTX group (41.7% MTX vs 23.5% placebo; P=0.04). No differences were observed in steroid-free endoscopic healing or other secondary endpoints. MERIT-UC was a 48-week trial consisting of a 16-week open label induction period followed by a 32-week double-blind, placebo-controlled maintenance period.

In the open-label period, patients with active UC despite prior conventional or anti-TNF therapy were treated with open label MTX (25 mg/week SC) and a 12-week steroid taper. At week 16, responders (clinical Mayo score ≤5 and steroid free since week 12) were randomized to continue MTX or placebo until week 48. Of the enrolled patients, 51% responded and 30% achieved remission at week 16. Of the responders, 84 patients continued into the placebo-controlled portion of the study, where 63% of placebo-treated patients and 66% of MTX-treated patients experienced a relapse (P=0.75). No significant difference was observed between placebo and MTX groups in the number of patients who remained relapse-free at week 48 (75% vs 85%, respectively). Thus, MTX does not represent a viable therapeutic option for long-term maintenance of remission in patients with UC.

Altogether, the efficacy of MTX in the induction and maintenance of remission in UC has been called into question. Although MTX offers some advantages over thiopurines, particularly in terms of observed risk for lymphoma in patients with UC, recent studies demonstrating its lack of efficacy have quelled optimism regarding its use. One potential use of MTX is in combination with an anti-TNFa biologic. Adding MTX to infliximab has been shown to reduce the immunogenicity of infliximab, IBD activity and infliximab dose.

In terms of safety, AEs that occurred with MTX in studies of the 2015 Cochrane review included transient leukopenia, migraine, nausea and dyspepsia, mild alopecia, mild increase in aspartate aminotransferase levels, peritoneal abscess, hypoalbuminemia, severe rash and atypical pneumonia.

Pulmonary toxicity, including MTX-induced pneumonitis, has been reported with MTX, most often occurring after weeks to months of low-dose oral therapy or sooner with relatively short-term use of higher doses. Studies have estimated pulmonary toxicity to develop in 1% to 8% of patients receiving low‐dose MTX. It is important to note that these estimates are not specific for UC patients, but rather for a collection of patients with a range of autoimmune and malignant conditions. A systematic review and meta-analysis of MTX use and risk for lung disease in non-malignant conditions, including IBD, found no increased risk for lung disease in MTX-treated patients. Regardless, if patients develop dyspnea, then lung involvement should be considered, and if pulmonary function tests show abnormal findings then MTX therapy may need to be stopped. Additionally, radiographic studies can be performed to search for interstitial lung prominence. In patients with RA who use methotrexate, interstitial lung disease has been reported in anywhere from 0.3 % to 11.6% of patients. MTX hepatotoxicity is another common complication of long-term MTX therapy. MTX-induced increases in serum ALT and AST are reported in approximately 14% and 8% of patients, respectively. However, the risk of serious liver adverse events with modern MTX regimens and monitoring protocols in patients with normal renal function appears to be low.

Supplementation with folic or folinic acid during treatment with MTX has been shown to lessen the frequency of certain adverse events. In a 2014 Cochrane systematic analysis, supplementation with any form of exogenous folate while on MTX therapy reduced the risk of GI adverse events, such as nausea and vomiting, by 26% and reduced the risk of developing abnormal hepatic enzyme elevations by 76.9%. Folic acid supplementation did not reduce the risk for mouth sores.