Indications and safety of newer IBD treatments in the older patient

Abstract

Purpose of Review

Treatment of inflammatory bowel disease (IBD) in the elderly requires special attention to treatment efficacy while considering drug safety, other medical comorbidities, and the patients’ risk for treatment related adverse events. In this article, we reviewed the indications and safety of the newer IBD therapies in the older IBD patient beyond anti-TNF agents, thiopurines, and corticosteroids.

Recent Findings

Vedolizumab, ustekinumab, and risankizumab have favorable side effect profiles with regards to infections and malignancy. Ozanimod has a favorable side effect profile with regards to infection and malignancy, however cardiac events and macular edema are potential risks. Tofacitinib and upadacitinib are associated with an increased risk of serious infections, herpes zoster, malignancy, and have potential for an increased risk of cardiac events and thrombosis.

Summary

From a safety profile perspective, vedolizumab, ustekinumab, and risankizumab should be considered first line treatment options for moderate-to-severe IBD in the elderly. Risk-benefit discussions are indicated for ozanimod, tofacitinib, and upadacitinib.

Introduction

The epidemiology of Inflammatory Bowel Disease (IBD) has been constantly evolving. While traditionally described as a disease of the young, a bimodal distribution of age is well established [1]. Approximately 25%–30% of patients with IBD are aged >60 years; this number is also likely to increase, as 10%–15% of new IBD diagnoses occurs among older patients (>60 years) [2, 3, 4•].

Older patients generally have additional medical comorbidities than younger patients, and as such, an increased risk of serious infections, opportunistic infections, malignancy and nonmelanoma skin cancer (NMSC) [5–7]. Furthermore, many IBD therapies (particularly anti-tumor necrosis factor (anti-TNF) agents, thiopurines, and corticosteroids) have been found to increase the risk of infection and malignancy in the elderly patient [8–12]. Combination therapy with anti-TNF agents and thiopurines posed the greatest risk for serious infection in patients aged ≥65 years compared to monotherapy with either agent [13]. Because of these risks there has been a hesitance to initiate biologics with lower utilization these novel therapies in geriatric patients [14–16]. These analyses have shown significant disparity between younger and older patients, with over 30% of elderly patients prescribed chronic steroid therapy for maintenance and less than 10% on immunomodulators or biologic therapy [15].

In a recent meta-analysis, frailty was demonstrated to be an independent predictor of mortality in IBD patients [17]. However, many elderly patients with IBD are not frail and require a risk-benefit discussion considering disease activity, disease severity, drug efficacy, drug safety, and the patient’s risks/comorbidities to determine appropriate therapy. This review focuses on the indications and safety of the newer IBD therapies in the older IBD patient beyond anti-TNF agents, thiopurines, and corticosteroids.

Vedolizumab

Indication

Vedolizumab is a gut-selective integrin (α₄β₇) inhibitor approved for the treatment of adult patients with moderately to severely active ulcerative colitis (UC) and Crohn’s Disease (CD) who have had an inadequate response with, lost response to, or were intolerant to conventional therapy or anti-TNF agents [18].

Safety

Due to its gut-selective mechanism, vedolizumab has been postulated to be safer than other biologic therapies. The induction and maintenance (CD: GEMINI-I and UC: GEMINI:II) trials for vedolizumab were some of the first biologic trials to include patients over 65 years of age, including patients ages 18-80 years [19, 20]. Patients over 65 only made up 2-4% of the cohorts for UC and CD.

Adverse Events (AEs)

A post-hoc analysis of the induction and maintenance data showed that safety was similar between all age groups when stratified into <35, 35 to 55, and >55 years of age [21]. Two retrospective matched case-control studies showed no significant difference in the rate of AEs between elderly and non-elderly patients on vedolizumab [22, 23]. Pugliese et al. matched cohorts of patients aged >65 (n=198) to 18-64 (n=396) with no significant differences seen in the incidence of AEs (0.13 and 0.10 per patient-year respectively). Shashi et al. matched cohorts of elderly patients (age >65; n=25) to non-elderly patients (age <65; n=100) on a 1:4 ratio based on gender and type of IBD. The most frequent side effects seen were rash, arthralgia, infection, and infusion reactions; all of which were not significantly different between elderly and non-elderly patients.

Prospectively collected data was retrospectively assessed from 172 consecutive biologic naïve patients with median age of 66 (interquartile range (IQR) 57.7-72.0) from the Sicilian Network for IBD who had been initiated on vedolizumab [24]. Because national guidance in Italy favors anti-TNF therapy as first-line, patients that were selected for vedolizumab already had reason to avoid anti-TNF; such as advanced age (71%; age > 60), history of malignant or pre-malignant conditions, previous serious infections with azathioprine or methotrexate, latent tuberculosis, and other significant comorbidities. Despite this, the data suggested a low incidence of AEs (14.5%), many of which were mild, and only 10 of which required discontinuation of therapy. Multiple retrospective comparisons of vedolizumab to anti-TNF therapy show at least comparable safety in terms of overall AEs and infections [25–28]. The cutoff for elderly in these studies was different, ranging from patients >50 years of age to patients >65.

Serious Infections

For the general population (ages 18-80) in GEMINI I and II, the rates of serious infection in those receiving vedolizumab vs. those who received placebo in the induction and maintenance phase were low. In a retrospective, multi-center cohort study comparing groups age >60 to age <40, there was a significantly higher rate of infection in those >60 years of age. Most were upper respiratory infections and the rate of discontinuation of therapy was not significantly different among both groups [29]. A retrospective cohort study of 497 patients >65 years old among the US national Veterans Affairs Healthcare System assessed safety profiles of vedolizumab, 5-aminosalicylates, and chronic corticosteroid use. The absolute risk of infection were similar in elderly IBD patients using vedolizumab and 5-aminosalicylates and favorable when compared to the cohort taking chronic steroids [30••].

In the above prospective Sicilian Network for IBD cohort (172 UC and CD patients) of elderly patients (median age 66, IQR 57.7-72.0) treated with vedolizumab, few infections were noted (three pneumonia, three cutaneous herpes simplex virus, two urinary tract infections, two Clostridium difficile, one otitis media, one genital mycosis, and an intra-abdominal abscess). Most of these infections were mild and did not require discontinuation of therapy. It was noted that CD patients had a higher incidence of infection compared to the UC patients [24]. A large retrospective study (n= 480 vedolizumab new users, 1152 anti-TNF new users) comparing vedolizumab to anti-TNF agents in adults age >65 revealed that there is a lower risk of infection-related hospitalization among patients vedolizumab, though it removed infections that were thought to be secondary to uncontrolled disease activity (intra-abdominal abscess and perianal abscess) [26].

Malignancy

For the general population (ages 18-80) in GEMINI I and II, the rates of malignancy and NMSCs in those receiving vedolizumab vs. placebo in the induction and maintenance phase were low. Only one malignancy (colon cancer) was found in the prospective Sicilian Network for IBD cohort (172 UC and CD patients) of elderly patients (median age 66, IQR 57.7-72.0) treated with vedolizumab [24]. In a comparison study of vedolizumab, 5-aminosalicylates, and chronic corticosteroid, the absolute risks of malignancy in elderly patients >65 years of age were similar between vedolizumab and 5-aminosalicylates and favorable when compared to the cohort taking chronic steroids [30••].

Ustekinumab

Indication

Ustekinumab is a human interleukin-12 and -23 antagonist indicated for the treatment of moderately to severely active Crohn’s Disease and ulcerative colitis [31].

Safety

Most data regarding the safety of ustekinumab in the elderly patient has been extrapolated from its induction (UNITI-I, UNITI-II) and maintenance (IM-UNITI) trials in CD and UC (UNIFI) [32, 33].

Adverse Events

General induction and maintenance data for both CD (UNITI) and UC (UNIFI) showed no significant difference in overall adverse events or serious AEs between the ustekinumab and placebo groups, consistent with previous rheumatology literature in psoriatic arthritis [34]. There was additionally no apparent relationship between dose and safety. In a retrospective analysis of patients age >60 vs matched non-elderly controls, there were no differences in the overall rates of AEs between non-elderly and elderly patients with CD [35••].

Serious Infections

General induction and maintenance data for both CD (UNITI) and UC (UNIFI) showed no significant difference in infections or serious infections between ustekinumab and placebo groups. Low rates of serious infections have been reported with use of ustekinumab in patients over 60 years of age (7-10% incidence) in three separate retrospective analyses [35••, 36, 37]. A small, retrospective multi-center comparison of ustekinumab (n=83) to vedolizumab (n=42) in CD showed comparable safety outcomes in patients > 60 years of age in terms of infections requiring hospitalization [38]. The rate of serious infections was 110.6/1000 patient-years for vedolizumab and 75.5/1000 patient-years for ustekinumab. Notably, about 25% of the patients developing infections had also received systemic steroids within 4 weeks.

Malignancy

Five patients in the UNITI trials developed eight NMSCs. Only three occurred in patients receiving ustekinumab. Three out of five patients were currently using or had previously used thiopurines. One case of metastatic small bowel adenocarcinoma and incidental carcinoid tumor after resection was reported in a patient receiving ustekinumab every 12 weeks in the UNITI trial. Seven patients were found to have a malignancy out of 825 on ustekinumab during the UNIFI trial. These consisted of one each of prostate, colon, renal papillary, and rectal cancers, as well as three cases of NMSC. Age of the patients who developed malignancy during this trial was not reported. Prospectively maintained data from the Nationwide study on genetic and environmental determinants of inflammatory bowel disease (ENEIDA) registry showed that the elderly experienced a higher occurrence of de novo neoplasms while on ustekinumab (4.3% vs. 0.7% in non-elderly), hypothesized to be related to age itself [35••].

Major adverse cardiovascular events (MACE)

No significant difference was found between ustekinumab and placebo in both UNITI and UNIFI trials.

Safety data in elderly from rheumatology

Two, small retrospective cohort studies have reported very low incidence of serious infections while utilizing ustekinumab for plaque psoriasis in elderly patients [39, 40].

Risankizumab

Indication

Risankizumab a humanized monoclonal antibody targeting interleukin 12 and is approved for the treatment of adult patients with moderate-to-severe Crohn’s Disease [41, 42].

Safety

There is no specific safety data available for the use of risankizumab in the elderly with CD. General safety data is available from the induction and maintenance trials which included patients ages 16-80 [41, 42].

Crohn’s Disease general induction (ADVANCE, MOTIVATE) and maintenance data (FORTIFY):

Serious Infections

The rate of serious infections was 6% in the risankizumab 360mg group, 3% in the 180mg risankizumab group, and 2% in the placebo group during maintenance therapy. One opportunistic infection (intestinal Aeromonas infection) was reported in the risankizumab 360mg group.

Liver Enzyme Abnormalities

Transient liver enzyme abnormalities were numerically higher in the risankizumab 360mg and 180mg groups compared to placebo during maintenance therapy.

Malignancy

No malignancies have been reported.

MACE

One nonfatal myocardial infarction (MI) occurred in a 49-year-old male with dyslipidemia and with a 34-year history of smoking in the risankizumab 360mg arm.

Safety data from dermatology

Of the 2,234 subjects with plaque psoriasis exposed to risankizumab, 243 subjects were 65 years or older and 24 subjects were 75 years or older. No overall differences in risankizumab exposure, safety, or effectiveness were observed between older and younger subjects who received Risankizumab [43].

Tofacitinib

Indication

Tofacitinib is a Janus Kinase (JAK) 1,2, and 3 inhibitor indicated for the treatment of adult patients with moderately to severely active ulcerative colitis, who have had an inadequate response or intolerance to one or more anti-TNF therapies [44].

Safety

There is limited safety data for the use of tofacitinib in the elderly with UC. General data regarding the safety of tofacitinib in the elderly patient has been extrapolated from its induction (OCTAVE-1, OCTAVE-2) and maintenance (OCTAVE-SUSTAIN) trials in ulcerative colitis [45–47].

Adverse Events

The OCTAVE trials showed no difference in overall AEs between the 10 mg twice daily tofacitinib and placebo groups [47]. A post-hoc analysis of the phase 2 and 3 induction studies, phase 3 maintenance study, and open-label, long-term extension study stratified safety data according to cohorts by age [48••]. Overall, there were no differences in AEs between tofacitinib and placebo. A higher percentage of patients in the elderly cohort (>65 years of age) had discontinuation of tofacitinib due to severe AEs. Most patients were treated with tofacitinib 10 mg twice a day, making it difficult to evaluate the effect of dosing on AEs.

Serious Infections

In the OCTAVE 1 and 2 trials, infections of any severity occurred at higher rates in the 10 mg tofacitinib groups (23.3% and 18.2%, respectively) than the placebo groups (15.6% and 15.2%). Serious infections were higher in the induction groups, but once transitioned to maintenance, there were no significant differences compared to placebo [47]. The post-hoc analysis of the elderly from the OCTAVE trial data identified that serious infections were comparable between age groups. However, incidence rates of herpes zoster events (non-serious) increased with age, highest among those ages 65 or older [48••].

Malignancy

Two patients developed NMSC during the induction trials. Three patients receiving tofacitinib during induction developed NMSC, all of which had a history of skin cancer previously as well as exposure to thiopurines in the past.

The post-hoc analysis of the elderly from the OCTAVE trial data indicated incidence rates of malignancies (excluding NMSC) as well as NMSC increased with increasing age [48••].

MACE

Three patients who received tofacitinib in the induction trials and one patient in each tofacitinib group in the maintenance trial had adjudicated cardiovascular (CV) events, predominantly acute coronary syndrome. Abnormal lipid levels and elevated creatinine kinase (CK) levels were found to be more frequent in the tofacitinib groups than the placebo groups in the OCTAVE trials. The increase in total cholesterol, high-density lipoprotein (HDL), and low-density lipoprotein (LDL) typically plateaued at about 4 weeks. This rise in lipid levels was not found to be correlated to increased risk of cardiac events.

Safety Data from Rheumatology

Despite limited data with UC, there is more literature available regarding tofacitinib safety in the elderly from its use in rheumatologic conditions. In fact, when tofacitinib received Food and Drug Administration (FDA) approval for the use of rheumatoid arthritis (RA) in 2012 [49], the FDA mandated Pfizer to conduct an additional post-marketing clinical trial due to concerns about potential increased risk of serious infections, MACE, and malignancy in the unapproved 10 mg twice daily dosing. It was this randomized, open-label, noninferiority safety-endpoint trial comparison between tofacitinib and anti-TNF, coined ORAL SURVEILLANCE, that initially led to the FDA requiring a box warning for MACE, specifically for the increased risk of pulmonary embolism and death associated with the 10 mg twice daily dosing in patients 50 years of age and older [50, 51].

Additionally, a recent abstract printed in the Annals of Rheumatic Diseases assessed CV events, infections requiring hospitalization, and herpes zoster in RA patients aged >60 years taking 5 mg tofacitinib twice daily [52]. After 1.5 year follow up, serious infection and incidence of herpes zoster were higher, while there was no increase in incidence of MACE, including venous thromboembolism.

Gastrointestinal perforations have been observed with the use of tofacitinib among patients with RA [53, 54]. The mechanism is unclear. None of these studies have demonstrated this phenomenon occurring more frequently in elderly patients.

Upadacitinib

Indication

Upadacitinib is a JAK 1 inhibitor approved for the treatment of adult patients with moderate-to-severe ulcerative colitis who have had an inadequate response or intolerance to one or more anti-TNF agents [55].

Safety

There is limited safety data for the use of upadacitinib in the elderly with UC. Most data available to date are from the induction (U-ACHIEVE and U-ACCLOMPLISH) and maintenance (U-ACCLOMPLISH) trials which included patients ages 16-75 [55].

Serious Infections

There were 4 instances of herpes zoster infection in the 45mg treatment group and six herpes zoster infections each in the upadacitinib 15 mg and 30 mg treatment groups. There were no instances of herpes zoster in the placebo group. Of those patients who developed herpes zoster, one 66-year-old patient treated with 15mg of upadacitinib developed severe herpes zoster involving the cranial nerve that resulted in drug interruption. This patient had never had shingles nor had received any herpes zoster vaccine previously.

Malignancies

One malignancy was reported both in the placebo (invasive breast cancer) and upadacitinib 15 mg (62-year-old female with invasive breast cancer) groups, and two malignancies (colon cancer and prostate cancer) were reported in the upadacitinib 30 mg group. NMSC was reported in three patients (including a 70-year-old and 74-year-old male) in the upadacitinib 30 mg group.

MACE

One acute myocardial infarction in the placebo group and one subarachnoid hemorrhage in the upadacitinib 30mg group were reported. There were no MACE recorded in the elderly.

Thrombosis

Two nonserious deep venous thrombosis (DVT) were reported in the upadacitinib 30 mg group; a left popliteal vein thrombosis in a 74-year-old man who was obese and a right axillary vein thrombosis in a 64-year-old man with concomitant serious COVID-19 pneumonia, acute respiratory failure, hypoxia, and diastolic congestive heart failure. Both DVT events were assessed by the study investigator as unrelated to study drug.

Safety data from rheumatology and dermatology

In a post-hoc analysis of pooled data in csDMARD-IR (conventional synthetic disease-modifying anti-rheumatic drug inadequate responder) and bDMARD-IR (biologic disease-modifying anti-rheumatic drug inadequate responder) patients with rheumatoid arthritis (RA), the overall safety profile of upadacitinib 15 mg and 30 mg was comparable across the two age subgroups (<65 years and ≥65 years of age) at week 12 [56].

Across five randomized Phase 3 upadacitinib RA trials, patients ≥75 years of age had an increased risk of serious infections [57], while patients ≥65 years of age had increased risk of herpes zoster and venous thromboembolism in the upadacitinib 15 mg group [58, 59].

In an integrated safety analysis of pooled data from three phase 3 trials of upadacitinib treatment in patients (12 to 75 years of age) with moderate-to-severe atopic dermatitis (AD), the exposure-adjusted rate of AEs was higher in patients ≥65 years of age receiving upadacitinib 30 mg compared to patients ≥65 years of age receiving upadacitinib 15 mg and patients <65 years of age receiving either upadacitinib 15 mg or 30 mg [60, 61].

Ozanimod

Indication

Ozanimod is a sphingosine-1-phosphate receptor agonist that is approved for the treatment of adult patients with moderate-to-severe ulcerative colitis [62].

Safety

A post hoc analysis from the phase 3 True North study examined the safety and efficacy of ozanimod in patients with moderately to severely active UC by age group: <60 years or ≥60 years [62, 63].

Infections

The overall incidence of nonserious infections with ozanimod therapy was similar to placebo during induction and higher than placebo during the maintenance period. The frequency of serious infections was less than 2% in each group. Rates of infection were lower in the older (≥60 years) patients receiving ozanimod during induction, and similar to the younger (<60 years) patients receiving ozanimod during maintenance therapy.

Malignancies

Cancer was diagnosed in 1 patient who received ozanimod during the induction period (basal-cell carcinoma). In the maintenance period, cancer was diagnosed in 4 patients (basal-cell carcinoma and rectal adenocarcinoma in 1 patient each who received ozanimod during the induction and maintenance, and adenocarcinoma of the colon and breast cancer in 1 patient each who received ozanimod during the induction period and placebo during the maintenance period). All malignancies were reported among patients < 60 years of age.

MACE

Bradycardia occurred more frequently with ozanimod therapy than with placebo during the induction period but not during the maintenance period. No cases of atrioventricular heart block occurred. Hypertensive crisis was observed in one patient each treated with ozanimod during induction and maintenance, and one patient in the maintenance placebo group. Cardiac events were similar among the older (≥60 years) and younger (<60 years) patients treated with ozanimod.

Liver Enzyme Abnormalities

Elevated liver aminotransferase levels were more common with ozanimod therapy than with placebo. Rates of elevation in liver aminotransferase levels were overall low and numerically higher in the younger (< 60 years) compared to the older (≥60 years) patients treated with ozanimod.

Macular Edema

Macular edema occurred in one patient (<60 years) receiving ozanimod during induction and one patient (≥60 years) receiving ozanimod during maintenance therapy.

Safety data from neurology

None of the clinical studies in relapsing multiple sclerosis (RMS) included elderly patients [64].

Conclusions

For the treatment of moderate-to-severe ulcerative colitis in the elderly, vedolizumab and ustekinumab had favorable safety profiles and should be considered as a first-line treatment in the appropriate older patient. Ozanimod should also be considered, though caution is warranted in those with cardiovascular risk factors and those at risk for macular edema. Both tofacitinib and upadacitinib can be considered in the treatment of moderate-to-severe ulcerative colitis in the elderly, however it can only be used after an inadequate response or intolerance to one or more anti-TNF agents. These agents increase the risk for serious infections (particularly herpes zoster), malignancy, NMSC, and should be used with caution in those with cardiovascular risk factors and history of thrombosis.

For the treatment of moderate-to-severe Crohn’s Disease in the elderly, vedolizumab, ustekinumab, and risankizumab all have favorable safety profiles and can be considered as first-line treatment option.

Prevention of drug related complications in the elderly are key and typically not significantly different from all patients on IBD therapies. Specifically, all IBD patients should be monitored closely with frequent lab monitoring, remain up to date with vaccinations, and undergo age-appropriate and risk factor appropriate cancer screenings. A summary of these recommendations is outlined in Table 1 [65, 66].

Table 1.

Practical Considerations for the Elderly Patient

Positioning Based on Safety	First Line Crohn’s Disease: Vedolizumab, Ustekinumab, Rizankizumab Ulcerative Colitis: Vedolizumab, Ustekinumab After careful Risk Assessment Ozanimod: Can be considered in UC   • Assess CV risk factors and macular edema history Tofacitinib and Upadacitinib: Can be considered in UC   • Assess risk for infection and malignancies, careful CV disease and thrombosis history   • Must have inadequate response or intolerance to one or more anti-TNF therapies
Lab Monitoring and Baseline Testing	Baseline For all patients initiating biologic therapy:   – Complete Blood Count (CBC) and Comprehensive Metabolic Panel (CMP)   – Hepatitis B serologies and tuberculosis screening   – Biomarkers (fecal calprotectin and/or C-reactive protein (CRP)) For those considering ozanimod:   – EKG   – Ophthalmologic exam if history of or at risk for macular edema (diabetes, uveitis, etc.) For those considering tofacitinib and upadacitinib:   – Fasting Lipid Panel Monitoring   – All patients should undergo periodic lab monitoring (CBC and CMP)   – Biomarkers (fecal calprotectin and CRP) should be repeated based on a treat-to-target approach   – Repeat lipid panel 8-12 weeks post induction in those receiving tofacitinib and upadacitinib
Health Maintenance Considerations	Vaccination Checklist   – Annual Influenza   – Pneumonia   – Hepatitis A and B   – Recombinant non-live zoster vaccine (even if previously vaccinated with live zoster vaccine)   – COVID-19 Age-Appropriate Cancer Screening Annual Dermatologic Exam Recommended Colon Cancer Screening and Surveillance in those with UC of any extent beyond the rectum and in CD patients with more than one third of colonic involvement after 8 years of disease activity

Even though caution should be taken when treating the elderly with IBD, it is imperative that these patients be treated following a treat-to-target approach as outlined by the Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE-II) initiative [67], As with all IBD patients, regardless of age, there are higher risks associated with uncontrolled disease, delays in appropriate medical therapy, risks associated with frequent or recurrent corticosteroid use, and increase patients’ morbidity and mortality.

The future is bright for treating the elderly with IBD with more novel therapeutics becoming available. We need more comparative and real-world safety data in the elderly, along with precision diagnostic medicine that can help us risk stratify and position current and future treatments for this vulnerable patient population.

Funding

The authors did not receive support from any organization for the submitted work.

Declarations

Kara De Felice has received speaker and consultant honoraria from Abbvie, Bristol-Myers Squibb, and Takeda.

Anita Afzali has received consulting honoraria from AbbVie, Janssen, Takeda, Eli Lilly, Bristol-Myers Squibb, Pfizer, TLL Pharmaceuticals, and DiaSorin. She has received speaking honoraria from AbbVie, Bristol Myers Squibb, Janssen, and Takeda. She has received research and grant funding AbbVie, Janssen, Takeda, Eli Lilly, Pfizer, and Bristol Myers Squibb. She is a co-founder and board member of IBD Horizons and Scrubs & Heels.

Financial interests

Benjamin Clement has no financial interests.