Selecting first-line advanced therapy for ulcerative colitis: A clinical application of personalized medicine

Abstract

Ulcerative colitis (UC) is a chronic autoimmune inflammatory disease that affects the colon, leading to symptoms of bloody diarrhea, abdominal cramps, and urgency. The treatment of UC has evolved over the past few decades from locally active anti-inflammatory compounds to more selective therapies that target specific arrays of the immune system. The challenge of selecting the first advanced therapy became apparent in this rapidly expanding landscape of medications. No current investigational tools, such as genetic, immunologic, or biological markers, can guide the identification of the safest and most effective therapeutic option for each patient. Hence, physicians must carefully assess patient/disease characteristics and match them with the most suitable drug through a clinically driven assessment. In this paper, we outline patient and drug characteristics that play a role in selecting first-line advanced therapies for UC and propose an algorithm for selection.

BACKGROUND

Crohn’s disease (CD) and ulcerative colitis (UC) are the two major types of inflammatory bowel disease (IBD). Although both diseases have much in common, fundamental phenotypic differences exist.[1,2,3,4] UC tends to cause bloody diarrhea, tenesmus, and mucous discharge and its involvement is limited to the mucosa of the colon, classically starting distally at the rectum, and spreading proximally. UC could result in different complications in severe diseases such as toxic megacolon or exsanguination.[3,4,5]

Management of UC follows a stepwise approach as opposed to CD, where risk stratification plays an essential role in determining how to select therapy.[6,7] An exception to this rule for UC is acute fulminant colitis,[8] where patients with UC are admitted to the hospital for rescue therapy through intravenous (IV) steroids, infliximab, or cyclosporine.[6] The treatment strategy currently adopted for UC and CD is the treat-to-target.[9] This strategy entails close follow-up and serial monitoring of response to treatment within a predetermined time frame using a pre-set treatment goal. Failure to reach the previously chosen goal triggers treatment escalation, which could be in the form of dose intensification of existing therapy, add-on therapy, or switching to another treatment option.[9] Many patients with UC successfully respond to first-line therapy, which has been primarily 5-aminosalicylic acid (5-ASA) derivatives for decades. 5-ASA derivatives can be given orally, rectally, or in combination and have a favorable safety profile.[6] Studies have reported clinical and endoscopic remission rates with 5-ASA derivatives that reach 70% and 60%, respectively.[10,11]

In clinical trials where at least 50% of included patients had left-sided or extensive disease, combination therapy (comprising oral and rectal treatment) demonstrated superiority. Conversely, in trials with ≥50% of patients diagnosed with proctitis or proctosigmoiditis, topical mesalazine showed superiority. High-dose oral mesalazine (≥3.3 g/day) consistently maintained the third position across various analyses, encompassing most patient groups and trials.[8,12]

While thiopurine monotherapy is not recommended for inducing remission in UC, its use in combination with anti-tumor necrosis factor (anti-TNF) agents is supported by evidence from the UC SUCCESS trial, which demonstrated that 39.7% of patients receiving combination therapy achieved remission, compared to 22.1% and 23.7% of patients receiving infliximab and azathioprine monotherapies, respectively.[13,14]

For the maintenance of remission in UC patients who have failed or are intolerant to 5-ASA, azathioprine and 6-mercaptopurine may be effectively employed.[15] Mercaptopurine treatment was proven to be superior to placebo in patients with active UC refractory to 5-ASA in a recent prospective, randomized, double-blind, placebo-controlled trial.[12] Despite these facts, up to 50% of patients with moderate to severely active UC fail to respond to first-line treatments and qualify for treatment escalation to advanced therapies.[5,16]

Advanced therapy for UC includes biological and non-biologic agents known as small molecules. Over the past two decades, multiple biologics have been developed that differ regarding frequency and route of administration, risk of infection, and potential for immunogenicity.[17,18,19] The traditional class of biologic therapy that has been used successfully to manage UC for more than two decades is the anti-tumor necrosis factor-alpha (anti-TNF α) class of biologics. For many years, anti-TNF α agents were the only existing form of biologics used for UC, with shortcomings that include a higher relative risk of causing opportunistic infections and potential for immunogenicity, which can lead to loss of response to therapy.[6,18,20,21,22,23] Three anti-TNF α therapies are currently approved for UC, which include infliximab, adalimumab, and golimumab.[22] Subsequently, selective leukocyte trafficking inhibitors (SLAMIs), or anti-adhesive therapies, were introduced as treatment options for UC.[24,25] This class of biologics has the advantage of being gut-selective with a negligible risk of causing opportunistic infection and a low potential for immunogenicity.[22]

On the other hand, the gut selectivity of SLAMIs also diminishes its therapeutic effect on extraintestinal disease manifestations (EIMs) of IBD.[24,26] Vedolizumab, an anti-alpha4beta7, is the only SLAMI currently approved for UC. Another humanized monoclonal immunoglobulin (IgG1) antibody is etrolizumab, which inhibits the α4β7 and αEβ7 integrins, compared to vedolizumab, which selectively blocks the α4β7 integrin.[27] Etrolizumab controls inflammatory effects on the gut lining in addition to trafficking of immune cells into the gut.[28] The HICKORY trial showed that more patients with moderately to severely active UC, previously treated with anti-TNF agents, achieved remission at week 14 with etrolizumab compared to placebo. However, there was no significant difference in remission at week 66 between groups among patients with a clinical response at week 14.[29]

More recently, anti-cytokines targeting the interleukin (IL) 12/23 pathway became a focus of drug development, with several anti-IL-12/23 and anti-IL-23 being developed and approved for UC.[30,31] Until recently, ustekinumab was the only anti-cytokine approved for induction and maintenance of remission for UC. Anti-cytokines, in general, are associated with a low risk of opportunistic infections and a low potential for immunogenicity.[30,31]

Non-biologics, known as small molecules, are the most recent addition to the drug armamentarium for UC and include Janus kinase (JAK) inhibitors and sphingosine-1 phosphate-1 (S1P1) inhibitors.[32] Small molecules are oral agents that target inflammation by acting intracellularly. JAK inhibitors target the Janus Kinase/signal transducers and activator of transcription (JAK/STAT) signaling pathway with a wide range of selectivity.[33] JAK inhibitors have been used successfully to treat other autoimmune diseases, including rheumatoid arthritis (RA) and atopic dermatitis (AD).[34] Three JAK inhibitors are currently approved for treating UC: Tofacitinib, upadacitinib, and filgotinib.[32] These agents are characterized by rapid onset of action, low potential for immunogenicity, and a modest effect on EIMs.[32] However, they are associated with specific systemic side effects such as increased risk of infection, metabolic derangements, and risk of venous thromboembolism (VTE).[32] S1P1 inhibitors are oral agents that interfere with the ability of lymphocytes to follow the S1P gradient into lymph nodes where inflammation incites, trapping them in lymph nodes. S1P1 inhibitors have been successfully used to treat multiple sclerosis (MS). S1P1 inhibitors are associated with an increased risk of infection, hepatotoxicity, and cardiotoxicity.[35] Currently, among the class of S1P1 inhibitors, only ozanimod has been approved for treating UC.[35] Etrasimod is another S1P1 inhibitor in the final stages of approval for treating UC [Table 1].[36]

Table 1.

Characteristics of different classes of advanced therapy used to treat ulcerative colitis

Class	Route	Frequency	Risk of infection	Risk of malignancy	Potential for immunogenicity	Effect on EIMs
Anti-TNF	IV/SC	2–8 weeks	High	Moderate	High	High
SLAMIs	IV/SC	2–8 weeks	Low	Low	Low	Low
Anti-cytokines	IV/SC	4–12 weeks	Low	Low	Low	Moderate
JAK inhibitors	Oral	Daily	High	Moderate	Low	High
S1P1 inhibitors	Oral	Daily	Moderate	Unknown	Low	Unknown

With this extended number of options for managing moderate to severe UC, the ability to select the first line of advanced therapies for each patient has become exceedingly challenging, especially in the absence of biomarkers that can help guide such selection. It is prudent to consider different clinical aspects carefully before selecting the appropriate advanced therapy. In the remaining parts of this article, we discuss various clinical elements that should be considered when determining the first choice of advanced treatment for moderate to severe UC.

PATIENT AND DISEASE CHARACTERISTICS

Age

Patients with IBD are typically diagnosed between the ages of 20 and 40 years.[37] However, some patients are diagnosed earlier or later.[37] For example, IBD is seldom diagnosed in older patients (>60 years of age) and is termed “Elderly-onset IBD.”[38] Furthermore, in improved healthcare worldwide, patients with IBD grow older with the disease and face the challenges of typical comorbidities that occur beyond 40.[39] Accordingly, age directly affects the selection of advanced treatment for UC. Patients older than 50 years have a higher risk of developing diabetes mellitus (DM), dyslipidemia, hypertension, and malignancy.[40] Additionally, this increases the risk of infection in this age group.[39,41] For these reasons, treatment selection must consider age to mitigate the risk of such side effects.[42] Anti-TNF therapy has been associated with the risk of infection, major adverse cardiovascular events (MACE), and solid tumors.[43] JAK inhibitors have been linked to the development of infection and metabolic derangements such as dyslipidemia and VTEs.[44] Similarly, S1P1 inhibitors have been associated with infection risk, macular edema, and arrhythmias.[35] In comparison, SLAMI[45] and anti-cytokines[46] have favorable safety profiles and seem to be the most rational first choice when the start of advanced therapy is decided in this age group.

Effectiveness

A knowledge gap exists regarding the comparative effectiveness of different UC therapies due to the limited number of head-to-head studies. The VARSITY trial directly compared the effectiveness of two biologics and provided valuable results that demonstrated the superiority of vedolizumab over adalimumab in terms of clinical remission (31.3% vs. 22.5%, P = 0.006) and endoscopic improvement (39.7% vs. 27.7%, P < 0.001) at week 52 within the VARSITY cohort of moderate to severe UC patients.[47] Multiple network meta-analyses (NMAs) have attempted to compare different biologics and non-biologic treatments of UC. Results have so far demonstrated comparable effectiveness.[11,18]

The phase 3 clinical program for etrolizumab, which included HIBISCUS I and II and GARDENIA, is the largest head-to-head program, enrolling over 3000 patients, and explored both induction and maintenance regimens.[48] In the HIBISCUS I and HIBISCUS II, etrolizumab was evaluated against adalimumab or placebo in adult patients with moderate to severe UC. Etrolizumab exhibited superiority over placebo for inducing remission in HIBISCUS I, but not in HIBISCUS II. In the pooled analysis, etrolizumab did not demonstrate superiority over adalimumab. Both studies reported good tolerability of Etrolizumab.[48] GARDENIA is the first phase three maintenance study which used infliximab as an active comparator in moderate to severely active UC. In this comparative study, etrolizumab did not achieve statistical superiority for the primary endpoint, but it demonstrated comparable clinical results to infliximab. However, a higher number of patients in the etrolizumab group reported serious adverse events, including serious infections, compared to those in the infliximab group (32 vs. 20).[7,49,50]

Risk of infection

Effectiveness is rarely the primary consideration when selecting advanced UC medication, as safety considerations are equally important and take priority over effectiveness. This is because, ultimately, the physician’s first ethical duty towards their patients is to “not harm.” To estimate the overall risk of infections or complications that a patient may face, it is advisable to thoroughly evaluate the patient’s comorbidities, including DM and other chronic diseases, vaccination records, history of infectious exposures, future risk of exposure through occupation or travel, and concurrent use of corticosteroids or immunosuppressant medications, before selecting a new advanced therapy.

a. Patient-related risks:

Malnutrition, advanced age, severe UC, congenital causes of immune deficiency, and acquired ones (e.g., human immunodeficiency virus (HIV) infection), are all considered risk factors for opportunistic infections (OIs). A case-control study of OI in IBD confirmed that older age – specifically being older than 50 years – resulted in a threefold increased relative risk of OIs compared to younger age.[51] Interestingly, being at either end of the body mass index (BMI) spectrum, i.e., malnourished, or obese, has also been linked to an increased risk of OIs. The challenges physicians face regarding OI extend far beyond establishing a diagnosis or selecting proper treatment, as these infections can significantly complicate a patient’s health status, leading to added morbidity, mortality, and the need for recurrent hospital visits and admissions for IBD patients. Pre-biologic screening work-up and guidance on how to treat latent tuberculosis (TB), hepatitis, or HIV co-infection, as well as advice on health optimization and proper vaccination before initiating new medication, are beyond the scope of this review. However, numerous valuable guidelines have been published.[52,53] This review summarizes the available evidence and provides a suggested scheme for selecting advanced UC therapies.

b. Medications-related facts:

Head-to-head comparisons of the safety of different classes of UC medications are sparse. While advanced UC medications are highly effective in controlling inflammation in IBD, they are associated with increased risks of severe infections and other side effects. As expected, various classes of advanced UC medications exhibit distinct risk profiles based on their mechanism of action, gut selectivity, the potential for drug–drug interactions, and the level of immunosuppression they induce.[54,55,56] Solitano et al.[57] recently conducted a systematic review and meta-analysis, analyzing evidence from 20 head-to-head studies to compare the safety profiles of advanced therapies in IBD, including biologics and small molecules. Compared to patients receiving anti-TNF treatments, UC patients treated with vedolizumab showed a 32% reduced risk of serious infections (11 cohorts; odds ratio (OR) 0.68; 95% confidence interval [CI] 0.56–0.83).

Interestingly, a subgroup analysis stratified by age did not reveal a significant difference in the rate of severe infections among older patients. Moreover, a further study that excluded non-serious gastrointestinal (GI) infections also showed no significant disparity between the two therapies (three cohorts; OR 0.68; 95% CI: 0.43–1.07).[57] A head-to-head comparison of anti-TNF and ustekinumab, derived from five studies, did not reveal any significant difference in severe infections between the two therapies within the mixed cohort of IBD patients. However, subgroup analysis based on disease phenotype indicated that ustekinumab led to a 51% reduced risk of severe infections in CD patients compared to anti-TNF treatments. Regrettably, a meta-analysis comparing anti-TNF and ustekinumab in the subgroup of UC patients was infeasible due to inadequate data availability.

Consequently, a knowledge gap persists regarding a direct safety profile comparison for UC patients. Similarly, the data is insufficient to conduct a meta-analysis comparing vedolizumab and ustekinumab in the UC patient population. Nonetheless, the analysis of the mixed IBD cohort (five studies; 1420 patients) demonstrated no significant disparity in serious infections between patients receiving either therapy. Notably, the subgroup analysis conducted among CD patients showed a 60% reduction in severe infections with ustekinumab.

Another comparative study that included 19,096 IBD patients on anti-TNF, 2420 on ustekinumab, and 305 on tofacitinib found that 44% of patients on anti-TNF therapy developed infections, with 7% requiring hospitalizations related to these infections. In comparison, patients in the tofacitinib group exhibited a 41% infection rate and a 6% hospitalization rate due to infections. Compared to anti-TNF therapy, a significantly lower risk of infection was observed with ustekinumab, while tofacitinib exhibited comparable risks in terms of infection (hazard ratio (HR) = 0.97; 95% CI: 0.75–1.24) and hospitalizations related to infections (HR = 0.59; 95% CI: 0.27–1.05).[43,58] Direct comparisons of infection risks between different classes of small molecules are presently lacking.

EIMs

Various EIMs are observed in IBD patients, affecting systems such as the musculoskeletal system, skin, liver, biliary tract, or eyes, with prevalence rates ranging from 6% to 47%.[59] Common anti-TNF-dependent pathways are shared between IBD and certain EIMs, such as arthritis, ocular manifestations, and skin-related EIMs.[60] Therefore, it is notsurprising that the class of anti-TNF biologics proves beneficial in treating UC patients with TNF-dependent EIMs.[61] This effectiveness has been confirmed in numerous studies for infliximab, adalimumab, and certolizumab, each assessed separately in studies.[62,63,64,65,66,67] The evidence supporting golimumab’s efficacy in EIMs is derived indirectly, extrapolated from studies of golimumab in patients with other immune-mediated inflammatory diseases (IMIDs) like RA and ankylosing spondylitis (AS).[68] In conclusion, it is safe to emphasize that the efficacy of anti-TNF agents is well-established for treating conditions such as axial spondyloarthropathy, peripheral arthritis, uveitis, episcleritis, erythema nodosum (EN), and pyoderma gangrenosum (PG), despite the absence of head-to-head comparison within the anti-TNF class.

Vedolizumab is an approved anti-integrin for treating IBD, functioning by selectively targeting lymphocyte trafficking to the site of inflammation, namely the gastrointestinal tract. Vedolizumab has the advantage of a favorable safety profile. Nevertheless, a recent meta-analysis revealed only weak evidence concerning vedolizumab’s efficacy in addressing EIMs, specifically arthritis, cutaneous issues, and primary sclerosing cholangitis (PSC).[69] This lack of effectiveness is notsurprising, given its targeted mechanism of action and the absence of shared inflammatory pathways with EIMs. When EIMs coincide with disease flare and active inflammation in UC patients, employing vedolizumab to attain clinical remission and indirectly addressing EIMs – whose severity corresponds to disease activity – appears rational. Nevertheless, its direct application for targeting EIMs is not advised due to limited evidence.

Ustekinumab is approved for treating IBD and other IMIDs, including psoriasis and psoriatic arthritis.[68] However, proper study of IBD-related EIMs still needs to be improved. Limited case reports and case series evidence suggest that ustekinumab could effectively treat peripheral musculoskeletal, ocular, and cutaneous EIMs.[70]

Like ustekinumab, JAK inhibitors are sanctioned for treating RA and psoriatic arthritis, potentially offering a foundation for their use in addressing IBD-related arthritis.[70] Moreover, JAK-STAT upregulation has been noted in patients with IBD and cutaneous EIMs, notably PG and EN.[71,72] The evidence for the possible effectiveness of tofacitinib and filgotinib is substantiated by their approval for IMIDs and supported by limited real-world evidence from case reports and series.

Currently, ozanimod and etrasimod are approved as therapies for moderate to severely active UC. To date, no available data evaluates this medication class’s efficacy in patients with EIMs.

Childbearing potential

Evaluating the childbearing potential of a female patient with IBD is necessary before prescribing therapy for IBD to avoid using medications detrimental to pregnancy-related outcomes.

Pregnancy

a. Fertility/preconception

Tofacitinib at supratherapeutic levels demonstrated an increase in the rate of post-implantation loss in animal studies, consequently negatively affecting the fertility of female rats.[73] Similarly, animal studies involving filgotinib showed impaired spermatogenesis and decreased male fertility.[74] A clinical trial (clinicaltrials.gov NCT03201445) is currently underway to assess the impact of filgotinib on human fertility. Apart from the results of the animal studies in JAK inhibitors, there is no current evidence that any of the classes of advanced UC therapies adversely affect male or female fertility. Until clinical trial results become available, it is advisable to consider switching patients on JAK or S1P inhibitors to another class.[75,76]

Systematic reviews and meta-analyses have confirmed that the prevalence of adverse pregnancy outcomes, including congenital malformations, stillbirth, early pregnancy loss, and premature birth, in IBD patients treated with anti-TNF, vedolizumab, and ustekinumab is consistent with the prevalence in the general population.[77,78] The combined prevalence rates were 0% (95% CI: 0–0%; I₂ = 0%) for stillbirth, 1% (95% CI: 1–2%; I₂ = 78.3%) for congenital malformations, 8% (95% CI: 6–10%; I₂ = 87.4%) for early pregnancy loss, 8% (95% CI: 5–10%; I₂ = 87.0%) for low birth weight, and 9% (95% CI: 7–11%; I₂ = 89.9%) for preterm birth. Based on the available evidence, discontinuing biologics during pregnancy is not recommended, particularly for patients with difficult-to-control disease, recent flares before conception, and those experiencing active disease.[79]

However, despite the confirmed safety of the majority of IBD medications, the potential consequences of fetal exposure to IBD medication during pregnancy continue to raise concerns among individuals with IBD and their healthcare providers. These concerns often lead to medication discontinuation before or during pregnancy. In a study assessing the views and perceptions of females with IBD regarding medication use during pregnancy, a significant portion (36%) of participants believed that all IBD medications could harm the health of unborn children. Contrary to established evidence, approximately 24% of participants tolerated symptoms instead of receiving medications, driven by their misconception that IBD medications are harmful.[80]

A qualitative study highlighted the concerns of women with IBD regarding fertility, pregnancy management, and the postpartum period, despite receiving regular obstetric and tertiary IBD care. The most significant worry among participants was the potential impact of their medication on pregnancy and offspring, with specific fears including concerns about medication effects on the child’s immune system and a general lack of data, leading to uncertainty about medication safety. Participants also expressed a cultural belief that taking medications during pregnancy contradicted maternal instinct and could potentially harm their babies, irrespective of disease severity or medication type.[81] Counseling patients before conception about the increased risk of UC disease flare during pregnancy and postpartum is crucial.[82] It aims to establish that the overall benefits of the medication outweigh any potential harm. Addressing patient concerns during these discussions can help resolve misunderstandings that might lead to medication non-adherence or discontinuation.

While evidence of the safety of vedolizumab and ustekinumab during pregnancy is limited, the few published studies have not documented any negative impact on pregnancy.[75] Given this limitation compared to the available data for anti-TNF agents, the latter class may appear preferable for expectant mothers to consider starting during pregnancy.

Animal studies on rats and rabbits have indicated the teratogenic potential of fetal exposure to tofacitinib, leading to internal and external soft tissue and skeletal malformations.[83] Similar findings were observed in filgotinib animal studies.[74] Due to the absence of human studies, JAK inhibitors are contraindicated in pregnancy. This lack of human safety data is also the basis for ozanimod and etrasimod being contraindicated during pregnancy.

b. Breastfeeding

Biologics are generally considered safe during breastfeeding and can be continued. However, data for small molecules is limited, and the manufacturing labels recommend discontinuing breastfeeding while on tofacitinib and filgotinib.[79]

Recommendations regarding the timing of the last dose of biologics concerning delivery, restarting biologics in the postpartum period, and any required alterations in the neonatal vaccination schedule are addressed in the updated European Crohn’s and colitis organization (ECCO) guidelines.[84]

Previous history of solid tumors

It has been suggested that immune suppression from biological treatments could be linked to an increased risk of cancer development in individuals undergoing such treatment. Although studies have been undertaken to evaluate this risk, most prior studies, and clinical trials have excluded patients with a history of cancer. Consequently, there is limited evidence regarding the potential for cancer recurrence risk associated with biologics.[85,86,87]

Currently, guideline recommendations regarding the optimal timing for resuming or initiating anti-TNF therapy in patients with a prior history of solid tumors are diverse, spanning a range of 2–5 years of drug holidays after the completion of cancer treatment.[88,89]

A recent systematic review established that patients with a cancer history when subjected to anti-TNF therapy, do not face an elevated risk of new or recurring cancer compared to a control group receiving non-biologic disease-modifying treatments. When considering specific cancer types investigated, no apparent variations in the risk of new cancer incidence or cancer recurrence were observed among individuals with a solid tumor malignancy or skin cancer background. This observation holds even when examining subgroups that exclude skin cancers.[85]

Real-world data and experience with newer biologics are comparatively briefer than those for anti-TNF therapy; nevertheless, it appears that vedolizumab and ustekinumab, as supported by the limited available data on IBD patients and data extrapolated from non-IBD studies in the case of ustekinumab, are not linked to an increased risk of cancer recurrence.[86]

In the ORAL Surveillance trial, there was a documented higher risk of malignancy associated with tofacitinib when contrasted with TNF inhibitors. The applicability of these findings to other JAK inhibitors remains uncertain.[90]

In an NMA conducted on randomized controlled trials (RCTs), JAK inhibitors demonstrated a notably elevated occurrence of all malignancies, including non-melanoma skin cancer (NMSC), in comparison to TNF inhibitors, but not when compared to placebo or methotrexate.[91] Similar estimations were derived from NMAs directly comparing JAK with TNF inhibitors.

Given the lack of sufficient evidence regarding the safety of small molecule use in patients with a history of cancer and considering the increased malignancy signal with tofacitinib, it is advisable to refrain from implanting these therapies within this group.

Drug characteristics

Onset of action

Rapid resolution of symptoms is an important treatment consideration for patients with moderate to severe UC. This helps improve their quality of life and prevents the need for prolonged corticosteroid use. While this swift onset of action is particularly crucial for hospitalized patients with severe UC, to reduce complications and the need for surgery, it is also significant for all individuals with UC who experience troubling symptoms of active diseases, such as bloody diarrhea, urgency, or incontinence. Small molecules offer the benefit of quick response, illustrated by tofacitinib as an example, where a decrease of one point in stool frequency and rectal bleeding score was observed within the initial 3 days of treatment.[92,93,94] In a comprehensive review and NMA that integrated both direct and indirect data from 14 trials focusing on the speed of relief from symptoms in patients with moderate to severe UC using various advanced therapies (excluding tofacitinib at Week 2), upadacitinib exhibited remarkable superiority over all other alternative advanced treatments in promptly resolving symptoms within the first 2 weeks. Subsequently, ozanimod demonstrated a relatively lower efficacy rate in achieving rapid symptomatic improvement when compared with JAK inhibitors and anti-TNF therapy. Nevertheless, ozanimod led to higher rates of symptomatic remission as time progressed, at Weeks 6 and 8. Lastly, vedolizumab and ustekinumab showed a prolonged time frame for symptom resolution in patients previously exposed to anti-TNF therapies, in contrast to those who were biologic-naïve.[95]

Other aspects

Risk of immunogenicity and need for concomitant immunosuppression

Given that biological agents are composed of large and complex proteins, there is the potential for them to induce the development of antibodies with a specific affinity for the administered agent. When this happens, the impact of immunogenicity on the effectiveness of biological treatments can be substantial. Therefore, it is advisable for patients who develop antibodies, which lead to a reduced response to the biological therapy, to consider transitioning to an alternative treatment option.

Research findings indicate that the risk of immunogenicity is inherent to all biological treatments, although the reported frequencies of anti-drug antibodies (ADAbs) formation exhibit notable variability. The highest reported rate, at 65.3%, was observed with infliximab therapy. Furthermore, ADAbs have been shown to reduce treatment efficacy and lead to a loss of treatment response. In the case of infliximab, there is an increased incidence of adverse events (AEs). Despite the variable nature of the immunogenicity risk, no clinical tools are currently available for predicting this risk in patients before initiating therapy. Moreover, while concomitant immunosuppression can help mitigate this risk, the combined treatment carries an increased risk of immunosuppression, susceptibility to infections, and side effects.[96]

The potential clinical consequences of reduced biological serum concentrations decreasing treatment effectiveness, and heightened safety concerns in the presence of immunogenicity are significant issues that require further research to develop effective treatment strategies.

Compared to biologics, small molecules do not carry the risk of immunogenicity; their most significant advantage is potentially promising sustained effectiveness. However, when administered orally, these drugs may have variable bioavailability and could be associated with an increased drug–drug interaction risk.[97]

Malignancy

The potential association between exposure to anti-TNF therapies and the subsequent risk of developing skin cancers, including melanoma and NMSC, initially arose from observational studies.[87] However, more recent and accumulating data, including findings from the TREAT long-term study of Crohn’s patients, has indicated that anti-TNF monotherapy does not increase the risk of malignancy.[98] It has been observed that adalimumab, when administered as part of combination therapy rather than as a monotherapy, was associated with a higher risk of NMSC (relative risk (RR) = 3.46; 95% CI: 1.08–11.06) and other types of neoplasms (RR = 2.82; 95% CI: 1.07–7.44).[99] This conclusion also gained support from a recent systematic review examining eleven studies investigating the relationship between anti-TNF treatments and malignancies, showing no increased risk. However, in one of the 11 studies, an elevated risk of lymphoma was reported in patients exposed to TNF inhibitors.[87]

Research into the risk of lymphoma associated with anti-TNF monotherapy has yielded mixed findings. Some studies have reported an elevated risk of lymphoma even when anti-TNF monotherapy was administered. In contrast, others have found no increased risk unless anti-TNF was combined with immunomodulators.[100] In a recent meta-analysis comprising 28 studies (20 retrospective and eight prospective), involving 298,717 IBD patients, the connection between tumor-necrosis factor inhibitors (TNFi) and malignancy was investigated in 11 studies (39.3%). Of these studies, 10 of them revealed no significant association, while one study reported an elevated risk of lymphoma in patients exposed to TNFi.[87] In one study that showed an increased risk of lymphoma with both combination therapy, thiopurine monotherapy, and anti-TNF monotherapy, a higher risk was observed with combination therapy. One potential bias of this study was that approximately 35% of patients who received anti-TNF monotherapy had prior exposure to thiopurines.[101]

Regarding vedolizumab, although there is limited long-term data and real-world evidence available, safety evaluations from clinical trials and GEMINI long-term safety (LTS) studies have not identified any significant increase in the risk of solid-organ or hematologic malignancies. The most common malignant condition was basal cell carcinoma, with an incidence of less than 1% in both UC and CD patients. The rates of malignancies across all types were 9.8 per 1000 person-years in UC and 8.3 in CD, suggesting that vedolizumab does not have a notable impact on the overall malignancy rates.[102]

A pooled analysis of six phase 2/3 studies for CD and psoriasis showed a good safety profile for ustekinumab. The incidence of malignancy (excluding NMSC) was low and comparable with that of the placebo. Moreover, in the IM-UNITI trial, malignancy rates were not increased compared to placebo across all age subgroups.[103,104,105]

Tofacitinib has been associated with an increased risk of neoplasms. This risk has also been observed in RA and psoriasis and the IBD population during the long-term extension (OLE) study named OCTAVE Open. In the ORAL surveillance study, which monitored patients with RA receiving tofacitinib and compared them to those receiving anti-TNFs over a 5.5-year follow-up, there was an elevated risk of malignancies (6.1% for tofacitinib vs. 3.8% for anti-TNFs), with a HR for adjudicated cancers (excluding NMSC) of 1.48 (95% CI: 1.04–2.09). Age above 65 and smoking were also identified as risk factors.[90,106]

Metabolic derangements such as glucose intolerance, dyslipidemia, electrolyte imbalance, or hormonal disturbances are not commonly observed with biological therapies.[107]

VTE

Patients with IBD have an inherently high risk of developing VTE due to excess circulating pro-inflammatory cytokines. This risk increases during disease activity; hence, patients admitted with acute flares should receive prophylactic treatment. JAK inhibitors have been linked with an increased risk of VTE, specifically in patients with multiple cardiac risk factors.[17,32,91,97,108,109] This association was observed in data from the oral surveillance program that identified an increased risk of VTE in old patients with RA and multiple cardiac risk factors treated with tofacitinib.[109] Accordingly, various authorities recommend avoiding use of JAK inhibitors in this patient population.[17,32,91,97,108,109]

Patient preference

It is essential to address patient preferences and values while selecting first-line advanced therapies for UC. While the above discussion focuses primarily on clinical factors, we acknowledge that patients may have different priorities or concerns that could influence their treatment decisions. As part of patient-centered care, shared decision-making could help align treatment choices with patient goals and values.[110,111,112]

Suggested algorithm for selection

There is no agreed-upon pathway to select the first choice of advanced therapy for UC. Furthermore, this selection process is not aided by objective tools such as genetic markers, serological tests, or biologic markers, similar to what is utilized in oncology. As such, the process depends solely on the physician’s ability to tailor therapy to the patient’s needs, based on clinical characteristics and corresponding matched drug characteristics. The authors’ proposed algorithm encompasses four significant clinical aspects: age, risk of infection, presence of EIMS, and childbearing potential. Assessing the patient’s age as a first step is crucial, as patients above 50 are vulnerable to infection and malignancy.

For this reason, this age group should favor the use of gut-selective agents and anti-cytokines. In patients younger than age 50, advanced therapies are otherwise considered equally favored. The second step in the algorithm involves a detailed assessment of the risk of infection, whether due to comorbidities or high-risk exposures, for example, occupation. In patients with a higher risk of infection, gut-selective agents and anti-cytokines should be prioritized over other advanced therapies. Conversely, if the risk of infection is considered low (average risk), advanced treatments are otherwise considered equally favored. Third, the presence of EIMs warrants special attention as some advanced therapies are proven more effective for EIMs than others. In the company of EIMs, anti-TNF α agents and JAK inhibitors have an advantage over other treatments and should therefore be favored. Finally, addressing childbearing potential is crucial, given that certain therapy classes, such as JAK and S1P1 inhibitors, are not proven safe during pregnancy and should be avoided accordingly. A detailed description of the proposed algorithm is outlined in Figure 1.

Figure 1.

A detailed description of the proposed algorithm for selection of advanced UC therapies

CONCLUSIONS

The medical management of UC is rapidly evolving through the introduction of newly developed, effective, and safe advanced therapies. As this large armamentarium of drugs collides with the challenge of selecting the ideal first treatment choice, matching patient and drug characteristics remains the best approach to navigate this expanding armament of medications. Future development of personalized medicine tools that aid in identifying therapies that better serve patient needs is a research priority.

Author contribution statement

Both authors, MSM and MHM, contributed equally to the conceptualization of this review article, the review of the literature, and the writing of the paper, including the final editing and revision. The suggested algorithm was created by MHM and reviewed by MSM.

Financial support and sponsorship

Nil.

Conflicts of interest

Dr. Mosli has served as a speaker for Janssen, Abbvie, Pfizer, Takeda, Hikma, Sandoz, and Organon; he also served as an advisory board member for AbbVie, Hikma, Janssen, Pfizer, Takeda, Amgen, BMS, Novartis, Ferring, Organon, Sandoz, and Falk.

Dr. Mukhtar has received speaker fees from Takeda, Pfizer, Ferring, and Amgen.