Positioning and sequencing of advanced therapies in inflammatory bowel disease: A guide for clinical practice

Table 1 Timeframe for assessing therapeutic effectiveness in inflammatory bowel disease and associated dosing regimens

Classe of drugs	Therapeutic regimens and timeframes
Aminosalicylates (mesalazine and sulfasalazine only for mild to moderate UC)	Maximum dosing orally (4.8 g/day) combined with topical therapy for 2-4 weeks
Steroids (budesonide, prednisone, hydrocortisone)	(1) Budesonide 9 mg/day for 2 weeks; (2) Prednisone 40 mg/day PO for 2 weeks; and (3) Hydrocortisone (300-400 mg/day) or methylprednisolone (60 mg/day) IV during 3-5 days in acute severe UC
Immunosuppressant (methotrexate and thiopurines)	(1) Methotrexate 25 mg/week IM or SC for 4-6 weeks (only for CD); and (2) Thiopurines 2.0-2.5 mg/kg daily PO for 12-16 weeks (only for maintenance of remission)
Anti-TNF (infliximab, adalimumab, certolizumab pegol and golimumab)	After 2 (adalimumab, golimumab) or 3 (infliximab, certolizumab pegol) loading doses and first maintenance dose, may include proactive TDM
Anti-integrin (vedolizumab)	After 3 Loading doses and 1-3 maintenance doses
Anti-IL-12/23 (ustekinumab); Anti-IL-23p19 (risankizumab, guselkumab and mirikizumab)	After 3 Loading doses and 1-3 maintenance doses
S1P receptor modulators (ozanimod and etrasimod)	(1) Ozanimod 0.92 mg/day for 10 weeks; and (2) Etrasimod 2 mg orally once a day for 12 weeks
Janus kinase inhibitors (tofacitinib and upadacitinib)	(1) Tofacitinib 10 mg orally twice daily for 8-16 weeks; and (2) Upadacitinib 45 mg orally once a day for 8-16 weeks (UC) or upadacitinib 45 mg orally once a day for 12 weeks (CD)

UC: Ulcerative colitis; TNF: Tumoral necrosis factor; S1P: Sphingosine 1-phosphate; IL: Interleukin; PO: Per oral; IV: Intravenous; IM: Intramuscularly; SC: Subcutaneous; CD: Crohn's disease; TDM: Therapeutic drug monitoring.

Table 2 Basic principles in positioning and sequencing advanced therapies in inflammatory bowel disease

Basic principles
Start any effective drug as early as possible
Be aware: The first drug chosen will likely be the most effective for controlling IBD, particularly in Crohn's disease
Avoid repeated courses of steroids before initiating advanced therapies. The need for steroids should alert clinicians to the likely necessity of starting steroid-sparing therapeutic strategies
Assess factors that may influence the pharmacokinetics of biologics, such as hypoalbuminemia, high inflammatory load, extensive gastrointestinal involvement, and others
Consider factors that may impact on the safety of different therapies
Use the best available evidence to guide the selection of initial therapy and, when appropriate, the subsequent sequencing of treatments
Consider the potential need for treatment escalation strategies in the context of more severe disease
Always think ahead: Which agent could also be effective as a second-line treatment?
Consider the patient as a whole: Take into account factors such as age, frailty, underlying comorbidities, extraintestinal manifestations, and others
The selection of advanced targeted therapy must take into account costs, access to treatment, and any barriers to receiving therapy

IBD: Inflammatory bowel disease.

Table 3 Practical pearls in positioning and sequencing advanced therapies in ulcerative colitis and the available evidence base

Practical pearls in positioning and sequencing advanced therapies in ulcerative colitis and the available evidence base
For first line use in moderate-to-severe UC, vedolizumab demonstrated significantly higher rates of clinical remission and mucosal healing at week 52 when compared to adalimumab (RCT)
Upadacitinib is the most effective therapy for moderately-to-severely active UC, in both biologic-naive and biologic-exposed populations (NMA)
In the clinical setting in which upadacitinib cannot be used as first-line therapy (due to label restrictions or contraindications), infliximab and vedolizumab are probably the most adequate therapies to be used in the induction of remission in biologic-naive patients with moderate to severe UC (NMA, RWE)
Infliximab, ozanimod, risankizumab, and guselkumab provide a greater clinical benefit in achieving induction remission compared to adalimumab and mirikizumab in biologic-naive patients with moderate-to-severe UC, when JAK inhibitors are excluded as a first-line treatment option (NMA)
Upadacitinib appears to be superior to other therapies in achieving clinical remission, endoscopic improvement and remission, and histological remission. Selective IL-23 inhibitors, such as risankizumab and guselkumab, also exhibited high efficacy in achieving these outcomes (NMA)
In the clinical setting of moderate to severe steroid-responsive or corticosteroid-dependent UC, where the patient is not at imminent risk of hospitalization, and considering the balance of effectiveness and safety, vedolizumab can be considered as first-line therapy, although ustekinumab and interleukin-23p19 inhibitors are also good options (RWE)
In patient's refractory to first-line therapy with vedolizumab, the use of infliximab, ustekinumab, IL-23p19 inhibitors or JAK inhibitors are effective in inducing remission (RWE)
Tofacitinib and ustekinumab showed comparable corticosteroid-free remission, early response rates, and mucosal healing in UC patients refractory to anti-TNF therapy (RWE)
Tofacitinib demonstrated significantly higher corticosteroid-free clinical remission, biochemical remission and fecal calprotectin ≤ 250 μg/g when compared to vedolizumab in anti-TNF experienced patients (RWE)
Vedolizumab was superior to infliximab in patients with moderate-to-severe UC who had failed a first subcutaneous anti-TNF (adalimumab or golimumab), in clinical and endoscopic outcomes (RCT)
Lymphocyte trafficking inhibitors (anti-integrins and S1P receptor modulators) demonstrated greater efficacy in TNF antagonist-naive compared to TNF antagonist-exposed patients (NMA)
S1P receptor modulators, such as ozanimod and etrasimod, are oral agents that may be considered as first-line therapy in patients with mild to moderate UC refractory to aminosalicylates (RCT, RWE)
Ustekinumab, mirikizumab, risankizumab guselkumab and etrasimod demonstrated efficacy in moderate-to-severe UC failed prior biologic therapy (RCT)
JAK inhibitors represent promising therapeutic options for ASUC, particularly in those with prior infliximab failure (systematic review)
Combining hydrocortisone with tofacitinib in ASUC increases the likelihood of treatment response and reduces the need for salvage therapies such as colectomy (RCT)
Upadacitinib demonstrated efficacy and safety comparable to infliximab in patients with ASUC, with no significant differences in colectomy rates (RWE)
In patients with moderate to severe UC without imminent risk of hospitalization, who are elderly, frail, have severe comorbidities, or are at high risk of major cardiovascular events or thromboembolic events, vedolizumab, ustekinumab, or IL-23p19 inhibitors are the preferred therapies, and JAK inhibitors should be avoided in these clinical contexts (NMA, RWE)
In the scenario where pharmacoeconomic issues are a priority, initial therapy with biosimilars makes the first-line choice more cost-effective

Janus kinase inhibitors (including upadacitinib) are not considered in biologic-naive patients in some countries, given United States Food and Drug Administration labeling restricting the use of this class of drugs to biologic/tumoral necrosis factor antagonist exposed individuals. ASUC: Acute severe ulcerative colitis; RCT: Randomized controlled trial; UC: Ulcerative colitis; NMA: Network meta-analysis; RWE: Real-world evidence; JAK: Janus kinase; IL: Interleukin; TNF: Tumoral necrosis factor; S1P: Sphingosine 1-phosphate.

Table 4 Practical pearls in positioning and sequencing advanced therapies in Crohn's disease and the available evidence base

Practical pearls in positioning and sequencing advanced therapies in Crohn's disease and the available evidence base
For first line use in active mild-to-moderate CD refractory to conventional therapy, anti-TNF therapy, vedolizumab, anti-IL 12/23, anti-IL-23p19 may be similarly effective (RWE, NMA)
Vedolizumab is more effective when used in the first line (RCT, RWE)
In the scenario where pharmacoeconomic issues are a priority, initial therapy with biosimilars of infliximab, adalimumab or ustekinumab makes the first-line choice more cost-effective
Anti-TNF therapy (infliximab or adalimumab) preferably combined with thiopurines (for infliximab) may be the first line of treatment in severe CD (stricturing or penetrating phenotype, extensive small bowel disease, complex perianal disease, high inflammatory load or severe extraintestinal manifestation) (RCT, RWE, NMA)
Anti-TNF and anti-IL12/23 therapy are similarly effective in bio-naive patients with uncomplicated, early-onset moderate to severe CD (RCT, RWE)
Vedolizumab, anti-IL12/23, and Anti-IL-23p19 may be considered as first-line choice when safety issues become outstanding (RWE, NMA)
After failure of the first anti-TNF, advanced second-line therapies are less effective, including a second anti-TNF (RCT, RWE)
Anti-IL 12/23, anti-IL-23p19 and upadacitinib agents are still effective after failure of one or more anti-TNF (RCT, RWE)
Anti-TNF, upadacitinib, and IL-12/23 or IL-23p19 inhibitors are also effective after vedolizumab failure (RWE)
Anti-TNF, upadacitinib, and IL-23p19 inhibitors are effective after anti-interleukin 12/23 failure (RWE)
Anti-IL-23p19 are more effective than IL-12/23 inhibitors after failure of one or more anti-TNFs (RCT), with unclear data regarding upadacitinib positioning in this setting; A second anti-TNF associated with an immunosuppressor could be considered as a second choice, after pharmacokinetic failure due to immunogenicity of the first anti-TNF (RWE). The use of upadacitinib may be particularly favored for patients with high clearance of biologics, hypoalbuminemia, colonic CD, concomitant axial spondyloarthritis, or perianal fistulizing disease refractory to anti-TNF therapy

Janus kinase inhibitors (including upadacitinib) are not considered in biologic-naive patients in some countries, given United States Food and Drug Administration labeling restricting the use of this class of drugs to biologic/tumoral necrosis factor antagonist exposed individuals. CD: Crohn's disease; IL: Interleukin; TNF: Tumoral necrosis factor; NMA: Network meta-analysis; RWE: Real-world evidence; RCT: Randomized controlled trial.

Table 5 Summary of common extraintestinal manifestations, their association with intestinal activity, and recommended therapies

Extraintestinal manifestation	Association with intestinal activity	Therapies
Peripheral arthritis (type 1)	Associated	Anti-TNF agents, vedolizumab, anti-IL agents, JAK inhibitors
Peripheral arthritis (type 2)	Independent	NSAIDs (with caution), methotrexate, anti-TNF agents, JAK inhibitors
Axial spondyloarthritis	Independent	Anti-TNF agents, JAK inhibitors
Uveitis	Independent	Anti-TNF agents, topical or systemic corticosteroids
Episcleritis	Associated	IBD therapy, topical corticosteroids
Pyoderma gangrenosum	Independent or associated	1st line option: Anti-TNF agents, systemic corticosteroids; 2nd line option: Cyclosporine; 3rd line option: JAK inhibitors, anti-IL agents
Erythema nodosum	Associated	IBD therapy, systemic corticosteroids
Psoriasis and psoriatic arthritis	Independent	1st line option: Anti-IL agents; 2nd line option: Anti-TNF agents; 3rd line option: JAK inhibitors
Primary sclerosing cholangitis	Independent	Treatment is independent of IBD treatment; Ursodeoxycholic acid, liver transplantation in severe cases
Osteoporosis	Independent	Treatment is independent of IBD treatment; Calcium, vitamin D, bisphosphonates
Venous thromboembolism	Associated	Treatment is independent of IBD treatment; Anticoagulation therapy
Autoimmune hemolytic anemia	Associated	Systemic corticosteroids, immunosuppressants

IL: Interleukin; TNF: Tumoral necrosis factor; JAK: Janus kinase; IBD: Inflammatory bowel disease; NSAIDs: Non-steroidal anti-inflammatory drugs.