A. Inflammatory bowel diseases
3. Managing patients with inflammatory bowel disease: conventional and evolving
conventional and evolving immunomodulatory therapies
3.1 Goals of IBD treatments
The goal of treatment in IBD has shifted over the years, from treating symptoms to controlling inflammation to achieving remission. IBD experts of the International Organization for the Study of IBD (IOIBD) group have defined therapeutic goals by consensus. They underlined the need for objective parameters of remission beyond the absence of symptoms of disease activity to assess response/remission. They also suggested targets for the management of IBD patients, to avoid the risk of long-term disease complications cause by bowel inflammation. The main targets in CD are clinical remission, defined by patient-reported outcome measures (PROMs) like resolution of abdominal pain and altered bowel habit from disease activity, and endoscopic remission or “mucosal healing,” defined as resolution of ulceration at ileocolonoscopy or resolution of findings of inflammation from cross-sectional imaging in patients who cannot be adequately assessed with ileocolonoscopy. In UC, the targets are clinical remission, defined as resolution of rectal bleeding and altered bowel habit related to the disease activity, and endoscopic remission, defined as mucosal healing, indicated by a Mayo endoscopy score of 0 or 1. Together, clinical and endoscopic remission define “deep remission,” which improves QoL, reduces need for hospitalization and surgery, and lowers colorectal cancer risk.74
Changing the treatment goal and targeting both clinical and endoscopic remission could change the course of the disease and slow its progress.
3.2 Conventional therapies in IBD
Understanding of the mechanisms that cause IBD to develop has improved over the last twenty years, leading to significant advances in effective IBD treatment.75 Choice of treatment depends on location and severity, drug efficacy, desire to minimize adverse effects, and the preferences of the patient. The treatment has 2 phases: the induction of response/remission followed by a maintenance period during which therapy should be continued to prevent relapse.
3.2.1 Aminosalicylates
Aminosalicylates, also known as 5-aminosalicylic acid (5-ASA) or mesalazine, can be used to induce and maintain remission in mild to moderate UC, but are not an effective
12 therapeutic option in CD.76 5-ASA’s can be delivered orally or to the rectum with enemas, foam, or suppositories, acting as a topical anti-inflammatory. Administering oral and rectal therapy together potentiates the effect of the drug.
3.2.2. Corticosteroids
Corticosteroids are usually used to induce remission in mild to moderate IBD which requires rapid symptom management. They are not considered as a maintenance therapy because they often cause high rate of long-term side effects and do not prevent relapse. Usually, patients are slowly tapered of steroids and introduced to corticosteroid-sparing drugs for long term management.77 For mild to moderate CD with disease located in the ileum and/or ascending colon Budesonide, an oral steroid, can be used to induce response. This
formulation of steroids is substantially metabolized in the first pass, leading to low systemic bioavailability that limits its systemic toxicity and lead to a selected effect on the GI tract.
More recently a multi-matrix (MMX) budesonide formulation was developed to induce response in UC when 5-ASA therapy was insufficient.
3.2.3 Immunomodulators
IBD patients who failed 5-ASA treatment or have become dependent on corticosteroids can be treated with immunomodulators agents like thiopurines (azathioprine and
6-mercapropurine) and methotrexate. Thiopurines can be used to maintain remission in CD and UC. Because it takes up to 6 months before patients see an effect, they cannot be used for induction or for steroids non-responder patients.78,79 Thiopurines can also be associated with serious adverse events. The enzyme thiopurine S-methyltransferase (TPMT) is
responsible for the metabolism of thiopurines. Polymorphism of this enzyme is common and can trigger accumulation of toxic metabolites linked to bone marrow suppression or
hepatotoxicity.80 TPMT activity should be assessed before thiopurine treatment is started and patients with no, or low, TPMT activity should not be treated with this enzyme.8182 Other adverse events like pancreatitis, allergic reaction, infection, and increased risk of cancer, especially in elderly patients (lymphoma, non-melanoma skin cancers, urinary tract cancers), have been reported for thiopurines.83
Methotrexate can be an alternative immunomodulator to azathioprine for CD induction and maintenance treatment but is ineffective in treating UC. Remission is usually induced by administering intramuscular injections of 25mg/week of methotrexate followed by
15mg/week po for maintenance. Folic acid supplements are required because methotrexate inhibits the enzyme dihydrofolate reductase, producing a state of effective folate deficiency.
Taking folic acid also improves some of the side effects of the drug 84,85 which include
13 nausea and vomiting, hepatotoxicity, bone marrow suppression, and pulmonary fibrosis.
Methotrexate is teratogenic in women and can cause azoospermia in men.
Immunomodulator monotherapy has lost its appeal, given its limited efficacy and side-effect profile, but it still plays an important role in “combotherapies”. Combining azathioprine and infliximab, an anti-tumor necrosis factor alpha (anti-TNFα) agent, improves disease control and reduces immunogenicity of the anti-TNFα.86,87 The latest guidelines recommend combining thiopurine at start of therapy with infliximab to induce remission in patients with moderate-to-severe CD non-responders to conventional therapy, but the effects of
combination with other biologic treatment are still uncertain. 88
3.3 Biologic treatments and small molecules in IBD
Dysregulation of the immune system in IBD patients stimulates production of proinflammatory cytokines like tumor necrosis factor (TNF)-α, which plays a key role in the pathogenesis of the disease and adhesion molecules. In the early 2000s, targeting those cytokines led to the development of TNF inhibitors. Infliximab, a chimeric monoclonal antibody between murine and human amino-acid sequences, was the first approved for both induction and maintenance of CD and UC. This revolutionized IBD management after the pivotal ACCENT and ACT trials were published.89,90 Since then, we have added an increasing array of biologic and small-molecule therapies to our medical arsenal,91 including newer drugs directed at inflammatory cytokines and leukocyte-trafficking molecules. Among these treatments approved for CD and UC are vedolizumab, which blocks the interaction between an integrin on the surface of gut-specific lymphocytes and a receptor on the vascular endothelium of the intestinal tract (α4β7 and MAdCAM-1, respectively), and ustekinumab, which is directed against the common p40 subunit of interleukin IL-12/23. A newer promising UC treatment strategy blocks the JAK/STAT signaling pathway. The latest accepted drug, tofacitinib, is also a promising target, since many cytokines activate JAK signaling during inflammatory response. Several other molecules in this category are in the last phases of investigation for CD treatments (filgotinib, upadacitinib etc.). These new therapeutic options are valuable because they open alternative pathways to therapy if one treatment fails. Many new pathways are in the pipeline, e.g., a sphingosine1-phosphate receptor modulator (a selective small molecule agonist for G protein-coupled S1P receptor [S1P1]), leads to internalization of the S1P1 receptor on the surface of C-C chemokine receptor type 7 positive lymphocytes, trapping these lymphocytes in lymph nodes.92
Patients should have a pre-immunosuppression screening that includes, at minimum, a tuberculosis and hepatitis B check, and should be counseled about lymphoma risk, and asked about vaccination status and personal or family cancer history.93
14 Many biologics have demonstrated therapeutic effects in IBD treatment but despite dramatic progress over the last few years, IBD therapies are far from sufficient. At the individual level, the first biologic treatment seems to be most effective and patients often have a diminished response to second-line biologics.94,95 Up to 30% of all patients newly diagnosed with IBD do not reach clinical remission and mucosal healing with their first anti-TNFa therapy (primary non-responders),96 and many stop responding to drugs every year (secondary non-responders)97. The annual risk of secondary non-response rate varies from 13% per patient year for infliximab (IFX)98 to 20% for adalimumab.99 Newer biologics targeting different inflammatory pathways pose the same problems as anti-TNF agents since many patients do not respond but there are few before-and-after comparison with anti-TNFa therapy. In 2019, the results of the VARSITY trial, the first head-to-head randomized controlled trial between biologic agents with different modes of action in IBD, were published.100 VARSITY compared the efficacy and safety of intravenous vedolizumab and subcutaneous adalimumab in patients with moderate-to-severe active ulcerative colitis. Head-to-head trials comparing other treatment options like etrolizumab (a monoclonal antibody against β7 integrin) and infliximab or ustekinumab and adalimumab are ongoing, with results expected in the next 5 years. These results might dramatically change our clinical practice.
Mechanisms underlying primary non-response are multifactorial and include disease aspect and characteristics and treatment strategy-related factors. The “one size- fits-all” approach is not appropriate for a many patients and the need to personalize care in IBD patients is high.
Clinicians should choose the right drug at the right time for the right patient, and shift their approach from “reactive” management driven by disease complications to “proactive”
management with the goal of preventing disease complications.
15