Ulcerative colitis treatment Flashcards
What is treatment for ulcerative colitis guided by
UC can be classified both by severity and by extent.[4] Treatment is guided by both factors. Distal disease (proctitis and left-sided disease, below splenic flexure) is generally amenable to topical therapies. Extensive disease (pancolitis, beyond splenic flexure) requires systemic therapy. Treatment differs also between management of acute flare-ups (severe or fulminant disease) and maintenance of remission (mild-to-moderate disease). Fulminant disease is managed as an emergency to prevent life-threatening complications such as toxic megacolon and perforation
How are acute episodes of mild-moderate distal colitis managed
Treatment of mild-to-moderate distal disease is with topical mesalazine or topical corticosteroids and oral mesalazine (5-aminosalicylic acid [5-ASA]). Rectal 5-ASA should be considered as the first-line therapy for patients with mild-to-moderately active distal UC.[29][28] Topical therapy with oral mesalazine therapy is more effective than either alone. Choice of topical, oral, or a combination of topical and oral therapy is guided by patient choice as well as effectiveness. A meta-analysis of 12 randomised controlled trials (RCTs) investigating the relative efficacies of oral and topical 5-ASA therapy, and a combination of the two, for adults with mild-to-moderately active UC concluded that combined 5-ASA therapy appeared superior to oral 5-ASAs for induction of remission.[30] Single topical doses of mesalazine have been shown to be as effective as multiple daily dosing in distal disease.[31] Once-daily oral dosing has also been shown to be as effective as conventional dosing, and is safe.[32][33] When using conventional corticosteroids rectally, it should be remembered that approximately half the dose is absorbed; this can cause adverse effects if the corticosteroid is used long term.[34][35][36] Patients refractory to these agents require oral corticosteroids. If there is inadequate response to oral prednisolone after 2 to 4 weeks, consider addition of oral tacrolimus in mild-to-moderate UC to induce remission
Describe the potential use of second-generation corticosteroids in the management of acute episodes of mild-moderate distal colitis
Second-generation corticosteroids, such as budesonide multi-matrix system, are starting to emerge as a primary treatment option in mild-to-moderate UC.[38][39] They are associated with significantly fewer corticosteroid-related adverse events than conventional corticosteroids.[40] Multi-matrix technology may facilitate adherence by reducing the pill burden
Describe the maintenance of remission in mild-moderate distal colitis
Most patients with mild-to-moderate disease require maintenance therapy. The patient and clinician often need to discuss and decide whether it is needed. Remission can be maintained with topical mesalazine suppositories in proctitis or enemas in left-sided disease. Topical therapy in combination with oral mesalazine is more effective than oral therapy alone. Topical mesalazine is effective in preventing relapse of quiescent UC in left-sided disease and proctitis,[42] and intermittent topical 5-ASAs appear to be superior to oral 5-ASAs for preventing relapse of quiescent UC.[30] Topical corticosteroids are not effective for maintaining remission. Oral beclometasone may also be considered for maintenance of remission depending on patient preference
Describe the management of acute episodes of mild-to-moderate extensive disease
An oral 5-ASA is the first-line treatment option. Complete remission within 4 weeks is seen in 80% of patients who receive a high daily dose. Sulfasalazine and mesalazine are first-line agents. There is more clinical experience with sulfasalazine than with mesalazine, balsalazide, or olsalazine. Delayed-release mesalazine 4.8 g/day for 6 weeks is more efficacious at inducing remission than 2.4 g/day and has a similar adverse-effect profile.[43] Oral corticosteroids are second-line if oral 5-ASAs are ineffective. This is usually effective within 1 to 2 weeks, after which it should be tapered very slowly. If there is inadequate response to oral prednisolone after 2 to 4 weeks, consider addition of oral tacrolimus in mild-to-moderate UC to induce remission.[37]
Second-generation corticosteroids, such as budesonide multi-matrix system, are starting to emerge as a primary treatment option in mild-to-moderate UC.[38][39] They are associated with significantly fewer corticosteroid-related adverse events than conventional corticosteroids.[40] Multi-matrix technology may facilitate adherence by reducing the pill burden
Describe the maintenance of remission in mild-to-moderate extensive disease
Oral 5-ASA therapy is required to control disease. It has been found to be superior to placebo for maintenance therapy in UC.[44] The optimum dose is between 2 and 3 g/day and does not have to be given in divided doses.[45][46][47][48][49] Patients requiring corticosteroid therapy for recurrent flare-ups should be treated with corticosteroid-sparing agents for refractory disease. Oral beclometasone may also be considered for maintenance of remission depending on patient preference
Describe severe colitis
Severe disease is defined as passage of ≥6 bloody stools daily, pulse rate of at least 90 bpm, temperature of at least 37.5°C (99.5°F), haemoglobin level of <105 g/L (10.5 g/dL), and erythrocyte sedimentation rate of at least 30 mm/hour. Patients should be treated with topical therapy and oral 5-ASA at maximal doses, and systemic corticosteroids. If symptoms persist despite maximal doses of oral and topical therapy, the patient should be admitted and treated with parenteral corticosteroids. After 3 days of parenteral corticosteroids, >8 stools on that day, or a stool frequency between 3 and 8 together with a CRP >428 nmol/L (45 mg/L), predicts 85% of patients who will require a colectomy. If patients do not improve after 3 days, treatment with ciclosporin or infliximab should be considered, or referral for surgery.[50][51] Infliximab has been shown to be superior to placebo in inducing remission of moderate-to-severely active UC.[52] Following a severe flare-up that has settled medically, many patients will need thiopurine therapy
Summarise the urgent treatment of fulminant distal and extensive colitis
Patients with fulminant colitis have >10 bowel movements daily with continuous or massive uncontrolled bleeding, or severe toxicity including the development of toxic megacolon (severe abdominal pain, tenderness, distension, and colonic dilation [expansion]) with signs of sepsis.[4] These patients should be admitted and parenteral corticosteroids commenced. Depending on the clinical situation, intravenous fluids may be needed, but there is no place for “bowel rest”. Most guidelines also recommend broad-spectrum antibiotics, although clinical trials have not demonstrated a beneficial effect on survival. Fulminant or severe colitis is seen in up to 15% of patients. Up to 20% of this subset progress to toxic megacolon, which carries with it the risks of perforation and death. Colectomy is indicated if the patient does not respond to, or worsens despite, aggressive medical therapy within 24 to 48 hours. Further waiting will rarely avoid the need for colectomy and carries a substantial risk of perforation, which is associated with 50% mortality in this context. Patients who are relatively stable and respond partially or sub-optimally to intravenous corticosteroids within 72 hours should be considered for infliximab or ciclosporin induction therapy.
Describe the delay of colectomy in the urgent management of distal and extensive colitis
Most practitioners try to avoid or delay colectomy. However, it should be emphasised that the decision to delay surgery and try rescue therapy with either infliximab or ciclosporin should be individualised, especially in cases of fulminant colitis as compared with severe or refractory colitis. There is evidence on the efficacy of ciclosporin and infliximab as rescue therapy (i.e., colectomy saving or delaying). One multicentred European trial looked at patients with corticosteroid refractory UC, treated with either infliximab or ciclosporin salvage therapy with a median follow-up of 5.4 years. Colectomy-free survival rates at 1 and 5 years were, respectively, 70.9% and 61.5% in patients who received ciclosporin and 69.1% and 65.1% in those who received infliximab. Long-term colectomy-free survival was independent from initial treatment. These long-term results further confirm the similar efficacy and good safety profile of both drugs and do not favour one drug over the other.[53] Observational studies have suggested that an intensified infliximab dosing regimen (an additional 1-2 infusions within the first 3 weeks of treatment) could benefit at least 50% of patients with acute severe UC, and reduce short-term colectomy rates by up to 80%.[54] However, the optimum dosing schedule and patient characteristics for maximal efficacy and safety need to be defined.
Describe the use of thiopurines in refractory disease
Thiopurines
Thiopurines (azathioprine and mercaptopurine) are recommended in corticosteroid-dependent patients and are effective agents for relapse prevention.[28][55][56] Thiopurine metabolite monitoring is becoming more widely available and can be used to optimise drug dosage, therefore enhancing efficacy
Describe the use of TNF-a inhibitors in refractory disease
Tumor necrosis factor (TNF)-alpha inhibitors
Infliximab is an established treatment for Crohn’s disease and has been shown to be effective in the treatment of refractory UC. It is effective as a long-term maintenance therapy for UC and it should be considered as an alternative to induce and maintain disease remission.[63][64]
Adalimumab and golimumab are approved by the US Food and Drug Administration (FDA) for inducing and sustaining clinical remission in adult patients with moderate-to-severe active UC who have had an inadequate response to immunosuppressants such as corticosteroids, azathioprine, or mercaptopurine. One systematic review found that adult patients with moderate-to-severe active UC receiving infliximab, adalimumab, or golimumab after the failure of conventional therapy were more likely to achieve clinical response and remission than those receiving placebo.[65] One randomised, double-blind, placebo-controlled trial evaluating the efficacy of adalimumab in the induction and maintenance of clinical remission in 494 patients with moderate-to-severe UC who received concurrent treatment with oral corticosteroids or immunosuppressants showed that it was more effective than placebo in inducing and maintaining clinical remission, and had the same frequency of serious adverse events.[66] Golimumab has been shown to induce clinical remission and mucosal healing in patients with moderate-to-severe active UC with a similar safety profile to other TNF-alpha inhibitors
Describe the use of vendolizumab in refractory disease
Vedolizumab
Vedolizumab, a monoclonal antibody against alpha 4 beta 7 integrin, has been shown to be more effective than placebo as induction and maintenance therapy for UC and has been through phase 3 trials.[69] Furthermore, one Cochrane review carried out a meta-analysis of four RCTs of vedolizumab, and found it to be more effective than placebo for inducing clinical remission, clinical response, and endoscopic remission in patients with moderate-to-severe active UC, and for preventing relapse in patients with quiescent UC.[70] Vedolizumab has demonstrated a favourable safety profile.[71] One meta-analysis of controlled trial data found that the efficacy of vedolizumab for the induction and maintenance of mucosal healing in UC was similar to that of TNF-alpha inhibitors,[72] and another suggested that vedolizumab may lead to a more sustained clinical response
Describe the use of tofacitinib in refractory disease
Tofacitinib
Tofacitinib is an oral small molecule Janus kinase (JAK) inhibitor. It is approved in Europe for the treatment of moderately to severely active UC in patients who have had an inadequate response, lost response, or were intolerant to either conventional therapy or a biological agent.[74]
Phase 3 RCTs have demonstrated that tofacitinib is superior to placebo for the induction and maintenance of remission of moderately to severely active UC (Mayo score 6-12) in patients previously treated with conventional therapy or a TNF-alpha inhibitor.[75]
One ongoing clinical trial (in patients with rheumatoid arthritis aged >50 years with at least one cardiovascular risk factor) reported an increased risk of blood clots in deep veins and in the lungs with tofacitinib at doses of both 5 mg and 10 mg twice daily, compared with a TNF-alpha inhibitor.[76] Combined with data from earlier studies, the risk of blood clots was found to be higher in patients taking the 10-mg twice daily dose (the induction dose for UC) and for those being treated for extended periods. Results also showed an increased risk of serious infections in patients aged >65 years
What is important to remember about tofacitinib
The European Medicines Agency (EMA) recommends that:
Tofacitinib should be used with caution in patients at high risk of blood clots.
A maintenance dose of 10 mg twice daily should not be used in patients with UC who are at high risk of blood clots unless there is no suitable alternative treatment.
Patients aged >65 years should also only be treated with tofacitinib when there is no alternative treatment.
The EMA lists the following high-risk factors for blood clots:[77]
Use of combined hormonal contraceptives or hormone replacement therapy
Heart failure
Previous heart attack
Previous venous thromboembolism, either deep venous thrombosis or pulmonary embolism
Inherited coagulation disorder
Malignancy
Patients undergoing major surgery.
Other risk factors that may increase the risk of blood clots and should be considered when prescribing tofacitinib are age, obesity (BMI >30 kg/m²), diabetes, hypertension, smoking, and immobilisation.[77]
The US Food and Drug Administration recommends that tofacitinib should be:
Avoided in patients with UC who may be at increased risk of thrombosis
Reserved as a second-line therapy for use in patients who have failed or cannot tolerate TNF-alpha inhibitors.
Tofacitinib should be prescribed at the lowest effective dose; the 10-mg twice daily dose should be limited to the shortest duration needed (minimum 8 weeks, maximum 16 weeks)
Describe the use of cyclosporin in refractory disease
Ciclosporin
Ciclosporin can be used to induce or maintain remission but requires very careful monitoring. Ciclosporin is controversial because of toxicity (drug-associated mortality is about 3%) and the long-term failure rate.[37][66][67] Serum cholesterol should be checked before giving the drug; low cholesterol levels can predispose patients to seizures.
