S. C. Ng; F. K. L. Chan; J. J. Y. Sung
Alimentary Pharmacology & Therapeutics. 2011;33(4):417-427. © 2011
Abstract and Introduction
Abstract
Background Up to one-third of patients with inflammatory bowel disease (IBD) do not respond to, or are intolerant of conventional immunosuppressive drugs. Although biological agents are alternative treatments, they may not be suitable or available to some patients.
Aim To review the evidence for use of nonbiological drugs in the treatment of patients with IBD refractory to corticosteroids or thiopurines.
Methods A literature search was performed using PubMed for English language publications with predetermined search criteria to identify relevant studies.
Results Published evidence from uncontrolled series and controlled clinical trials has been used to produce a practical approach relevant to clinical practice which incorporates the indication, optimal dose, and side effects of various therapies including tacrolimus, methotrexate, thalidomide, tioguanine, mycophenolate mofotil, leucocyte apheresis, nutritional therapy, antibiotics, probiotics, allopurinol, rectal acetarsol and ciclosporin in the treatment of patients with refractory ulcerative colitis and Crohn's disease. Approaches to optimise thiopurine efficacy are also discussed.
Conclusions Patients with IBD refractory to corticosteroids or thiopurines may respond to alternative anti-inflammatory chemical molecules, but the evidence base for many of these alternatives is limited and further trials are needed.
Introduction
The medical management of patients with refractory inflammatory bowel disease (IBD) remains a challenge. Up to one-third of patients with IBD are intolerant of,[1] and a further 10% are unresponsive to thiopurine.[2] Although anti-tumour necrosis factor (anti-TNF) drugs have proven to be effective in patients with Crohn's disease (CD)[3] and ulcerative colitis (UC),[4] only approximately one-fifth of all initially treated CD and UC patients are in remission at 1 year. There is still a large gap in the therapeutic armamentarium of both conditions. Additionally, in many developing countries around the world where the incidence of IBD is increasing,[5,6] funding of anti-TNF agents, if available, is limited to only a small proportion of patients.[7] Patients with active disease in whom surgery may not be appropriate will require ongoing treatment to maintain remission. There is a lack of controlled data comparing different treatment strategies for patients who have failed standard therapies. In patients with refractory disease, methotrexate, tacrolimus, leucocyte apheresis, enteral nutrition, thioguanine(tioguanine) or thalidomide may have a role, but the benefit of anti-bacterial therapy in IBD remains controversial. With recent advances in our understanding of thiopurine metabolism, dose optimisation and therapeutic manipulation to avoid toxicity is possible. In this review, we have discussed the evidence of efficacy, optimal dose, drug monitoring and adverse effects of these anti-inflammatory therapies in the treatment of patients with resistant UC and CD; although subjective, they are based on published experience.
Methods
Search was performed on PubMed of all original research studies and reviews published in English-language journals, with a last cut off publication date of March 2010, using the following keywords alone or in combination: Crohn's disease, ulcerative colitis, refractory, resistant, tacrolimus, methotrexate, thalidomide, tioguanine, mycophenolate mofotil, leucocyte apheresis, nutritional therapy, antibiotics, probiotics, allopurinol, arsenic suppository and ciclosporin enema. Abstracts presented at the Digestive Disease Week (DDW), European Crohn's and Colitis Organisation (ECCO) Meeting, and United European Gastroenterology Week (UEGW), within the last 10 years were also included. In contrast to published guidelines or consensus statements,[8,9] this review is intended neither to be a systematic review, nor an evaluation of the merits of different levels of evidence. It is intended as a selection of the most relevant publications that demonstrate points of therapeutic importance in optimisation of existing treatment regimens, and novel therapeutic approaches, relevant to the treatment of patients with refractory IBD. Double-blind placebo-controlled studies are included when available, but the evidence for most of these drugs has been based on uncontrolled cohort studies, retrospective series and expert review articles. For the purpose of this review, we have defined 'conventional therapy' as 'mesalazine (mesalamine)', corticosteroids or thiopurines. We have included studies exploring the use of alternative drugs in patients with IBD refractory to these standard therapies.
Main Stream Evidence-based Drug
Methotrexate. Methotrexate is effective in IBD but the mechanisms by which methotrexate reduce inflammation remain unclear. Putative pathways include the inhibition of cellular proliferation, downregulation of inflammatory mediators and the induction of apoptosis.[10–12] In UC, the only double-blind, placebo-controlled trial from Israel compared low-dose oral methotrexate 12.5 mg weekly to placebo in 67 active UC patients. There was no significant difference in the induction or maintenance of remission between the two groups, although the lack of benefit may relate to the lower dose of methotrexate used.[13] In contrast, uncontrolled studies with small sample size, varying doses or route of adminstration have shown that methotrexate is effective in maintaining remission in patients with steroid-dependent UC intolerant of thiopurines.[14,15] In a retrospective study, 23 patients intolerant or resistant to thiopurines were treated with subcutaneous methotrexate 20–25 mg weekly. Remission was achieved in 11 patients and symptomatic improvement in three patients.[16] A recent retrospective series from London showed that two-thirds of UC patients refractory to and intolerant of thiopurines responded to oral methotrexate.[17] In a randomised comparative trial of low-dose oral methotrexate (15 mg/week) vs. mercaptopurine (MP, 1.5 mg/kg/day) vs. 5-aminosalicylate (ASA) in 72 steroid-dependent patients (half had UC), remission rates at 30 weeks was 79%, 58% and 25% for methotrexate, MP and 5-ASA respectively.[18] More comparative studies with different doses and different routes of administration are required in UC before any definite conclusions can be drawn.[19] Two well-designed controlled trials have confirmed the efficacy of parenteral methotrexate in steroid-dependent or steroid-refractory, thiopurine-naïve CD patients.[20,21] The benefit of methotrexate in patients with CD who have failed thiopurines has only been subjected to one small uncontrolled study.[17]
Practice points and adverse effects: Data supporting the use of methotrexate for the induction and maintenance of remission in refractory UC have been based on small retrospective series. Although the exact dose and route of administration for treating such patients are unclear, most series have achieved a benefit with parenteral methotrexate 25 mg weekly (with weekly folic acid) for 3 months followed by oral methotrexate 15 mg weekly. Methotrexate, intramuscularly or subcutaneously, is effective in steroid-dependent or -refractory CD patients. The benefit of methotrexate in CD patients who have failed thiopurines, and vice versa, is less clear. The onset of peak of methotrexate is achieved after 12 weeks of treatment. Main adverse effects include bone marrow suppression and liver toxicity. Monitoring of complete blood count and liver function tests at regular intervals (approximately three monthly) is recommended. In patients with persistently abnormal liver function tests of unknown cause, methotrexate should be discontinued and liver biopsy should be performed due to the risk of hepatic fibrosis. Methotrexate is not suitable for women of child bearing age and it is contraindicated in pregnancy due to embryo-toxicity.[22]
Alternative Anti-inflammatory Molecules
Tacrolimus. Tacrolimus is a calcineurin inhibitor. It has similar mechanisms of action to ciclosporin by inhibiting the production of interleukin (IL)-2 and T lymphocyte activation.[23] Several uncontrolled series have shown that it is effective in the treatment of patients with UC, including those who are intolerant or refractory to conventional immunomodulators.[24–29] The only controlled trial of tacrolimus in UC from Japan randomised 20 steroid-refractory UC patients into each of the following arm: high trough level (10–15 ng/mL whole blood), low trough level (5–10 ng/mL whole blood) and placebo. At the end of 2 weeks, significantly more patients in the high trough (68%) and low trough groups (38%) responded compared with placebo (10%).[30] Twenty percent of patients achieved clinical remission and 79% of patients had mucosal healing.[30,31] In the medium term, oral tacrolimus is effective in UC patients resistant to conventional therapy, including some who are refractory to anti-TNF drugs. Half of those with UC achieved remission at a median follow-up of 5 months.[32] In a study of 14 patients with severe steroid-refractory UC, 64% of patients were in remission at about 6 months.[29] In a German study of 31 patients with steroid-refractory IBD, 65% achieved remission at 1 year.[33,34] In a long-term prospective study from Japan, cumulative colectomy-free survival was 62% at 65 months. Colectomy-free survival was significantly higher in patients who have responded to tacrolimus within 30 days than those who have not.[35] These data are important in helping to predict patients who will eventually require a colectomy. Rectal tacrolimus is effective in patient with refractory distal colitis. In a study of 19 patients with refractory left-sided colitis or proctitis, three-quarter of patients responded after 4 weeks of tacrolimus enema (2–4 mg) or tacrolimus suppository (2 mg).[36] A randomised placebo-controlled study of tacrolimus enema in distal UC is currently in progress in Australia.
In perianal fistulising CD, one controlled trial has shown that oral tacrolimus was superior to placebo, although fistula healing was not different between the two groups.[37] In luminal CD, the benefit of tacrolimus has only been demonstrated in small uncontrolled studies.[28,33,34,38–40]
Practice points and adverse effects: Tacrolimus is an effective alternative therapy for patients with refractory UC and luminal and perianal fistulising CD. Response is superior in patients with UC than those with CD.[33,34] It has a rapid onset of action usually within 2 weeks, therefore it can also be used as a bridge to thiopurine. Start 0.1 mg/kg/day oral tacrolimus in two divided doses, and measure serum trough levels at 2 weeks, followed by every 6–8 weeks and aim for trough level of 5–10 ng/mL. Consider dose reduction or cease treatment if renal impairment develops. Common side effects of tacrolimus include hypertension, paraesthesia, tremor and headache. Hypomagnesaemia, renal impairment (usually reversible), hyperglycaemia or gastrointestinal disturbances may be present in about half of the treated patients.[30] The more predictable oral bioavailability and better side-effect profile makes tacrolimus more favourable compared with ciclosporin.[41] Opportunistic infection is an important consideration,[42] and standard prophylaxis with co-trimoxazole has been recommended by the ECCO in patients on triple immuno-immunomodulators with one of these being a calcineurin inhibitor or an anti-TNF agent.[43]
Thalidomide Thalidomide has re-emerged as a potent anti-inflammatory and immunosuppressive drug. The effects of thalidomide relate, in part, to the down-regulation of TNF-α, and the inhibition of angiogenesis.[44] It also inhibits NFκB activity, and suppresses IL-12.[45,46] Several uncontrolled studies have shown that thalidomide is effective in patients with refractory luminal and fistulising CD, and those with oral and upper gastrointestinal CD. In an open-label study of 12 male patients with steroid-dependent luminal CD treated with low-dose thalidomide (50–100 mg each night), 70% of patients responded and 20% were in remission by 3 months. The onset of action may be as rapid as 2 weeks.[47] In a separate study from Chicago using higher doses of thalidomide (200–300 mg each night), three-quarter of patients responded at 1 month, and 40% were in remission at 3 months.[48] In both these studies, most of the patients were naïve to biological drugs. In a retrospective series from St Mark's Hospital London, 25 treatment-resistent CD patients received a median dose of thalidomide 100 mg each night and 75% and 60% with luminal and fistulising disease respectively, responded at 12 months. Half of those with fistulising disease achieved healing. Most patients have failed azathioprine, MP, methotrexate, and some have also failed anti-TNF drugs.[49] In patients who have responded to infliximab, thalidomide can be used as a bridging therapy to maintain remission.[50]
Practice points and adverse effects: In uncontrolled studies of luminal and fistulising CD, thalidomide is effective and has steroid-sparing properties. Response and remission rates are 70% and 20% respectively. Efficacy usually occurs within 4 weeks. Long-term use is often limited by toxicity in particularly peripheral neuropathy. Start with a dose of 25–50 mg nocte, and increase to 100 mg if tolerated. Baseline nerve conduction study can be performed if available locally although no studies have evaluated the significance of abnormal baseline nerve conduction study on clinical outcome. Side effects of thalidomide include teratogenicity, drowsiness, peripheral neuropathy and rash. Peripheral neuropathy has been reported in up to 50% of patients, and in most patients it is mild and reversible. The incidence of neuropathy is related to the total cumulative dosage, and most cases of neuropathy occur after 40–50 g of thalidomide. Patients are required to use strict contraceptive measures whilst on thalidomide and must not conceive during, or up until at least 6 months after stopping the drug (manufacturer's recommendation).
Mycophenolate Mofotil. Mycophenolate mofotil (MMF) selectively inhibits lymphocyte proliferation.[51] It has been used to treat patients with thiopurine-refractory IBD, but its efficacy has not been supported by controlled trials.[52–55] In a series from the UK, 17 of 70 patients with resistant UC and CD were maintained in remission with MMF for a mean duration of 33 months.[52] At 5 years follow-up, approximately one-fifth of patients achieved steroid free remission, one-fifth discontinued treatment due to side effects, and half required an escalation in medical therapy or surgery because of failure of the therapy.[55] Gastrointestinal toxicity, usually manifested as diarrhoea, is the most common side effect of MMF.[56] The induction of colitis with histological features similar to those associated with intestinal Graft vs. Host disease has been reported in patients treated with MMF.[57] There is currently no convincing evidence of the efficacy of MMF in the treatment of IBD, and its use in this condition should be confined to trial settings.
Arsenic Suppository/Ciclosporin Enema. In patients with proctitis or distal UC refractory to topical 5-ASA, a combination of oral corticosteroids with rectal 5-ASA or immunomodulators, can be used. Experimental therapies such as arsenic (acetarsol) suppositories[58] or ciclosporin enemas[59,60] may have a role in very resistant cases.[61,62] In a small prospective open-label study, ten patients with intractable proctitis were treated with arsenic suppositories 250 mg twice daily for 4 weeks. Nine of ten patients achieved symptomatic and sigmoidoscopic improvement within 2 weeks. Side effects were minimal and arsenic levels dropped rapidly when acetarsol was withdrawn.[58] The mechanism of action of arsenic is unclear. Open trials of ciclosporin enemas for refractory distal UC have shown favourable results although a placebo-controlled study of ciclosporin enema 350 mg daily vs. placebo in 40 patients with mild to moderately active distal UC have shown no difference in symptom improvement after 4 weeks of treatment.[63] In patients with resistant proctitis, acetarsol suppositories or ciclosporin enemas may enable some patients to achieve remission prior to the consideration of surgery.
Alimentary Pharmacology & Therapeutics. 2011;33(4):417-427. © 2011
Abstract and Introduction
Abstract
Background Up to one-third of patients with inflammatory bowel disease (IBD) do not respond to, or are intolerant of conventional immunosuppressive drugs. Although biological agents are alternative treatments, they may not be suitable or available to some patients.
Aim To review the evidence for use of nonbiological drugs in the treatment of patients with IBD refractory to corticosteroids or thiopurines.
Methods A literature search was performed using PubMed for English language publications with predetermined search criteria to identify relevant studies.
Results Published evidence from uncontrolled series and controlled clinical trials has been used to produce a practical approach relevant to clinical practice which incorporates the indication, optimal dose, and side effects of various therapies including tacrolimus, methotrexate, thalidomide, tioguanine, mycophenolate mofotil, leucocyte apheresis, nutritional therapy, antibiotics, probiotics, allopurinol, rectal acetarsol and ciclosporin in the treatment of patients with refractory ulcerative colitis and Crohn's disease. Approaches to optimise thiopurine efficacy are also discussed.
Conclusions Patients with IBD refractory to corticosteroids or thiopurines may respond to alternative anti-inflammatory chemical molecules, but the evidence base for many of these alternatives is limited and further trials are needed.
Introduction
The medical management of patients with refractory inflammatory bowel disease (IBD) remains a challenge. Up to one-third of patients with IBD are intolerant of,[1] and a further 10% are unresponsive to thiopurine.[2] Although anti-tumour necrosis factor (anti-TNF) drugs have proven to be effective in patients with Crohn's disease (CD)[3] and ulcerative colitis (UC),[4] only approximately one-fifth of all initially treated CD and UC patients are in remission at 1 year. There is still a large gap in the therapeutic armamentarium of both conditions. Additionally, in many developing countries around the world where the incidence of IBD is increasing,[5,6] funding of anti-TNF agents, if available, is limited to only a small proportion of patients.[7] Patients with active disease in whom surgery may not be appropriate will require ongoing treatment to maintain remission. There is a lack of controlled data comparing different treatment strategies for patients who have failed standard therapies. In patients with refractory disease, methotrexate, tacrolimus, leucocyte apheresis, enteral nutrition, thioguanine(tioguanine) or thalidomide may have a role, but the benefit of anti-bacterial therapy in IBD remains controversial. With recent advances in our understanding of thiopurine metabolism, dose optimisation and therapeutic manipulation to avoid toxicity is possible. In this review, we have discussed the evidence of efficacy, optimal dose, drug monitoring and adverse effects of these anti-inflammatory therapies in the treatment of patients with resistant UC and CD; although subjective, they are based on published experience.
Methods
Search was performed on PubMed of all original research studies and reviews published in English-language journals, with a last cut off publication date of March 2010, using the following keywords alone or in combination: Crohn's disease, ulcerative colitis, refractory, resistant, tacrolimus, methotrexate, thalidomide, tioguanine, mycophenolate mofotil, leucocyte apheresis, nutritional therapy, antibiotics, probiotics, allopurinol, arsenic suppository and ciclosporin enema. Abstracts presented at the Digestive Disease Week (DDW), European Crohn's and Colitis Organisation (ECCO) Meeting, and United European Gastroenterology Week (UEGW), within the last 10 years were also included. In contrast to published guidelines or consensus statements,[8,9] this review is intended neither to be a systematic review, nor an evaluation of the merits of different levels of evidence. It is intended as a selection of the most relevant publications that demonstrate points of therapeutic importance in optimisation of existing treatment regimens, and novel therapeutic approaches, relevant to the treatment of patients with refractory IBD. Double-blind placebo-controlled studies are included when available, but the evidence for most of these drugs has been based on uncontrolled cohort studies, retrospective series and expert review articles. For the purpose of this review, we have defined 'conventional therapy' as 'mesalazine (mesalamine)', corticosteroids or thiopurines. We have included studies exploring the use of alternative drugs in patients with IBD refractory to these standard therapies.
Main Stream Evidence-based Drug
Methotrexate. Methotrexate is effective in IBD but the mechanisms by which methotrexate reduce inflammation remain unclear. Putative pathways include the inhibition of cellular proliferation, downregulation of inflammatory mediators and the induction of apoptosis.[10–12] In UC, the only double-blind, placebo-controlled trial from Israel compared low-dose oral methotrexate 12.5 mg weekly to placebo in 67 active UC patients. There was no significant difference in the induction or maintenance of remission between the two groups, although the lack of benefit may relate to the lower dose of methotrexate used.[13] In contrast, uncontrolled studies with small sample size, varying doses or route of adminstration have shown that methotrexate is effective in maintaining remission in patients with steroid-dependent UC intolerant of thiopurines.[14,15] In a retrospective study, 23 patients intolerant or resistant to thiopurines were treated with subcutaneous methotrexate 20–25 mg weekly. Remission was achieved in 11 patients and symptomatic improvement in three patients.[16] A recent retrospective series from London showed that two-thirds of UC patients refractory to and intolerant of thiopurines responded to oral methotrexate.[17] In a randomised comparative trial of low-dose oral methotrexate (15 mg/week) vs. mercaptopurine (MP, 1.5 mg/kg/day) vs. 5-aminosalicylate (ASA) in 72 steroid-dependent patients (half had UC), remission rates at 30 weeks was 79%, 58% and 25% for methotrexate, MP and 5-ASA respectively.[18] More comparative studies with different doses and different routes of administration are required in UC before any definite conclusions can be drawn.[19] Two well-designed controlled trials have confirmed the efficacy of parenteral methotrexate in steroid-dependent or steroid-refractory, thiopurine-naïve CD patients.[20,21] The benefit of methotrexate in patients with CD who have failed thiopurines has only been subjected to one small uncontrolled study.[17]
Practice points and adverse effects: Data supporting the use of methotrexate for the induction and maintenance of remission in refractory UC have been based on small retrospective series. Although the exact dose and route of administration for treating such patients are unclear, most series have achieved a benefit with parenteral methotrexate 25 mg weekly (with weekly folic acid) for 3 months followed by oral methotrexate 15 mg weekly. Methotrexate, intramuscularly or subcutaneously, is effective in steroid-dependent or -refractory CD patients. The benefit of methotrexate in CD patients who have failed thiopurines, and vice versa, is less clear. The onset of peak of methotrexate is achieved after 12 weeks of treatment. Main adverse effects include bone marrow suppression and liver toxicity. Monitoring of complete blood count and liver function tests at regular intervals (approximately three monthly) is recommended. In patients with persistently abnormal liver function tests of unknown cause, methotrexate should be discontinued and liver biopsy should be performed due to the risk of hepatic fibrosis. Methotrexate is not suitable for women of child bearing age and it is contraindicated in pregnancy due to embryo-toxicity.[22]
Alternative Anti-inflammatory Molecules
Tacrolimus. Tacrolimus is a calcineurin inhibitor. It has similar mechanisms of action to ciclosporin by inhibiting the production of interleukin (IL)-2 and T lymphocyte activation.[23] Several uncontrolled series have shown that it is effective in the treatment of patients with UC, including those who are intolerant or refractory to conventional immunomodulators.[24–29] The only controlled trial of tacrolimus in UC from Japan randomised 20 steroid-refractory UC patients into each of the following arm: high trough level (10–15 ng/mL whole blood), low trough level (5–10 ng/mL whole blood) and placebo. At the end of 2 weeks, significantly more patients in the high trough (68%) and low trough groups (38%) responded compared with placebo (10%).[30] Twenty percent of patients achieved clinical remission and 79% of patients had mucosal healing.[30,31] In the medium term, oral tacrolimus is effective in UC patients resistant to conventional therapy, including some who are refractory to anti-TNF drugs. Half of those with UC achieved remission at a median follow-up of 5 months.[32] In a study of 14 patients with severe steroid-refractory UC, 64% of patients were in remission at about 6 months.[29] In a German study of 31 patients with steroid-refractory IBD, 65% achieved remission at 1 year.[33,34] In a long-term prospective study from Japan, cumulative colectomy-free survival was 62% at 65 months. Colectomy-free survival was significantly higher in patients who have responded to tacrolimus within 30 days than those who have not.[35] These data are important in helping to predict patients who will eventually require a colectomy. Rectal tacrolimus is effective in patient with refractory distal colitis. In a study of 19 patients with refractory left-sided colitis or proctitis, three-quarter of patients responded after 4 weeks of tacrolimus enema (2–4 mg) or tacrolimus suppository (2 mg).[36] A randomised placebo-controlled study of tacrolimus enema in distal UC is currently in progress in Australia.
In perianal fistulising CD, one controlled trial has shown that oral tacrolimus was superior to placebo, although fistula healing was not different between the two groups.[37] In luminal CD, the benefit of tacrolimus has only been demonstrated in small uncontrolled studies.[28,33,34,38–40]
Practice points and adverse effects: Tacrolimus is an effective alternative therapy for patients with refractory UC and luminal and perianal fistulising CD. Response is superior in patients with UC than those with CD.[33,34] It has a rapid onset of action usually within 2 weeks, therefore it can also be used as a bridge to thiopurine. Start 0.1 mg/kg/day oral tacrolimus in two divided doses, and measure serum trough levels at 2 weeks, followed by every 6–8 weeks and aim for trough level of 5–10 ng/mL. Consider dose reduction or cease treatment if renal impairment develops. Common side effects of tacrolimus include hypertension, paraesthesia, tremor and headache. Hypomagnesaemia, renal impairment (usually reversible), hyperglycaemia or gastrointestinal disturbances may be present in about half of the treated patients.[30] The more predictable oral bioavailability and better side-effect profile makes tacrolimus more favourable compared with ciclosporin.[41] Opportunistic infection is an important consideration,[42] and standard prophylaxis with co-trimoxazole has been recommended by the ECCO in patients on triple immuno-immunomodulators with one of these being a calcineurin inhibitor or an anti-TNF agent.[43]
Thalidomide Thalidomide has re-emerged as a potent anti-inflammatory and immunosuppressive drug. The effects of thalidomide relate, in part, to the down-regulation of TNF-α, and the inhibition of angiogenesis.[44] It also inhibits NFκB activity, and suppresses IL-12.[45,46] Several uncontrolled studies have shown that thalidomide is effective in patients with refractory luminal and fistulising CD, and those with oral and upper gastrointestinal CD. In an open-label study of 12 male patients with steroid-dependent luminal CD treated with low-dose thalidomide (50–100 mg each night), 70% of patients responded and 20% were in remission by 3 months. The onset of action may be as rapid as 2 weeks.[47] In a separate study from Chicago using higher doses of thalidomide (200–300 mg each night), three-quarter of patients responded at 1 month, and 40% were in remission at 3 months.[48] In both these studies, most of the patients were naïve to biological drugs. In a retrospective series from St Mark's Hospital London, 25 treatment-resistent CD patients received a median dose of thalidomide 100 mg each night and 75% and 60% with luminal and fistulising disease respectively, responded at 12 months. Half of those with fistulising disease achieved healing. Most patients have failed azathioprine, MP, methotrexate, and some have also failed anti-TNF drugs.[49] In patients who have responded to infliximab, thalidomide can be used as a bridging therapy to maintain remission.[50]
Practice points and adverse effects: In uncontrolled studies of luminal and fistulising CD, thalidomide is effective and has steroid-sparing properties. Response and remission rates are 70% and 20% respectively. Efficacy usually occurs within 4 weeks. Long-term use is often limited by toxicity in particularly peripheral neuropathy. Start with a dose of 25–50 mg nocte, and increase to 100 mg if tolerated. Baseline nerve conduction study can be performed if available locally although no studies have evaluated the significance of abnormal baseline nerve conduction study on clinical outcome. Side effects of thalidomide include teratogenicity, drowsiness, peripheral neuropathy and rash. Peripheral neuropathy has been reported in up to 50% of patients, and in most patients it is mild and reversible. The incidence of neuropathy is related to the total cumulative dosage, and most cases of neuropathy occur after 40–50 g of thalidomide. Patients are required to use strict contraceptive measures whilst on thalidomide and must not conceive during, or up until at least 6 months after stopping the drug (manufacturer's recommendation).
Mycophenolate Mofotil. Mycophenolate mofotil (MMF) selectively inhibits lymphocyte proliferation.[51] It has been used to treat patients with thiopurine-refractory IBD, but its efficacy has not been supported by controlled trials.[52–55] In a series from the UK, 17 of 70 patients with resistant UC and CD were maintained in remission with MMF for a mean duration of 33 months.[52] At 5 years follow-up, approximately one-fifth of patients achieved steroid free remission, one-fifth discontinued treatment due to side effects, and half required an escalation in medical therapy or surgery because of failure of the therapy.[55] Gastrointestinal toxicity, usually manifested as diarrhoea, is the most common side effect of MMF.[56] The induction of colitis with histological features similar to those associated with intestinal Graft vs. Host disease has been reported in patients treated with MMF.[57] There is currently no convincing evidence of the efficacy of MMF in the treatment of IBD, and its use in this condition should be confined to trial settings.
Arsenic Suppository/Ciclosporin Enema. In patients with proctitis or distal UC refractory to topical 5-ASA, a combination of oral corticosteroids with rectal 5-ASA or immunomodulators, can be used. Experimental therapies such as arsenic (acetarsol) suppositories[58] or ciclosporin enemas[59,60] may have a role in very resistant cases.[61,62] In a small prospective open-label study, ten patients with intractable proctitis were treated with arsenic suppositories 250 mg twice daily for 4 weeks. Nine of ten patients achieved symptomatic and sigmoidoscopic improvement within 2 weeks. Side effects were minimal and arsenic levels dropped rapidly when acetarsol was withdrawn.[58] The mechanism of action of arsenic is unclear. Open trials of ciclosporin enemas for refractory distal UC have shown favourable results although a placebo-controlled study of ciclosporin enema 350 mg daily vs. placebo in 40 patients with mild to moderately active distal UC have shown no difference in symptom improvement after 4 weeks of treatment.[63] In patients with resistant proctitis, acetarsol suppositories or ciclosporin enemas may enable some patients to achieve remission prior to the consideration of surgery.
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