Crohn's Disease Information on Treatment Medication Causes & Signs

Perianal manifestations occur in almost half of patients with Crohn's disease and often respond poorly to conventional therapies. The introduction of anti-tumour necrosis factor alpha agents (e.g. infliximab) has altered the management of patients who fail first and second line medical and surgical therapies. Methods: We performed a literature search of the PubMed database using the Medical Search Headings infliximab, perianal Crohn's disease, fistulae, cost and safety. We also performed a manual search using references from these articles, review articles and proceedings from major gastroenterology meetings. Results: Use of infliximab, at a dose of 5mg/ kg at intervals of 0, 2 and 6 weeks, results in significant improvement in disease in approximately 70% of patients with fistulae. Prior examination under anaesthesia with placement of non-cutting seton sutures in fistula tracks is a useful adjunct in many patients. Preliminary results show a benefit from maintenance infliximab therapy and from concomitant use of immunosuppressants such as azathioprine. No clinical or biochemical markers have been identified which predict nonresponse to infliximab, although its use is contraindicated in patients with strictures. Acute infusion reactions are the most common side-effect of infliximab therapy and they are usually mild. Despite initial fears, the incidence of opportunistic infection is low. There is inadequate information, at present, regarding a possible increase in incidence of lymphoma with infliximab therapy. Infliximab is expensive compared with established therapies and its use will increase the lifetime cost of treating Crohn's disease. Conclusion: While infliximab is a useful adjunct in selected patients, the cornerstones of management of perianal Crohn's are essentially unchanged

Perianal manifestations occur in almost half of patients with Crohn's disease and include fissures and fistulae-in-ano, abscesses and sinuses. The introduction of the tumour necrosis factor alpha (TNFa) antagonist infliximab, with a reported beneficial response rate of 66% to 78%, has led many clinicians to re-evaluate the management of this difficult condition and, in particular, the role of surgery.

The mucosal inflammatory process in Crohn's disease results from disproportionate activation of the T-helper 1 (Th-1) subclass of lymphocytes. Activated Th-1 cells produce numerous cytokines including tumour necrosis factor alpha (TNF-a). Expression of these Th-1 type cytokines has been shown to correlate with relapse and remission in Crohn's disease and TNF-a, in particular, is known to stimulate mucosal inflammation.

Infliximab is a chimeric monoclonal antibody against TNF-a. A monoclonal immunoglobulin-Gl antibody with high affinity and specificity for recombinant and natural human TNF-a is raised in mice. Genetic engineering techniques are used to replace the murine constant regions with their human equivalents while retaining the murine antigen-binding regions. The resulting mouse-human chimeric antibody has reduced immunogenicity and improved pharmacokinetics in humans.

Infliximab neutralises the functional activity of TNF-a by blocking it from binding to the p55 and p75 TNF receptors on mucosal lymphocytes. It also binds transmembrane TNF-a expressed on activated Th-1 lymphocytes leading to cytotoxic cell killing. The finding that newer compounds with specific anti-p55 or anti-p75 actions such as Etanercept are not as effective in Crohn's disease suggested that Infliximab has other modes of action. It is now known that its binding induces apoptosis of activated mucosal T-cells and inhibits production of granulocyte-macrophage colony-stimulating factor by mucosal T-cells. Further novel targets of infliximab therapy are still under investigation.

Despite this recent advance, the primary goals of management of perianal Crohn's disease remain unchanged; relief of symptoms, control of sepsis and preservation of an intact anal sphincter. In this article, the literature regarding the role of infliximab in perianal Crohn's disease is reviewed.
Management of Perianal Disease in Crohn's patients

Confirmation of the diagnosis of Crohn's disease and its extent is determined by a combination of examination under anaesthesia (EUA), colonoscopy and small bowel contrast studies. First line treatment includes prolonged antibiotic therapy with metronidazole or ciprofloxacin and urgent external drainage of any associated abscesses. Perianal disease is improved in the majority of cases following treatment with metronidazole, with complete resolution in more than half of the cases, although it may cause peripheral neuropathy with prolonged use. In patients with an incomplete response to initial therapy, an EUA should be performed to identify and anatomically define any fistulae. The presence of Crohn's proctitis should be specifically sought and definitive surgical management deferred in these patients.

Superficial fistulae and very low transsphincteric or intersphincteric fistulae may, occasionally, be successfully managed by fistulotomy or fistulectomy. These techniques, however, must be used with care in the setting of Crohn's disease due to the risk of sphincter damage and nonhealing. In carefully selected patients, local advancement flaps may be appropriate in an attempt to heal quiescent fistulae. All other fistulae should be managed by the insertion of draining seton sutures or catheters to prevent premature healing of the skin resulting in recurrent abscess formation. Concomitant medical therapy should be optimised, often by the addition of azathioprine or 6-mercaptopurine, although other options include rectal mesalazine and topical steroids. epeat EUA should be scheduled every six weeks to evaluate healing and to change the Seton or catheter to a smaller size if possible. In patients who fail to respond, magnetic resonance imaging (MRI) may be helpful to characterise the fistula and is better than clinical examination in the exclusion of deep abscesses. Patients whose disease is not controlled by an appropriate course of combined medical and surgical therapy should be assessed for their suitability for infliximab therapy.
Use of Infliximab

In a double-blind randomised controlled trial, infliximab therapy (5mg/kg infusion at 0, 2 and 6 weeks) was associated with a rapid initial improvement with a median time to response of 14 days after the first dose. Sixty eight per cent of patients with fistulous disease experienced at least a 50% reduction in the number of draining fistulae, while 55% had a complete response, defined as the absence of drainage despite gentle pressure. A cohort of patients treated with a higher dose of 10mg/kg did not have an improved response. These initial findings have been largely borne out in clinical practice although some differences have been noted due to different dosing regimens and scoring systems. In particular, the rate of complete responses is consistently lower ranging from 16.6% to 34.6%.

Despite its promising initial response rate, the relapsing nature of Crohn's disease is essentially unchanged by infliximab. Several treatment strategies are currently being evaluated in an effort to prolong the initial response to infliximab. In the original trial, 11% of the patients treated with infliximab developed perianal abscesses in the course of their treatment, compared with only 3% of those treated with placebo. It is postulated that the high rate of abscess formation is caused by closure of the external opening of the fistula before the internal track has healed due to the rapid action of infliximab. Endorectal ultrasound assessment and MRI studies have confirmed that the fistula tract persists radiologically, despite an apparent clinical response to infliximab treatment. Incision and drainage of abscesses or placement of a non-cutting seton suture prior to commencing of infliximab therapy reduces the incidence of abscess formation." It is recommended that Seton sutures be removed two to six weeks after the fistula has ceased draining. In addition, a recently reported nonrandomised controlled trial of EUA with seton placement, prior to treatment with infliximab, demonstrated a significant increase in response and duration of response. The study also documented a significant reduction in fistula recurrence, when compared with infliximab alone.

A median duration of response of 12 weeks following infliximab is found in all published series. Loss of clinical response correlates with the time at which serum levels of infliximab become undetectable.[ 25] Maintenance therapy with infliximab, therefore, may prolong the duration of response. The ACCENT 2 trial examined maintenance therapy with 5mg/kg infliximab versus placebo every eight weeks in patients with Crohn's disease who had fistulae and an initial response to infliximab. It demonstrated a complete response of 48% at 30 weeks and 36% at 54 weeks for patients treated with maintenance infliximab, which was significantly higher than the response in the placebo treated group. An affiliated trial in patients with luminal Crohn's disease, ACCENT 1, demonstrated that episodic treatment of relapse with infliximab was not as effective as planned maintenance therapy.

The short duration of prior immunosuppressant therapy in some patients may be a confounding factor in quantifying infliximab response, as these medications do not exert their full effect for up to nine months. An association between concomitant immunosuppressant therapy and improved response and remission rates, as well as prolonged response, has been demonstrated in several trials. This has been attributed to lower rates of human anti-chimeric antibody formation while taking immunosuppressants. It is possible that induction of healing with infliximab followed by 6-mercaptopurine ( 6-MP) or azathioprine as long-term maintenance therapy may prolong remission. A single uncontrolled study with introduction of either 6-MP or azathioprine at the time of commencing infliximab produced complete closure of fistulae for at least six months in 75% of patients, with a median time to response of two weeks.

A possible role for infliximab in the perioperative period remains anecdotal, but is currently under evaluation. Some authors suggest that complex perianal fistulae should be managed with infliximab prior to surgery. This may be sound logic if definitive surgical procedures, including fistulectomy, fistulotomy or an advancement flap are being considered, as it is generally advised that such procedures should not be attempted until sepsis has been adequately treated. Infliximab should not be used to defer surgical drainage of perianal sepsis.
Response Prediction

The potential side-effects of infliximab are serious and the cost of treatment is high. Therefore, early identification of the 30% to 40% of patients with perianal Crohn's disease who do not respond to infliximab therapy is important. In patients who respond to infliximab, a remission will be induced in 65% of cases using one dose only. In general, patients who do not improve after the first two infusions will not respond and treatment should be discontinued.

As previously noted, concomitant immunosuppressant therapy improves response rates to infliximab and has also been shown to prolong remission. Two studies have identified smoking as a predictor for poor response to infliximab and smoking has also been linked to earlier relapse. Other clinical features such as young age and isolated colitis have been linked to improved response, while previous surgery seems to confer a worse outcome. However, these findings have not been confirmed by subsequent studies. Low pre-treatment serum TN-alpha levels were associated with improved response, but conversely serum TNF-alpha was undetectable in some nonresponders. Several serological markers have been shown not to significantly affect response to infliximab including ASCA (anti-Saccharomyces cerevisiae antibodies) and pANCA (perinuclear antineutrophil cytoplasmic antibodies). In addition, genetic factors including various polymorphisms in the TNF-a promoter, TNF Receptor-1 and TNF Receptor-2 genes do not affect response to infliximab.

Currently, stricture formation is the only clinical feature that excludes patients from a trial of infliximab therapy.
Risks Associated with Infliximab Therapy

Since infliximab is a novel compound, information is still being gathered as to its potential side-effects. All patients commenced on infliximab in the setting of a clinical trial are being followed-up to evaluate long-term safety.

Most reported adverse events are mild and not necessarily related to infliximab. In clinical trials, 84.4% of patients treated with infliximab reported mild adverse events, compared with 62.5% of those receiving placebo. Reported events included headache (22.6%), nausea (16.6%), upper respiratory tract infection (16.1%), abdominal pain (12.1%) and fatigue (10.6%). Major adverse events likely to be related to infliximab occurred in 4.4% of patients and these included pneumonia (0.9%), fever (0.9%) and dyspnoea (0.7%).

Acute infusion reactions occurred in 6% to 8% of patients, usually at second or subsequent infusions. ost infusion reactions are mild or moderate and symptoms improve substantially or resolve with infusion rate adjustments and treatment with paracetamol, antihistamines and steroids. Discontinuation of therapy is necessary in less than 2% of patients. Anaphylaxis, however, has been reported. Maintenance therapy may reduce the incidence of acute infusion reactions, possibly by inducing immunological tolerance. Re-treatment of patients with prior infusion reactions is possible using premedication with paracetamol and antihistamines, steroids being added for those with severe reactions. Formation of antihuman chimeric antibodies, which occurs in 13% to 28% of patients, is associated with an increased risk of infusion reactions.

Administration of immunosuppressants with infliximab reduces human antichimeric antibody development and has been recommended to reduce infusion reactions.

In addition to acute infusion reactions, delayed type hypersensitivity reactions have been described in 25% of patients given repeat treatment two to four years after the previous dose of Infliximab. These reactions manifested predominantly as myalgia, rash, fever and polyarthralgia, occurring 3 to 12 days following infusion and resulting in hospitalisation in 60% of cases; although prompt resolution of symptoms occurred with corticosteroid therapy.

Up to 60% of patients treated with infliximab develop a rise in autoantibodies, including anti-nuclear antibodies and antibodies to double-stranded DNA. However, few develop clinical features of systemic lupus erythematosis, with four documented cases in the literature of drug-induced lupus associated with infliximab use in Crohn's disease, all of which resolved spontaneously.

There is an increased risk of opportunistic infections in patients treated with infliximab. Latent tuberculosis should be considered in all patients and treated, as deemed necessary, prior to commencing infliximab therapy due to the increased risk of developing active tuberculosis (especially extrapulmonary) during or after infliximab use. A series of severe histoplasmosis capsulatum infections in infliximab-treated patients has recently been reported, with the majority of cases occurring in regions where histoplasmosis is endemic. There are also several case reports of listeria and pneumocystis carina infection after infliximab use.

A randomised controlled trial of infliximab treatment in patients with moderate to severe heart failure found a significantly increased risk of hospitalisation or death as a result of worsening heart failure in those treated with 10mg/kg of infliximab. In addition, 47 cases of heart failure associated with infliximab use have been reported to the Food and Drug Administration (FDA) in the USA, 38 were new onset heart failure and half of these patients had no risk factors for the development of heart failure. On the basis of these findings, the FDA has recently recommended that infliximab should not be used for any indication in patients with known congestive heart failure.

There are some reports of an increased incidence of lymphoma with infliximab therapy. The incidence of lymphoma in Crohn's disease has been variously reported as normal or increased. case series of eight lymphomas reported to the FDA in the first 121,000 patients treated with infliximab, demonstrated a median of eight weeks between initial infliximab infusion and diagnosis of lymphoma. This latent period is very similar to that seen in the development of lymphoma after solid organ transplantation. Since then, an additional 39 lymphomas have been reported in patients treated with infliximab. However, there is not sufficient evidence at present to establish a causal relationship between infliximab and lymphoma.

Two cases of neurological deficits associated with demyelination have been reported in patients receiving infliximab for rheumatoid arthritis. No similar cases, however. have yet been reported in patients with Crohn's disease.

The reported adverse effects must be considered in the context of increasing experience with the drug, which has been used in more than 150,000 patients in the USA alone. Nonetheless, long-term data are lacking at present and patients who have received infliximab should continue to be monitored carefully over a prolonged period of time.
Cost of Infliximab

Hay and Hay (1992(a),1992(b) conducted the most comprehensive study of treatment costs in Crohn's disease, producing an algorithm for the lifetime cost of the management of patients with Crohn's disease. They found that surgery and hospitalisation accounted for 70% of total costs and medications for 11%. Medication that reduced hospitalisation and surgical procedures, therefore, would greatly reduce overall costs. They estimated that a treatment that doubled medication costs but reduced all other costs by 20% would reduce overall spending by 13%. Despite the more widespread use of expensive medications such as immunosuppressants, recent publications have confirmed that medications still account for less than 20% of total costs. The introduction of infliximab would be expected to reduce the rate of hospitalisation of patients with both fistulous and luminal disease and a study performed in the University of Chicago demonstrated a significant decrease in hospitalisation, outpatient visits and surgery in the year following treatment with infliximab.

However, infliximab must be administered in a day-centre setting and may precipitate the need for surgery due to abscess formation or undiagnosed strictures. In addition, a recent Markov model cost-utility study of infliximab, compared with 6-MP and metronidazole as initial medical management of perianal Crohn's disease, estimated the incremental cost of infliximab to be $355,450/QALY.

The extremely high cost of infliximab, combined with its short duration of action and newer protocols recommending regular retreatment, mean that it may significantly increase the cost of treating patients with Crohn's disease in the short-term.

Last updated Jan 4/07