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Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Corticosteroids: when, which, how much and how
  5. Side effects
  6. Prevention of side effects
  7. Discussion
  8. Acknowledgements
  9. References

Background  Corticosteroids are a well-established treatment for active Crohn’s disease and have been widely used for decades. It has become apparent, however, that a proportion of patients either fails to respond to corticosteroids or is unable to withdraw from them without relapsing. Furthermore, their use is associated with a range of side effects, such that long-term treatment carries unacceptable risk.

Aim  To review the evidence regarding the appropriate use of corticosteroids in Crohn’s disease, along with their side effects, safety and alternatives.

Methods  To collect relevant articles, a PubMed search was performed from 1966 to November 2006 using the terms ‘steroid’, ‘corticosteroid’, ‘glucocorticoid’, ‘prednisolone’, ‘prednisone’, ‘methylprednislone’, ‘hydrocortisone’, ‘dexamethasone’ and ‘budesonide’ in combination with ‘Crohn(s) disease’. Relevant articles were reviewed, as were their reference lists to identify further articles.

Results  When used correctly, corticosteroids are a highly effective, well tolerated, cheap and generally safe treatment for active Crohn’ disease. Nevertheless, approximately 50% of recipients will either fail to respond (steroid-resistant) or will be steroid dependent at 1 year. Newer alternatives to corticosteroids are not, however, without risk themselves and, moreover, are not necessarily available universally.

Conclusions  Steroids are used widely to treat Crohn’s disease, a situation that is unlikely to change in the near future. Accordingly, efforts should be made to ensure that they are used correctly and that their side effects are minimized. Reference is made to recently published guidelines and a simplified ‘users guide’ is presented.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Corticosteroids: when, which, how much and how
  5. Side effects
  6. Prevention of side effects
  7. Discussion
  8. Acknowledgements
  9. References

Corticosteroids (CS) have long been employed for the treatment of Crohn’s disease, but their use remains controversial. CS often ameliorate the symptoms of acute Crohn’s disease, but adverse drug reactions, steroid dependency and the relative inability of these agents to heal the mucosa have led to their role in the management of Crohn’s disease being questioned. The introduction of biological agents, such as the anti-tumour necrosis factor-α (anti-TNF- α) drugs, has provided an effective alternative to CS for the treatment of acute Crohn’s disease, although concerns remain concerning their long-term safety and efficacy. Furthermore, their high cost has led to variable access throughout the world, leaving many gastroenterologists unable to prescribe these therapies freely (Figure 1). Do CS still have a role in the management of Crohn’s disease at the beginning of the 21st century?

image

Figure 1.  Gastroenterologists’ perceptions of availability of infliximab in their own countries. As the information was not made available by the manufacturer or distributor of infliximab, gastroenterologists around the world were contacted and asked to estimate what proportion of their country’s population had access to infliximab to induce remission for active Crohn’s disease. African gastroenterologists provided data for more than one country.

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Pharmacology

Corticosteroids have a wide range of actions on a plethora of cells throughout the body. Details of the cellular mechanisms involved in their action is beyond the scope of this study and has been reviewed in detail elsewhere.1–3 In brief, CS reduce inflammation through the glucocorticoid receptor. Within the cell, cortisol has three major actions. First, in combination with the glucocorticoid receptor, it interacts with glucocorticoid responsive elements facilitating or inhibiting transcription of specific DNA sequences that code for inflammatory or anti-inflammatory proteins (DNA-dependent regulation). Secondly, activated glucocorticoid receptors combine with other transcription factors (e.g. nuclear factor-κB) to reduce production of inflammatory proteins (protein inference mechanisms). Finally, non-genomic activation of anti-inflammatory proteins can occur via the glucocorticoid receptor.1 However, in addition to the anti-inflammatory actions of CS, they reduce diarrhoea by other mechanisms including stimulation of sodium and water absorption, probably via the apical sodium pump.4

Response to corticosteroids

Conventional CS (prednisone/prednisolone) are potent anti-inflammatory agents and are undoubtedly effective in treating the symptoms of acutely active Crohn’s disease as shown by two large randomized placebo-controlled trials (Table 1). The first, the National Cooperative Crohn’s Disease Study (NCCDS) performed in the USA, was published in 1979.5 The steroid arm of this study described 162 patients with active Crohn’s disease [Crohn’s disease activity index (CDAI) >150; mean CDAI – 242] randomized to receive either oral prednisone at a dose of 0.5–0.75 mg/kg tapering over 17 weeks, or placebo. Remission at 17 weeks was achieved in 60% of the steroid-treated patients, double that seen in the control group (P = 0.0004).

Table 1.   Placebo-controlled trials of steroid response and natural history studies
Number Steroid/daily doseRemission (%)Response (%)PeriodSteroid dependence (%)Reference
  1. * Includes eight patients initially treated with intravenous methylprednisolone 60 mg/day for 5 days; † Paediatric patients.

Placebo-controlled studies
 85Prednisone 0.5–0.75 mg/kg60 18 weeks Summers et al.5
 47Prednisolone 48 mg83 17 weeks Malchow et al.6
Natural history studies
 109Prednisolone 1 mg/kg483230 days36Munkholm et al.7
 74Prednisone 40–60 mg582630 days28Faubion et al.8
 60Prednisolone 40 mg* Budesonide 9 mg403530 days24Ho et al.9
 26†Not stated622730 days31Tung et al.10

These findings were subsequently echoed by the European Cooperative Crohn’s Disease Study (ECCDS) in which 215 patients with active Crohn’s disease (CDAI >150; mean CDAI – 229) were randomized to receive either placebo, 3 g of sulfasalazine, 48 mg of 6-methylprednisolone tapered over 6 weeks, or a combination of the two drugs.6 Two further courses of treatment were allowed if remission was not achieved by 6 weeks. Remission by 18 weeks’ treatment was achieved in 83% of the steroid-treated group, compared with 38% of placebo recipients, 50% of sulfasalazine-treated patients and 78% of the combination group.

Four large studies have examined the natural history of prednisolone usage in Crohn’s disease, one in a paediatric population. Munkholm et al. prospectively studied patients with Crohn’s disease diagnosed between 1979 and 1987 in Copenhagen County, Denmark. Of the 196 patients, 109 received treatment with prednisolone, 1 mg/kg/day tapering to a maintenance dose of 10–15 mg for a further 3½ months. Remission at 30 days was observed in 48%, response in 32% and no response (steroid resistance) in 20%.7 These findings were consistent with those of the NCCDS and ECCDS. Importantly, however, the investigators went on to examine what happened to steroid-treated patients during and after steroid withdrawal. The inability to withdraw steroids, or relapse within 30 days of withdrawal (i.e. steroid dependence) was seen in 36% of all steroid-treated patients. A further population-based study from the Mayo Clinic, Rochester, followed 173 patients (74 steroid-treated) diagnosed with Crohn’s disease between 1970 and 19938 while a hospital-based study from the UK described 80 patients diagnosed between 1998 and 2003, 60 of whom received steroids.9 The results in these patients were similar to Munkholm’s cohort with the US and UK studies showing remission at 30 days in 58% and 40%, partial response in 26% and 35%, steroid resistance in 16% and 25%, and steroid dependence in 28% and 24% respectively. The Mayo clinic has recently also reported results for their paediatric patients diagnosed between 1940 and 2001.10 These broadly reflect those of the adult population with 62% in remission, 27% having a partial response and 12% being steroid resistant at 30 days, while 31% were steroid dependent at 1 year.

Taken together, these findings show that, although the majority of patients with active Crohn’s disease respond rapidly to steroid treatment, about a half will be either steroid resistant or steroid dependent at 1 year.

Corticosteroids and mucosal healing

Mucosal healing is increasingly recognized as an important end point in clinical trials. Additionally, it has been advocated that this should be the target for routine clinical practice.11 Severe mucosal inflammation is an independent risk factor for postoperative disease recurrence.12 Furthermore, increased faecal inflammatory markers are also independent predictors of disease relapse,13 suggesting that clinical remission is most likely to be maintained when the mucosa is healed.

As remission-inducing drugs, CS compare favourably with thiopurines (slower onset of action),14 nutritional therapy (difficulties with adherence to therapy)15, 16 and antibiotics (lower response rates),17 and are at least as effective as biological agents.18, 19 However, unlike thiopurines, nutritional therapy and biologics which have mucosal healing rates of 50–75%,20–23 mucosal healing is only achieved in up to 33% of patients taking CS.22–24 Therefore, when steroids reduce the acute symptoms of Crohn’s disease, they frequently do so without healing the underlying cause.

Corticosteroids: when, which, how much and how

  1. Top of page
  2. Summary
  3. Introduction
  4. Corticosteroids: when, which, how much and how
  5. Side effects
  6. Prevention of side effects
  7. Discussion
  8. Acknowledgements
  9. References

Evidence regarding the use of steroids in Crohn’s disease is, in many areas, sparse. Data regarding CS usage for ulcerative colitis are not necessarily applicable to patients with Crohn’s disease and are, therefore, not included in this review.

Indications for corticosteroids

The inability of CS to heal mucosa, coupled with the plethora of associated side effects makes decisions concerning their commencement and cessation immensely important. Numerous guidelines have been published concerning the medical treatment of Crohn’s disease.25–27 Without exception, they agree that CS have a role in the treatment of active Crohn’s disease but have no role in maintaining remission.

There are three important questions that must be addressed when prescribing conventional CS for Crohn’s disease. First, are the symptoms caused by inflammation? This requires the exclusion of other causes of symptoms such as infectious colitis, dietary triggers, bile salt malabsorption, small bowel bacterial overgrowth, iatrogenic diarrhoea caused by the use of drugs such as NSAIDs or antibiotics, or overflow diarrhoea resulting from constipation.25, 28 Secondly, do specific circumstances exist whereby using conventional CS may place the patient at increased risk? Examples include fistulating disease, prolonged use of high-dose CS in the preoperative setting and the presence of an abscess. Thirdly, how and when will the steroids be stopped? Plans to stop CS should be made at the same time that they are prescribed. This may involve lifestyle measures such as stopping smoking, or commencing steroid-sparing agents (immunomodulators or biological agents). The decision to use CS should also be influenced by a patient’s previous response, or lack of response to steroids and the side effects experienced.25

Current guidelines are in agreement regarding the role of conventional CS in Crohn’s disease.25, 27 While they are not recommended as first-line therapy in mild to moderate Crohn’s disease, they may be used when patients fail to respond to standard therapy such as sulfasalazine/5-aminosalicylic acid (5-ASA), or a topically acting CS such as budesonide (depending on the site of inflammation). While many use antibiotics to induce remission, controlled data to support this are limited.

For moderate–severe disease, oral CS are viewed as first-line therapy for the induction of remission25, 27, while parenteral steroids are recommended when there is no response to oral steroids after 7–14 days, and for severe-fulminant disease.27

Inappropriate use

Guidelines suggest that CS are not indicated for the treatment of fistulating Crohn’s disease.29 Indeed, uncontrolled trials suggested that their use in such patients may increase the need for surgery.30, 31 There is also evidence to suggest that when used for enterovesical fistulae, steroids may decrease the chance of healing the fistula medically.32 Similarly, in patients with an abdominal mass resulting from an abscess, steroid usage is associated with an increased risk of sepsis and even death.6

It has traditionally been thought that maintenance therapy with CS is ineffective. Prior to the NCCDS and ECCDS, a study described 64 symptom-free patients with Crohn’s disease who were randomized to receive 7.5 mg prednisolone daily or placebo for up to 3 years. Withdrawal caused by disease recurrence was seen in 30% in both groups. A Cochrane review combined the results of this study with the eligible subgroup of patients from the NCCDS and ECCDS and found that CS were no more effective in preventing relapse in Crohn’s disease than placebo.33

However, the maintenance arm of the ECCDS described a subgroup of patients (those with a treatment-induced remission) in whom maintenance therapy was more effective in the steroid-treated than nonsteroid-treated patients.6 Furthermore, a small study suggested that 0.25 mg/kg methylprednisolone/day prevented relapse at 6 months.34 Finally, by definition, steroid-dependent patients can be maintained in remission by long-term CS therapy. The dose required to do so will vary between patients. Of course, the debate regarding whether this is steroid dependence or effective maintenance therapy is largely semantic and is, in any event, irrelevant; the disadvantages of long-term steroids make their use as maintenance agents untenable.

Budesonide also fails to maintain remission with no difference in relapse at 1 year between patients receiving 3 or 6 mg of budesonide, or placebo.35–37

The ability to predict which patients are unlikely to respond to steroids (other than those whose symptoms are not related to active inflammation – see earlier) would be of great use. Clinical characteristics associated with steroid resistance include prior bowel resections, perianal disease and a high pretreatment CDAI.38 Likewise, steroid dependence is more likely to occur in patients who smoke, with colonic and nonfibrostenotic disease, and whose disease onset occurred early in life.39 Furthermore, recurrent courses of steroid over the preceding 3 years, or a recent course of steroids, predict relapse after steroid withdrawal.40

Despite this, it is not currently possible to predict who will fail to respond to CS therapy; advances in the field of pharmacogenetics, combined with further definition of clinical features may one day allow identification of steroid-refractory and steroid-dependent patients prior to treatment.

Finally, CS should not be used recurrently. Any patient requiring steroids more frequently than yearly should be started on a steroid-sparing agent.25, 27

Choice of corticosteroid

Systemic CS commonly used in the management of Crohn’s disease include hydrocortisone and methylprednisolone (parenteral); prednisolone, prednisone and budesonide (oral); and hydrocortisone or prednisolone (rectal). Comparative data regarding efficacy and tolerability are, with the exception of budesonide, relatively few.

Budesonide, unlike prednisolone and prednisone, undergoes extensive first-pass hepatic metabolism and is, therefore, associated with fewer systemic side effects (see below). Its efficacy as a treatment for mild to moderate ileocaecal Crohn’s disease has been demonstrated in high quality, randomized, placebo-controlled trials41, 42 and comparative trials with either mesalazine43 or conventional CS.44–48 In these trials, an 8 week course of 9 mg of budesonide/day resulted in remission in 48–69% of patients, a significantly greater percentage than reached remission in the 5-ASA or placebo-treated patients. Although none of the trials comparing budesonide with prednisolone or prednisone found one to be superior to the other, a Cochrane review has shown that budesonide is less effective than conventional CS at inducing remission [pooled odds ratio 0.69, 95% confidence interval (CI) 0.51–0.95].49 This may, in fact, be related to the high first-pass metabolism of budesonide. Crohn’s disease is a transmural disease and also affects lymph nodes and mesenteric fat. As only 11% of budesonide is systemically available,50 steroid delivery to areas other than the mucosa will presumably be lesser with budesonide than with prednisolone.

However, budesonide is associated with fewer (albeit dose-related) side effects (such as moon face, hirsutism and acne) than conventional CS (pooled odds ratio 0.38, 95% CI 0.28–0.53), and is less likely to cause suppression of endogenous cortisol production.49 Therefore, it is indicated in preference to conventional CS to induce remission in patients with mild to moderate ileocaecal Crohn’s disease.25, 27 Unfortunately, the availability of budesonide is limited in some countries due to its cost (approximately 40-fold more expensive than conventional CS; €300 for an 8-week course of budesonide 9 mg/day compared with €9 for a 6-week tapering course of prednisolone).

Comparative trials of other steroids are lacking. There is little to choose between prednisone and prednisolone (the active form). However, in patients with severe liver disease prednisolone should be used in preference to prednisone because the latter requires hepatic conversion to the former. Likewise, methylprednisolone and hydrocortisone are both acceptable intravenous treatments for severely active Crohn’s disease; the former steroid has a lesser mineralocorticoid effect and is, therefore, preferred by some.27 Although dexamethasone has negligible mineralocorticoid effects, its use is less widespread.

Adrenocorticotrophic hormone (ACTH) 120 U/day has been shown to be as effective as hydrocortisone 300 mg/day51 in inducing remission in severe Crohn’s disease. Its use is not, however, widespread, perhaps in part due to its association with adrenal haemorrhage.52

Route of administration

The use of oral prednisolone and prednisone is supported by data from randomized placebo-controlled trials (Table 1),5, 6 as is the use of oral controlled-release budesonide.42 There is no evidence to suggest that divided oral doses, as advocated by some,53 are more effective than single daily doses. Moreover, steroids can cause insomnia particularly if doses are taken later in the day. We, therefore, advocate a single daily dose in the morning. This may also decrease the occurrence of hypothalamic-pituitary-adrenal (HPA) axis suppression (see later).54

However, the practice of giving intravenous steroids to patients failing to respond to oral therapy is based more on experience than on evidence. A retrospective study of 49 patients receiving 5 days of intravenous steroids showed that remission was achieved in 76%55 and, in the comparative trial of ACTH and hydrocortisone mentioned above, remission was achieved in 93% of the steroid-treated patients.51 Response to intravenous steroids is also rapid; in the same trial; approximately 80% of patients responded within 5 days of treatment. Placebo-controlled trials of intravenous CS in patients with severe Crohn’s disease would, however, be unethical.

It has been suggested that infusions of steroids may hold some advantage over intermittent bolus therapy, the former mode of administration leading to higher plasma concentrations in a trial using prednisolone.56 There is, however, no evidence to support one regimen over the other and, particularly with hydrocortisone which is normally given every 6 h, the difference in efficacy, if any, is likely to be small if evidence from other conditions is applicable.57

Likewise, application of topical CS by enema or suppository lacks an evidence base but is sometimes used as an adjunctive therapy to induce remission in patients with distal Crohn’s disease.25 While this approach may achieve high levels of steroid in the rectal mucosa, it ignores the fact that Crohn’s is a transmural disease. Furthermore, systemic absorption and CS-related side effects are not necessarily avoided by this route of administration. For example, pharmacokinetic studies have demonstrated systemic bioavailability of 2–90% when hydrocortisone acetate foam is administered as an enema compared with an intravenous dose.58–61 Although in most individuals the risk of systemic side effects is probably low, one study showed that 4 weeks of treatment with prednisolone enemas resulted in HPA axis suppression.62 Furthermore, Cushing’s syndrome,63 avascular necrosis of the knees64 and acute adrenal insufficiency65 are all reported in association with steroid enemas. Finally, due to the fact that the venous drainage from the lower rectum is systemic rather than portal and therefore bypasses hepatic first-pass metabolism, suppositories may deliver a higher proportion of the drug to the systemic circulation than do enemas.66

Steroid dosing

There is a lack of evidence comparing the efficacy of different doses of steroids in patients with Crohn’s disease. In general, based on the available trials,5–8, 42 oral doses of prednisolone ranging from 40–60 mg/day or 0.75–1 mg/kg/day, or budesonide 9 mg/day are advised for the treatment of active disease.25, 27 In practice, prednisolone doses towards the lower end of this range are used by most; although there may be a slight dose response, remission rates were broadly similar in the above studies suggesting that higher doses lack marked additional benefit. One consideration, however, is that patients with small bowel disease may absorb less of a prednisolone dose (66–90%) than do healthy controls67, 68 and may, therefore, require increased doses to achieve a response. Finally, in the paediatric population doses are more variable with up to 2.5 mg/kg prednisolone/day described for the treatment of Crohn’s disease.16

Standard intravenous steroid doses of hydrocortisone 300–400 mg/day51, 55 or methylprednisolone 60 mg/day9 are probably as effective as each other. Dose ranging studies do not exist and there is no reason to believe that higher doses will do much other than increase side effects.

Are there any circumstances in which lower doses of oral steroids can or should be used? Although completely without an evidence base, it is not uncommon practice to recommence patients on a submaximal steroid dose if they relapse during or shortly after steroid withdrawal. This is frequently effective and is, in our opinion, entirely reasonable, as it is essentially a prolongation of steroid weaning. Otherwise, steroids should be initiated at a high dose to effect remission, followed by a gradual withdrawal.

Steroid weaning

The commonly used practice of weaning steroids over several weeks after a 1- to 2-week induction period is thought to decrease the chance of relapse.25 Evidence for this remains anecdotal. Indeed, the only trial comparing two steroid withdrawal regimens, one occurring over 4 weeks, the other over 12 (both after 3 weeks of intramuscular methylprednisolone 40 mg/day), found no difference in relapse rates between the two, although the trial may have been underpowered.40

Nevertheless, experience suggests that, at least in a proportion of patients, weaning decreases the chance of rapid relapse. The use of a standardized weaning regimen within a department allows rapid identification of patients who are likely to become steroid dependent25 and, therefore, the timely introduction of steroid-sparing agents. Furthermore, weaning is normally necessary because of the effects of exogenous CS on the HPA axis.

Side effects

  1. Top of page
  2. Summary
  3. Introduction
  4. Corticosteroids: when, which, how much and how
  5. Side effects
  6. Prevention of side effects
  7. Discussion
  8. Acknowledgements
  9. References

The benefits of CS in Crohn’s disease must be measured against their potential for both short- and long-term side effects. During treatment of active Crohn’s disease CS-related adverse effects are seen in 55% of patients treated with prednisolone 40 mg/day and 33% of patients treated with budesonide 9 mg/day.44 The occurrence and severity of most adverse events is dependent on the dose and duration of CS therapy, with the incidence of side effects increasing after 2–3 weeks. These adverse effects are protean and well known, and include cosmetic effects (Cushingoid appearance and acne), psychological effects (mood disturbance, insomnia and even psychosis), ocular complications (glaucoma and cataracts) and the more insidious but serious metabolic consequences (hypertension, hyperglycaemia and HPA axis suppression).

Patients with Crohn’s disease are at particular risk of three steroid-related side effects – metabolic bone disease, infectious complications and growth failure – and this section will focus on these adverse events. It must be noted, however, that inflammation also contributes to each of these side effects and that induction of remission with a short course of steroids may decrease their severity in the long term.

Musculoskeletal side effects

Both CS and Crohn’s disease can cause osteopenia, osteoporosis, osteonecrosis and osteomalacia.69, 70 While CS are often used as a scapegoat for the low bone mass seen in inflammatory bowel disease (IBD) (prevalence 30–60%), other important contributing factors include active inflammation and malabsorption of calcium and vitamin D.71 Indeed, a recent study showed that low bone mineral density is frequently detected at diagnosis in patients with IBD72 and, although a 2-month course of CS in patients with active Crohn’s disease has been shown to cause significant bone loss, it is unclear whether CS or Crohn’s disease is responsible.73 CS-induced bone loss is due to a combination of reduced bone formation and increased bone resorption,74 and is highest in the first months of therapy.75 It is dose dependent and occurs at prednisolone doses greater than 5 mg/day, although lower doses also carry some risk.76 After discontinuation of CS, osteoblast function recovers and new bone formation recurs, although bone mass rarely returns to pre-treatment levels.77

Long-term steroids are associated with an osteoporotic fracture rate of 30–50%, mostly at sites of high trabecular bone content such as the vertebrae, hips and pelvis.78 Attempts to minimize bone loss by using alternate day therapy failed to reduce fracture rates.79

Osteonecrosis refers to infarction of the cellular components of bone and is strongly associated with CS use in IBD, although it is also reported in steroid-naïve patients with Crohn’s disease.80 Unlike osteopenia and osteoporosis, the risk of developing osteonecrosis is idiosyncratic rather than dose dependent. The prevalence of osteonecrosis in CS-treated patients is 0.5–4%.70, 81 In IBD, osteonecrosis tends to involve multiple joints, most commonly the hips, shoulders and knees, often bilaterally.70

Another complication of CS use is pseudoarthropathy. This occurs during steroid withdrawal and can appear at prednisolone doses of less than 20 mg/day. It is characterized by transient proximal myalgias and arthralgias but is, fortunately, self-limiting with further slow steroid withdrawal. Resolution may, however, take several months.82

Sepsis

Corticosteroids probably increase infection risk. A meta-analysis of 71 controlled trials using CS for all indications found they were associated with a relative risk of infection of 1.6 (95% CI 1.3–1.9) and a relative risk of death from any cause of 2.6 (95% CI 1.2–5.3). The increased risk, however, was only associated with cumulative prednisone doses greater than 700 mg83 and was less for patients with gastrointestinal diseases.

Of special importance in Crohn’s disease is first the risk of exacerbating complications of perforating disease (abscesses and fistulae) with CS use, and secondly, the possible association between high-dose preoperative CS use and postoperative infectious complications.84 In the ECCDS, 3 of 43 patients who presented with an abdominal mass and were treated with CS died from sepsis.6 More recently, a retrospective case–control study showed that those with penetrating disease who developed intra-abdominal or pelvic abscesses were more likely to have received CS than either patients with penetrating disease who did not develop an abscess (OR 9.03, 95% CI 2.4–34), or patients with equally active nonpenetrating disease who did not develop an abscess (OR 9.31, 95%CI 1.03–83).85 It is unclear, however, whether differences in referral pattern may have led to selection bias in this study.

The TREAT Registry, established to evaluate the safety of drugs used in Crohn’s disease, contains data from more than 6000 patients. A recent report showed that the use of prednisone, but not infliximab, was associated with an increased risk of serious infections (OR 2.21, 95% CI 1.46–3.34) and mortality (OR 2.10, 95% CI 1.15–3.83).86 However, for infectious complications, medication being taken at the time of the infectious complication was excluded from the analysis: the increased risk of serious infections was related to previous exposure to CS. Furthermore, in patients with rheumatoid arthritis treated with anti-TNF-α agents, the risk of serious skin and soft tissue infections is increased fourfold compared with patients taking disease-modifying drugs.87

In contrast, some practitioners suggest that, when used in conjunction with antibiotics, steroids are an effective treatment for fistulae due to the fact that they treat the underlying cause, namely active luminal Crohn’s disease.53 Similarly, patients with an abdominal mass have also been safely treated with a combination of steroids and antibiotics. Although not preventing surgery in most cases, this strategy allows for operations to be performed electively rather than precipitously.53

Whether preoperative steroid use increases the risk of postoperative sepsis is not entirely clear. Although some trials demonstrate a relationship between the two, the majority do not (Table 3). Furthermore, the picture is complicated by the fact that patients undergoing surgery with active disease are more likely to be taking CS than those with inactive disease. If there is an increased risk, it is likely to be related to long-term, high-dose CS use.84

Table 3.   Studies examining the effects of steroid use on the risk of septic complications of surgery for patients with Crohn’s disease
Subjects (operations)ComplicationsMultivariate analysisFindingsReference
  1. Excluded studies: Price LA Br J Surg 1968 (ulcerative colitis only). Morgenstern L et al. Am J Surg 1972 (not Crohn’s disease). Schrock TR et al. Ann Surg 1973 (Heterogenous patient group – unable to extract data for Crohn’s disease).

  2. * Ulcerative colitis and Crohn’s disease; † Excludes pneumonia/urinary tract sepsis.

159* (88 CD)AllYesDose dependent. >40 mg increased riskAberra et al.84
343 (566)AllYesIncreased risk of intra-abdominal sepsis with usage >1 month. No dose-related dataYamamoto et al.137
368 (429)All postoperative complications including nonseptic†YesFor ‘long-term’ (undefined) corticosteroids, increase when all complications taken together. No data for sepsis alone.Post et al.138
397Sepsis, morbidity, mortalityNoNo increased riskBruewer et al.139
87Intra-abdominal sepsisNoNo increased riskYamamoto et al.140
130AllNoNo increased riskHeimann et al.141
51 (89)Wound infections, intra-abdominal abscess, mortalityNoNo difference in steroid dose between those with or without complicationsAllsop and Lee142
46 (118)Wound infections, intra-abdominal abscessNoNo increased riskKundsen et al.143

Growth retardation

Children with Crohn’s disease are at particular risk of growth impairment with case series demonstrating growth retardation in 15–40%.88, 89 Two randomized trials have shown improved linear growth in children treated with enteral nutrition compared with CS, presumably due to a combination of improved nutrition and a reduction in both intestinal inflammation and CS exposure.90, 91 The relative contribution to growth retardation of CS92, 93 and other factors such as active disease,89 inflammatory cytokines,94 altered levels of hormones and sex steroids,94, 95 and nutrition96 is unclear. Certainly some studies suggest that CS exposure is of lesser importance and that active inflammation is the predominant influence;89 the balance of risk between using CS to control inflammation while contributing to growth retardation requires careful consideration.

Prevention of side effects

  1. Top of page
  2. Summary
  3. Introduction
  4. Corticosteroids: when, which, how much and how
  5. Side effects
  6. Prevention of side effects
  7. Discussion
  8. Acknowledgements
  9. References

In general, CS should always be used at the lowest effective dose for the shortest time. Furthermore, due to its superior side effect profile, budesonide should be used in preference to conventional CS for inducing remission of ileocolonic Crohn’s disease.25 It must be noted, however, that data supporting this assertion, at least with regard to the serious side effects outlined above, are limited.49, 97

Hypothalamic-pituitary-adrenal axis suppression

The risk of suppressing the HPA axis is related to, but not completely dependent on the dose and length of treatment with CS.54 While doses greater than 10 mg of prednisone/day consistently suppress the HPA axis, lower doses can also impair adrenal function.98–100 Although short courses of CS are unlikely to cause clinically important suppression of the HPA axis, it has been reported with only 5 days of treatment.101 Weaning allows the adrenal glands to recover in the majority of patients, although this can take up to a year. Furthermore, the risk of clinical adrenal insufficiency is increased by acute stress (such as surgery) and such events should be covered by an increase in steroid dose. Tetracosactrin (for example, Synacthen (Alliance Pharmaceuticals, Chippenham, UK)) tests are useful in identifying patients who require a prolonged steroid wean and have been shown to be abnormal in 65% of patients with IBD who had received CS.102 In this study, HPA suppression was particularly likely to occur in patients with a past history of CS usage, especially if it was recent (within 15 months).102 Although these results might suggest that all patients who have received steroids for longer than 3 weeks should undergo a tetracosactrin test during weaning, the realities of many healthcare systems make this impractical. Certainly, however, gastroenterologists should have a low threshold for using tetracosactrin tests and should be vigilant for signs of adrenal insufficiency, particularly in high-risk patients.

Bone loss

All patients should be encouraged to follow conservative measures to minimize their risk of developing osteoporosis. These include discontinuing smoking, limiting alcohol consumption, taking regular weight-bearing exercise and ensuring adequate dietary intake of calcium (1000–1500 mg/day).25 The judicious use of DEXA scanning helps identify patients at risk of fractures, albeit imperfectly.103 Rapid bone loss occurs on commencing CS and co-prescription of calcium and vitamin D has been shown to decrease this, at least for trabecular bone.104 As this is a cheap and well-tolerated treatment, we concur with the suggestion that it should be given to all patients with IBD while receiving CS.105 Of course, many patients with established osteoporosis will already be taking prophylaxis in the form of bisphosphonates.25, 103

Alternatives to conventional corticosteroids

While conventional CS are effective at inducing remission, there are times where alternative therapies are desirable. Table 2 lists therapies that may be used instead of CS, including a summary of the data comparing each to placebo and CS where available. While there are data from an underpowered CS crossover trial, antibiotics have no placebo-controlled evidence supporting their use. The thiopurines and methotrexate are effective, although the action of onset is slow and the latter has only been shown to be effective if given intramuscularly. Biological agents offer promise, although they lack long-term safety data. It must, however, be noted that patients recruited to trials of new therapeutic agents, e.g. biologicals, are often steroid dependent or steroid resistant.19 Such patients are less likely to respond to medical therapy than those recruited to the original steroid trials. Therefore, remission rates are likely to be lower in the former group.

Table 2.   Alternatives to steroids for inducing remission of active Crohn’s disease
DrugDoseDurationEvidenceReference
Meta-analysesRPCTEquivalence vs. steroids
  1. +, evidence showing drug superior to comparator; –, evidence showing that the drug is not superior to comparator; ±, conflicting evidence concerning efficacy; 0, no evidence available; N/A, not applicable; U, underpowered studies.

  2. * Subgroup analysis suggests efficacy for colonic Crohn’s disease; † Meta-analysis of data suggests clinically insignificant benefit over placebo.

Corticosteroids40–60 mg/1 mg/kg17 weeks++N/A5, 6, 118
Budesonide9 mg8–16 weeks++49, 118
Sulfasalazine3–4.8 g17 weeks−*5, 6, 119
5-ASA1.5–4 g6–16 weeks+†±±118, 120, 121
Ciprofloxacin/metronidazole250–500 mg t.d.s.Variable00−/U17
Azathioprine2–3 mg/kg17 weeks++5, 14, 118
6-Mercaptopurine0.5–1.5 mg/kg17 weeks++5, 14, 118
Methotrexate25 mg i.m.16 weeks++0118, 122
Infliximab5 mg/kg 1 infusion4 weeks0+019, 118, 123
Adalimumab160/80 mg weeks 0 + 24 weeks0+0124
Enteral nutritionVariableVariable0015

Table 4 lists therapies that may be used to maintain CD remission (alternatives to using CS inappropriately). Budesonide, and probably 5-ASAs and sulfasalazine, have no role to play in this setting. Two studies support the use of nitroimidazole antibiotics to maintain surgically induced remission. Otherwise, the thiopurines, methotrexate and the biological agents have the most compelling data supporting their use.

Table 4.   Agents for maintenance of remission in Crohn’s disease
DrugDoseDurationEvidenceReference
Meta-analysesRPCT
  1. +, evidence showing drug superior to comparator; –, evidence showing that the drug is not superior to comparator; ±, conflicting evidence concerning efficacy; 0, no evidence available.

  2. * Colombel JF et al. Presented at Digestive Diseases Week (2006); † Selby W et al. Presented at British Society of Gastroenterology (2005); ‡ Rifabutin, clarithromycin and clofazamine.

Corticosteroids40–60 mg/1 mg/kg12–24 months5, 6, 118, 125
Budesonide3–6 mg12 months49, 118, 126
Sulfasalazine3–4.8 g24 months5, 6
5-ASA1.5–4 g12 months±118, 127, 128
Nitroimidazole antibioticsVariable (drug dependent)3–12 months0±129, 130
Azathioprine2–2.5 mg/kg6–24 months++14, 118, 131
Methotrexate15 mg weekly40 weeks0+132
Infliximab5 mg/kg30–54 weeks++118, 133, 134
Adalimumab40 mg s.c. every other week54 weeks0+*
ProbioticsVariableVariable00135
Anti-MAP antibiotics‡Variable (drug dependent)Variable±±136

Discussion

  1. Top of page
  2. Summary
  3. Introduction
  4. Corticosteroids: when, which, how much and how
  5. Side effects
  6. Prevention of side effects
  7. Discussion
  8. Acknowledgements
  9. References

It might be argued that, with the advent of the ‘biological era’ an article reviewing steroid usage in Crohn’s disease is anachronistic. However, the use of steroids to induce remission in patients with Crohn’s disease remains widespread and, if done correctly, is effective and safe.

Steroids have been used in the treatment of Crohn’s disease for several decades. Therefore, most gastroenterologists are familiar with their beneficial and adverse effects. Until a similar level of familiarity is gained with the newer biological agents, a proportion of gastroenterologists will, understandably, opt to stick with ‘the devil they know’. Indeed, emerging side effects associated with biological therapies106–108 are likely to prolong this process.

Furthermore, advances in practice take time to dissipate from large specialist centres into the wider medical community. Therefore, while the role of centres of excellence in pushing the boundaries of IBD management is vital, opinion leaders must also remember that the realities of managing IBD outside such organizations may be very different. Dismissing a well-understood and largely safe treatment whilst it is still being widely used is of limited value to many readers, particularly when the alternatives may have restricted availability (Figure 1). It is for these reasons that efforts must continue to improve the way we use steroids.

Why then is steroid misuse still a problem? In many ways steroids are a victim of their own success. The response rates of greater than 90% achieved in some trials51 are far greater than those seen for any other medication used to treat Crohn’s disease. Moreover, the conventional CS are cheap, widely available and easy to administer. Steroids therefore represent a tempting quick fix for both physician and patient alike. The temptation to prescribe them recurrently can thus be great. Furthermore, the phenomenon of steroid dependence, which occurs in about a third of patients (Table 1), encourages inappropriately long courses of steroids. Finally, because the agents available to maintain remission in Crohn’s disease have limited efficacy, frequent relapses are common for a proportion of patients. None of these reasons is, however, an adequate excuse for steroid misuse and, although thiopurines, methotrexate and biological agents all have safety issues, long-term steroid use is both ineffective and dangerous.

What more is there to learn about steroids?

Despite the wealth of experience gained over the years, high quality controlled data defining how to use steroids remain limited. This is partly a financial issue: the pharmaceutical industry is unlikely to sponsor expensive drug trials with little chance of recouping their expenses and public funding of such studies is limited. Therefore, advances in this area rely on the laudable, often collaborative efforts such as those produced by GETAID (Groupe d’Etudes Therapeutiques des Affections Inflammatoires du Tube Digestif).109 However, studies examining the use of steroids in Crohn’s disease need careful consideration due to the amount of time and expense involved; the remission rates achieved with current steroid usage are unlikely to be improved dramatically, therefore trials addressing this issue would be of limited value. By contrast, efforts should be concentrated on areas like steroid dependence and the minimization of side effects.

Better use of steroids

An alternative to improving our use of currently available steroids is to develop steroids or delivery systems with more acceptable side effect profiles. Budesonide was developed for this reason and other formulations, such as beclomethasone diproprionate,110 may prove effective in Crohn’s disease. Alternatively, new delivery systems may allow targeted delivery with fewer systemic side effects. Dexamethasone loaded into autologous erythrocytes, while still at an experimental stage, shows some promise, perhaps even as a safe maintenance agent.111 Similarly both Eudragit-L-coated112 and ethylcellulose/glassy amylase-coated113 prednisolone metasulphobenzoate provide targeted delivery of a poorly absorbed salt of prednisolone to the colon and may, therefore, prove useful in the treatment of Crohn’s colitis. Furthermore, the advent of steroid-sensitizing agents, such as the interleukin-2 receptor antibody, basiliximab, which is showing promising results in steroid-resistant ulcerative colitis,114 may one day prove useful in steroid-resistant Crohn’s disease. Mechanisms of steroid resistance and strategies for dealing with this phenomenon have recently been reviewed.115

Finally, the rapid advances witnessed in the fields of IBD genetics and pharmacogenetics over recent years may, in future, allow more accurate identification of patients who will respond to steroids. For example, the DLG5 113A allele is associated with steroid resistance,116 and it has been suggested that MDR-1 pharmacogenetics may also help predict who will respond to steroid therapy.117

Limited availability of alternatives to conventional steroids

It is unfortunate that the cost of budesonide and biological agents limits their availability to a large proportion of the world’s population. Access to, for example, infliximab varies markedly throughout the world (Figure 1). In some countries, infliximab is funded for those with private insurance but is not freely available otherwise, while in other countries infliximab is available in accordance with guidelines. For the majority of the world’s population, however, access to infliximab is extremely limited other than for those who can afford to pay for it themselves. Unfortunately, it seems unlikely that this situation is likely to change markedly for some time yet and therefore, at least in some countries, steroids will continue to be used widely for the foreseeable future.

Steroids: a user’s guide

The clear guidelines produced by the likes of the European Crohn’s and Colitis Organisation25 and the American Gastroenterological Association27 (amongst others) provide excellent models for the use of steroids in Crohn’s disease (Figure 2). We present here a distillation of the evidence (and lack of evidence) in what we hope is a user-friendly form. Inevitably much of it (like the above-mentioned guidelines) is opinion based and is indicated as such.

image

Figure 2.  Steroids: A user’s guide. Recommendations are based on evidence graded as follows (based on Eccles et al.).144 Dark shading of boxes – recommendation Grade A: high quality evidence (well-designed randomized controlled trials, meta-analyses or systematic reviews); light shading – recommendation Grade B: some evidence (well-designed cohort or case–control studies); no shading – recommendation Grade C: low quality evidence or consensus (uncontrolled or no studies). HPA axis, hypothalamic-pituitary-adrenal axis.

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Acknowledgements

  1. Top of page
  2. Summary
  3. Introduction
  4. Corticosteroids: when, which, how much and how
  5. Side effects
  6. Prevention of side effects
  7. Discussion
  8. Acknowledgements
  9. References

We would like to thank all the gastroenterologists who provided us with information for Figure 1. We would also like to thank Mr Paul Rose for his help in preparing Figure 1.

Declaration of Personal interests: Professor Gibson has served as a speaker, a consultant or an advisory board member for Schering Plough Ltd, Centocor, Abbott Australasia Pty Ltd, Ferring Pharmaceuticals Pty Ltd, Pharmatel Fresenius Kabi Pty Ltd, Altana Pharma Pty Ltd and Falk Pharma, and has received research funding from Ferring Pharmaceuticals Pty Ltd, Pharmatel Fresenius Kabi Pty Ltd and Altana Pharma Pty Ltd. Dr Gearry has received research funding from Pharmatel Fresenius Kabi Pty Ltd. Dr Sparrow has received research funding from Ferring Pharmaceuticals Pty Ltd. Declaration of Funding interests: None

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  6. Prevention of side effects
  7. Discussion
  8. Acknowledgements
  9. References
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