What is the Optimal Therapy for Crohn's Disease: Step-up or Top-down?

Ming Valerie Lin; Wojciech Blonski; Gary R Lichtenstein

Disclosures

Expert Rev Gastroenterol Hepatol. 2010;4(2):167-180. 

In This Article

So Which One is Better? Step-up versus Top-down

Step-up Therapy

The current clinical practice and recommended treatment for CD[127] groups the therapeutic agents in a step-up manner according to the different CD severity levels,[57,128] with an ultimate goal to maintain clinical remission (Figure 1). The term 'step-up' refers to a sequential treatment strategy that often begins with a less effective, potentially less toxic treatment strategy, such as aminosalicylates, antibiotics or budesonide, with escalation to the highly effective but potentially more toxic treatment strategies, such as prednisone, immunomodulators and biological therapy, in patients who failed each line of therapy. In this strategy, one would avoid overtreating and unnecessary exposure to the risk of developing adverse events, especially in a subgroup of patients who may do well with the standard paradigm. For the same reason of toxicity, physicians are often reluctant to advance therapy resulting in patients not being adequately treated and developing tissue damage with the prolonged period of uncontrolled inflammation.

Figure 1.

Step-up versus top-down treatment approach for patients with Crohn's disease.
ASA: Aminosalicylate; AZA: Azathioprine; MTX: Methotrexate; SPS: Sulfasalazine.
Modified from [127] with permission from John Wiley & Sons, Inc.

Top-down Therapy

Studies have shown that most patients treated with the conventional step-up therapy go on to develop stricturing or penetrating disease.[2,3,81] Ideas of using highly effective but potentially more toxic treatment strategies early in the course of a chronic illness to prevent disease progression and disability are now the center of focus in the treatment of patients with CD. Data from CD-related medical claims (October 1994–September 1995) in a 1994 integrated claims database showed that CD requiring hospitalization accounts for greater than 50% of healthcare costs.[129] Jewell et al. presented data looking at the influence of anti-TNF-α (infliximab) on resources in CD in the UK, comparing 6 months pre- and post-infliximab treatment and found that there were 1093 fewer bed days, fewer investigations and an unchanged number of out-patient standard follow-up visits.[130] The number of abdominal operations was halved, with 33 fewer examinations under anesthesia. This finding was consistent with some of our own trials.[80,81] It is estimated that approximately 80% of patients will require at least one surgical resection over a lifetime and that by 20 years following the current treatment standard paradigm, rates of surgical intervention will remain high despite earlier and increasing use of immunomodulators,[116] so it may not be unreasonable to administer these highly effective but potentially more toxic treatment strategies early in the course of a chronic illness.

D'Haens et al. evaluated the efficacy of early combination therapy versus conventional therapy, and the authors were able to demonstrate significant mucosal healing in 73% of patients treated with early immunosuppressive therapy compared with 30% in the conventional treatment group at the end of 104 weeks (p = 0.0028).[126] Since the data from the endoscopic substudy the of ACCENT I trial have demonstrated a better outcome with mucosal healing associated with the scheduled rather than episodic use of infliximab,[122,131] it could be hypothesized that this therapy could potentially alter the natural history of the disease. However, when assessing the actual number of analyzed patients for whom an endoscopic evaluation was performed it was relatively low (58 patients[122] and 40 patients[131]), which makes the data difficult to interpret.

There was a greater proportion of patients who achieved early clinical remission at week 14 (p = 0.0001) and week 26 (60 vs 36%; p = 0.0062)[126] in the early combined immunosuppression therapy group. This was consistent with previous studies.[80,92,98] They were also able to show a significant difference with respect to the number of patients in remission without corticosteroids and without surgery at weeks 26 and 52. A sustained clinical benefit was also observed in the early combination therapy group. Patients assigned to combination immunosuppression had a more rapid drop in CDAI scores and IBD questionnaire compared with patients receiving conventional therapy.[126] In their study, there were no important differences in the occurrence of adverse events between the two groups. All of these factors could argue favorably for the early initiation of combination therapy.

Corticosteroids are ineffective in maintaining remission, preventing new flares or inducing mucosal healing.[110] Their use has also been demonstrated as a predictor for poor outcome.[8,132] During the D'Haens study, patients assigned to early immunosuppression therapy had a reduced need of corticosteroids in the early phase of the disease compared with those in the conventional group.[126] However, this must be interpreted in the context that patients in the step-up group received multiple doses (>2) of corticosteroids before the initiation of immunomodulators, while patients in the top-down group received corticosteroids only if the flare was refractory to infliximab. Many clinicians would commonly introduce an immunomodulator with the need for a second course of corticosteroids instead of waiting for a third course, and this could lead to the step-up patients receiving more corticosteroids than desired.

We have good evidence that the use of other anti-TNF therapies in CD suggest that earlier introduction is associated with improved clinical outcomes.[98,133] However, aside from evaluating efficacy, the long-term safety and pharmacoeconomics are crucial factors to consider when initiating early combination versus sequential immunosuppressive therapy. There is mounting evidence that combination therapy may not be any more effective, nor as safe, as sequential monotherapy[134] and thus safety issues remain a major concern in the top-down approach. The combination of immunomodulator and biologics reduces antibody formation, infusion reaction and loss of response.[135] However, it is used at the expense of increased risk of TB, opportunistic infections and malignancy. The risks of lymphoma and hepatosplenic T-cell lymphoma have been found to be associated with long-term immunomodulator use.[62,136] More importantly, even if we concede that some form of 'top-down' therapy is better for sicker patients with a more ominous prognosis, a great proportion of patients with mild disease would be overtreated. These are some of the considerations that must be factored into our decision-making, and the benefits of aggressive medical therapy may not outweigh the risks. On the contrary, clinicians may be inclined to delay aggressive treatment owing to the concern that potential rare, but serious adverse effects despite the fact that a meta-analysis of 21 placebo controlled trials that enrolled a total of 5356 individuals has shown that anti-TNF therapy was not found to be associated with an increased risk of death (0.21 vs 0.05%; 95% CI: 0.21–0.29), malignancy (0.24 vs 0.39%; 95% CI: −0.45–0.18) or serious infection (2.09 vs 2.13%; 95% CI: 0.45–0.65) when compared with placebo controls[100] and that at the end of D'Haens' study, 76% of patients in the conventional treatment group were receiving an antimetabolite.[126] Delaying treatment could lead to increased and prolonged mucosal damage. The cost for initiating treatment may be higher in patients receiving early combination therapy compared with the sequential step-up therapy, but when taking into account the difficulty of measuring indirect costs, such as cost of lost productivity, quality of life, hospitalization and surgery rate, it may be more costly in the long term.

Although there is encouraging evidence showing benefit from early aggressive treatment in patients with 'early' rheumatoid arthritis, in our CD patient population, 'early' disease is not as clearly defined as in rheumatoid arthritis. We need a more appropriate definition to guide us on the initiation of therapy. When D'Haens et al. designed their trial, infliximab was recommended for use as an episodic agent.[126] With recent studies showing that scheduled dosing is better than episodic therapy, it may underestimate the potential benefits of early combination therapy.[122,137] The final critique on the D'Haens' study was the fact that it was not blinded, which may be necessary for medication dosage adjustment, but may also have influenced the reports of disease status. It appears that the ideal treatment strategy for CD remains uncertain. A longer duration of follow-up is required before it will be possible to evaluate whether infliximab is a disease-modifying anti-CD drug. However, the key may not be the agent, but when the agent is introduced.

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