Editorial

 

Infliximab in Crohn's disease

 

Infliximab (IFX) is a chimeric monoclonal antibody (75% human/25% mouse) belonging to the IgG-1 class that is intended to specifically block cell receptors, as well as circulating TNFα, a Th-1 response cytokine with marked proinflammatory activity. Hence, the administration of IFX (Remicade^®, Centocor, Malvern, PA; Schering-Plough, Kenilworth, NJ, USA), a novel biological therapy, results in a marked, powerful, mainly anti-inflammatory therapeutic effect in receiving subjects (1).

Clearly established indications for its use in Crohn's disease (CD) include the management of moderate to severe inflammatory flare-ups, and patients with associated fistulas; its clinical administration received U.S. FDA approval in October 1998, and its use has notably spread worldwide ever since (2,3). IFX is not indicated in the presence of fibrous stenosis (relative contraindication), or in patients with associated extraintestinal infection (absolute contraindication), regardless of origin (bacterial, viral, fungal) or site.

Various drugs have been commonly used in the treatment of CD in daily practice for disease acute and chronic stages, in order to prevent recurrent flare-ups from developing.

Drugs considered being first-choice for CD such as sulfasalazine, aminosalycilates and corticoids are used both to treat acute periods and to prevent relapses. If a patient is unresponsive to these drugs or when either corticoid-dependence or corticoid-refractoriness develops medication is then changed and immunomodulating drugs are selected instead, as a second, long-term therapeutic echelon.

Among drugs belonging to this second group, azathioprine (AZA) or its direct metabolite 6-mercaptopurine (6-MP) and methrotexate (MTX), until then used in the prevention of solid organ rejection for transplanted patients and in the control of autoimmune joint disease such as rheumatoid arthtitis (RA) and ankylosing spondylitis (AS), are most commonly administered.

Overall, both in CD and ulcerative colitis (UC), immunosuppressing drugs have proven highly effective in the clinical setting, with a good safety profile and excel-lent efficacy in terms of cost-benefit (4-6).

The arrival of infliximab (IFX) in the therapeutic armamentarium as a third-step drug for the control of CD, represents a significant change, as it manages to rapidly and effectively reduce intestinal inflammation on the one hand, and represents the first medical treatment to ever induce fistula closure in the context of this disease on the other hand, which it consistently does in a high percentage of patients (around 60%).

In 1977 Targan et al. were first to report on a controlled clinical trial of IFX in patients with moderate to severe inflammatory CD flare-ups, with an initial response rate of 81% at week 4, following a single intravenous infusion of 5 mg/kg versus 17% in the placebo group. Clinical remission was achieved in 33% of treated patients, versus 4% among those who received placebo. A small proportion of patients who did not respond to the initial infusion did respond to a second dose 4 weeks later (7).

For the treatment of fistula-complicated CD with IFX, where three intravenous infusions at a dosage of 5 mg/kg were administered in weeks 0, 2, and 6, Present et al. (8) included in their study 98 patients and found that 62% responded to IFX versus 26% amongst those treated with placebo. Of actively treated patients, 55% attained a complete closure of fistulas versus 13% of those randomized in the placebo group (p = 0.001).

Following the excitement engendered by results obtained in these early studies a huge proportion of treated patients was seen to relapse within 8-12 weeks after having completed their first therapy course. In contrast, patients receiving IFX recall doses every eight weeks showed significantly prolonged clinical benefits (9).

These results were confirmed by the ACCENT I study, the reported trial with the largest series of patients under IFX maintenance therapy thus far (10). This study included 573 patients with active CD who were administered an initial IFX infusion. During week 2, 58% of patients showed a good clinical response. Responders were subsequently allocated to three follow-up groups for 54 weeks -a placebo-treated control group, a group with IFX 5 mg/kg in an endovenous infusion every 8 weeks, and a group receiving a 10 mg/kg endovenous infusion every 8 weeks. Among patients treated with IFX 5 mg/kg, clinical response was still ongoing by week 30 in around 50%, and by week 54 in 35%. Those who received 10 mg/kg had not improved response rates when compared to subjects receiving 5 mg/kg.

In parallel with other trials, this study has consistently revealed that IFX may induce a relevant, virtually complete reduction of bowel inflammatory lesions, as confirmed by both endoscopic and histologic examination (11).

Regarding its mechanism of action, IFX blocks both circulating soluble TNFα (sTNF) and cell membrane-associated TNFα (mTNF), and may induce apoptosis (programmed cell death) in peripheral blood monocytes using the caspase activation pathway both in patients with CD and healthy individuals. Similarly, IFX administration results in apoptosis in T (CD4 +) lymphocytes at the intestinal lamina propria (12,13).

IFX effects are likely different in RA and CD. Soluble TNFα neutralization is its main mechanism of action in the former, whereas in the latter this effect does not suffice, as lymphocyte apoptosis at the bowel's lamina propria is considered of paramount importance for its therapeutic effect. This explains why the administration of etanercept, another monoclonal anti-TNF antibody, is effective in RA -as it neutralizes sTNFα- but is not indicated in CD -as it cannot block mTNFα receptors (14).

Several attempts have been made to explain unresponsiveness to IFX observed in 20-30% of patients, and to unveil potential predictive factors for response, particularly in patients with fistulous CD.

Louis et al. (15) demonstrated that response to IFX therapy was associated with the presence of extensive systemic inflammation, as indirectly measured by high C-reactive protein (CRP) levels. Thus, in a study including 226 patients with CD, response rates were higher among patients with high CRP levels (>5 mg/L) versus those with normal CRP levels (76 versus 46%, p = 0.004, OR: 0.26), and no relation whatsoever to TNFα polymorphisms such as the high-output, -308A TNFα variant was seen.

The only factor so far reported, that is clearly predictive for response is the concomitant use of immunosuppressors, such as AZA, 6-MP, and MTX (16,17).

In this issue of our journal, Luna-Chadod et al. analyzed a series of response predictive factors in a series of 108 patients with fistulizing CD within a multicenter study that was carried out in seven hospitals in the Autonomous Region of Madrid, and they found no significant factors associated with response, similarly to other previously reported studies on this topic (18).

Quality of life is pretty impaired in patients with CD, both at the physical and psychological level, with a relevant degree of dysfunction both in its own right and when compared to other chronic conditions. Thus, Gregor et al. found that measurements of health-related quality of life (HQoL) parameters in patients with controlled CD were similar to those of individuals suffering from severe angina, which is associated with serious labor disability (19).

Various studies have been performed regarding the effect of IFX on HQoL in patients with CD, clearly showing its effectiveness both for acute and long-term maintenance therapy (20,21).

In this issue, Cadahia et al. study the short-term improvement brought about by IFX in a series of 25 patients with fistulous CD using two tests -a general (SF-36) and a specific (IBDQ) test, which they compare to Crohn's disease activity index (CDAI)- along acute management and after 1 month following acute therapy completion. Similarly to other authors, they found a significant improvement in parameters assessing physical function and disease activity, with no noticeable changes in social function, which is better preserved than physical function (22).

Reactions to IFX infusion are thought to develop as a consequence of anti-infliximab antibodies (ATIs) and are a well known complication, their incidence being estimated as 13-18% of treated patients. They may be both early and late reactions. Regarding immediate reactions, the most common ones consist of mild symptoms such as facial reddening or serious anaphylactic responses such as dyspnea and hypotension. A reduction of the infusion rate suffices in most cases to treat this problem, and infusions may be completed in spite of these reactions, provided they are mild and temporary.

ATI development is on the one hand associated with a more frequent development of infusion reactions with successive doses, and on the other hand with reduced IFX treatment response rates. Concomitant immunosuppressive therapy, previous intravenous hydrocortisone infusions, and shorter intervals between IFX infusions have all been suggested to notably reduce both the frequency and severity of allergic reactions to IFX administration (23,24).

Most common late reactions to IFX infusion include pain and swelling of several joints, which are usually treated with NSAIDs and/or corticoids. The frequency of reactions to IFX infusion, both early and late, is similar in adults and children (25).

Regarding the development of infectious adverse affects, tuberculosis is a well-known, relevant one. In a review of FDA-provided data on a total of 150,000 patients treated with IFX until March 29, 2001, 70 subjects had developed tuberculosis after a mean therapy course of 12 weeks, and 40 of these had extrapulmonary involvement; most cases were reactivations of a latent, previous disease (26).

In a recently published review in our country, which was performed under the auspices of "Sociedad Española de Reumatología", and which included 71 centers, an estimated incidence of 1.9 per 10⁵ was reported for year 2000, which diminished to 1.1 per 10⁵in 2001. Since the adoption of systematic screening procedures for tuberculosis before IFX therapy onset (routine chest x-rays and PPD test) incidence has noticeably decreased, and only one case has been reported in the first 5 months of 2002, in the study reported by Gómez-Reino et al. (27).

The safety profile of IFX has been carefully analyzed in an extensive series of 500 patients with CD who were treated at the Mayo Clinic and received an average of three infusions each, with a mean follow-up of at least 17 months. Six percent of patients treated with this regimen developed a significant side effect, which most commonly included acute infection episodes. Therefore, clinicians treating these patients with this sort of drugs must set up a close monitorization program, so that the development of potential complications -including infection, reactions to infusion, and autoimmune disturbances- may undergo early detection and thus be prevented (28).

As regards the development of potential IFX-related neoplasms it is as yet un-known whether long-term administration of this new biologic therapy may result in an increased incidence of malignancies -both lymphomas and solid tumors- from increased immunosuppressive effects brought about by the concomitant use of other drugs (AZT or MTX); such incidence, however, does not seem to be currently increa-sed, and cumulative experience with the use of IFX is now extensive, since around 340,000 patients had already received this drug worldwide by late 2002.

Other indications of IFX treatment are CD-related systemic complications. Thus, in a series of 13 patients who had moderate to severe pyoderma gangrenosum, the administration of IFX resulted in complete skin lesion healing in all patients (29).

However, it looks like IFX administration is not going to be extended for the treat-ment of patients with ulcerative colitis (UC), since results thus far obtained in controlled studies on a series of patients with UC did not result in the desired beneficial effects (30).

The therapeutic armamentarium for CD has notably expanded in the last few years, particularly with the contribution of the so-called biologic therapies, whose one and only representative for CD is currently infliximab. These therapies effectively heal the inflamed intestinal mucosa, close associated fistulas, and notably modify the disease clinical course.

Novel molecules such as CDP-571, CDP-870, alpha-4 integrin, ICAM-1, CNI-1493, and so on are being studied -some of them already in phase-2 or -3 trials; they have demonstrated an outright efficacy in preclinical studies so far.

New studies to adequately identify the presence of response predictive factors for these new biologic therapies are clearly needed, so that they may be more appropriately administered to rigorously selected patients.

In the near future we may likely tailor CD therapy based on the genetic, clinical, biochemical, and serologic profile of each patient suffering from this complex disease.

L. Rodrigo Sáez

Service of Digestive Diseases. Hospital Central de Asturias. Oviedo

 

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