The aim of current treatment for Crohn's disease (CD) is to induce and maintain a complete remission, with the mainstay of treatment for active CD being the use of corticosteroids, mesalazine and the immune modulators azathioprine and methotrexate. The efficacy of prednisone and budesonide has been well established and these induce remission in up to 80% of patients. However, some patients are steroid refractory, others remain steroid-dependent and many suffer from severe side-effects. Mesalazine therapy has yielded conflicting results, some studies reporting efficacy, and others being negative. Both azathioprine and methotrexate have been shown to be effective in maintaining remission in steroid-dependent patients. Unfortunately, some patients do not respond to these standard therapies, and thus, possible additional immune-modulating therapies have been initiated.

Monoclonal antibodies directed against the T-cell proteins CD4 and intergrin a4b7, have shown encouraging results. Clinical data also exist for antibodies against tumour necrosis factor-a and interleukin (IL)-10. In humans, a phase II clinical study has shown encouraging results in CD using IL-10 therapy. Although these clinical studies are still in the early stage the prolonged use of antibody therapy has been shown to be much safer than previously considered. Further studies are required to establish whether these possible new therapies are efficacious and safe alternatives for the treatment of CD. [Research & Clinical Forums 20(3):11-18, 1998. © 1998 Wells Medical Holdings Ltd.]

Introduction

Current standard medical therapy for active Crohn's disease (CD) consists of corticosteroids, mesalazine and the immune modulators azathioprine and methotrexate. The efficacy of prednisone in CD has been well established in the North American and European CD studies, and up to 80% of patients initially respond to such treatment[1]. A number of studies have demonstrated that budesonide is effective in active CD of the terminal ileum, and consistently caused less systemic side-effects than prednisone[2,3]. When compared with prednisone, budesonide seemed to be slightly less effective, but was superior to mesalazine. Maintenance treatment with budesonide postponed relapses, but the relapse rate after one year of budesonide treatment was similar to controls[4]. Mesalazine therapy of CD has yielded conflicting results, some studies reporting efficacy, and others being negative. Meta-analysis of mesalazine maintenance therapy of CD indicates a small (15%) treatment effect that may be obscured by the relatively high (20%) placebo response rates in such studies[1,5-7]. Despite early negative data, azathioprine and 6-mercaptopurine (6-MP) have been demonstrated to be safe and effective in CD, and azathioprine is usually used in steroid-dependent patients in order to maintain remissions. It is also used in the treatment of active perianal fistulae[8-10]. One of the disadvantages of azathioprine treatment is the slow onset of action, taking approximately 3 months following oral administration. Furthermore, approximately 10% of patients cannot tolerate azathioprine as a consequence of a mutation in one of the enzymes involved in 6-MP metabolism, or because of allergic reactions[10-12]. Preliminary data suggest that iv. loading results in a faster onset of action of azathioprine, and a controlled study is ongoing[13]. Methotrexate has been shown to be effective in steroid-dependent CD patients, has a rapid onset of action and has a steroid-sparing effect[14-17]. In psoriasis, methotrexate therapy was related to a high incidence of liver fibrosis, but in more recent studies in rheumatoid arthritis, this complication was not observed. Although controlled data are lacking, liver fibrosis does not seem to occur at an increased rate in methotrexate-treated Crohn's patients. One early study demonstrated efficacy of high-dose cyclosporin in active CD, but when administered at a lower dose, cyclosporin did not reduce the incidence of relapses in patients with chronically active CD[18-21]. Although an uncontrolled study suggested that iv. cyclosporin administration may close enterocutaneous or perianal fistulae, the long-term efficacy of this approach remains uncertain, and cyclopsorin therapy is associated with substantial toxicity[22].

Hence, the therapeutic armamentarium in CD has been significantly enhanced in recent years, and the prudent use of budesonide, azathioprine and methotrexate may reduce the complications of long-term steroid use, while keeping a significant number of patients in clinical remission. Nonetheless, some patients do not respond to standard therapy or remain steroid-dependent. In this patient population, a novel possible treatment -- immune-modulating therapy -- has been investigated.

Rationale For Cytokine-Targeting Therapies

Many cytokines are produced at an increased rate in active CD, and in addition, other inflammatory substances including histamine, eicosanoids, platelet-activating factor and nitric oxide are also involved in the inflammatory process. Hence, the key question is whether inhibition of a single inflammatory mediator can ever be an effective approach in CD. Indeed, although the mechanism(s) of action of azathioprine and methotrexate remain obscure, corticosteroids and mesalazine are known to inhibit inflammation at multiple levels. Several studies have demonstrated increased production of pro-inflammatory cytokines in inflammatory bowel disease (IBD) including interleukin (IL)-1, IL-2, tumour necrosis factor (TNF)-a and chemokines in CD, and with the exception of IL-6, the cytokine response is usually limited to the mucosal compartment[23-33]. Novel animal models for IBD have significantly increased the understanding of the cytokine response in IBD[34]. The lessons learned from these models can be summarised as follows: 1) the entire mucosal inflammatory response can be induced by a subpopulation of T cells within the CD4+ compartment, while other CD4+ cells can inhibit activation. In several models there is no need for CD8+ T cells or B cells. Alterations of T-cell regulation, for example by mutations of the T-cell receptor a-chain, have IBD as a major phenotype; 2) the severity of the IBD, secondary to disturbed immune regulation, frequently depends on the genetic background; 3) as yet, no specific pathogens have been implicated in the pathogenesis of IBD in genetically manipulated animals. However, in certain models mucosal inflammation is dependent on the presence of intestinal bacteria, and hence seems to be antigen-driven; 4) a lack of anti-inflammatory cytokines may result in increased local production of pro-inflammatory cytokines.

These observations are all compatible with the hypothesis that CD is a consequence of ill-controlled, antigen-dependent (CD4+) T-cell activation, that results in a high production of pro-inflammatory cytokines within the mucosal compartment. In this view, recruitment of monocytes and neutrophils, as well as activation of the vascular endothelium, are secondary to T-cell activation. Although it remains to be shown whether this hypothesis is accurate, it has provided a framework for the design of novel therapeutic strategies; eg., a reduction of the antigenic pressure, inhibition of the activation of specific T-cell subpopulations, neutralisation of pro-inflammatory cytokines, and an increase in the tissue levels of anti-inflammatory cytokines. These would all be expected to have a beneficial effect in CD. In fact, several interventions that are believed to be beneficial in active CD may act by one or more of these mechanisms. For example, elemental diets and antibiotics are expected to reduce the antigenic load within the intestinal lumen. However these interventions are rather non-specific and do not cause a complete remission in a large fraction of patients. Here we will briefly discuss therapies that target T cells and cytokines.

Interference With T-Cell Function

Of the many possible targets on T cells, the CD4 molecule and the gut homing integrin a4b7 have been targeted in IBD. The CD4 molecule is expressed by T-helper cells, and is necessary for T-cell receptor signal transduction following presentation of antigen by human leucocyte antigen (HLA) class II molecules. In view of the important role of CD4+ T cells in transplantation rejection and various (auto-)immune diseases, several groups have generated specific CD4-recognising monoclonal antibodies. These antibodies inhibit antigen-dependent activation of T cells by interfering with binding of the CD4 molecule to the constant region of the HLA class II molecule, and by blocking signal transduction via the T-cell receptor. In addition, some of these antibodies cause depletion of CD4+ T cells. The anti-CD4+ antibody cMT-412 was used in an uncontrolled phase I study in 12 patients with steroid-refractory CD[35,36]. In this dose-escalating investigation, the antibody was administered intravenously at doses of 10, 30 and 100 mg/day for 7-consecutive days. The acute toxicity of the antibody was mild, and consisted mainly of febrile episodes that only occurred after administration of the first dose. The antibody dose-dependently reduced the number of CD4+ T cells, and the CD4+ T-cell counts remained reduced throughout the 12-week study period. As the CD8+ counts did not alter, the antibody caused a profound reduction of the CD4/CD8 ratio. In general, treatment was well tolerated and no opportunistic infections were observed. In all patient groups the CD activity index (CDAI) diminished, and the reduction was larger in those patients who received the highest antibody dose. As this initial experience has not been followed by controlled studies, the efficacy of this approach in CD remains unknown. Blockade of the a4b7 integrin is another approach which interferes with T-cell activation in CD. This integrin is the major "gut homing receptor" of T cells, that by binding to its ligand MAdCAM, is responsible for the specific recirculation of T cells through the intestinal mucosa[37-39]. In subhuman primates, antibodies which neutralised a4b7 have reduced the severity of IBD, but human studies have not been reported[40].

Cytokine-Targeting Therapies

Various pro-inflammatory cytokines are induced in CD, and of these, interferon (IFN)-g, TNF-a, and IL-12 are attractive candidates for therapeutic interventions. Indeed, neutralisation of these cytokines has been demonstrated to reduce the severity of experimental colitis in various mouse models[41-46]. Only anti-TNF-a antibodies have been investigated in clinical studies. An uncontrolled study in 10 patients with steroid-refractory CD demonstrated unexpected and dramatic therapeutic effects. A very rapid reduction in circulating C-reactive protein, phospholipase A2 and IL-6 levels was observed after a single infusion of the monoclonal antibody cA2, the CDAI was importantly reduced, and healing of intestinal ulcerations was observed in most patients[47]. Subsequently, these data were confirmed in a larger placebo-controlled study[48]. Moreover, when repeated every 8 weeks, the antibody maintained remissions in virtually all patients who had responded to initial treatment during the 44-week study period. Regarding short-term toxicity, the administration of cA2 was only associated with fever, wheezing and transient hypotension in a minority of patients, but the effects of long-term toxicity remains unknown. The mechanism of action of anti-TNF-a antibodies in CD has not been completely elucidated, and inactivation of "free" as well as membrane-bound TNF-a may be involved[49]. There is an anti-inflammatory cytokine called IL-10 that interferes with antigen-dependent T-cell activation and inhibits the release of many pro-inflammatory cytokines by monocytes[50-55]. Inactivation of the IL-10 gene in mice causes a subtle immune dysregulation that results in a severe IBD, complicated by the formation of adenocarcinomas[56]. The severity of the disease is dependent on the genetic background of the mice, the colitis does not occur in germ-free animals, and the mucosal cytokine profile indicates increased production of pro-inflammatory cytokines including TNF-a, IL-1a and IFN-g. The IBD in IL-10 negative/negative mice responds to repeated administration of anti-TNF-a and anti-IFN-g, and when initiated early in life (before the age of 3 weeks), can be prevented by treatment with recombinant IL-10. In human volunteers, IL-10 reduced endotoxin-induced TNF-a release in vivo and significantly mitigated pulmonary neutrophil recruitment, coagulation activation and release of chemokines[57,58]. A phase II dose-escalating study in steroid-refractory patients with CD indicated the safety of repeated iv. dosing, and more IL-10 than placebo-treated patients responded to therapy[59]. Large controlled studies have been initiated to investigate the efficacy of subcutaneously administered recombinant human IL-10 in CD patients.

Conclusions

Clinical studies using T-cell or cytokine-targeting therapies have been initiated in CD. Presently, such therapies will be largely restricted to patients with active CD that do not respond to standard therapies. Most studies have not been designed to assess efficacy, but the short-term safety of these approaches has been remarkably good. Based on theoretical considerations, repeated administration of chimeric antibodies is expected to induce human-anti-chimeric-antibodies (HACAs). Indeed, such antibodies have been demonstrated in a small percentage of patients, but even some HACA-positive patients have been successfully retreated with cA2. As the anti-TNF-a antibodies are thought to cause immune suppression, specific long-term complications, including an increased susceptibility to infections and the manifestation of lymphomas may be expected, but the incidence of such side-effects remains unknown. Anti-inflammatory cytokines such as IL-10 can also be administered safely, and have induced remissions in certain patients. Larger ongoing controlled studies are necessary in order to confirm these preliminary findings, and to position IL-10 within the therapeutic armamentarium in CD. As IL-10 is involved in the maintenance of the normal tolerance towards the indiginous intestinal flora, it is tempting to speculate that IL-10 may be used to prevent recurrence of CD or to maintain remissions. Other interesting target cytokines in CD include IFN-g and IL-12, and several groups are designing therapies that specifically target these cytokines. It is possible that early immune-modulating therapy will alter the natural history of CD, by resetting the balance between pro- and anti-inflammatory mechanisms within the intestinal mucosa. If certain interventions prove to be "disease-modifying", the therapeutic approach in CD will need considerable rethinking.

Last updated May 25, 1999

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