GASTROENTEROLOGY 2000;118:S68–S82
`
`Therapy of Inflammatory Bowel Disease
`
`BRUCE E. SANDS
`Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital and Harvard Medical School,
`Boston, Massachusetts
`
`In the last decade, substantial gains have been made
`in the treatment of inflammatory bowel disease (IBD).
`Refinements in drug formulation have provided the
`ability to target distinct sites of delivery, enhancing the
`safety and efficacy of older agents. Immunosuppres-
`sive agents beyond corticosteroids have assumed a
`routine part in the care of patients with IBD. Moreover,
`as the century closes, we stand at the threshold of
`unprecedented advances in knowledge of the pathogen-
`esis of ulcerative colitis and Crohn’s disease. Simulta-
`neous progress in biotechnology has fostered the
`development of new agents that strategically target
`pivotal processes in disease pathogenesis. This review
`covers agents currently used in the treatment of IBD
`and seeks to provide an overview of emerging thera-
`pies.
`
`An appreciation of the current state of knowledge of
`
`inflammatory bowel disease
`the pathogenesis of
`(IBD) is essential to understanding emerging therapies
`(Figure 1). The mucosal inflammation that is characteris-
`tic of IBD is the culmination of a cascade of events and
`processes initiated by antigen. This antigen-driven re-
`sponse may be an appropriate one directed against an
`unrecognized pathogen, or an inappropriate response to
`an otherwise innocuous antigen.1 Diverse animal models
`of IBD point to nonpathogenic bowel flora as an essential
`factor in this process.2,3 Available data support at least
`two broad mechanisms by which intestinal epithelium
`may participate in initiation of mucosal immune re-
`sponses:
`(1) by transducing inflammation across the
`epithelium through release of cytokines, chemokines, and
`other proinflammatory substances4; and (2) by serving as
`antigen-presenting cells (APCs).5
`Normally, antigen is taken up and processed by an
`APC and then presented in the context of major histocom-
`patibility complex (MHC). T cells recognize a specific
`antigenic epitope upon binding to the T-cell receptor in
`conjunction with an appropriate MHC molecule. The
`ultimate response may vary at least in part depending on
`whether a classic APC, such as a macrophage, or a
`nonclassic APC, such as an enterocyte, presents antigen.
`Evidence suggests that when enterocytes participate in
`
`individual, T-cell
`antigen presentation in a normal
`tolerance will result.6 However, in IBD, T-cell activation
`is more likely to result when enterocytes serve as the
`APC.5
`Binding of the MHC class II antigen on the APC and
`T-cell receptor–CD4 complex confers antigen specificity
`in T-cell activation, but is not sufficient to initiate a
`response.7 A second, costimulatory signal is not antigen
`specific, but is essential to T-cell activation. When a B7
`molecule on the surface of the APC binds CD28 on the
`T-cell surface, activation occurs. Without this second
`signal, T-cell tolerance or apoptosis may occur. Within a
`few days of activation, T cells express a second B7 ligand,
`CTLA-4, which inhibits interleukin (IL)-2 expression
`and further T-cell proliferation, thereby dampening the
`response.8,9 Interaction of CD40 with CD40 ligand
`provides another costimulatory stimulus.10
`Specific characteristics of the antigen and the second
`signal also determine whether cell-mediated immunity or
`humoral immunity will predominate. In animal models,
`distinct patterns of T-cell cytokine production distin-
`guish between two primary subsets of CD4-positive
`T cells. Cells producing large amounts of IL-2 and
`interferon (IFN)-g are involved primarily in cell-
`mediated immunity and are categorized as T helper 1
`(Th1) cells. IL-4, IL-5, and IL-10 are cytokines character-
`istically produced by Th2 cells and facilitate humoral
`immunity.11
`Although animal models of IBD show clear polariza-
`tion toward Th1 or Th2 responses, the situation in
`humans is less clear.12 Studies in patients with established
`Crohn’s disease have generally supported the predomi-
`nance of Th1 responses.13,14 In ulcerative colitis, en-
`
`Abbreviations used in this paper: ADCC, antibody-dependent
`cell-mediated cytotoxicity; APC, antigen-presenting cell; 5-ASA,
`5-aminosalicylate; AZA, azathioprine; ICAM-1, intercellular adhesion
`molecule 1; IFN, interferon; IL, interleukin; MAdCAM-1, mucosal
`addressin cell adhesion molecule 1; MHC, major histocompatibility
`complex; 6-MP, 6-mercaptopurine; rhIL, recombinant human interleu-
`kin; 6TG, 6-thioguanine; Th, T helper; TNF, tumor necrosis factor;
`TPMT, thiopurine methyltransferase; VCAM-1, vascular cellular adhe-
`sion molecule 1.
`r 2000 by the American Gastroenterological Association
`0016-5085/00/$10.00
`
`

`

`February Supplement 2000
`
`THERAPY OF INFLAMMATORY BOWEL DISEASE S69
`
`Figure 1. Pathogenesis of IBD as it relates to therapy. MTX, methotrexate; SCFA, short-chain fatty acids. Adapted from Sands.143
`
`hanced humoral immunity appears to predominate, but
`evidence for classical Th2 predominance is otherwise less
`secure. It is also unclear whether the cytokine patterns
`found in patients at the time of onset of disease are
`necessarily comparable with those obtained from patients
`with well-established IBD.15
`Macrophages also participate in shaping the mucosal
`immune response. IFN-g produced by activated T cells
`leads to activation of macrophages. Activated macro-
`phages produce IL-12 and IL-18, thereby favoring the
`differentiation of Th1 cells.16–18 IFN-g secreted by Th1
`cells also inhibits differentiation of Th2 cells.19 Con-
`versely, production of IL-10 by Th2 cells diminishes Th1
`responses.20 Activated macrophages also produce a host of
`proinflammatory cytokines, including IL-1, tumor necro-
`sis factor (TNF), and the chemokine IL-8.
`TNF, in particular, has a broad spectrum of proinflam-
`matory effects of importance in IBD. Production of TNF
`leads to activation of other macrophages in an autocrine
`fashion. When bound to the cell surface, TNF may
`
`provide a costimulatory signal, thereby further augment-
`ing T-cell responses.21 TNF induces expression of adhe-
`sion molecules by vascular endothelium, permitting the
`influx of newly recruited inflammatory cells into the
`mucosa. TNF also has a procoagulant effect in the
`vascular endothelium and promotes local release of nitric
`oxide, platelet-activating factor, and prostacyclin. Granu-
`locytes are activated by TNF by (1) inducing integrins on
`their surface promoting attachment to endothelium and
`subsequent diapedesis into the mucosa, (2) priming them
`for response by generating superoxide radical production
`in granules, and (3) inducing granule release.22 Finally,
`TNF may enhance production of metalloproteinases that
`may participate directly in local tissue breakdown.23
`Recruitment of inflammatory cells from the systemic
`circulation is a critical step in amplification of the
`inflammatory response. This occurs through a well-
`coordinated process involving integrins and selectins
`expressed on the surface of leukocytes, and selectins and
`members of the immunoglobulin superfamily, such as
`
`

`

`S70 BRUCE E. SANDS
`
`GASTROENTEROLOGY Vol. 118, No. 2
`
`intercellular adhesion molecule 1 (ICAM-1) and vascular
`cellular adhesion molecule 1 (VCAM-1), expressed on the
`endothelium. Selectins on the surface of lymphocytes,
`monocytes, and granulocytes in circulation permit initial
`attachment of these cells to the vascular endothelium.
`Subsequent binding of integrins to a member of the
`immunoglobulin superfamily strengthens this attach-
`ment, activates the leukocyte, and permits diapedesis
`into the mucosa.24 a4-Integrins may be of particular
`relevance to IBD.25 a4b1 is found on most monocytes
`and lymphocytes and binds to VCAM-1, whereas a4b7
`confers selective homing of lymphocytes to intestinal
`tissue through binding with mucosal addressin cell
`adhesion molecule 1 (MAdCAM-1).26 ICAM-1 binds
`mainly monocytes and neutrophils bearing b2-inte-
`grins.24 Leukocytes then migrate along a gradient of
`chemokines and chemoattractants into the submucosa
`and mucosa.
`Once present, these cells elaborate numerous nonspe-
`cific inflammatory substances. Chief among these are
`products of arachidonic acid metabolism, including throm-
`boxanes, leukotrienes, prostaglandins, and free radicals,
`including reactive oxygen metabolites and nitric oxide.
`Local release of neuropeptides may also modulate the
`inflammatory response.27 Finally, repair of the injured
`epithelium occurs with the participation of a variety of
`growth factors, short-chain fatty acids, and trefoil pro-
`teins.
`
`Goals of Therapy and Choice
`of Agent
`Choice of therapy for a particular patient involves
`consideration of diverse factors relating to drug and
`patient characteristics. Patient characteristics include
`age, diagnosis, severity of signs and symptoms, responsive-
`ness to initial therapy, ability to adhere to prescribed
`therapy and follow-up, presence of comborbid conditions
`or special states such as pregnancy or nursing, and
`distribution of disease. Genetic composition may also
`play a role in responsiveness to a given agent, either
`through differences in pathogenetic lesion or drug metabo-
`lism. Drug characteristics of importance include pharma-
`codyanamic considerations (mode of action, time to onset
`of biological effect, therapeutic index, and maximal
`therapeutic effect) and pharmacokinetic factors (absorp-
`tion, distribution, peak levels and persistence in the
`relevant compartment, metabolism, and excretion).
`Disease manifestations vary widely, so it is not surpris-
`ing that clinical trials have also varied in endpoints and
`design. Historically, the goal of therapy has been to
`ameliorate signs and symptoms of the disease (i.e.,
`
`treatment of active disease). Complete relief of inflamma-
`tory symptoms represents a higher level of response and
`has been called ‘‘clinical remission’’
`in some trials.
`However, carefully conducted studies of corticosteroid
`therapy in Crohn’s disease have shown a poor correlation
`between relief of symptoms, even when complete, and
`mucosal healing on endoscopy. Particularly in Crohn’s
`disease, therapies may produce symptomatic relief with-
`out mucosal healing.28 Paradoxically, these agents may
`ameliorate symptoms in the short term but not prevent
`postinflammatory sequelae that often necessitate surgery.
`Agents that accomplish both relief of symptoms and
`mucosal healing are likely to become increasingly impor-
`tant in the treatment of these diseases, particularly as the
`safety of these agents improves.
`Therapies that prevent the recurrence of inflammation
`and symptoms of IBD play an important role in manage-
`ment. In Crohn’s disease, it is useful to distinguish
`between therapies that maintain remission induced by
`medical treatment and surgically induced remission.
`Healing of fistulas in Crohn’s disease has emerged as
`another goal of therapy worthy of separate consideration
`because of the disproportionate effect that this complica-
`tion can have on the patient’s quality of life.
`
`Agents in Current Use
`Agents currently used in the treatment of IBD
`vary widely in their applications and adverse effects
`(summarized in Tables 1 and 2).
`
`5-Aminosalicylates
`The 5-aminosalicylates (5-ASAs) may be roughly
`divided into the sulfa-free agents, which include mesala-
`mine, olsalazine, and balsalazide, and their parent com-
`pound, sulfasalazine. The 5-ASA agents possess a broad
`spectrum of biological effects of potential relevance to
`their efficacy. Aminosalicylates have long been known to
`inhibit the cyclooxygenase and 5-lipoxygenase pathways
`of arachidonic acid metabolism.29 These agents may also
`alter the immune response at a more fundamental level,
`by diminishing antibody secretion and lymphocyte func-
`tion.29 5-ASA may act as a scavenger of reactive oxygen
`metabolites,29 reduce neutrophil and macrophage chemo-
`taxis,30,31 and protect intestinal epithelium by enhancing
`expression of heat shock proteins.32
`In ulcerative colitis, 5-ASA agents are effective for use
`in mild to moderate disease and as maintenance therapy.
`The therapeutic gains of sulfa-free agents include the
`development of mesalamine enemas for topical therapy of
`distal colonic disease, and improved safety and tolerance
`of oral agents with avoidance of the undesirable effects of
`
`

`

`February Supplement 2000
`
`THERAPY OF INFLAMMATORY BOWEL DISEASE S71
`
`Table 1. Medications Commonly Used to Treat IBD
`
`Crohn’s disease
`
`Ulcerative colitis
`
`Active disease
`
`Maintenance
`
`Active disease
`
`Mild-
`moderate
`
`Moderate-
`severe
`
`Fistula
`
`Medical
`remission
`
`Surgical
`remission
`
`Distal
`colitis
`
`Mild-
`moderate
`
`Moderate-
`severe
`
`Maintenance
`
`1a
`1
`
`1
`
`1a
`1
`2
`
`2
`2
`2
`
`1d
`
`2
`2
`
`1
`
`2
`1
`1
`
`1
`1
`1d
`
`1
`
`2
`2
`
`1
`
`2
`2
`2
`
`1
`?
`1d
`
`1
`
`2
`1/2
`
`?
`
`2
`2
`2
`
`1
`?
`2
`
`1c
`
`2
`1c
`
`1c
`
`2
`2
`2
`
`1c
`?
`2
`
`?
`
`1
`1
`
`2
`
`1
`1
`1d
`
`1d
`2
`1d
`
`?
`
`1b
`1
`
`2
`
`1b
`1
`2
`
`2
`2
`2
`
`?
`
`2
`2
`
`2
`
`2
`1
`1
`
`1d
`2
`1d
`
`?
`
`1
`1
`
`1c
`
`2
`2
`2
`
`1d
`2
`2
`
`?
`
`Class/drug
`
`5-ASA
`Enema
`Oral
`Antibiotics (metroni-
`dazole, cipro-
`floxacin, others)
`Corticosteroids,
`classic and
`novel
`Enema, foam,
`suppository
`Oral
`Intravenous
`Immunomodulators
`6-MP/AZA
`Methotrexate
`Cyclosporine
`Biological response
`modifiers
`Infliximab
`
`aDistal colonic disease only.
`bFor adjunctive therapy.
`cSome data to support use; remains controversial.
`dSelected patients.
`
`sulfa. The efficacy of these agents in ulcerative colitis has
`generally been comparable with sulfasalazine.33–38 Simi-
`lar efficacy, despite higher molar concentrations of 5-ASA
`in the doses of sulfa-free agents, has led to speculation
`that sulfasalazine yet possesses therapeutic qualities be-
`yond 5-ASA alone.
`By contrast, the newer 5-ASAs have provided gains in
`efficacy over sulfasalazine in Crohn’s disease. Large coop-
`erative trials in the United States and Europe showed the
`efficacy of sulfasalazine in active disease, but only for
`patients with a colonic component to their illness.39,40
`Comparisons of some of the newer 5-ASAs with placebo
`(Pentasa [Roberts Pharmaceutical Corp., Eatontown,
`NJ41]; Asacol [Procter & Gamble Pharmaceuticals, Cin-
`cinnati, OH42]) and with oral corticosteroids (Salofalk
`[Dr. Falk Pharma GmbH, Freiburg, Germany43,44]) have
`shown favorable responses, particularly among patients
`with small bowel disease. Metanalysis indicates that the
`efficacy of 5-ASA agents in maintenance therapy is more
`easily shown in surgically induced remission than in
`remission induced by medication.45
`
`Antibiotics
`Considering the central role postulated for bacte-
`rial flora in IBD, there is a paucity of data regarding the
`role of antibiotics in IBD therapy. A long empiric
`
`tradition has supported their use in Crohn’s disease.46
`This effect is presumed to be through alteration of the
`bacterial flora. Metronidazole47 and quinolones48 may
`also possess innate immunomodulatory activity. Clinical
`trials have shown the efficacy of metronidazole in mild to
`moderate Crohn’s disease,49,50 in treatment of perianal
`disease,51 and in postsurgical prophylaxis.52 Ciprofloxa-
`cin has also been used to treat active disease and fistulas,
`either as a single agent or in combination with metroni-
`dazole.53–55 Convincing demonstrations of the efficacy of
`antibiotics in ulcerative colitis have been lacking, al-
`though a recent trial has suggested benefit from ciprofloxa-
`cin in maintenance of remission.56 Until this can be
`confirmed in a larger trial of improved design, the use of
`antibiotics in ulcerative colitis should be confined largely
`to intravenous antibiotics as adjunctive therapy for
`patients with severe, refractory colitis.57
`
`Corticosteroids
`Corticosteroids are among the longest used agents
`in the treatment of IBD58 and continue to be appropriate
`for use in some patients with active disease. At pharmaco-
`logical doses, the biological effects of corticosteroids,
`both beneficial and deleterious, are numerous. Corticoste-
`roids profoundly affect both immunologic and inflamma-
`tory responses. They diminish production of a host of
`
`

`

`S72 BRUCE E. SANDS
`
`GASTROENTEROLOGY Vol. 118, No. 2
`
`Table 2. Medications Commonly Used to Treat IBD and
`Selected Adverse Effects
`
`Agent
`
`5-ASA
`Sulfasalazine
`
`Sulfa-free (mesala-
`mine, olsalazine,
`balsalazide)
`
`Antibiotics
`Metronidazole
`
`Ciprofloxacin
`
`Corticosteroids
`Classic
`
`Novel
`
`Immunomodulators
`6-MP/AZA
`
`Methotrexate
`
`Cyclosporine
`
`Biological response
`modifiers
`Infliximab
`
`Adverse effects
`
`Anorexia, dyspepsia, nausea/vomiting;
`hemolysis, neutropenia, agranulocy-
`tocis; folate malabsorption; reversible
`male infertility; neuropathy; see also
`sulfa-free 5-ASAs
`Headache; drug fever, rash; paradoxical
`exacerbation of colitis; pancreatitis;
`hepatitis; pericarditis; pneumonitis;
`nephritis; secretory diarrhea (olsala-
`zine)
`
`Anorexia, nausea/vomiting, dysgeusia;
`disulfiram-like effect; peripheral neu-
`ropathy
`Nausea/vomiting; headache, restless-
`ness; rash; pseudomembranous coli-
`tis; elevated transaminases; sponta-
`neous tendon rupture
`
`Sleep disturbance, mood disturbance,
`acne, striae, hirsutism, adrenal sup-
`pression, proximal myopathy, glucose
`intolerance, hypertension, narrow
`angle glaucoma, cataracts, pseudo-
`tumor cerebri, infection, edema,
`impaired wound healing, growth retar-
`dation, osteoporosis, aseptic necrosis
`Budesonide CIR: adrenal suppression at
`doses 9 mg/day in 2 divided doses
`and higher, but occurrence of classic
`corticosteroid adverse effects similar
`to placebo144
`
`Nausea; drug fever, rash, arthralgia; leu-
`kopenia; thrombocytopenia; pancre-
`atitis; hepatitis; infection
`Anorexia, nausea/vomiting; bone marrow
`suppression; megaloblastic anemia;
`alopecia; abortifacient; hepatic fibro-
`sis; interstitial pneumonitis; neu-
`ropathy
`Reversible or irreversible decrease in
`renal function; hypertension; tremor,
`headache, paresthesia, seizure; hyper-
`trichosis; hepatotoxicity; infection; lym-
`phoma; gingival hyperplasia
`
`Upper respiratory and other infections;
`acute or delayed hypersensitivity reac-
`tions; lupus-like reaction; ?lymphoma
`
`proinflammatory cytokines, including IL-1and IL-6, the
`chemokine IL-8, the Th1 cytokines IL-2 and IFN-g, and
`the Th2 cytokines IL-4 and IL-5.59 Interference with
`nuclear translocation of NF-kB may play a role in this
`global inhibition.60 Corticosteroids also directly inhibit a
`variety of leukocyte functions, including adherence, chemo-
`taxis, and phagocytosis,61 and interfere with metabolism
`
`of arachidonic acid and production of eicosanoids.62 Drugs
`may be administered orally,
`intravenously in severe
`disease, or rectally for topical therapy of distal colitis.
`Although corticosteroids have been repeatedly shown
`to be highly effective in the short-term treatment of acute
`flares of Crohn’s disease and ulcerative colitis, their value
`in maintenance therapy has never been shown. In Crohn’s
`disease,63 and to a lesser extent in ulcerative colitis, a
`substantial number of patients are unable to discontinue
`therapy without recurrent symptoms, whereas others fail
`to respond altogether. Novel corticosteroids with high
`potency and low bioavailability have been developed as a
`means of minimizing the adverse systemic consequences
`of corticosteroids.64 An enema formulation of budesonide
`and a controlled ileal release formulation of budesonide
`are available outside the United States for treating distal
`colitis and Crohn’s disease, respectively.64 These agents
`minimize the occurrence of classic corticosteroid side
`effects, but do not improve on either short- or long-term
`efficacy.
`
`Immune Modulation
`Thioguanine derivatives: 6-mercaptopurine and
`azathioprine. The thiopurine agents 6-mercaptopurine
`(6-MP) and azathioprine (AZA) are used in Crohn’s
`disease and ulcerative colitis primarily for those patients
`who are resistant or dependent on corticosteroids for
`steroid-sparing effect. AZA is a prodrug, yielding 6-MP.
`The final active metabolite, 6-thioguanine (6TG), is
`incorporated into ribonucleotides, thereby exerting an
`antiproliferative effect on mitotically active lymphocyte
`populations. 6-MP and AZA may also possess direct
`anti-inflammatory properties and inhibit cytotoxic T-cell
`and natural killer cell function. Although it has been
`speculated that AZA may possess immunosuppressive
`properties beyond that of 6-MP,65 the drugs are used
`interchangeably. AZA is generally dosed as 2.0–2.5
`mg/kg body wt, whereas 6-MP is most often dosed at 1.5
`mg/kg body wt.
`Early studies in IBD were often confounded by the
`long time to response with these agents. Metanalysis
`confirmed the data of Present et al.,66 showing improved
`response when treatment continued beyond 4 months.67
`An attempt to shorten the time to response through
`intravenous loading of AZA did not improve on the
`efficacy or time to response of oral dosing. Remission
`rates were identical at 8 weeks.68 In Crohn’s disease,
`6-MP and AZA have value in the treatment of active
`disease (although they must be used with other therapies
`initially because of their slow onset of action), and as
`maintenance therapy in medically or surgically induced
`remission.
`
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`

`February Supplement 2000
`
`THERAPY OF INFLAMMATORY BOWEL DISEASE S73
`
`Levels of erythrocyte 6TG seem to correlate more
`highly with response than dosing based on weight.69
`Both response and bone marrow suppression to the
`thiopurine agents are regulated at least in part by genetic
`composition of the patient. Metabolism of 6TG is
`accomplished by the enzyme thiopurine methyltransfer-
`ase (TPMT). Heterozygous individuals possessing one
`wild-type TPMT gene and one low-activity TPMT gene
`require reduced dosage to avoid leukopenia, but also
`experience a high rate of remission commensurate with
`high levels of 6TG.69 Recessive individuals with two
`low-activity genes are likely to experience profound
`leukopenia. However, the safety and efficacy of using
`TPMT genotype and metabolite levels to guide therapy
`require prospective confirmation before use in routine
`practice may be recommended.
`Methotrexate. Used widely in the treatment of
`rheumatoid arthritis and psoriasis, methotrexate pos-
`sesses immune modulating and anti-inflammatory prop-
`erties. Although the mode of action is not completely
`understood, a variety of effects have been reported,
`including impaired DNA synthesis through inhibition of
`dihydrofolate reductase, generation of adenosine, de-
`creased expression of IL-1, and induction of apoptosis.70
`Promising open-label observations led to studies confirm-
`ing the efficacy of intramuscular methotrexate in steroid-
`dependent Crohn’s disease,71 but not in ulcerative coli-
`tis.72 In contrast with rheumatoid arthritis, parenteral
`administration seems to be important in Crohn’s disease,
`particularly among patients with small bowel disease in
`whom drug absorption may be impaired. In contrast with
`use in rheumatoid arthritis, the drug is generally admin-
`istered intramuscularly because of concerns about dimin-
`ished absorption. The usual doses administered in clinical
`trials (15–25 mg weekly) have also been somewhat higher
`than those administered to treat rheumatoid arthritis.
`Time to onset of response may be more rapid with
`methotrexate than with the thioguanine derivatives. The
`efficacy of methotrexate as a maintenance therapy in
`Crohn’s disease is currently being studied.71
`Cyclosporine. This cyclic peptide has found appli-
`cation in the treatment of severe Crohn’s disease and
`ulcerative colitis. The mode of action of cyclosporine is
`well characterized. Cyclosporine forms a complex with
`cyclophilin within the cell. This complex inhibits calci-
`neurin, a serine threonine phosphatase responsible for
`activating proinflammatory transcription factors. By in-
`hibiting nuclear factor of activated T cells, cyclosporine
`prevents production of IL-2, as well as IFN-g, TNF-a,
`granulocyte-macrophage colony–stimulating factor, and
`IL-4. Consequently, cyclosporine diminishes cytokine
`
`production and exerts an antiproliferative effect on
`lymphocytes.73
`A double-blind, placebo-controlled trial in patients
`with active Crohn’s disease who were resistant to or
`intolerant of corticosteroids showed short-term efficacy of
`oral cyclosporine.74 Onset of action was rapid, occurring
`in most patients by 2 weeks. Subsequent studies have
`shown that low-dose oral cyclosporine is not effective
`maintenance therapy.75 As shown in Table 2, adverse
`effects associated with cyclosporine are prohibitive and
`deter widespread use of this agent. Therefore, the drug is
`only rarely used to treat select Crohn’s disase patients
`with severe, acute flares unresponsive to other therapies,
`and occasionally in the treatment of fistulas,76 primarily
`as a continuous intravenous infusion.
`In ulcerative colitis, cyclosporine may be effective in as
`many as 82% of patients hospitalized for severe flares
`refractory to intravenous corticosteroids.77 The drug is
`administered as a continuous infusion at 4 mg · kg21 ·
`day21. Patients who are elderly or who have mild
`impairment of renal function may be given lower doses,
`from 2 to 3 mg · kg21 · day21. Careful monitoring of
`cyclosporine levels is necessary, with a goal of maintain-
`ing whole blood levels between 300 and 400 ng/mL by
`monoclonal radioimmunoassay.78 Rapid response with
`infusion is considered by many to be a bridge to
`long-term immunomodulatory therapy with AZA, which
`may significantly reduce the rate of relapse.79 However,
`data from randomized, controlled trials of this strategy
`are lacking. Cyclosporine enemas are ineffective in left-
`sided colitis.80 A microemulsion of cyclosporine with
`superior oral absorption may prove to be an alternative to
`continuous intravenous infusion.81
`
`Biological Response Modifiers
`Infliximab. The FDA approval of infliximab in
`October 1998 introduced an entirely novel agent for the
`treatment of Crohn’s disease. Infliximab is the first
`example of a biological response modifier used in the
`treatment of IBD, a chimeric monoclonal IgG1 antibody
`directed against TNF. The antibody neutralizes TNF and
`effectively clears it.82 As an IgG1, it may also effect cell
`lysis through complement fixation or antibody-depen-
`dent cell-mediated cytotoxicity (ADCC).83
`Early, open-label studies in Crohn’s disease showed a
`high rate of response accompanied by significant and
`rapid mucosal healing.84 Dose escalation studies showed a
`lower rate of response and less durable response with
`infusion of 1 mg/kg body wt, leading to further examina-
`tion of 5-, 10-, and 20-mg/kg doses.85
`The first randomized, placebo-controlled trial of inflix-
`imab looked at response rates 4 weeks after a single,
`
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`S74 BRUCE E. SANDS
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`GASTROENTEROLOGY Vol. 118, No. 2
`
`blinded infusion. All patients had moderate to severely
`active disease despite other therapies or had previously
`failed immunomodulator therapy. A single infusion
`yielded a decrease in the Crohn’s Disease Activity Index
`(CDAI) by 70 or more points 4 weeks after infusion
`among 65% of infliximab-treated patients, compared
`with 17% response among placebo patients. The highest
`rate of response was observed among patients treated with
`5 mg/kg (81%), with somewhat lower rates of response
`among those treated with 10 or 20 mg/kg (50% and
`64%).86
`Patients who maintained their response 8 weeks after
`being treated (73 of the 108 patients initially random-
`ized) were rerandomized at week 12 to placebo or 10
`mg/kg infliximab every 8 weeks for 4 additional infu-
`sions. A trend toward significance was observed in
`response at week 44 (8 weeks after the last infusion) for
`infliximab-treated patients, compared with placebo.87
`Quality of
`life was consistently higher and serum
`C-reactive protein levels were consistently lower among
`patients who received infliximab. A significant difference
`was seen in the rate of remission at week 44 with
`infliximab compared with placebo (52.9% vs. 20%, P 5
`0.013).87 These data suggest that repeated dosing with
`infliximab may provide useful maintenance therapy,
`particularly among patients who initially achieve remis-
`sion. A definitive study of maintenance therapy is being
`conducted presently.
`Serendipitous observations of fistula healing in early
`studies led to a randomized controlled trial of infliximab
`for this indication. Patients with enterocutaneous fistula
`were randomized to infusions of placebo or 5 or 10 mg/kg
`of infliximab given at weeks 0, 2, and 6. The major
`endpoint was closure of 50% or more of the fistulas in a
`given patient for 2 successive visits one month apart. The
`percentage of patients who achieved response was signifi-
`cantly higher among patients treated with 5 or 10 mg
`infliximab (68% and 56%, respectively) compared with
`placebo (26%, P 5 0.002 and 0.02, respectively).88 In
`addition, complete closure of fistulas over at least a
`1-month period was achieved by a significantly greater
`proportion of infliximab patients compared with placebo.
`Median duration of response was 3 months. These data
`unequivocally showed the efficacy of infliximab in heal-
`ing fistulas in Crohn’s disease.
`The short-term safety profile of infliximab in clinical
`trials seems to be favorable. A somewhat higher rate of
`upper respiratory infections, generally not severe,
`is
`observed with treatment.86 Acute infusion reactions with
`short-term treatment were infrequent, but potentially
`limiting. A new observation shortly before the drug was
`marketed was the occurrence of delayed hypersensitivity
`
`reactions 3–10 days after retreatment.89 Patients treated
`in early protocols were permitted open-label treatment.
`Ten of the 40 patients retreated after this delay of more
`than 2 years developed a variety of adverse reactions,
`including rash, myalgia, fever, arthralgias, and facial
`swelling. Patients were observed to have high titers of
`human antichimeric antibodies after, but not necessarily
`before, reinfusion.
`The limited data available suggest that delayed hyper-
`sensitivity was less likely to occur among patients who
`received their initial infusions as a series of 3, or who had
`concurrent treatment with an immunomodulator. Comple-
`ment levels were not affected, and the precise immuno-
`logic mechanism is not known. A long-term protocol of
`repeated dosing currently being performed in rheumatoid
`arthritis incorporates a series of three induction doses,
`concurrent methotrexate, and a 2–3-month retreatment
`interval with very little observed hypersensitivity, de-
`layed or acute.90 To date, 6 patients treated with
`infliximab in clinical trials have developed lymphoprolif-
`erative disorders (4 with rheumatoid arthritis, 1 with
`Crohn’s disease, 1 with human immunodeficiency virus
`infection).91 The relationship between infliximab and
`these malignancies remains unknown.91 Additional long-
`term data in larger numbers of patients and comparison
`with untreated populations are needed to obtain a more
`precise estimate of the risk of lymphoma attributable to
`this agent.
`A consequence of the fast-track approval of infliximab
`for Crohn’s disease is the relatively small body of
`knowledge available to guide therapy. Clinical experience
`has expanded this knowledge base in the course of
`treating more than 18,000 patients in the first year since
`infliximab was introduced. The vague wording of the
`approved labeling ensures considerable variation in how
`the drug may be used. Although suggesting that inflix-
`imab is appropriate treatment for patients with moder-
`ately to severely active disease who have not responded
`adequately to conventional therapy, the label leaves the
`definition of conventional therapy to the prescriber. In
`addition, the label notes that safety and efficacy is not
`established beyond one dose for patients with no fistula or
`3 doses for those with fistula.
`It is not surprising that infliximab is frequently being
`used in repeated dosing as symptoms reoccur. This is
`particularly true for patients who have failed to respond
`to or tolerate other therapies, or who may have high
`surgical risk. However, this treatment strategy may not
`be an ideal way to suppress the disease, and regular
`dosing before symptoms recrudesce may be preferable.
`Additional labeling for maintenance therapy awaits the
`completion of further studies. (See Figure 2 for suggested
`
`

`

`February Supplement 2000
`
`THERAPY OF INFLAMMATORY BOWEL DISEASE S75
`
`Figure 2. Proposed guidelines for treatment of Crohn’s disease with infliximab. MTX, methotrexate.
`
`guidelines on therapy with infliximab based on consider-
`ations of current knowledge and labeling of this agent.)
`
`Emerging Agents
`A growing number of novel biological and tradi-
`tional, compound-based agents are under investigation in
`clinical trials in IBD. Considerable attention has been
`devoted to biological agents, which translate the explo-
`sion of knowledge of basic mechanisms of disease into
`therapy. Many more biological agents have been studied
`in Crohn’s disease than in ulcerat