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Diagnosis and managementof infiammatory bowel diseaseAllison Nightingale

Inflammatory bowel disease (IBD) is the collectivename for ukerative colitis (UC) and Crohn's disease

(CD), which characteristically run a chronic, andlargely unpredictable, relapsing and remitting coursein terms of both frequency and severity. Around onein 700 people are affected with IBD in the UK, whichcommonly occurs between the ages of 15 and 40,although any age group can be affected (Loftus, 2004).Treatment of active disease episodes with a combinationof drugs, diet and appropriately timed surgery, andmaintenance of remission thereafter form the basis ofmanagement. This article aims to give a brief overviewof the currently available and emerging medical opfionsand medical management strategies.

AetiologyThe cause is uncertain buf if is clear fhaf genes,interacting wifh an environmental trigger(s), probablythe normal bacterial flora, lead to an abnormalimmunological reaction and play a huge part in thedevelopment of the disease (Hart ef al, 2002). Theresults of an exfensive study of DNA from over 2000patients in the UK has led to the discovery of threenew genes associated with susceptibility to CD, inparticular lack of ability fo clear bacteria from cells (TheWellcome Trust, 2007). Although a direct genetic causeis not certain, current knowledge and undersfandingof disease behaviour should subsfantially advance thedevelopment of more specific and targeted treafmenfs,as well as enable older treatments to be used in moreeffective ways.

Smoking is probably the strongest environmentalrisk facfor for fhe development of CD and oftenproduces a worse course of disease (Johnson ef al,2005). Sufferers are more likely to be smokers than non-smokers, in parf icular women who smoke, thereforesmoking cessation strategies should form an integralparf of fhe managemenf plan. The deleterious effectsof smoking are unclear buf may have some effect onthe blood supply to the intestine. Conversely, smokingappears to be protective of UC, which fends to beassociated wifh non-smokers or ex-smokers.

DiagnosisDiagnosis includes a combination of symptomhistory and presenting clinical features supported by

AbstractInflammatory bowel disease (IBD) is a chronic conditioncharacferized by unpredictable relapses and periods of remission.The cause is uncertain, but genes interacting with environmentaltriggers may play a part. Symptoms of IBD vary according to thedisease site and severity. Accurate diagnosis is critical and ismade through a combination of symptom history review, clinicalfeatures and laboratory tesfs. Treafmenf strategies focus onresolving symptoms as well as improving quality of life. A number oftreatment options are available including 5-ASAs, corticosteroids,immunomodulator and biological therapies, and should bediscussed with each patient. Where appropriate, a full nutritionalassessment should be performed. Patient support and educationare essential to improve concordance with treatment, and IBDnurses, where present, are crucial to care and optimizing treatment.

Altis.

Cambridge.

.le IS an inflammatory bowel disesse nurseAddenbrookes NHS Foundation Trust

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Box 1. Differential diagnosisof IBD" Ulcerative colitis

Crohn's diseaseMicroscopic colitis, e.g. collagenous colitis,lymphocytic colitisInfection, e.g. yersinia, ileocaecaltuberculosisMalignancy, e.g. colorectal cancer,lymphoma,Irritable bowel syndrome (IBS)Drugs, e.g. non-steroidal anti-inflammatorytreatment (NSAIDs)Malabsorption, e.g. coeliacIschaemic colitisAppendix massBehcet's vasculitis

laboratory findings from blood tests including raisedinflammatory markers sucb as C-reactive protein anderythrocyte sedimentation rate. Stool culture, includingClostridium difficile toxin, is essential to excludeinfection. Radiological imaging of tbe bowel and directvisualization of tbe mucosa by ileo-colonoscopy, withbiopsy of tbe mucosa for histological analysis, usuallyprovides confirmation. Tbe advent of wireless capsuleendoscopy bas improved the diagnosis of small bowelCD (Lasbner, 2006).

Many conditions can mimic IBD {Box I); it istberefore essential to exclude tbese, in particularinfective causes, to ensure tbat tbe most appropriate andeffective treatment is instituted (Guan, 2000).

Clinical features and symptomsSymptoms tend to be variable according to diseasesite and severity, and altbougb CD and UC are

Anaemia and low iron can lead to fatigue in IBD.

symptomatlcally similar tbere are some distinctivedifferences in terms of features and disease behaviour{Box 2), whicb may affect the overall management.Features comn:ion to both include:

• Frequent and urgent bloody diarrhoea {bloody incolonic Crobn's) often associated witb mucus

• Tenesmus• Crampy abdominal pain• Anorexia, weight loss and fever can be a feature of

tbe more severe disease• Fatigue—possibly due to anaemia and low iron levels

{may persist even in remission)• Stricturing or narrowing of the intestine in CD can

lead to obstructive symptoms such as constipationand vomiting in association with abdominal pain

• Toxic mega colon (dilation of the colon) can be afeature of severe colitis.Extra intestinal manifestations principally involving

the joints, skin and eyes are seen in botb conditions{Ketbu, 2006). Some, but not all, are related to activeintestinal inflammation and often resolve on treatment.One or more of tbese manifestations can occursimultaneously and tend to be more common in colonicdisease. Gallstones and renal stones may be a feature ofsmall bowel CD as a result of malabsorption of a varietyof minerals.

TreatmentPrevious treatment strategies bave simply focused onresolving symptoms and making patients feel better.However, mucosal healing and maximizing quality oflife tend to be tbe ultimate goal of modern approachesto treatment. Options largely depend on diagnosis,disease site and severity, and sbould include discussionwith tbe patient as part of tbe decision-making process.

AminosalicyiatesAminosalicylates {5-ASAs) are anti-inflammatory drugstbat act at various levels of the immune response andare indicated for the treatment of mild to moderatelyactive UC and the maintenance of remission.Aminosalicylates tend to be of limited benefit forremission in CD, although there is some evidence tosuggest a reduction in post-surgical recurrence of thedisease, limited to the small bowel if used in high doses(Lochs etai, 2000).

The active 5-ASA molecules are designed to reachthe colon through a number of different mechanismssucb as:

Slow, continuous release throughout the intestine(Pentasa)

m Modified release or pH-dependent (Asacol MR,Salofalk and generic Ipocol and Mesren MR)

- Azo-bond (sulphasalazine, balsalazide, olsalazinej.Liquid-retention enemas, foam enemas and

suppositories are available for rectal or left-sideddisease, but combined use of oral and topical therapy

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Box 2. Differences between Crohn'sand ulcerative colitis

FactorDistribution

Crohn's diseaseCan affect any part of thegastrointestinal tract

disease

Ulcerative colitisAffects large bowel only

Endoscopy findings Rectum frequently spared

Radiology

Histology

Diet

Inflammation discontinuouswith presence of 'skip lesions'

Bowel wall is thickened and hasa 'cobble stone' appearanceowing to deep ulcers and edema

Strictures are commonDeep fistures and fistulae arecommonAsymmetrical inflammation

Presence of discrete granulomasare almost diagnostic

Inflammation is transmural

The increase in white cells tendto be lymphocytes

Remission can be achieved withelemental and maintained withexclusion diets

Clinical presentation Patients often thin and can bemalnourished owing to intestinalmalabsorption of nutrients

Diarrhoea - only sometimeswith blood

Abdominal mass common

Rectum always affectedInflammation is continuous anduniform

Bowel wall is thin with loss ofvascular pattern

Occur less commonlyOccur less commonly

Symmetrical inflammation

Granulomas are rare but may bein association with damaged cellsInflammation is usually confinedto mucosaThe increase in white cells tendto be polymorphs

No benefit on inflammatoryprocess with these diets

Weight loss usually related tothe severity of active disease

Diarrhoea with blood is common

Rarely occurs

appears to be more effective than either used aloneeven in extensive disease (Marteau et al, 2005). Thechoice and potential efficacy of the drug may belargely dependent on disease site and behaviour; forexample, an azo-bonded preparation may be moreeffective in left sided disease, and modified release orpH-dependent preparations in more extensive disease.Factors such as severe diarrhoea or concomitantmedications may alter the colonic environment,thereby affecting optimal release. Therefore, it is oftenworthwhile considering a slow-release formula in thesecircumstances. The generic formulations have notbeen subject to the same controlled clinical trials asproprietary formulations and, at least anecdotally, havebeen associated with relapse in previously

stable patients. Therefore prescribing by brand maybe important

Treatment is generally well tolerated but headaches,abdominal pain and paradoxically, a worsening ofcolitis symptoms can occur and dose reduction ortreatment cessation may be necessary. Renal andmyeloproliferative disorders are a reported risk andtherefore renal function and full blood count shouldbe monitored regularly (Van Staa et al, 2004).

There is a reported reduction in the risk ofdeveloping colorectal cancer associated withlongstanding and extensive UC by as much as 75% withall forms of 5-ASA (Eaden et al, 2000). This informationshould serve to improve concordance with takingmaintenance medication. Novel treatment strategies.

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Mucosal healing and maximizing quaiityof life tend to be the ultimate goal

of modern approaches to treatment

including high dosing, rectal gels and simplifieddosing regimens, should also improve tolerability andacceptability (Kane. 2005).

CorticosteroldsCorticosteroids remain the standard treatment for moresevere and usually extensive active disease. Theygenerally bring a rapid relief of symptoms but arenot recommended for maintenance in view oftheside-effect profile, including moon face, weight gain,acne, dyspepsia, mood swings, diabetes and septiccomplications, which often outweigh the benefits(Faubion et al, 2001). Prednisolone is the mostcommon oral preparation and enemas, in the formof foam (Predfoam, Colifoam) or liquid preparations(Predsol, Predenema, Entocort) and suppositories(Predsol) are available for diseases confmed to theleft colon; however, combined use of oral and topicaltherapy appears to be more effective in clinicalpractice. Osteoporosis is a risk of long-term therapy,although reduced bone density can also occur aftera short course of treatment. Therefore concomitantprescribing of calcium and vitamin D3 supplementsis recommended with additional bone densitometryfor patients likely to be taking steroids for 3 monthsor more (Compston, 2003).

Budesonide is a topically acting steroid tableteffective in the terminal ileum and right colon, andis therefore more suitable for CD. It is associatedwith fewer side-effects than conventional steroidsbecause of less systemic bioavailability, owing tofirst-pass metabolism in the liver and should beconsidered as an alternative where possible (Kane etal, 2002). A targeted oral preparation of prednisolonemetasulphobenzoate, used topically in distal UC,seems to be similarly effective throughout the colon(Cameron et al, 2003) and should be available forcommercial use in the future.

In severe cases, hospitalization for intravenoustherapy with hydrocortisone or methyl prednisolonemay be required with immunomodulators formaintenance of remission.

Immunomodulatory therapyThiopurinesAlthough unlicensed, azathioprine and its metabolite,6-mercaptopurine, are effective immunosuppressiveagents in both CD and UC, but the exact mechanismof action is not clear (Ansari et al, 2002). In additionto a disease modifying effect on the immune response,thiopurines also have steroid sparing properties.

although delayed efficacy of up to 12weeks usuallymeans that concomitant steroid treatment is necessaryto control more immediate symptoms. Reversiblebone marrow toxicity and hepatitis are a risk, so closemonitoring ofthe blood count and liver function oninitiation of treatment and subsequently every 2-3months is essential. Approximately 30% of patientswill have to stop treatment as a result of side effectssuch as nausea, vomiting, flu-like illness, bone marrowsuppression or lack of clinical response. The agent6-mercaptopurine can be substituted safely in manycases where patients are intolerant of azathioprine (Leeset al, 2007). Although lymphoma has been reported.the benefits outweigh the risks and a recent review byFraser et al (2002) confirms the long-term safety ofthese treatments.

MethotrexateMethotrexate is generally indicated in patientsintolerant or resistant to azathioprine, but seems tobe more effective in CD than UC (Feagan et al, 2000).In clinical trials, weekly injections of 25 mg haveproved effective in achieving remission, which can bemaintained with a dose of 15 mg weekly. The drug canalso be administered orally. Side-effects such as rash,nausea, diarrhoea and stomatitis are fairly common,and although co prescription of folic acid can help,treatment withdrawal is necessary in around 5% ofpatients, Methotrexate should be avoided in pregnancy,breastfeeding and conception, for males included,until at least 3 months after the last treatment asmethotrexate is teratogenic.

CiclosporinCiciosporin is a fungal metabolite that has a specificaction on lymphocytes and is rapidly effective inthe treatment of severe refractory UC, avoiding theneed for colectomy in some cases (Campbell et al,2005). It is usually given intravenously followed byoral administration as a 'bridge' to maintenancetherapy with the slower acting thiopurines, althoughoral therapy is also effective. Prophylaxis againstopportunistic infections with co-administration of co-trimoxazole may be indicated, especially if concomitantimmunosuppression therapy is used or duringprolonged treatment, although 3-6 months is the usualrecommendation.

Nephrotoxicity limits the use of ciclosporin,although other side-effects such as hirsuitism, tremorand gingival hyperplasia can be problematic. Lowerdoses may minimize these effects (Van Assche et al,2003). Blood tests including full blood count, renalfunction, magnesium, cholesterol and blood pressureshould be checked before treatment. Ciclosporin levels,renal function and full blood count are recommendedat defined intervals thereafter. A number of drugs willaffect ciclosporin levels and for the same reason,

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Common food intoiei nines iiiciude wheat, yeast, dairy prodiu in and caffeine.

patients should be advised to avoid grapefruit andits juices.

Biological therapiesInfliximab is a monoclonal chimeric (mouse/human)antibody licensed to treat severe active CD and hasbeen associated with mucosal healing and closure offistulae (Present et al, 1999). It binds to and neutralizesthe effect ot tumour necrosis factor (TNF)-a, a potentprointlammatory mediator, which is overexpressedin active disease. It is administered by intravenousinfusion and therefore requires hospitalization,although day treatment is usual. The response israpid with the benefits usually seen in 1-2 weeksand sustained for 8-12 weeks, but patients oftenrequire repeat treatments as maintenance (Rutgeertset al, 2004). It is also effective in UC (Rutgeerts et al,2005) and has recently been given a licence for usein moderate to severe cases. Adalimumab, a fullyhumanized anti-TNF treatment recently licensed foractive CD, is given by subcutaneous injection, therebyavoiding tbe need for hospital treatment, and hasalso proved effective in some patients who no longerrespond to infliximab (Sandborn et al, 2007). A numberof other anti-TNF treatments, including certolizumabpergol, are undergoing clinical trials (Schreiber et al,2005).

Although infliximab is now well established foruse in moderate to severe CD, treatment is governedby the National Institute of Health and ClinicalExcellence (NICE), according to guidelines first drawnup in 2002. Clinical experience however, suggeststhat it might be more effective, and prevent much ofthe tissue destruction if it was given earlier in a 'topdown' approach with immunomodulators, such as

azathioprine, rather than the more traditional 'stepup approach'. Unlike steroids, it actually has an affecton the underlying disease process (D'Haens, 2006).This is likely to be viewed with caution given thepost-marketing reports of an increased incidence ofhepatosplenic T-cell lymphoma (Mackey et al, 2007),which is rare but usually fatal, and also a rise in casesof tuberculosis associated with treatment (Rampton,2005). This is likely to apply to all anti-TNF treatmentsand perhaps for the time being, they should be reservedfor the most severe cases following full counselling ofthe risks and benefits involved.

Nutritional support and primarydietary therapyMany patients with IBD are malnourished, often owingto the effects ofthe underlying disease process butalso because they avoid certain foods perceived to becontributing to symptoms or food altogether, in aneffort to reduce pain (Razack and Seidner, 2007). It istherefore essential that a full nutritional assessmentbe performed by a specialist dietitian with appropriatesupplementation instituted as indicated.

DietElemental liquid diets have proved very effective asprimary treatment of active CD and are at least aseffective as oral steroids, but treatment does requireconsiderable motivation and dietetic support (Riordanet al, 1993). The exact mechanism of action is unclearbut it appears to have an anti-inflammatory effectin addition to restoring optimum nutritional status(O'SuUivan and O'Morain, 2001). Although manypatients relapse on return to normal eating, remission

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can be maintained if followed by an exclusion diet andsubsequent programmed food reintroduction withavoidance of those foods found to provoke symptoms Areduction in dietary fat and fibre seemto have a positive effect as demonstrated by the successof a low fat, fibre-limited exclusion (LOFFLEX) diet(Woolner et al, 1998). The most common intolerancesinclude wheat, yeast, dairy products and caffeine.

Primary dietary treatment provides a safe andeffective alternative to drug treatment and unlikecorticosteroids, does not lead to osteoporosis (Dear etal, 2001). It is not effective in UC however, and patientsare simply advised to eat a wide-ranging diet so long asit does not appear to consistentlytrigger symptoms.

Antibiotics, probioticsand prebioticsAntibiotics such as ciprofloxacin and metronidazole,are used to treat diarrhoea owing to bacterialovergrowth ofthe small intestine resulting fromstrictures or scarring because of long-standing disease.They are also used to treat active CD as well as septiccomplications (Guslandi, 2007). They appear to havean anti-inflammatory as well as antibacterial action,but their use in UC is less well documented, apart fromprophylaxis in acute severe UC before the exclusion ofan infective cause. Conversely, in view ofthe associationof bacteria and inflammation with the developmentof IBD, probiotics, and even prebiotics, are creating

Anti-inflammatory benefits of complementarytherapies such as aloe vera have been noted.

much interest and have, perhaps, been more successfulin colitis than in CD. Further investigation is neededbefore these can be widely adopted into clinical practicesuccessfully (Sartor, 2004).

Adjunctive treatmentsAntidiarrheal agents, such as codeine phosphate andloperamide, may be used with caution but should beavoided in active disease. Although diarrhoea mayresolve, underlying inflammation remains unaffectedand complications such as perforation may arise.Resection ofthe terminal ileum can result in diarrhoeaowing to malabsorption of bile salts and is usuallytreated with colestyramine (Questran). Concomitantmedication needs to be taken an hour before, orat least 4 hours after, a dose as absorption may beaffected. Supplements of fat-soluble vitamins are alsorecommended if used long-term.

SurgeryIt is beyond the realms of this article to discuss thesurgical options in detail. Suffice to say removal of thecolon (colectomy) in the case of medically refractoryUC provides the only permanent cure (Travis,2004), whereas surgical management of CD involveslimited resection ofthe most diseased intestine andmanagement of sepsis, i.e. drainage of abscesses andfistulae. Stricturoplasty can sometimes be performed,thereby preserving intestinal length in the case of shortstrictures (Roy and Kumar, 2004).

Complementary therapiesPoor response, or unacceptable side-effects associatedwith conventional therapy, can cause many patientsto turn to complementary or homeopathic therapies(Langmead and Rampton, 2006). Although theevidence base for their use and potential efficacy issparse and may simply lie in stress reduction, anti-inflammatory benefits have been associated withpreparations such as aloe vera, essential oils andacupuncture. Awareness that a patient might be takingthese treatments is important as they might adverselyinteract with conventional therapy.

Education and supportSupport and education are essential to improveconcordance with treatment. Patients with UC arefive-times more likely to relapse if they fail to taketheir 5-ASA therapy (Kane, 2005) and those requiringhospitalization owing to relapse and subsequenttreatment of disease complications cost the NHS20-times more than patients in remission (Bassi et al,2004). IBD nurse specialists, where present, have beenable to make a significant impact on care delivery andoptimize treatment outcomes providing telephonesupport, continuity and early access to prompt, effectivetreatment and advice when symptoms recur, with

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improved patient satisfaction (Nightingale et al, 2000).Preliminary findings from the ongoing National IBDAudit support this.

Everyday Living support serviceCompanies such as Procter & Gamble PharmaceuticalsUK are also working closely with health professionalsto improve support for patients and have recentlydeveloped the Everyday Living patient support service{Figure I). Aimed at newly diagnosed patients withUC taking 5-ASA (mesalazine) treatments, thiswill be an invaluable resource for patients and theirfamilies, especially in centres where there is no IBDnurse specialist. The resource should also complementservices where posts already exist.

Although it is ofthe utmost importance that patientstake their medication regularly and appropriately, aholistic approach to management is essential in dealingeffectively with a disease that impacts on many aspectsofthe lives of both the patients and their families.Patients often have issues relating to altered bodyimage, not only resulting from the effects ofthe diseaseor surgery, but also from the treatments themselves,particularly oral steroids. Many fear or suffer actualincontinence and are too embarrassed to talk abouttheir problems with friends and family, which oftenleads to social isolation and a poor quality of life.Support groups such as The National Association forColitis and Crohn's Disease (NACC) help to raise theprofile of IBD and ofters an extensive range of servicesincluding information booklets, counselling andpeer support (see Further information). They work inpartnership with health professionals to campaign forimproved services for patients, raising funds to furtherresearch.

ConclusionInflammatory bowel disease is complex andmultifactoral, generally requiring a multidisciplinaryteam approach to management, involving thegastroenterologist, nurse specialist and dietitian,supported by radiological and histological services.Close collaboration with the colorectal surgeons isalso essential to ensure appropriately timed surgery.Patients need to take regular medication even whenwell, or follow specific advice, which often requiresconsiderable lifestyle adaptations in order to reducethe incidence of relapse and prevent complications.Regular follow-up and periodic investigations arealso necessary to monitor the effects of treatment,especially immunomodulatory, biological therapy andcolonic surveillance, in order to detect early changesof colorectal cancer, all of which can be intrusive tonormal day-to-day life.

Education regarding disease management and self-help strategies are paramount to improve concordanceand achieving optimal outcomes. This might be best

The Everyday Living support service, supported by Procter& Gamble Pharmaceuticals, aims to enhance the patientexperience, improve patients' well-being and provideeducation on the long-term management of ulcerative colitis.It has many differentbut complementarycomponentsincluding:• A telephone

support service• Intermittent

letters and diseaseawareness leaflets

• Quarterly lifestylemagazines

• Dedicated patientwebsite.

Website: www.everyday-living.co.ukTelephone: 0800 234 6389

Figure 1. The Everyday Living patient support service.

provided by IBD nurse specialists, although equityof such roles throughout the UK remains a concernfor patients and is the subject of a major campaignby NACC. Significant advances in knowledge andunderstanding ofthe disease process have greatlyextended the range of more specific treatment optionsfor IBD, and gives new hope to patients suffering fromthese debilitating conditions.

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Key PointsThe management of inflammatory bowel disease (IBD) is complexand multifactoral and requires a multidisciplinary team approach.Significant advances in research into IBD have led to thedevelopment of more specific and effective treatments.Primary dietary therapy offers a safe and effective alternativeto drug treatment in the management of CD.Patients who are non-concordant in taking their medications andfollowing appropriate advice are at significant risk of relapse.Education and support are essential in helping patients to betterunderstand their disease and develop self management strategies.IBD nurse specialists are associated with improved managementoutcomes and increased patient satisfaction.IBD is an unpredictable chronic relapsing and remitting diseasethat has a huge impact on many aspects on the lives of patientsand their families and therefore, a holistic approach to care is likelyto be more effective.

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Useful informationFor more information contact the NACC information line on0845 130 2233 {weekdays 10.00-13.00). Alternatively call 0845130 3344 to talk to someone who has colitis or Crohn's disease(weekdays 18.30-21.00) or visit www.nacc.org.uk

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