Medical Treatment of Inflammatory Bowel Disease


Drug class

Method of administration, dosage

Side effects

Surveillance

Corticosteroids

Oral: prednisone or prednisolone 40 mg/day to 0.8–1 mg/kg/day (single dose)

Intravenous: methylprednisolone 0.8–1 mg/kg/day

Oral with ileocecal delivery: budesonide 9 mg/day (single dose)

Topical betamethasone 5 mg/100 mL (enema once a day)

Cushingoid syndrome

Neuropsychological signs

Cosmetics

Diabetes, high blood pressure

Osteoporosis

Ocular

Risk of infection

Vitamin D and calcium supplementation

Initial measurement of bone mineral density

Optional potassium supplementation

5-Aminosalicylates

Oral: mesalazine 2–4 g/day (in one or two daily doses)

Topical (suppositories and enemas): mesalazine or sodium p-aminosalicylate (1 g/day)

Hypersensitivity (fever, headache)

Tubulointerstitial nephritis

Acute pancreatitis

Interstitial lung disease

Pericarditis, myocarditis

Creatinine concentration, 2 times a year

Methotrexate

Parenteral (subcutaneous or intramuscular) or oral (varaible inter- and intra-individual absorption)

Methotrexate: 25 mg/week (single dose) as induction, could be reduced to 15 mg/week as maintenance

Digestive intolerance

Stomatitis

Headache, asthenia

Interstitial lung disease

Elevated transaminases

Contraception (teratogenicity)

Folate by mouth 24 h after injection

Noninvasive markers of liver fibrosis

Pulmonary radio if cough

Thiopurines

Oral: azathioprine 2.5 mg/kg/day (single dose)

Oral form; 6-mercaptopurine 1–1.5 mg/kg/day (single dose)

Myelotoxicity: neutropenia, lymphopenia

Digestive intolerance

Immunoallergic reaction (acute pancreatitis)

Elevated transaminases

Opportunistic infections (Epstein-Barr virus, cytomegalovirus)

Increased risk of lymphoma and nonmelanoma skin cancer

Regular monitoring of blood count and transaminases

TPMT (thiopurine-methyltransferase) genotype

Dermatologic surveillance (once a year)

Anti–tumor necrosis factor agents

Intravenous: infliximab induction regimen (5 mg/kg at weeks 0, 2, and 6) ; maintenance regimen 5 mg/kg every 8 weeks

Subcutaneous: adalimumab induction regimen (160 mg at week 0 and 80 mg at week 2), maintenance regimen (40 mg/1–2 week)

Subcutaneous: golimumab induction regimen (200 mg at week 0 and 100 mg at week 2), maintenance regimen (50–100 mg for4 weeks according to body weight)

Allergic reactions to infusions and local reactions at injection site

Opportunistic infections (bacterial, fungal, viral)

Dermatological and rheumatologic paradoxical effects

Possible increased risk of melanoma

Screening for sepsis, quantiferon, pulmonary radio, serology (HIV, hepatitis B and C viruses)

Contraindication if malignancy within the past 5 years

Vaccination status

Vedolizumab

Intravenous: vedolizumab induction regimen (300 mg at weeks 0, 2, and 6) ; maintenance regimen (300 mg for 4–8 weeks)

Rhinopharyngitis

Headache

Digestive infections?

Screening: sepsis, quantiferon, pulmonary radio, serology (HIV, hepatitis B and C viruses)

Contraindication if malignancy within the past 5 years

Vaccination status




19.2.1 New Concepts



19.2.1.1 Is There Still Room for First-Line Conventional Therapies (Aminosalicylates and Corticosteroids)?


The clinical benefit of 5-aminosalicylates in Crohn’s disease is still under debate. A recent meta-analysis of mild to moderate Crohn’s disease showed that its benefit was close to that of placebo [1]. In addition, indications for the use of 5-aminosalicylates’ have been decreasing over time, even among patients with mild Crohn’s disease [2] with few symptoms and an absence of risk factors for a complicated evolution. In the postoperative setting, 5-aminosalicylates could be given to prevent recurrence since they demonstrated mildly but significantly better efficacy than placebo at a dosage of 4 g/day [3]. Concerning safety, these agents have a good tolerance profile, requiring kidney function surveillance twice a year.

In 2016 corticosteroids maintain a central role in the management of the first flare of Crohn’s disease, particularly in the early course, whatever the severity or extent of lesions. For decades, corticosteroids’ efficacy has been demonstrated in randomized controlled trials [4] and study population cohorts [5, 6]. Nonetheless, the two main limitations of steroid use in Crohn’s disease are its side effects and its lack of efficacy as a maintenance therapy. Importantly, steroids have no impact on mucosal healing of inflammatory endoscopic lesions. Budesonide represents an alternative to “conventional” corticosteroids, with a better safety profile due to its 90 % extraction by the liver. Because budesonide is delivered in the terminal ileum and right colon, it could be considered at a dosage of 9 mg/day in patients with Crohn’s disease with mild to moderate flares in these locations, providing clinical remission in nearly 50 % [7].

Thus, a short steroid course remains a pivotal treatment in patients with active disease. It should be followed by quick tapering (within 3 months) to limit exposure and avoid side effects. In the case of steroid-refractory Crohn’s disease, including dependence, failure, and intolerance, immunosuppressants and/or biologics should be considered.


19.2.1.2 Early Use of Immunosuppressants (Thiopurines and Methotrexate)


For more than 30 years, thiopurines (azathioprine and 6-mercaptopurine) have been considered as the referential maintenance therapy in refractory Crohn’s disease, providing sustained, steroid-free remission [811]. However, because most patients who previously responded to thiopurines relapse with time after drug withdrawal, these agents are considered as having only a suspensive action [12, 13]. To modify the course of Crohn’s disease and limit thiopurine exposure, it was expected that an early treatment with thiopurines could be beneficial. This strategy was explored in two recent randomized control trials. Unfortunately, no clinical benefit of early treatment with thiopurines was observed in the first 3 years compared with controls who received a placebo in a Spanish trial [15] or a conventional step-up approach in a French one [14]. Moreover, one-third of the patients randomized in the control arm in the French study did not require any immunosuppressants during the study period. This suggests that giving thiopurine to patients with early Crohn’s disease with several poor prognostic factors – age at diagnosis <40 years, active luminal disease requiring steroids, perianal lesions at diagnosis – may lead to overtreatment in many patients. Indeed, beyond the risk of opportunistic infection [16] or hematologic and liver toxicities, a neoplastic risk related to thiopurines is now well established; an increased risk of lymphoma [17] and nonmelanoma skin cancer were observed in the large, prospective CESAME cohort [18]. Thus, the trend of early azathioprine administration is declining because biologics have better efficacy than thiopurines [19] and an equivalent safety profile. At the moment, azathioprine is started after a first flare in the case of noncomplicated steroid-refractory disease [2] and, more often, in combination with an anti-TNF agent (cf. Sect. 19.2.1.3).

Methotrexate is the other conventional immunosuppressant that can be used in Crohn’s disease. Its efficacy is established by two randomized controlled trials and confirmed by further meta-analysis and seems comparable to that of thiopurines [2023]. The parenteral route is preferred, with weekly 25-mg methotrexate injections followed by maintenance at a lower dose. Despite more rapid action than thiopurines and no increased risk of induced malignancy, methotrexate is usually limited to patients with previous azathioprine failure or intolerance and is associated with anti-TNF agents, as in inflammatory rheumatisms [24].


19.2.1.3 When Starting an Anti-TNF Early, Should We Also Administer an Immunosuppressant?


Available since 1998, anti-TNF agents have dramatically changed the management of Crohn’s disease. Two drugs that have shown efficacy as induction and maintenance treatments are available: infliximab [25, 26] and adalimumab [27, 28]. Usual indications for anti-TNF agents are refractory and severe luminal Crohn’s disease after failure or intolerance of systemic steroids, including budesonide, and conventional immunosuppressants. In addition, the efficacy of infliximab has been demonstrated in fistulizing disease, particularly for anoperineal lesions [29]. Beyond their well-known clinical benefit, anti-TNF agents also allow patients to be weaned from steroids, provide mucosal healing, and may prevent bowel damage that leads to strictures and/or fistulas and surgical resections.

Benefit of anti-TNF agents is inversely correlated with the duration of Crohn’s disease; that is, it is better for early lesions, before bowel destruction [30]. This explains the current trend toward earlier and longer treatment with anti-TNF agents. In practice, these drugs could be considered early in the case of an extended and severe first attack of Crohn’s disease, mainly when associated with complicated anoperineal lesions. In the case of a steroid-refractory course, anti-TNF agents are more effective than conventional immunosuppressants; this point has been demonstrated only with infliximab over azathioprine. In addition, the combination therapy associating an anti-TNF agent with an immunosuppressant – so-called combotherapy – is the most effective strategy, as shown in the SONIC trial [19]. At the moment, the long-term safety and duration of such combotherapy and how to manage therapeutic deescalation in patients in remission are pending issues.

Concerning anti-TNF tolerance, most side effects are shared by both infliximab and adalimumab. Neoplastic risk related to anti-TNF agents has been scrutinized and was suggested only for melanoma (odds ratio, 1.88) [31]. Infection risk, mainly concerning opportunistic infections, is increased by anti-TNF agents per se, but also by age and associated steroids and immunosuppressants [32]. Importantly, cases of tuberculosis developed while taking anti-TNF agents have become the exception since the implementation of systematic screening before starting treatment. Other common anti-TNF agent side effects are the occurrence of immunologic paradoxical manifestations involving the skin (psoriasis-like and/or eczema-like) or the joints.


19.2.1.4 Is There Still Room for Surgery in the Anti-TNF Era?


Nearly 20 % of patients with Crohn’s disease are diagnosed with a form complicated by obstruction, intra-abdominal abscess, or fistula [33], leading to early surgery, especially when the complications occur in within the short terminal ilium. Despite advances in medical treatment, the vast majority of patients with Crohn’s disease will require surgery during their lifetime because of complications or treatment failure. Nowadays, laparoscopy has become the standard surgical approach in Crohn’s disease, even for complicated forms [34]. Last, the combination of intestinal resections and medical therapies, such as biologics that have a low impact on surgical outcomes, is more frequent.


19.2.1.5 Initial Therapeutic Strategy: Graduated Approach or Early Combotherapy?


In the absence of a demonstrated benefit to start conventional immunosuppressants early, two major approaches could be discussed with regard to Crohn’s disease.



  • The first is a step-up strategy, from steroids to immunosuppressants and then to anti-TNF agents following gradual therapeutic escalation in the case of failure. This careful approach is usually well accepted by patients and could be cost-effective. However, the late introduction of powerful therapies may undertreat the most severe forms, favoring bowel damage and intestinal surgery.


  • The second is a maximal strategy that immediately proposes the most effective approach – namely, the combotherapy between an immunosuppressant and an anti-TNF agent, followed if possible by deescalation once a deep remission of Crohn’s disease is obtained, including the absence of symptoms and normal biologic and endoscopic findings. Such an approach is supposed to modify the natural history of Crohn’s disease. Conversely, it leads to the overtreatment of patients exposed to long-term and multiple periods of immunosuppression, increasing the risk of infections and malignancies as well as direct costs.


19.2.2 What to Do in Clinical Practice?



19.2.2.1 Therapeutic Algorithm


In 2016, the initial therapeutic strategy for Crohn’s disease is usually a quick step-up approach taking into account disease severity and the patient’s prognostic factors. The best established factors associated with a poor disease course are young age at diagnosis, stenosing and penetrating phenotyp, anoperineal and/or rectal location, upper and extensive gastrointestinal tract involvement, and severe endoscopic lesions.

To summarize, a therapeutic algorithm [35] has been proposed for managing Crohn’s disease at diagnosis (Fig. 19.1): steroids alone in mild disease or associated with immunosuppressants in moderate disease without a poor prognosis and without complications; early anti-TNF agents with or without immunosuppressants in severe disease and in moderate forms with poor prognostic factors and/or extensive intestinal involvement and/or perianal lesions.

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Fig. 19.1
Proposed algorithm for treating Crohn’s disease (From Peyrin-Biroulet et al. [35]). TNF tumor necrosis factor, MRI magnetic resonance imaging

In the case of a loss of response to an anti-TNF agent, two primary therapeutic options should be considered before surgery or new therapeutic agents are administered: optimizing the drug (reducing the dosing interval or increasing the dose) or switching to another anti-TNF agent – both ideally according to pharmacokinetics.

Vedolizumab has now become an alternative to anti-TNF agents in Crohn’s disease. This intravenously administered humanized monoclonal antibody specifically targets the α4β7 integrin and selectively blocks gut lymphocyte trafficking. It can be use as induction and maintenance therapy after anti-TNF failure [36].


19.2.2.2 Monitoring Patients and Adjusting Therapy


Following the development of the therapeutic armamentarium for Crohn’s disease, new therapeutic goals emerged during the past decade. Mucosal healing and the prevention of bowel damage are desirable and achievable. Because there is a poor correlation between clinical symptoms and objective inflammation in Crohn’s disease [37], closely monitoring a patient using biomarkers (fecal calprotectin– and protein C–reactive dosages, anti-TNF pharmacokinetics), endoscopy [38], and magnetic resonance imaging [39] identify early therapeutic changes if inflammation is not controlled.


19.2.3 Preventing Postoperative Recurrence: A Special Setting


Crohn’s disease most commonly affects the terminal ileum and right colon. Despite therapeutic progress, almost 75 % of patients have surgery during their lifetime as a result of structuring or penetrating complications [40]. After bowel resection, 70–90 % of patients develop significant endoscopic postoperative recurrence on the neoterminal ileum and the anastomosis within 1 year [41], 60 % have a clinical recurrence at 10 years [42], and 70 % will undergo a new surgery at 20 years [43]. Because endoscopic recurrence predicts clinical recurrence, an endoscopic evaluation 6 months after surgery is recommended in order to start treatment early. This strategy has recently been validated by a randomized controlled trial [44]. A therapeutic algorithm for the prevention of postoperative recurrence is proposed in Fig. 19.2 [45].

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Fig. 19.2
Strategy for the prevention and treatment of postoperative recurrence of Crohn’s disease (From Buisson et al. [45])



19.3 Ulcerative Colitis



19.3.1 Mild to Moderate Forms



19.3.1.1 Are Salicylates and Corticosteroids Still Cornerstones of Ulcerative Colitis Treatment?


The efficacy of 5-aminosalicylates has been demonstrated in ulcerative colitis. They remain the standard initial treatment in mild to moderate disease and the first-line maintenance therapy [46, 47]. In population studies, nearly half of patients with ulcerative colitis are controlled with 5-aminosalicylates alone. In active proctitis, topical 5-aminosalicylates administered via suppositories or enemas have also shown good efficacy – better than topical steroids – and should be given first [48, 49]. European Crohn’s Colitis Organisation (ECCO) guidelines on 5-aminosalicylate use in mild to moderate ulcerative colitis are summarized in Table 19.2 [50].
Oct 30, 2017 | Posted by in ABDOMINAL MEDICINE | Comments Off on Medical Treatment of Inflammatory Bowel Disease
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