Crohn's Disease Treatment in Germany

Inflammatory bowel diseases – Crohn's disease and ulcerative colitis – are relapsing conditions involving chronic inflammation of various parts of the gastrointestinal tract, with the development of diarrhoea and abdominal pain.

Intestinal inflammation is caused by cell-mediated immune responses in the gastrointestinal mucosa. The precise cause remains unclear, but research findings suggest that the abnormal immune response is triggered by a multifactorial genetic predisposition. No specific environmental, dietary or infectious agent responsible for IBD has been identified. During the immune response, inflammatory mediators are released, including cytokines, interleukins and tumour necrosis factor.

Despite the similarities between Crohn's disease and ulcerative colitis, in most cases the two forms of IBD can be distinguished. In about 10% of cases the colitis cannot initially be distinguished and is termed "indeterminate colitis"

Epidemiology

Inflammatory bowel disease can develop at any age, but most often begins before the age of 30, with peak incidence at 14–24 years. A second, smaller peak occurs at 50–70 years; however, this group may also include cases of ischaemic colitis.

IBD is more common in people of Northern European and Anglo-Saxon descent, and among Ashkenazi Jews it is recorded 2–4 times more often than in other people of Caucasian descent from the same geographical area. Incidence is lower in Central and Southern Europe, South America, Asia and Africa. No sex differences in the incidence of IBD have been observed. The risk in first-degree relatives of patients with IBD is 4–20 times higher, and their absolute risk reaches 7%. Familial predisposition is considerably more pronounced in Crohn's disease than in ulcerative colitis. Several genetic mutations underlying susceptibility to Crohn's disease have been identified.

Smoking is thought to contribute to flare-ups of Crohn's disease, but to reduce the risk of developing ulcerative colitis. Appendectomy, performed as surgical treatment for acute appendicitis, also reduces the risk of ulcerative colitis. Non-steroidal anti-inflammatory drugs, oral contraceptives and the use of antibiotics in childhood may increase the risk of IBD.
For reasons that are not understood, people of higher socio-economic status may have an increased risk of developing Crohn's disease.

Extraintestinal manifestations

In both Crohn's disease and ulcerative colitis, organs other than the intestine may be affected. Most extraintestinal manifestations are considerably more common in ulcerative colitis. Extraintestinal manifestations of inflammatory bowel disease can be divided into 3 groups:

1. Disorders that usually run a parallel course, i.e. they worsen and subside together with IBD flare-ups: these include peripheral arthritis, episcleritis, aphthous stomatitis and erythema nodosum. The arthritis is migratory and transient, and as a rule involves the large joints.

2. Disorders clearly associated with IBD but appearing independently of its activity: these include ankylosing spondylitis (Bechterew's disease), sacroiliitis, uveitis, pyoderma gangrenosum and primary sclerosing cholangitis.

3. Disorders that result from disturbed intestinal physiology: these arise when severe Crohn's disease of the small intestine develops. Malabsorption may occur after extensive resection of the ileum and is accompanied by deficiency of fat-soluble vitamins, vitamin B12 and minerals, which manifests as anaemia, hypocalcaemia, hypomagnesaemia, clotting disorders and demineralisation of bone tissue. In children, malabsorption is accompanied by delayed growth and development. Other manifestations include the formation of urinary stones, hydroureter and hydronephrosis, gallstone formation and amyloidosis.

Thromboembolic complications may develop as a result of multiple factors and belong to all three categories of extraintestinal manifestations.

Maintenance therapy

• 5-aminosalicylic acid;
• corticosteroids;
• immunomodulators;
• biological agents (anti-cytokine drugs);
• in some cases – antibiotics (for example, metronidazole, ciprofloxacin) and probiotics.

Drugs used in inflammatory bowel disease

5-aminosalicylic acid (5-ASA, mesalamine)

5-ASA blocks the production of prostaglandins and leukotrienes. Since 5-ASA is active only in the lumen and is rapidly absorbed in the proximal small intestine, oral formulations with delayed absorption must be used.
Drugs in this class:

• sulfasalazine;
• olsalazine (a 5-ASA dimer);
• balsalazide (5-ASA conjugated with an inactive component).

5-ASA formulations with an acrylic polymer coating providing delayed release of the active substance:

• Asacol HD®
• Delzicol®
• Pentasa®
• Lialda®
• Apriso®

All of these 5-ASA formulations are approximately equivalent from a therapeutic point of view.

5-ASA is also available as suppositories (500 or 1,000 mg at bedtime or twice a day) and as enemas (4 g at bedtime or twice a day) for the treatment of proctitis and left-sided colitis; combined with oral 5-ASA, their efficacy increases. Patients who cannot tolerate enemas because of rectal irritation are prescribed 5-ASA as a foam.

Corticosteroids

Corticosteroids are used to treat flare-ups of most forms of IBD when 5-ASA drugs are not sufficiently effective. However, corticosteroids are not suitable for maintaining remission.

In severe forms, intravenous hydrocortisone or methylprednisolone is indicated; in moderately severe disease, prednisone may be given orally. Once symptoms improve, the dose is gradually reduced until the patient is switched to maintenance therapy with 5-ASA or immunomodulators.

For proctitis and left-sided colitis, hydrocortisone enemas or rectal foam are prescribed.

Budesonide is a corticosteroid with a marked therapeutic effect on the gastrointestinal tract and minimal suppressive effect on the adrenal glands. Oral budesonide has fewer side effects than prednisolone and can effectively maintain remission for 8 weeks. The drug is approved for the treatment of small-bowel Crohn's disease, and for ulcerative colitis an enteric-coated, extended-release form is available.

Immunomodulators

• azathioprine and 6-mercaptopurine
• methotrexate
• cyclosporine and tacrolimus.

Azathioprine and its metabolite 6-mercaptopurine suppress T-cell function and can induce T-cell apoptosis. They are effective with long-term use, reduce the need for corticosteroids and are able to maintain remission for several years.

Cyclosporine is effective in severe ulcerative colitis when there is no response to corticosteroids and biological agents and colectomy becomes indicated.

Tacrolimus is an immunosuppressant that is also used in organ transplantation; it is comparable to cyclosporine in efficacy and may be prescribed to patients with severe or refractory ulcerative colitis who do not require hospitalisation.

The antimetabolites azathioprine, 6-mercaptopurine and methotrexate are also used in combination therapy with biological agents.

Biological agents

TNF inhibitors

Infliximab, certolizumab, adalimumab and golimumab are antibodies to tumour necrosis factor. Infliximab, certolizumab and adalimumab are used in Crohn's disease, in particular to prevent or delay postoperative relapse. Infliximab, adalimumab and golimumab have shown efficacy in the treatment of ulcerative colitis, including refractory and corticosteroid-dependent forms of the disease.

• infliximab is approved for the treatment of Crohn's disease and ulcerative colitis;
• adalimumab is approved for the treatment of Crohn's disease and ulcerative colitis;
• certolizumab has been approved for the treatment of Crohn's disease;
• golimumab is approved for use in patients with ulcerative colitis.

Monotherapy with anti-TNF agents is effective both for induction therapy and for maintaining remission; however, some studies have shown better short-term results when anti-TNF agents were given in combination with a thiopurine (in particular azathioprine) or methotrexate. Nevertheless, given the possible increase in adverse effects with combination therapy, treatment recommendations must be individualised.

Other biological drugs

Vedolizumab and natalizumab are antibodies to leucocyte adhesion molecules. Vedolizumab has been approved for moderate and severe ulcerative colitis and Crohn's disease.

Ustekinumab is approved for patients with moderate and severe Crohn's disease in whom conventional therapy has failed.

Small-molecule drugs

Small-molecule agents are medicinal substances with a molecular weight < 1 kilodalton. They are taken orally and, unlike monoclonal antibodies, are not immunogenic.

Tofacitinib is a small-molecule drug that inhibits Janus kinases 1-3 and is approved for use in adult patients with moderate to severe ulcerative colitis.

Antibiotics and probiotics

Antibiotics

Antibiotics may be effective in Crohn's disease, but their use in ulcerative colitis is limited, except in cases of toxic colitis, for example, metronidazole. Many experts recommend using metronidazole and ciprofloxacin in combination. The efficacy of the non-absorbable antibiotic rifaximin is also being studied.

Probiotics

Various non-pathogenic microorganisms (in particular symbiotic Escherichia coli, Lactobacillus species, Saccharomyces) taken daily as probiotics may effectively prevent the development of inflammation in the small intestine.