The treatments of Crohn’s disease

struktura infliximabu

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The treatment of Crohn’s disease is depending on the specific symptoms and clinical history of each patient. In addition the use of some drugs is still controversial. However, it is possible to outline a general scheme of action (also called algorithm) for the treatment of Crohn’s disease. The treatment is organized in two steps: 1) Induction of remission; 2) Maintenance of remission. Below I will quickly describe some drugs used and their target. Using as reference the paper of Dr. Baumart and Dr. Sandborn published on Lancet, I will also mention some of the new therapies that are tested in Clinical trial.

Scheme of Action for Crohn’s Disease treatment.

1) Induction of remission: is achieved by the use of medications that reduce the inflammation, the main manifestation of the diseases.

  • The 5-aminosalicylates (5-ASA), such as Sulfasalazine, are often used as a first-line therapy for intermediate/moderate disease. Sulfasalazine successfully interferes with the synthesis of eicosanoids (local mediators of inflammation which are responsible for the warmth, swelling, dolor and redness typical of inflamed area) and some local pro-inflammatory cytokines. Sulfasalazine does not act systematically (reducing in this way its toxicity) but as a pro-drugs: when ingested it is not active in the stomach but it is broken down by the bacterial flora in the colon into 5-aminosalicylic acid (5-ASA) and sulfapyridine, which then inhibit the enzymes like cyclooxygenase and lipoxygenase reducing the production of eicosanoids and prostaglandins.
  • The corticosteroids, such as budesonide and prednisone, are used for first-line therapy for more severe disease. The corticosteroids can act by blocking cell mediated immunity: they inhibit the intracellular signaling (activation of NFkB) which promotes production of pro-inflammatory molecules such as IL-2 and INFg. Corticosteroids also inhibit synthesis of eicosanoids by blocking phospholipase A2 through the promotion of lipocorting 1 expression (for more detail check this NEJM paper). The potent therapeutic effect is followed by adverse side effects: the strong immune-suppression induced may allow opportunistic infections, osteoporosis, diabetes, skin fragility and others.  Although budesonide is less potent as immune-suppression agent than prednisone, it has much less adverse side effect because its action is not systemic. This is due to its rapid hepatic conversion to well-tolerated metabolites and its strong affinity for corticosteroid receptor (for more details check Greenberg et al.).
  • The tumour necrosis factor (TNFa) inhibitors, such as the Infliximab, have been shown to be very effective in treating moderate/severe pathology. Infliximab is a chimeric-antibody (murine and human antibody) that irreversibly binds and blocks the TNFa, a cytokines involved in the inflammation process. Due to the presence of murine sequences in Infliximab that may induce rejection, a fully human antibody is used instead: Adalimumab.
  • Surgery is usually used to treat Crohn’s disease complications such as fistulae, strictures, bowel obstruction or intense inflammation. The surgery aim to remove the inflamed part of the intestine.

2) Induction of remission: although many of the previous listed medicaments can be used, the one with less adverse side-effect are normally preferred. Budesonide is normally used instead of prednisone because it doesn’t affect bone density (and cause osteoporosis). Infliximab or Adalimumab, can be used when the disease is particularly severe.

The most common therapy uses Mercaptopurine immune suppressive drugs such as azathioprine. The azathioprine is a pro-drug that is activated in the body and converted into purine analogue (adenine and guanine) blocking DNA synthesis. Fast growing cells such as white blood cells during an inflammation, are particularly sensible to that inhibition. It has got few adverse side effects in the short time but in a long term it has been shown to be a carcinogen.

The algorithm of Crohn’s disease medical menagement (from Baumgart and Sandborn, Lancet)

Investigated treatments for Crohn’s disease

The medications used in clinic (listed above) are not always specific for Crohn’s disease. Corticosteroid, for example, can be used to induce a generalized immune-suppression for many different diseases as they act systemically. But the ability to act so strongly and so systematically, make them responsible for many adverse side effects. Therefore, it is necessary to develop new therapies that specifically target the tissues where the inflammation goes on. Below I report a list of experimental drugs that are being tested in clinical trial to determine their efficacy and possible toxicity (taken from Baumgart and Sandborn, Lancet):

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