The treatments of Crohn’s disease

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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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The Crohn’s Disease

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Hi Guys!

As the beginning of my first post-doc at the Harvard Medical School is coming closer, I decided to focus many of my future posts (although I won’t stop talking about the more important discoveries in science and their consequences in understanding reality and society) on the specific topic of my studies: the Crohn’s disease.  I will explore how molecular biology strongly improve our knowledge of this disease (and more generally of immunology), I will comment on new discoveries and their importance, I will discuss new therapies and I will provide plenty of resources to be updated on this unknown and painful disease. Whoever wants to share their pathological and human experience or the experimental discoveries will be welcome to write on the BLOG. So guys, if you want to understand Crohn’s disease do not miss to read EducereX!!!!

Introduction to Crohn’s Disease

The Crohn’s disease is chronic inflammation that may affect any part of gastro-intestinal tract (from mouth to anus). The Vienna classification (1998) classified Crohn’s disease based on the anatomical location and occurrence of complication.

With respect to anatomical location at diagnosis the classification is:

1.          ILEOCOLIC Crohn’s disease which affects both Ileum (last part of small intestine connected to the large one) and large intestine (21% of cases)

2.              Crohn’s ILEITIS which affects only the Ileum (47% of cases)

3.          Crohn’s COLITIS which affects the large intestine (28% of cases) and it is difficult to distinguish from ulcerative colitis (another idiopathic IBD).

4.          Crohn’s disease of the upper gastrointestinal tract (3%).

With respect to behavior of Crohn’s disease and occurrence of complications:

1.   stricturing: the intestine wall gets thicker and the bowel narrow until eventually completely obstruct the passageways of food: bowel obstruction (which is a main complication). This is mainly due to swollen of intestine wall (due to the inflammation) and scar tissue that reduce the bowel diameter (17%).

2. penetrating: the inflammation creates fistulae (abnormal passageways) that connect intestine to other epithelial tissues such as skin (explaining the skin rush). The frequency is 13%.

3. inflammatory: the most common pathology that causes inflammation without other complication such as stricturing and fistulae with a frequency of 70%.

The clinical symptoms can be summarize as follow:

  • Abdominal Pain
  • Diarrhea (bloody diarrhea if inflammation is at its worse)
  • Fever (in the worse case)
  • Vomiting
  • Weight loss
  • Ulcer (in some cases)

Epdemiology of Crohn’s disease.

This previously unknown disease is becoming very popular and important in the western world (with highest rate in Northern Europe, North America and UK) as is where, worldwide, the pathology is more common. The Crohn’s & Colitis American Foundation estimates that around 1.4 million of Americans suffer of Inflammatory Bowel Disease (IBD). The IBD is a terminology which groups a series of chronic inflammation of gastro-intestinal tract of which Crohn’ disease and ulcerative colitis represent the 2 more frequent conditions.

As reported by Lancet (Baumgart at al., The Lancet, 2007), in North America Crohn’s disease affects white individual with a frequency of 43.6 per 100,000 persons, a much higher frequency when compare with other ethnical group: Hispanic with 4.1 individuals per 100,000, Asian with 5.6 individuals per 100,000 and African-American people with 29.8 individuals per 100,000. These epidemiology data strongly suggest an hereditary cause of Crohn’s disease: in the next post I will comment on the genetic and other causes of the Crohn’s disease discovered so far by scientists.