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):

The causes of Crohn’s disease

Schematic of NOD2/CARD15 gene.

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The Causes of Crohn’s disease are still unknown. However, statistical studies (that do not give causative explanations but only strong suggestions) indicate that Crohn’s disease may be caused by both genetic and environmental factors (in other words a genetic predisposition may enhance the effects of an environmental factor). Today, I don’t want to just list the causes but I want also try to explain the scientific method used to achieve this knowledge.

Genetic Cause:

1)    To determine whether a disease has genetic causes the first thing to do is to statistically study the frequency of a disease first in a population (as shown in the previous post) and subsequently compare with the frequency in a specific family whose members show the pathology. If the frequency of the disease within the family members is higher than the average frequency of the general population, a genetic cause of the disease is highly probable (because the genetic errors are transmitted from parents to the offsprings).

Þ   As reported  by Satsangi and colleagues (see the paper here), statistical studies from clinical data show that 5-10% of Crohn’s disease patients have a first-degree relatives with the same pathology with a concordance for disease type (see previous post) of about 70-80%.  Therefore, the risk of developing Crohn’s disease for a person with a first-degree relative with the disease is about 15 times higher than the average risk in the population. Particularly important studies involve twins: a much higher correlation of Crohn’s disease is calculated in monozygotic twins (37%; twins with identical genome) than in dizygotic twins (7%; twins with non-identical genome).

2)    The second step is to find the gene or the genes responsible for the pathology that have been transmitted from parents to their children. One of the most common strategies used by scientist is the Genome Wide Scan to identify susceptibility loci (or region) in the Chromosomes. This approach consists in sequencing small regions (marker sequences such as micro-satellites, SNPs, RFLPs, etc…) throughout genome of all the members of an affected family in order to identify chromosomal loci transmitted with high frequency to the sick members of the family and with less frequency to the healthly members. The analysis of those frequencies using dedicated algorithms is called genetic linkage (for more technical information check here) and allow to find susceptibility loci where it is possible to identify and subsequently study several genes.

Þ   Using this approach, no single locus has been found but many susceptibility loci have been described on chromosomes 1, 3, 5, 6, 12, 14, 16 and 19 (for references see Baumgart and Carding). This result implicates that Crohn’s disease is a polygenic disease making even more difficult the challenge to describe the causes. More detailed studies have linked specific genes to the diseases: Nod2/Card15 a pattern recognition receptor involved in immune response against microbes present in the intestinal tract and its mutations have been associated with Crohn’s disease in white population; Mhc (major hystocompatibility complex) receptor responsible for the presentation of intracellular proteins to lymphocytes.

3)    Once the responsible genes are identify by statistical analysis, the scientists start studying the function of the proteins (codify by the genes) within the cell and how its disruption may affect the cell and the immune-response as whole. The possible experiments to be performed are in such a big number (depending also from the function of the protein its-self) that it is not possible to list them all. However, some common approaches are often very informative. One example is the disruption of the homologue gene (gene with the same function in a different specie) in a mouse model called “knockout” that allows to subsequently study the phenotype of the animal and the molecular outcome.

Þ   Structural studies of NOD2 have shown that it consists of 3 domains: a CARD domain responsible for activation of a signaling protein NFkB, a NOD domain responsible for the oligomerisation of the protein and a Leucine-rich region responsible for bacterial recognition (typical example of the modular structure of the proteins).

Þ   The knockout mouse model for NOD2 do not fully fit the human Crohn’s disease (further suggesting the multi-factorial causes for this disease) but it gives important notions. The absence of a functional NOD2 alter normal signaling within the intestinal cells leading to abnormal activation of NFkB and production of pro-inflammatory cytokines (which may be one cause of the chronic inflammation). It will be interesting also understand if and how a deregulation of NOD2 in intestinal cells may influence the activity of so called T helper 1 lymphocytes.

 

Environmental causes:

The evidences for environmental factors rely entirely on statistical analysis and therefore have to be intended only as suggestion of causes (for references see Baumgart and Carding).

The LIFE STYLE may be one of the major factors:

  • Smoking drastically aggravates the course of Crohn’s disease accelerating the need for surgical intervention.
  • Bacterial or viral infection may trigger an excessive immune-reaction
  • Excessive sanitation may reduce the exposure of children and adults to microbial and other environmental antigen limiting the fully maturation of mucosal immune system that subsequently may over-react to safe bacteria or antigen.
  • Stress seems to increase the incidence of relapse in patient with quiescent disease.
  • Diet may play a role although weak data are presented so far.

 

Many other studies will be required for a fully understanding of the molecular mechanism involved and the cells interaction. Remained tuned on E-ducereX to be updated!