Sunday, March 24, 2013

New Protocols for IBD Treatment


IBD Primary Therapy Treatment Protocol


The current trend in treating IBD is to take a more aggressive approach to early treatment.   The historical treatment regimen would generally consist of two parts:

1.        The use of corticosteroids such as prednisone in a fairly high dose to stop the immediate damage being caused by inflammation and induce remission.
2.       The use of fairly low side effect drugs with lower efficacy, such as the 5-ASA drugs.

The treatment approach would then follow a continuum from lower side effect/lower efficacy to higher side effect/higher efficacy.  A common progression a decade ago may have been as follows (depending on the location effected):
1.       Take Pentasa/Asacol (Mesalamine), 2 grams (.8 grams for Asacol) daily
2.       Take Pentasa/Asacol (Mesalamine), 4 grams (1.6 grams for Asacol) daily*
3.       Move on to sulfasalazine. 
4.       Add in metronidazole and/or ciprofloxacin**
5.       Move to Azathioprine, 6-mercaptopurine and methotrexate.
6.       Go to using Infliximab
7.       Perform moderate surgical interventions
8.       Go to long term corticosteroid use
9.       Perform extreme surgical intervention go to Total Parenteral Nutrition (1)

The approach protocol has changed greatly due to more evidence-based approaches in recent years.  First, there is a general recognition that corticosteroids greatly reduce inflammation but don’t necessarily impact the underlying disease activity (they treat and even stop the symptoms, but not the cause).  Second, there are targeted approaches to medicines based on the problem, and surgery is recommended more to address point issues (e.g. structuring) as opposed to general treatment.  As an example, fistulizing disease had a separate treatment regimen (generally surgically focused), that isn’t addressed above.  The abilities of drugs like Cipro/Flagyl and the TNF-alpha drugs to close fistulae (and have better long-term outcomes) has reduced the “surgery first” approach in most cases.  Third, there is a move toward using more aggressive (though with potentially larger side effects) treatments earlier. 

The primary reason for taking a more aggressive initial approach to treatment is bowel preservation.  Once damage progresses to the point of structuring, it cannot be reversed.  The original Step-up approach allowed early bowel damage in non-responsive patients.  Because of this and because of new evidence on the 5-ASA (mesalamine) drugs (and several other immunosuppressants) in Crohn’s being less effective than initially thought, and because of the introduction of the biologics (the anti-TNF-alpha drugs), new treatment regimens were proposed in the past 5 years.(2)

Based on the evidence from the past few years, the following are the current consensus guidelines for the treatment of the disease:
Mild Ileocaecal Crohn’s:
1.     Give Budesonide to induce remission
2.     Monitor in remission to determine if any maintenance therapy is needed.

Moderate/Severe ileocaecal Crohn’s:
1.     Give Budesonide (Prednisone if non-localized Crohn’s) coupled with an Anti-TNF-Alpha agent
a.       Choose the Anti-TNF-Alpha agent based on cost, availability, and lifestyle impact
2.     For maintenance, continue the Anti-TNF-Alpha agent
3.     Switch to another TNF-Alpha agent if ineffective (3,4)
4.     Targeted surgery as needed

There is some evidence that Azathioprine and 6-mercaptopurine can induce remission quicker with the anti-TNF-Alpha agents, but the work in this area is still sparse.  Given the risk profiles of these drugs, more research on joint therapy v. monotherapy is needed.  Methotrexate in combination with ant-TNF-Alpha agents has not shown efficacy over monotherapy and should be dropped from the regimen. (5)

For UC, 5-ASA (especially topical) has some efficacy in inducing and maintaining remission in mild-to-moderate disease.(6)  Additionally, there are topical hydrocortisone and budesonide therapies that are effective in achieving remission.  As such, the following are recommendations for UC:

Mild UC:
1.     5-ASA (preferably topical) and Budesonide/Hydrocortisone enema to induce remission
2.     5-ASA for maintenance

Moderate/Severe UC:
1.     5-ASA (preferably topical) and Budesonide/Hydrocortisone enema to induce remission
2.     Anti-TNF-alpha Agents
3.     Colectomy

As with Crohn’s, the effectiveness of Azathioprine and 6-mercaptopurine in the treatment are UC are still effective, but slow in inducing remission.  (7)

All of the above are general guidelines based on the current research and consensus treatment protocols.  There may be economic reasons to use different treatments, acute presentations requiring immediate interventions, lack of responsiveness or tolerance of treatments due to side effects, and other factors that may support a deviation from the above.  If your doctor does deviate, ask them why and to provide supporting, recent, high quality evidence (and, as always, do your own homework!)  In a similar vein, keep current with the latest research - bigger, better controlled studies can disprove earlier work, and new treatments are always appearing.

Bottom Line


·         The treatment protocols to induce remission and maintain it have changed dramatically over the past 10 years – if your GI doc hasn’t kept up, it’s time to change providers or educate your current one.
·         Earlier, more aggressive treatment with anti-TNF-alpha drugs is now the current gold standard approach for moderate-to-severe IBD.
·         Older drug regimens (like 5-ASA for Crohns and widespread systemic steroid use) are no longer standard regimens.


*The efficacy of 5-ASA drugs in continuing remission v. placebo will be the subject of a future post.
** Another future post will look at combinatorial therapies with antibiotics and where they are appropriate. 

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1.     Sandborn, W. J., and B. G. Feagan. "Mild to moderate Crohn's disease–defining the basis for a new treatment algorithm." Alimentary pharmacology & therapeutics 18, no. 3 (2003): 263-277.
2.     Panaccione, R., Paul Rutgeerts, W. J. Sandborn, B. Feagan, S. Schreiber, and S. Ghosh. "Review article: treatment algorithms to maximize remission and minimize corticosteroid dependence in patients with inflammatory bowel disease." Alimentary pharmacology & therapeutics 28, no. 6 (2008): 674-688.
3.     Danese, Silvio, JF. Colombel, Walter Reinisch, and P. J. Rutgeerts. "Review article: infliximab for Crohn’s disease treatment–shifting therapeutic strategies after 10 years of clinical experience." Alimentary pharmacology & therapeutics33, no. 8 (2011): 857-869.
4.     Feagan, Brian G., Marc Lemann, Ragnar Befrits, William Connell, Geert D'Haens, Subrata Ghosh, Pierre Michetti et al. "Recommendations for the treatment of Crohn's disease with tumor necrosis factor antagonists: An expert consensus report." Inflammatory bowel diseases (2012).
5.     Alfadhli, A. A. F., J. W. D. McDonald, and B. G. Feagan. "Methotrexate for induction of remission in refractory Crohn’s disease." Cochrane Database System Rev 4 (2004).
6.     Feagan, Brian G., and John K. MacDonald. "Oral 5-aminosalicylic acid for induction of remission in ulcerative colitis." Cochrane Database Syst. Rev 10 (2012).
7.     Kornbluth, Asher, and David B. Sachar. "Ulcerative colitis practice guidelines in adults: American college of gastroenterology, practice parameters committee."The American journal of gastroenterology 105, no. 3 (2010): 501-523.

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