Sunday, October 27, 2013

IBD in the Modern Age

Today's Treatment Regimes Come of Age


As the 1960’s passed into the 1970’s, medicine became more evidence-based and less experiential.  Regional Enteritis became Inflammatory Bowel Disease, and the suppositions that ulcerative colitis and Crohn’s disease were different disorders.  Over the next few decades, most of the major treatments now in use would be developed and the modern treatment regimen would slowly coalesce.

1970’s


The 1970’s built upon some of the discoveries of the 1960’s and increased the use of drugs originally developed for other purposes.  While there were still surgery-first advocates, medical interventions were on the rise and some of the first larger scales studies and epidemiological reviews were done.(1)

Diet became a large focus of treatment for IBD over the course of the decade.  Everything from elemental diets to low residue diets were proposed.  While these were viewed favorably, evidence was not in great supply.(2)  Some of the early work on high fiber diets also occurred in this decade.  These diets showed some promise and no increased formation of obstructions, but it would be another few decades before this idea began to take hold again.(3)  

Aside from the diet focus, there was a renewed interest in sulphasalazine for the treatment of IBD, primarily ulcerative colitis.  The efforts looked to quantify the optimal dosing based on defining the dose-response curve and minimizing the side effects.  The increased evidence-based focus led to the deprecation of sulphasalazine over the next decade in favor of drugs with similar efficacies but fewer side effects. (4,5)

1980’s


The decade that brought us hair bands and the first United States President to share the big screen with a chimpanzee also brought new classes of drugs to treat IBD.  Azodisal Sodium was investigated as a replacement for suphasalazine, and had a better safety profile.  It was found to be slightly better than the 5-ASA drugs, but with a higher level of side effects.  Though still a potentially viable drug, it is not regularly prescribed.(6)

Intravenous cyclosporine was similarly proposed as a treatment for ulcerative colitis, and worked well compared to placebo.  Cyclosporine was put forth as an alternative to 6-MP/Imuran for severe UC treatment, and was in use until the introduction of Infliximab and similar Anti-TNF drugs took hold.(7)

A new trend in dietary treatment of Crohn’s disease was engineered in the 1980’s (though the idea had been proposed earlier) – the use of the elemental diet.  The elemental diet consists of nutrients that are already broken down, requiring minimal work from the GI tract (or no work in the case of TPN).  Generally it is consumed by the patient, though a nasogastric tube can deliver it as well.  The efficacy is fairly high, and it is still in use, but the liver needs to be constantly monitored due to the offloading of some of the GI functions and patients sometimes have difficulty tolerating it.(8)

1990’s – Today


The modern era of IBD treatment has largely been focused on the anti-TNF alpha drugs.  Inflixmab hit the IBD world by storm in 1998, showing efficacy in the treatment of fistulae in Crohn’s disease patients without requiring surgery.(9) Adalimumab followed in 2008 for Cronh’s disease, and permitted anti-TNF treatment without needing an infusion.  Indications for ulcerative colitis came for Adalimumab in 2012.(10)  In the same year (2008), certolizumab was approved for the treatment of Crohn’s disease as well (though a UC treatment indication is still pending).(11)

There are innumerable research studies ongoing, and hopefully future treatments will bear as much fruit as those of the last decade for IBD.  While a cure is still not available, the treatment advances over the last few decades have enabled life-altering improvements for patients. 

Bottom Line


·         IBD treatment has changed dramatically over the years.  New treatments in the last decade have substantially improved outcomes.
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1.       Cooke, W. T., E. Mallas, P. Prior, and R. N. Allan. "Crohn's disease: course, treatment and long term prognosis." QJM 49, no. 3 (1980): 363-384.
2.       O'Morain, C., A. W. Segal, and A. J. Levi. "Elemental diets in treatment of acute Crohn's disease." British medical journal 281, no. 6249 (1980): 1173.
3.       Heaton, K. W., J. R. Thornton, and P. M. Emmett. "Treatment of Crohn's disease with an unrefined-carbohydrate, fibre-rich diet." British medical journal2, no. 6193 (1979): 764.
4.       Dissanayake, A. S., and S. C. Truelove. "A controlled therapeutic trial of long-term maintenance treatment of ulcerative colitis with sulphasalazine (Salazopyrin)." Gut 14, no. 12 (1973): 923-926.
5.       Khan, AK Azad, D. T. Howes, J. Piris, and S. C. Truelove. "Optimum dose of sulphasalazine for maintenance treatment in ulcerative colitis." Gut 21, no. 3 (1980): 232-240.
6.       Sandberg-Gertzen, H., G. Järnerot, and W. Kraaz. "Azodisal sodium in the treatment of ulcerative colitis. A study of tolerance and relapse-prevention properties." Gastroenterology 90, no. 4 (1986): 1024.
7.       Lichtiger, Simon, and DanielH Present. "Preliminary report: cyclosporin in treatment of severe active ulcerative colitis." The Lancet 336, no. 8706 (1990): 16-19.
8.       O'Moráin, C., A. W. Segal, and A. J. Levi. "Elemental diet as primary treatment of acute Crohn's disease: a controlled trial." British medical journal (Clinical research ed.) 288, no. 6434 (1984): 1859.
9.       Present, Daniel H., Paul Rutgeerts, Stephan Targan, Stephen B. Hanauer, Lloyd Mayer, R. A. Van Hogezand, Daniel K. Podolsky et al. "Infliximab for the treatment of fistulas in patients with Crohn's disease." New England Journal of Medicine 340, no. 18 (1999): 1398-1405.
10.   Reinisch, Walter, William J. Sandborn, Daniel W. Hommes, Geert D'Haens, Stephen Hanauer, Stefan Schreiber, Remo Panaccione et al. "Adalimumab for induction of clinical remission in moderately to severely active ulcerative colitis: results of a randomised controlled trial." Gut 60, no. 6 (2011): 780-787.

11.   Schreiber, Stefan, Mani Khaliq-Kareemi, Ian C. Lawrance, Ole Østergaard Thomsen, Stephen B. Hanauer, Juliet McColm, Ralph Bloomfield, and William J. Sandborn. "Maintenance therapy with certolizumab pegol for Crohn's disease." New England Journal of Medicine 357, no. 3 (2007): 239-250.

Sunday, October 20, 2013

Vedolizumab

Vedolizumab - A Possible Alternative for Anti-TNF-Alpha Non-Responders


Vedolizumab (the name rolls off the tongue almost as well as adalimumab) is a monoclonal antibody (the –mab in the name refers to this class of drugs).  Monoclonal antibodies are biological agents that are clones of the same parent and that target the same epitope (the unique part of an antigen).  In this case, Vedolizumab binds to integrin α4β7 (part of the cell’s signaling system).  This provides Vedolizumab with an interesting risk-benefit possibility – the selective targeting of inflammation in the intestines (due to the targeting of α4β7 ) without binding to other areas in the body, reducing any systemic effects.(1)

Vedolizumab has gotten through two phase III trials for Crohn’s and Ulcerative Colitis as a potential new therapy, providing yet another biologic option that targets a different mechanism than the trio of anti-TNF-alpha drugs currently approved for IBD treatment.  The drug is going through a final Phase III trial to evaluate its long term safety.  The trials (dubbed GEMINI) involve 2,700 patients, and include both Crohn’s and Ulcerative Colitis patients.  They are placebo controlled and involve patients that showed lack of responsiveness to traditional treatments (including anti-TNF-alpha drugs and steroids).  The looked to the drug to both induce and maintain remission.

For induction therapy in ulcerative colitis, the following were the findings:

47.1 percent of patients receiving vedolizumab achieved clinical response compared to 25.5 percent of patients receiving placebo (p < 0.001), 16.9 percent achieved clinical remission versus 5.4 percent receiving placebo (p = 0.001), and 40.9 percent of vedolizumab-treated patients experienced mucosal healing compared to 24.8 percent of patients receiving placebo (p=0.001).

Similarly, for the maintenance of remission, the study found the following:

41.8 percent and 44.8 percent of patients receiving vedolizumab every eight and four weeks, respectively, were in clinical remission at week 52, compared to 15.9 percent of patients who received placebo (p < 0.001). 56.6 percent and 52.0 percent of patients treated with vedolizumab every eight and four weeks, respectively, achieved durable clinical response (defined by a response at both week six and week 52), compared to 23.8 percent of patients receiving placebo (p=0.01, p < 0.001, respectively).

One item of interest on the maintenance study – the dose/response curve appears to flatten (or even decline) at a monthly dosing regimen.  Initial safety results found that “no increase in rates of serious, opportunistic or enteric infections was observed with vedolizumab”.(2)

The latest publication looked at the individuals in the population suffering from Crohn’s disease.  The initial study looked at the results related to induction therapy.  The findings were as follows:

At week six, clinical remission was seen in 14.5 percent of patients randomized to vedolizumab versus 6.8 percent who received placebo (p=0.02). At six weeks, no significant difference was observed in CDAI-100 response between the vedolizumab and placebo groups (31.4 percent versus 25.7 percent, respectively [p=0.23])

The induction therapy numbers for Crohn’s disease don’t appear to be as promising as those for UC.  The higher clinical remission numbers are promising, but the CDAI-100 numbers showed minimal difference.  There are multiple reasons that could be responsible, from the randomization of the population to a longer term needed to show efficacy to a lack of efficacy for inducing maintenance.  The numbers for maintenance show some positives as well:

At week 52, remission was seen in 39.0 percent and 36.4 percent of patients randomized, respectively, to vedolizumab every eight weeks or every four weeks versus 21.6 percent of the patients receiving placebo (p < 0.001, p=0.004, respectively). CDAI-100 response was seen in 43.5 percent and 45.5 percent of patients randomized, respectively, to vedolizumab every eight weeks or every four weeks versus 30.1 percent of patients receiving placebo at week 52 (p=0.01, p=0.005 respectively). Glucocorticoid-free remission was seen in 31.7 percent and 28.8 percent of patients taking oral glucocorticoids at baseline randomized, respectively, to vedolizumab every eight weeks or every four weeks versus 15.9 percent of patients receiving placebo at week 52 (p=0.02, p=0.04, respectively).

Again, the numbers are promising but not unwaveringly so.  The safety numbers are similar, but with a few deaths that would need further investigation:

The most common adverse events reported in the 814-patient vedolizumab arm (>8.0 percent) were Crohn’s disease exacerbation, arthralgia, pyrexia, nasopharyngitis, headache, nausea and abdominal pain. The most common adverse events reported in the 301-patient placebo arm (≥8.0 percent) were Crohn’s disease exacerbation, headache, arthralgia, pyrexia, abdominal pain, nausea, and nasopharyngitis. Five deaths occurred during the study period, four among patients receiving vedolizumab (one death each from Crohn’s disease with sepsis, intentional overdose of prescription medication, myocarditis, and septic shock) and one in the placebo group (from bronchopneumonia)(3)

While the numbers look like there is potential, there is one factor that the authors note and may have artificially increased the aggregate numbers for the vedolizumab group.  Specifically, the individuals who were response in the induction phase were selected to have vedolizumab in the maintenance phase, in addition to an open label group.  The responsive group may indicate there is a particular genotype or other factor that will indicate who is responsive, or it could represent a particularly “healthy” portion of the population from the start.  Teasing out these numbers and finding the long term safety profile may require large population monitoring post-approval, but it appears that this may be a viable alternative therapy for at least a portion of the non-responsive patient population with UC and Crohn’s disease.  Approval for both indications is currently in progress in the US and Europe.

Bottom Line


·         Clinical trials with vedolizumab show promise in a high risk population of IBD patients.
·         The UC responsiveness for induction and maintenance was good.  For Crohn’s, it appears the maintenance numbers were better than induction numbers.
·         Vedolizumab is likely to be a second-line treatment (at least initially) for those with IBD that are non-responsive to anti-TNF-alpha therapies.
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1.    Soler, Dulce, Tobias Chapman, Li-Li Yang, Tim Wyant, Robert Egan, and Eric R. Fedyk. "The binding specificity and selective antagonism of vedolizumab, an anti-α4β7 integrin therapeutic antibody in development for inflammatory bowel diseases." Journal of Pharmacology and Experimental Therapeutics 330, no. 3 (2009): 864-875.
2.    Feagan B, Rutgeerts P, Sands B, et al. Vedolizumab as Induction and Maintenance Therapy for Ulcerative Colitis. N Engl J Med. 2013;369;8:699-710.

3.    Sandborn W, Feagan B, Rutgeerts P, et al. Vedolizumab as Induction and Maintenance Therapy for Crohn’s Disease. N Engl J Med. 2013;369;8:711-721.

Sunday, October 13, 2013

IBD in the Age of Medicine

Historical Treatment of IBD:  Medical Treatment Overtakes Surgery

In 1859, Sir Samuel Wilks characterized Ulcerative Colitis as being differentiated from dysentery.  In 1932, Dr. Burrill Crohn, along with Dr. Leon Ginzburg and Dr. Gordon Oppenheimer, described a regional ileitis with granuloma formation, which would later be tagged “Crohn’s Disease”.(1)  The last article covered the treatments up through the turn of the century (1900) – this posting will cover the other historical treatments up through the present regimen. 

1950’s


The primary treatment for regional ileitis was surgical intervention, however there were other proposed treatments that were put forth.  On the moderate side, Cooke puts forth a regime that treats the symptoms (if not the underlying disease) and has many corollaries in today’s treatments, stating “It seems to me, therefore, that the basic background for treatment lies in an adequate period of rest, preferably with a sanatorium type of regime with supportive measures directed towards counteracting anaemia, protein deficiency or electrolyte depletion. This can best be done by a high protein low fat diet with due regard to any question of milk sensitivity, potassium supplements, Vitamin B.12 injections and folic acid.”  While vitamins are the subject of another posting, treating anemia and dehydration symptoms, coupled with rest (though not too much) is generally an adjunct treatment today.  Similarly, the high protein, low fat diet is still put forth as a good diet candidate (though the evidence for direct impact is wanting).(2)

In the same period, Machella put forth the use of cortisone to treat both Crohn’s Disease and Ulcerative Colitis.  A corticosteroid (which resulted in a Nobel prize), cortisone was not widely available as commercial production was limited through most of the early 1950’s.(3)  Corticosteroids are still used to treat inflammation, and prednisone would take over (being up to 4 times more effective than cortisone) within a few years as the treatment of choice.(4)

The other treatment being used in the first half of the century was x-ray therapy.  In addition to treating carcinomas of the colon, x-rays were used to treat areas of disease.  X-rays were found to cause mucosal damage, and the use of them in treating primary IBD were discontinued by the 1960’s.(5)

1960’s


The 60’s represented a decade of change in the treatment of Crohn’s Disease and Ulcerative Colitis.  What was a primarily invasive treatment regime (surgery was the still treatment of choice), or had potentially damaging outcomes (x-ray treatment) or resulted in dangerous side effects (corticosteroids) moved toward a more traditional medical approach that had a lot in common with today’s treatments.  A focus on anti-inflammatories and immunomodulators for many diseases resulted in new treatment options from IBD.  These had fewer side effects than corticosteroids and gradually took the place of early surgical intervention in most cases.

The use of sulfa drugs (antimicrobials that were used before modern antibiotics to treat infections), specifically Sulfasalazine, was popularized as a treatment for IBD.  In addition to being an antibiotic, it had an immunosuppressive and an anti-inflammatory capability and had shown some success in treating rheumatoid arthritis.  There were numerous side effects, including severe depression and infertility, which led to the use of one of its more innocuous metabolites, 5-aminosalicylic, in treating IBD by the mid 1960’s.  The 5-ASA drugs, including Asacol and Pentasa, had significantly fewer side effects with a similar efficacy profile.  The 5-ASAs are still used to treat mild Crohn’s and Ulcerative Colitis (though their efficacy has been called into question).(6)

Azathioprine (Imuran), an immunosuppressant used in organ transplants, was applied to Crohn’s and Ulcerative Colitis treatments during the 1960’s.  6-mercaptopurine, for which azathioprine is a prodrug, and azathioprine itself were used to treat both forms of IBD, however the clinical research at the time was light and mostly based on case-study anecdotal results.(7)  Both drugs had high side effects, including leukopenia and pancreatitis, but some individuals were able to better tolerate the 6-MP regimen.  Later clinical evidence confirmed the efficacy of the drugs in IBD treatment, including the closing of fistulae, and they remain a staple of treating active IBD today.(8)*

The 1950’s and 1960’s showed tremendous advances in the treatment of Crohn’s Disease and Ulcerative Colitis.  Several staples in the stable of drugs used to treat the conditions today were first applied, including immunosuppressants and anti-inflammatory treatments.  While many of the treatments were based on anecdotal evidence, the next decades showed an increase in clinical trials related to IBD.

Bottom Line


·         The 1950’s and 1960’s saw the development of many of the treatments for IBD still in use today. 
·         The major trend during the period was a move away from surgical intervention toward medical treatment.

* Many of the drugs were used in limited patients or for other purposes in prior decades – a trend that continues with new drugs.
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1.       Crohn, Burrill B., Leon Ginzburg, and Gordon D. Oppenheimer. "Regional ileitis." Journal of the American Medical Association 99, no. 16 (1932): 1323-1329.
2.       Cooke, W. T. "Nutritional and Metabolic Factors in the Aetiology and Treatment of Regional Ileitis: Hunterian Lecture delivered at the Royal College of Surgeons of England on 28th April 1955." Annals of The Royal College of Surgeons of England 17, no. 3 (1955): 137.
3.       Machella, Thomas E., and O. Roger Hollan. "The effect of cortisone on the clinical course of chronic regional enteritis and chronic idiopathic ulcerative colitis." Transactions of the American Clinical and Climatological Association62 (1950): 67.
5.       LEE, EC GRUEBEL, and B. Dowling. "Problems in the Surgical Manag, ement of Crohn's Disease of theColon." Afr. Med 50, no. 45 (1971): 914.
6.       Golde, DavidW. "Aetiology of regional enteritis." The Lancet 291, no. 7552 (1968): 1144-1145.
7.       Parks, A. G., B. C. Morson, and J. S. Pegum. "Crohn's disease with cutaneous involvement." Proceedings of the Royal Society of Medicine 58, no. 4 (1965): 241.
8.       Pearson, David C., Gary R. May, Gordon H. Fick, and Lloyd R. Sutherland. "Azathioprine and 6-mercaptopurine in Crohn diseaseA meta-analysis." Annals of internal medicine 123, no. 2 (1995): 132-142.

Sunday, October 6, 2013

Crohn's, Colitis, and PPACA

Affordable Healthcare Act and IBD

The Patient Protection and Affordable Care Act (pejoratively or positively referred to as Obamacare in certain circles) largely went into effect in the United States on October 1 2013.   No law in recent history has generated as much controversy, ranging from a Supreme Court decision as to its constitutionality to a deadlocked Congress shutting down the federal government, in large part due to arguments over the law.  The reporting of the law is all over the map, and the Onion’s satire (http://www.theonion.com/articles/man-who-understands-8-of-obamacare-vigorously-defe,34022/) isn’t far off in terms of general understanding of the law.(1)  This blog post stays away from the political process and makes no determinations about the overall value of the law, but focuses instead on the impact to those with IBD.  The general impact of the law on cost or breadth of coverage is beyond the scope of this blog.
The full act is extremely dense and a very long read, requiring extensive legalese to interpret it.  A few of the areas, however, are easier to understand and have direct applicability to those who suffer from Crohn’s Disease and Ulcerative Colitis.
The first area with direct applicability is titled “Improving Access to Innovative Medical Therapies”, or the less glamorous “Section VII”.  The primary focus of this section is on creating a mechanism for generic versions of biological therapies to be made available.  The first therapy that is likely to be impacted by those being treated for IBD is infliximab (Remicade), which does not go off-patent until 2018.  Because biologicals are much harder to duplicate than traditional drugs, extensive clinical trials are required for generic manufacturers.  That said, expect the cost of Remicade or its biosimilar brethren to drop precipitously in 2018, followed by Humira and Cimzia a few years later.(2) 
Prescription drug coverage in general is now mandatory under the new act.  Insurers will no longer be permitted to offer an “optional” drug plan, and any costs for drugs count toward your out-of-pocket maximum spend.  Those of us paying thousands of dollars a month on treatments will now have that amount capped, and providers are required to provide at least one drug from every category and class in the US pharmacopeia.(3)
The second area of interest is based on pre-existing conditions.  Traditional health insurance providers were able to discriminate against those with IBD when enrolling in private insurance coverage, either by denying coverage or by charging higher rates.  In 2010, the pre-existing condition contingency was removed for any new insurance coverage issued or applied for if the applicant was under 19 years of age.  In January 2014, insurers will not be able to deny coverage to nor charge higher rates for sufferers of IBD.(4)
Of further interest is the coverage of children and young adults under 26.  Any child under 26 is eligible to be kept under their parent’s plan, even if they are financially independent.  Young adults with IBD who may have intermittent work histories due to illness-related breaks in employment will now have better gap coverage by remaining on their parent’s plans.(5)
How well the affordable care act helps those living below the poverty level will vary by state, and whether the federal government should be involved in healthcare is a debate for another blog.  There are at least a few direct benefits, as detailed above, to those with IBD that will take place over the next several years. 

Bottom Line

·         There are specific benefits in the Affordable Care Act for those with IBD.  These include:
o   Required drug benefits, with an out-of-pocket maximum, even on biological.
o   A new pathway for generic versions of the anti-TNF-alpha drugs in the future.
o   Guaranteed coverage without higher premiums with Crohn’s or Colitis as a pre-existing condition.
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