Trends in Biologic Therapy for Crohn's Disease: Where Are We and Where Are We Going?

Uma Mahadevan-Velayos, MD

Associate Professor of Clinical Medicine; Director of Clinical Research, University of California San Francisco Center for Colitis and Crohn's Disease, San Francisco, California

Introduction

The approach to the standard of care for the management of Crohn's disease has changed dramatically over the past 10 years with the advent of biologic therapy. Although in the past therapy was predicated on control of symptoms, the goals of care have now changed to encompass sustained corticosteroid-free remission, mucosal healing, and a decrease in surgeries and hospitalizations. Biologic therapy, as of today, comprises either anti-tumor necrosis factor (TNF)-alpha agents (the chimeric IgG1 monoclonal antibody, infliximab; the fully human IgG1 monoclonal antibody, adalimumab; and the humanized antibody Fab' fragment, certolizumab pegol) or anti-alpha-4 integrin agents (the humanized monoclonal antibody, natalizumab). Infliximab is approved for reducing signs and symptoms and inducing and maintaining clinical remission in adult and pediatric patients with moderately to severely active disease who have had an inadequate response to conventional therapy, and for reducing the number of draining enterocutaneous and rectovaginal fistulas and maintaining fistula closure in adult patients with fistulizing disease.[1] Adalimumab is approved for reducing signs and symptoms and inducing and maintaining clinical remission in adult patients with moderately to severely active Crohn's disease who have had an inadequate response to conventional therapy, as well as for reducing signs and symptoms and inducing clinical remission in these patients if they have also lost response to or are intolerant to infliximab.[2] Certolizumab pegol is approved for reducing signs and symptoms of Crohn's disease and maintaining clinical response in adult patients with moderately to severely active disease who have had an inadequate response to conventional therapy.[3] Natalizumab is approved for inducing and maintaining clinical response and remission in adult patients with moderately to severely active Crohn's disease with evidence of inflammation who have had an inadequate response to, or are unable to tolerate, conventional Crohn's disease therapies and inhibitors of TNF-alpha.[4] With the more aggressive course of care come questions and concerns about the true benefit and safety of long-term biologic therapy. Although these questions are not fully answered at this time, what we do know about which patient will benefit from biologic therapy and how best to use these agents to increase efficacy and reduce adverse events is addressed in this clinical review.

Who Should Receive Biologic Therapy?

When the first biologic agent was approved for use in Crohn's disease in 1997, biologic therapy was considered a "last resort," when all other conventional therapies had failed. This was known as the "step-up" approach, where patients may start with conventional agents such as 5-aminosalicylates, antibiotics, or corticosteroids, move up to immunomodulators such as azathioprine/6-mercaptopurine or methotrexate, and only then consider anti-TNF-alpha therapy. This is not the case today, where a "top-down" approach is increasingly being used. In this strategy, the biologic agent may be the first therapy introduced in the appropriate patient. Although not all patients are candidates for anti-TNF-alpha therapy, those who are, will be best served with timely and judicious use of these agents to prevent complications rather than temporize them when they occur. So who is a candidate? Any patient with moderate-to-severe Crohn's disease is a candidate for biologic therapy, regardless of how long they have had disease -- 1 month or 10 years. Patients with corticosteroid-refractory disease, corticosteroid-dependent disease, or even those who are just candidates for corticosteroid therapy should be considered. Patients with significant perianal disease and high-risk postoperative disease should also be considered.

Crohn's disease has a heterogeneous presentation. In a study of 2000 patients with Crohn's disease assessing long-term disease behavior, a stricturing or penetrating complication developed in 60%. Twenty-year actuarial rates of inflammatory, stricturing, and penetrating disease were 12%, 18%, and 70%, respectively.[5] In a population-based study from Olmsted County, Minnesota, Faubion and colleagues[6] reported that only 43% of the Crohn's disease population from 1970 to 1993 had received corticosteroid therapy, suggesting that over 50% of the population has mild-to-moderate disease; these patients will never be candidates for corticosteroids, nor by extrapolation, anti-TNF-alpha therapy. However, at 1 year, of the 43% who received corticosteroids, prolonged response was seen in only 32%, corticosteroid dependence in 28%, and surgery in 38%, suggesting that those patients who receive corticosteroids or are candidates for corticosteroids are at risk for progression to more severe disease, and should be considered for anti-TNF-alpha therapy. This finding was supported by another study[7] that looked at factors on initial presentation that predicted a disabling course of Crohn's disease; 3 such factors were identified: corticosteroid use, perianal disease, and age < 40 years old.

In a study that examined the natural history of fistulas in Crohn's disease, fistulizing disease was found to occur in up to 33% of patients.[7,8] Infliximab,[9] adalimumab,[10] and certolizumab pegol[11] have all shown benefit for this difficult-to-manage complication. Any patient with significant perianal Crohn's disease is a candidate for anti-TNF-alpha therapy because it is the only treatment approved by the US Food and Drug Administration for this indication (specifically, infliximab), and aside from tacrolimus,* which is off-label for Crohn's disease, infliximab is the only agent to show benefit in a randomized trial with fistula closure as the primary endpoint.[12] Another group for which anti-TNF-alpha therapy has shown benefit where other conventional agents (aside from ornidazole* and metronidazole*) have not, is among patients with an ileocolonic resection. In a small randomized trial, infliximab was found to be superior to placebo for preventing endoscopic recurrence at 1 year (9.1% for infliximab compared with 84.6% in the placebo arm; P = .0006).[13] Patients with predictors of rapid disease recurrence after surgery (perforating disease, multiple surgeries) should also be considered strongly for anti-TNF-alpha therapy.[14]

How Should Biologic Therapy Be Optimized?

Several studies have shown that the introduction of biologic agents earlier in the disease course (before the development of complications), leads to better response. In the CHARM (Crohn's trial of the fully Human antibody Adalimumab for Remission Maintenance) trial,[15] adalimumab given at a dose of 40 mg weekly or every other week, was found to be superior to placebo in maintaining remission for 56 weeks in patients with active Crohn's disease. However, the earlier in a patient's disease course the drug was given, the better the response. Patients with disease of less than 2 years' duration had a remission rate of 51% at 56 weeks compared with 44% for those with disease of 2 to < 5 years' duration and about 35% for those with disease for ≥ 5 years.[16]

Data suggest that the use of biologic therapy in combination with immunomodulators is more effective than either therapy alone. Although subgroup analysis of the large clinical trials[17] did not show a benefit associated with the use of biologic therapy given in combination with immunomodulators over biologic therapy alone, 1 large prospective trial, SONIC[18] (Study of Biologic and Immunomodulator Naive Patients in Crohn's Disease), did demonstrate benefit. In this study, 508 adult patients with moderate-to-severe Crohn's disease, median disease duration of 2.3 years, and no previous exposure to immunomodulators or biologic therapy, were randomly assigned to receive azathioprine* 2.5 mg/kg; infliximab 5 mg/kg at weeks 0, 2, 6, and then every 8 weeks; or combination therapy* with both agents. Of the 169 patients who received combination therapy, 57% were in corticosteroid-free clinical remission at week 26 (the primary study endpoint) vs 44% of those who received infliximab alone (P = .02) and 30% of those who received azathioprine alone (P < .001 vs combination therapy, and P = .006 vs infliximab). At week 50, results were similar -- with 46%, 35%, and 24% of patients, respectively, in corticosteroid-free remission. At week 26, mucosal healing had occurred in 44% of patients who received combination therapy vs 30% of those who received infliximab alone (P = .06) and 17% of those who received azathioprine alone (P < .001 for the comparison with combination therapy, and P = .02 for the comparison with infliximab). Serious infections developed in 3.9% of patients in the combination therapy group, 4.9% of those in the infliximab monotherapy group, and in 5.6% of patients in the azathioprine group, suggesting that at 1 year, infectious complications were not increased by the use of combination therapy. Although the findings of this study are impressive, it is important to keep in mind that this does not answer the question of whether patients who fail to respond to azathioprine monotherapy will experience a similar benefit with combination therapy as patients who were naive to both therapies.

Another important question to be addressed, is how long should therapy be continued? Cost and safety are certainly factors that come into play with long-term biologic therapy. A recent systematic review assessed the efficacy of anti-TNF-alpha therapy beyond 1 year.[19] Infliximab, adalimumab, and certolizumab pegol were all effective in maintaining remission in luminal Crohn's disease, and infliximab and adalimumab for fistulizing Crohn's disease, for > 1 year, with a low-risk safety profile. A prospective French study, STORI (Stop Infliximab in Patients With Crohn's Disease)[20] looked at 115 patients with Crohn's disease who were treated with infliximab plus an immunomodulator for at least 1 year, and in stable remission for at least 6 months. Infliximab was discontinued, and 39% of patients relapsed within 1 year. Factors predictive of relapse were endoscopic disease activity, elevated C-reactive protein level, low serum hemoglobin, and infliximab trough levels < 2 µg/mL. Of course, one must keep in mind that once patients stop a biologic agent, they may not be able to resume therapy with that same agent due to the formation of antibodies. In addition, patients who have been exposed to 1 TNF antagonist and lost response or who were intolerant, can respond well to treatment with a second anti-TNF-alpha agent, but not as well as if they were anti-TNF-alpha naive.[21,22]

Despite optimizing therapy, some patients with Crohn's disease may slowly lose response to anti-TNF-alpha therapy. When this occurs, a full evaluation should be conducted: Does the patient have an infection such as Clostridium difficile or bacterial overgrowth? Did a stricture or fistula develop? Did antibodies against the biologic agent develop or did the patient simply lose response to its mechanism of action? At this time, commercial assays to test for drug levels and the formation of antibodies to drug are only available for infliximab. For a patient who is losing response to infliximab, checking drug levels at either the midpoint between infusions or at trough is helpful.[23] If infliximab levels are > 12 µg/mL at the midpoint between infusions, or just detectable at trough, then there is adequate drug in the patient's serum. In this case, increasing the dose or changing to a different anti-TNF-alpha agent will not be helpful. If drug levels are low or undetectable, however, then increasing the dose of infliximab would be beneficial. If antibodies are present, then switching to a different anti-TNF-alpha agent is the best option. Low serum trough levels and the formation of antibodies against adalimumab have also been associated with poor response,[24] but unfortunately, an assay is not commercially available at this time.

For those patients with Crohn's disease who do not respond to anti-TNF-alpha therapy or who have lost response to these agents, natalizumab, a biologic agent with a different mechanism of action (alpha-4 integrin inhibitor), provides a good alternative. As noted previously, this agent has been shown to be effective for the induction and maintenance of clinical response and remission in adult patients with moderate-to-severe Crohn's disease with evidence of inflammation who have had an inadequate response to, or are unable to tolerate, conventional Crohn's disease therapies and inhibitors of TNF-alpha.[25] Due to concerns regarding progressive multifocal leukencephalopathy (PML), a rare demyelinating disease, which is estimated to occur in 1/1000 users,[26] natalizumab is limited to use in those patients who have failed to respond to anti-TNF-alpha therapy.
Summary Points: Optimizing Biologic Therapy for Crohn's Disease

Data show that introduction of biologic agents at an early stage in the disease course, before the development of strictures and need for surgery, leads to significantly improved outcomes. The use of combination therapy with a biologic agent and an immunomodulator is more effective than monotherapy for achieving sustained remission. On the basis of current best evidence, once a biologic agent is effective in a given Crohn's disease patient, it should be continued indefinitely because stopping therapy is associated with a significant risk for disease flare, and restarting or changing the agent does not result in the same level of benefit.[14]
What are the Benefits of Biologic Therapy Beyond Remission?

The biologics have provided clinicians the opportunity to think beyond symptomatic remission to potential disease-modifying endpoints. Infliximab,[17] adalimumab,[27] and certolizumab pegol[28] have shown benefit for the induction and maintenance of remission in patients with Crohn's disease. As noted previously, all 3 of these anti-TNF-alpha agents have demonstrated efficacy in the treatment of fistulizing Crohn's disease as well, with the strongest data available for infliximab, in a randomized controlled trial with closure of fistulas as the primary endpoint.[12] Corticosteroid withdrawal is another important benefit of biologic therapy, and has been clearly demonstrated for infliximab and adalimumab.[ 18,29] Natalizumab is also effective for the induction of corticosteroid-free clinical remission.[25] Mucosal healing is also emerging as an important endpoint in the treatment of Crohn's disease, and may be associated with a reduction in relapse rates,[20] need for surgical intervention,[30] and colorectal cancer.[31] The presence of deep ulcerations on colonoscopy in patients with Crohn's disease is predictive of a more aggressive disease course, with increased rates of penetrating complications and colectomy.[31] In the STORI trial, mucosal healing was one of the key predictors of maintenance of clinical remission after infliximab discontinuation.[20] Treatment with infliximab-based strategies also resulted in mucosal healing in the Study of Biologic- and Immunomodulator-Naive Patients in Crohn's disease (SONIC) trial.[18] Mucosal healing has been demonstrated to a lesser extent with the other biologic agents as well -- certolizumab pegol,[32] adalimumab,[33] and natalizumab.[34] Finally, although subgroup analysis of the major trials suggests a reduction in hospitalizations associated with the use of anti-TNF-alpha agents, overall national trends point to an increase in hospitalizations and outpatient visits for patients with inflammatory bowel disease, suggesting that additional studies are needed over time to determine the true impact of biologic therapy on long-term outcomes in Crohn's disease.[35,36]
Safety

A meta-analysis of placebo-controlled trials evaluating the efficacy and safety of anti-TNF-alpha therapy for Crohn's disease identified 21 studies with 5356 individuals, and found that TNF antagonists did not increase the risk for death, malignancy, or serious infection.[37] Unfortunately, because most trials are 6 months to 1 year in length, this finding does not adequately address the overall safety concerns. In general, biologic therapy does pose an increased risk for complications. The rate of serious infections with anti-TNF-alpha therapy is estimated to be 4%-5% based on data for infliximab and extrapolated to the other anti-TNF-alpha agents.[38] Prevention and early recognition is the key. Patients should be tested for previous exposure to tuberculosis and hepatitis B, because initiating therapy can lead to serious re-activation of these latent infections. Although bacterial infections are the most common complication, viral and fungal infections should also be considered, particularly in endemic areas. Additionally, patients should be vaccinated against preventable infections, although live virus vaccines can only be given before initiating therapy.

Although general malignancies (except perhaps skin cancer) do not seem to be increased with the use of anti-TNF-alpha agents,[39] the risk for lymphoma may be increased; however, given a patient's previous exposure to thiopurines (eg, the immunomodulatory agents, azathioprine and 6-mercaptopurine), an actual independent risk rate is not known. Other potential complications associated with the use of anti-TNF-alpha agents include much rarer events such as optic neuritis, lupus-like syndrome, and aggravation of congestive heart failure, as well as the more common psoriaform rash, which can be seen in up to 20% of patients.[40] For natalizumab, an additional safety concern is the risk for PML. As of April 2010, there have been 46 cases of PML reported after exposure to natalizumab, consistent with an overall risk of 1/1000.[41] To date, all post-marketing cases have occurred after 12 months of therapy and have been in patients with multiple sclerosis. Because the efficacy of natalizumab in Crohn's disease will be known by month 6 of therapy, for the reluctant patient, treatment can be initiated and a decision made at 6 months whether to continue, with minimal risk for PML, in that timeframe, based on the timing of occurrence of the known cases of PML.

Concerns about the risks associated with the use of biologic therapy for Crohn's disease must therefore be weighed against the debilitating effect of the disease itself in the patient with moderate-to-severe disease. Prevention of preventable diseases via vaccination and ensuring appropriate screening/maintenance care is important. A checklist of key health maintenance issues has been published and is an effective tool to ensure that the patient is up to date in his or her general healthcare maintenance.[42]

Conclusion

Crohn's disease is a complex and heterogeneous disorder. For those patients with markers predictive of a disabling disease course (corticosteroid use, perianal disease) or who have had surgery already, particularly for perforating disease, biologic therapy has shown benefit in clinical trials and epidemiologic analysis for induction and maintenance of remission. Additional benefits beyond clinical remission may include fistula closure, corticosteroid withdrawal, mucosal healing, and reduction in hospitalizations and surgeries. These potential benefits must be weighed against the safety of these agents when making treatment decisions. Biologic therapy has been associated with an increased risk for serious infections, lymphoma, and other rarer adverse events. As we consider therapy for Crohn's disease in the future, the benefits of biologic therapy, as based on current best evidence, and as outlined in this clinical review, in the appropriate candidate, appear to far outweigh the risks. Given the benefit of these agents, early intervention to achieve greater efficacy and prevent complications of disease, as well as optimizing the use of biologic therapy with concomitant immunomodulators and sustained therapy, are becoming the standard of care.

Disclosure: Uma Mahadevan-Velayos, MD, has disclosed the following relevant financial relationships:
Served as an advisor or consultant for: Centocor, Inc.; Abbott Laboratories; UCB Pharma, Inc.; Elan Pharmaceuticals, Inc.; Takeda Pharmaceutical North America, Inc.

References

1. REMICADE (infliximab). Prescribing Information. Malvern, Pa: Centocor Otho Biotech Inc.; 2009.
2. HUMIRA.® (adalimumab). Prescribing Information. North Chicago, Ill: Abbott Laboratories; 2010.
3. Cimzia®(certolizumab pegol). Prescribing information. Smyrna, Ga: UCB, Inc.; 2009.
4. TYSABRI (natalizumab). Prescribing information. San Francisco, Calif: Elan Pharmaceuticals, Inc.; 2010.
5. Cosnes J, Cattan S, Blain A, et al. Long-term evolution of disease behavior of Crohn's disease. Inflamm Bowel Dis. 2002;8:244-250.
6. Faubion WA Jr, Loftus EV Jr, Harmsen WS, Zinsmeister AR, Sandborn WJ. The natural history of corticosteroid therapy for inflammatory bowel disease: a population-based study. Gastroenterology. 2001;121:255-260.
7. Beaugerie L, Seksik P, Nion-Larmurier I, Gendre JP, Cosnes J. Predictors of Crohn's disease. Gastroenterology. 2006;130:650-656.
8. Schwartz DA, Loftus EV Jr, Tremaine WJ, et al. The natural history of fistulizing Crohn's disease in Olmsted County, Minnesota. Gastroenterology. 2002;122:875-880.
9. Present DH, Rutgeerts P, Targan S, et al. Infliximab for the treatment of fistulas in patients with Crohn's disease. N Engl J Med. 1999;340:1398-1405.
10. Colombel JF, Schwartz DA, Sandborn WJ, et al. Adalimumab for the treatment of fistulas in patients with Crohn's disease. Gut. 2009;58:940-948.
11. Schreiber S, Lawrance IC, Thomsen OO, Hanauer SB, Bloomfield R, Sandborn WJ. Randomised clinical trial: certolizumab pegol for fistulas in Crohn's disease -- subgroup results from a placebo-controlled study. Aliment Pharmacol Ther. 2010. [Epub ahead of print]
12. Sands BE, Anderson FH, Bernstein CN, et al. Infliximab maintenance therapy for fistulizing Crohn's disease. N Engl J Med. 2004;350:876-885.
13. Regueiro M, Schraut W, Baidoo L, et al. Infliximab prevents Crohn's disease recurrence after ileal resection. Gastroenterology. 2009;136:441-450 e1; quiz 716.
14. D'Haens GR, Panaccione R, Higgins PD, et al. The London Position Statement of the World Congress of Gastroenterology on Biological Therapy for IBD With the European Crohn's and Colitis Organization: When to start, when to stop, which drug to choose, and how to predict response? Am J Gastroenterol. 2010. [Epub ahead of print]
15. Colombel J, Sandborn WJ, Rutgeerts P. Adalimumab induces and maintains clinical response and remission in patients with active Crohn's disease: The results of the CHARM trial. Gastroenterology. 2006;130:686d.
16. Schreiber S, Reinisch W, Colombel JF, et al. Early Crohn's disease shows high levels of remission to therapy with adalimumab: sub-analysis of CHARM. Gastroenterology. 2007;132:A-147.
17. Hanauer SB, Feagan BG, Lichtenstein GR, et al. Maintenance infliximab for Crohn's disease: the ACCENT I randomised trial. Lancet. 2002;359:1541-1549.
18. Colombel JF, Sandborn WJ, Reinisch W, et al. Infliximab, azathioprine, or combination therapy for Crohn's disease. N Engl J Med. 2010;362:1383-1395.
19. Oussalah A, Danese S, Peyrin-Biroulet L. Efficacy of TNF antagonists beyond one year in adult and pediatric inflammatory bowel diseases: a systematic review. Curr Drug Targets. 2010;11:156-175.
20. Louis e, Vernier-Massouille G, Grimaud JC, et al. Infliximab discontinuation in Crohn's disease patients in stable remission on combined therapy with immunosuppressors. A prospective ongoing cohort study. Gastroenterology. 2009;136:A-146.
21. Sandborn WJ, Rutgeerts P, Enns R, et al. Adalimumab induction therapy for Crohn's disease previously treated with infliximab: a randomized trial. Ann Intern Med. 2007;146:829-838.
22. Sandborn WJ, Feagan BG, Stoinov S, et al. Certolizumab pegol for the treatment of Crohn's disease. N Engl J Med. 2007;357:228-238.
23. Afif W, Loftus EV, Jr., Faubion WA, et al. Clinical utility of measuring infliximab and human anti-chimeric antibody concentrations in patients with inflammatory bowel disease. Am J Gastroenterol. 2010;105:1133-1139.
24. Karmiris K, Paintaud G, Noman M, et al. Influence of trough serum levels and immunogenicity on long-term outcome of adalimumab therapy in Crohn's disease. Gastroenterology. 2009;137:1628-1640.
25. Sandborn WJ, Colombel JF, Enns R, et al. Natalizumab induction and maintenance therapy for Crohn's disease. N Engl J Med. 2005;353:1912-1925.
26. Yousry TA, Major EO, Ryschkewitsch C, et al. Evaluation of patients treated with natalizumab for progressive multifocal leukoencephalopathy. N Engl J Med. 2006;354:924-933.
27. Hanauer SB, Sandborn WJ, Rutgeerts P, et al. Human anti-tumor necrosis factor monoclonal antibody (adalimumab) in Crohn's disease: the CLASSIC-I trial. Gastroenterology. 2006;130:323-333; quiz 591.
28. Schreiber S, Khaliq-Kareemi M, Lawrance IC, et al. Maintenance therapy with certolizumab pegol for Crohn's disease. N Engl J Med. 2007;357:239-250.
29. Colombel JF, Sandborn WJ, Rutgeerts P, et al. Adalimumab for maintenance of clinical response and remission in patients with Crohn's disease: the CHARM trial. Gastroenterology. 2007;132:52-65.
30. Allez M, Lemann M, Bonnet J, Cattan P, Jian R, Modigliani R. Long term outcome of patients with active Crohn's disease exhibiting extensive and deep ulcerations at colonoscopy. Am J Gastroenterol. 2002;97:947-953.
31. Rutter M, Saunders B, Wilkinson K, et al. Severity of inflammation is a risk factor for colorectal neoplasia in ulcerative colitis. Gastroenterology. 2004;126:451-459.
32. Hebuterne Xea. Endoscopic improvement in patients with active Crohn's disease treated with certolizumab pegol: first results of the music clinical trials. Gut. 2008;57:A-15.
33. Rutgeerts P, Geboes K, Camez A, et al. Adalimumab induces and maintains mucosal healing in patients with moderate to severe ileocolonic Crohn's disease -- first results of the EXTEND Trial. Gastroenterology. 2009;136:A-116.
34. Rutgeerts P. Effects of natalizumab on gut healing in a phase 3 study of active Crohn's disease therapy (ENACT-1). Gastroenterology. 2004;126:A-208.
35. Ananthakrishnan AN, McGinley EL, Binion DG, Saeian K. A nationwide analysis of changes in severity and outcomes of inflammatory bowel disease hospitalizations. J Gastrointest Surg. 2010. [Epud ahead of print]
36. Ananthakrishnan AN, McGinley EL, Saeian K, Binion DG. Trends in ambulatory and emergency room visits for inflammatory bowel diseases in the United States: 1994-2005. Am J Gastroenterol. 2010;105:363-370.
37. Peyrin-Biroulet L, Deltenre P, de Suray N, Branche J, Sandborn WJ, Colombel JF. Efficacy and safety of tumor necrosis factor antagonists in Crohn's disease: meta-analysis of placebo-controlled trials. Clin Gastroenterol Hepatol. 2008;6:644-653.
38. Lichtenstein GR, Feagan BG, Cohen RD, et al. Serious infections and mortality in association with therapies for Crohn's disease: TREAT registry. Clin Gastroenterol Hepatol. 2006;4:621-630.
39. Oussalah A, Chevaux JB, Fay R, Sandborn WJ, Bigard MA, Peyrin-Biroulet L. Predictors of infliximab failure after azathioprine withdrawal in Crohn's disease treated with combination therapy. Am J Gastroenterol. 2010;105:1142-1149.
40. Fidder H, Schnitzler F, Ferrante M, et al. Long-term safety of infliximab for the treatment of inflammatory bowel disease: a single-centre cohort study. Gut. 2009;58:501-508.
41. Tan CS, Chen Y, Viscidi RP, Kinkel RP, Stein MC, Koralnik IJ. Discrepant findings in immune responses to JC virus in patients receiving natalizumab. Lancet Neurol. 2010;9:565-566.
42. Moscandrew M, Mahadevan U, Kane S. General health maintenance in IBD. Inflamm Bowel Dis. 2009;15:1399-1409.

I skipped over some of it, but this is very interesting. Thanks for posting this, David.

Any patient with moderate-to-severe Crohn's disease is a candidate for biologic therapy, regardless of how long they have had disease -- 1 month or 10 years. Patients with corticosteroid-refractory disease, corticosteroid-dependent disease, or even those who are just candidates for corticosteroid therapy should be considered. Patients with significant perianal disease and high-risk postoperative disease should also be considered.

Try telling the fat cats in the UK this!!!
Over here it's a post code lottery, and the consultants don't have a say in it.

effdee said:

I skipped over some of it, but this is very interesting. Thanks for posting this, David.

Click to expand...

Glad you found it interesting!

Astra101 said:

Try telling the fat cats in the UK this!!!
Over here it's a post code lottery, and the consultants don't have a say in it.

Click to expand...

What do you mean, Joan? Can you elaborate?

I think she is referring to the decision making process for prescribing a biologic is not laid down by the consultants, but by a bunch of 'gate-keepers' called the Primary Care Trusts. These are the local level health boards who decide what the NHS budget is really spent on in their area. So if they don't think an expensive drug, or surgical procedure, is worth it they can decide not to allow it to be used, or just not give that department any budget at all if they so desire. Hence the so called postcode lottery.

Currently the PCT's are making the consultants review every patient on the biologics, justifying why they are on it, and in some cases asking for justification for every single dose given.

This is just the start of 'our Dave we're all in it together Cameron's privatisation of every public service that is held dear to the British people. Ooops better not get political.

David in Seattle said:

As we consider therapy for Crohn's disease in the future, the benefits of biologic therapy, as based on current best evidence, and as outlined in this clinical review, in the appropriate candidate, appear to far outweigh the risks.

Click to expand...

This sentence seems to say it all for me. If EJ must go the Remi route in the near future, studies like this and the testimonials on this forum will certainly ease my mind a great deal. Thanks David!!

Astra101 said:

Any patient with moderate-to-severe Crohn's disease is a candidate for biologic therapy, regardless of how long they have had disease -- 1 month or 10 years. Patients with corticosteroid-refractory disease, corticosteroid-dependent disease, or even those who are just candidates for corticosteroid therapy should be considered. Patients with significant perianal disease and high-risk postoperative disease should also be considered.

Try telling the fat cats in the UK this!!!
Over here it's a post code lottery, and the consultants don't have a say in it.

Click to expand...

Agreed Astra,
Looking at this I would be better on a biologic as moderate to severe crohns and corticosteroid dependant....but I have to fail on aza first and therefore wreck a bit more of my GI tract...great. Not that I'm going to!

Beth has summed it up David, in a nut shell!
xxx

Astra101 said:

Beth has summed it up David, in a nut shell!
xxx

Click to expand...

I hate to open an old wound, but this is the same argument the anti-government run hc crowd in the US screamed from the roof tops. Federal bureaucrats have no business in medical decisions!! I'm no Sarah Palin fan, but this is what she meant when she spoke of "death squads".

It sounds like the NHS & PCT's have adopted a "bottom up" approach to treating IBD, rather than a "top down". This has been the accepted technique, though it is being questioned in the literature of late, and recent research does appear to be heading in the "top down" direction, at least for certain patients. "Bottom up" is of course less expensive, at least in the short term, and no doubt this is part of the reason for the current preference, but as this paper attests, evidence seems to be mounting that it does not produce the best outcome for all patients.

Needless to say, I'm not familiar with anyone's personal medical situation, and I am not making a case for "bottom up".

Dexky, I agree we should not get into a heated political debate here, but I have to say, I could not disagree more with your last statement. We already have "death panels" in the US health system. They are the private, money-driven insurance companies, which routinely deny claims to the detriment of their clients. Recent figures for the state of California:

Claims denial rates by leading California insurers, first six months of 2009:

• PacifiCare -- 39.6 percent
• Cigna -- 32.7 percent
• HealthNet -- 30 percent
• Kaiser Permanente -- 28.3 percent
• Blue Cross -- 27.9 percent
• Aetna -- 6.4 percent

I understand your frustration, but surely you don't really believe a private, profit-driven corporation would care more about the health of your family than would a properly constructed, operated and funded public system.

I'm not an expert on UK politics, but I gather from Beth's statement that the troubles being face by NHS as mentioned in this thread can be linked to privatization efforts by David Cameron, Conservative Prime Minister, and head of the British Conservative party. In other words, a person whose world view and priorities are in agreement with Palin's.

No human-built system is without flaws. I don't doubt the NHS, Health Canada, Australia's Medicare, etc., are not perfect, and that all such systems could stand improvement. But the US's private approach is the most costly in the world, and yet we still live shorter lives and have higher rates of things like infant mortality than just about any other industrialized nation, while leaving 10s of millions of people uninsured (precise numbers are hard to come by, but in 2006 the Census Bureau put the number at around 45 million). I think the facts are quite clear. I believe a properly constructed, managed and funded single payer government system would not only cost much less, it would also serve the population much, much better than the profit-driven system we now have in the US.

David in Seattle said:

I'm not an expert on UK politics, but I gather from Beth's statement that the troubles being face by NHS as mentioned in this thread can be linked to privatization efforts by David Cameron, Conservative Prime Minister, and head of the British Conservative party. In other words, a person whose world view and priorities are in agreement with Palin's.

Click to expand...

You are indeed on the money. There have always been winners and losers in the NHS, and there always will be unless someone finds a magic money tree. In the past it has been a case of doctors being able to prescribe biologics if they deem the need is sufficient. And yes, they are here somewhat conservative with a small 'c' on taking on new drugs so it has tended to be the 'bottom up' approach. My consultant said last year that was changing gradually as they have seen what the biologics can do and how safe in clinic they are now with pre-screening/etc. Following the general election earlier this year Cameron and his cronies have decided to overhaul the NHS costing a quoted £3bn whilst cutting £20bn from the budget over the next 4 years - all of which was not mentioned in the election manifesto. Just before Christmas my consultant recommended me not to move house/area because I may not be able to continue Humira, due to a new consultants being less inclined to fight for a continuation prescription for a 'new to them' patient, that hospital not being able to prescribe Humira as some smaller units will be closing, or the PCT will make it soo difficult to jump through the administration hoops that some will just give up. That's if there are the administrators to run the hospital.

Dave were all in it together Cameron wants GP's to band together into 'commissioning' groups to buy services off the cheapest provider. And I read something about deregulating of health care providers to allow private companies to bid, or tender, for those contracts. This is privatisation in all but name. Something the Conservatives are very keen on. 'Small goverment, Big Society' is what we keep hearing. If people realised just what he's doing their would be riots, but because he's dressed it up with 'spin' the shortsighted in our society... sigh, well they will find out when they are ill, or old. Everything that has been privatised has been a flipping disaster after disaster. And Labour haven't exactly done a great job on that front either.

There have been a number of articles in the BMJ (British medical journal) from medics saying the changes he wants are being scheduled too fast, are too risky, and will cost more than the projected £2 - 3bn at a time when budgets are being squeezed to breaking point. What is going to break is patient care.

As for Palin, she made some extremely offensive and unjust remarks about our NHS. It isn't perfect, but I think it's a fantastic public service, run for the public and the good of the country, not shareholders. And that is the way it should stay.

The other thing about all the cuts is the peripheral knock on effects; like unemployment is already rising and hence so will the benefits bill.

Phew. It's 1am, I better stop there before I get too political.

Beth - Thanks for the insights. It's amazing how similar politics are one place to another. But I guess that's mostly because wherever you go, and whatever the system or circumstances, humans are pretty much the same animal.

I agree with Beth. There is no magical money tree so there will always be rationing. The problem is when politicians start getting involved in the rationing process. It is often not based on patient need. NICE is supposed to address that by being 'impartial' but the problem with nice is the lag time between new evidence or treatment and them producing new guidelines. The new changes in the nhs are unwanted by most medics, particularly gp's. For gps it is a poisoned chalice- they are clinicians not commissioners or managers yet they have been given dramatically less money to pay for managers who can run the business side of things. Ultimately they will be forced to make the harsh decisions, manage a huge organisation with no management skills and be blamed when it fails by patients, secondary care colleagues and politicians.
Health care should not be in the political arena. It should not be used to score political points. It should be self contained and run by clinicians, academics and patient panels.
Having said all of that I would still rather be in the uk. When I read some of the threads on here where people are not taking ANY meds, let alone biologics because they have no insurance it makes me want to weep. What is Crohns doing to their GI tract just because they live somewhere where they need health insurance but cannot afford it or didn't think they would need.

David in Seattle said:

private, money-driven insurance companies, which routinely deny claims to the detriment of their clients.

Click to expand...

David, I work for UPS and have excellent insurance from Aetna, who I see at the bottom of your list. However, they routinely deny nearly every test EJ has but on appeal from the hospital's billing dept. and the realization that we won't be sending the hospital a check, they(so far) have always come through. I wonder if your figures have already been adjusted for appeals. It hasn't been our experience that the hospital waits for approval. They do what the docs feel needs to be done and then worry about who's paying. I have no doubt that many, especially those like yourself without a dx, have a very different experience. I also have no doubt that once EJ is off my insurance in the future, my opinions and experience may change dramatically.

You are an incredibly intelligent man and I (nor Sarah Palin, definitely not Sarah) have any business debating you. Like most of the supposed 80% of Americans who are satisfied with our health coverage, I am more afraid of the unknowns and our govts. track record for running....anything.

Dexky - Thank you for the very nice compliment! I hope whatever system you find yourself in, it continues to meet the needs of your son & the rest of your family :thumright: