What is the Optimal Therapy for Crohn's Disease: Step-up or Top-down?

[David in Seattle]

Ming Valerie Lin; Wojciech Blonski; Gary R Lichtenstein
Expert Rev Gastroenterol Hepatol. 2010;4(2):167-180. © 2010 Expert Reviews Ltd.

Abstract and Introduction
Abstract

Crohn's disease (CD) is an idiopathic chronic inflammatory disorder of the digestive tract, which is incurable. Present therapeutic guidelines follow a sequential step-up approach that focuses on treating acute disease or 'inducing clinical remission' and subsequently aims to 'maintain clinical response'. In view of the chronic relapsing–remitting disabling disease course, new treatment approaches have been sought with the ultimate end point of disease course modification and mucosal healing. A recent preliminary study from D'Haens et al. has provided evidence suggesting that reversing the treatment paradigm from a 'step-up' to a 'top-down' approach may positively alter the natural course of this illness. Their findings indicate that early use of biologic therapy, in combination with immunomodulators, resulted in remission occuring more rapidly than the conventional 'step-up' treatment, with a longer time period to relapse, a decreased need for treatment with corticosteroids, a faster reduction in clinical symptoms, rapid decline in biochemical inflammatory markers (C-reactive protein) and improved endoscopic mucosal healing. These results, supported by previous studies on infliximab use, may hold a promising outcome of fewer stricturing complications, hospitalizations and surgeries for patients with CD. However, we need to better define the timing and candidates for the 'top-down' approach as we are still uncertain about the safety data and the long-term benefits if biologic agents are given as routine maintenance treatment, since most of the trials in CD have been short term, and approximately 30% of patients might have been overtreated. Future clinical trials will be crucial in answering these questions.
Introduction

Crohn's disease (CD) is a chronic inflammatory disorder of the digestive tract with a wide spectrum of clinical presentations and an unpredictable disease course. The estimated annual prevalence and incidence of CD in the USA are 50 per 100,000 and five per 100,000, respectively.[1] CD is more prevalent in Western countries, and although it was found to be a disease affecting all age groups, it is more commonly diagnosed in adults during the second and third decades of life. Despite the advancements made in understanding the etiology and pathogenesis of the disease, CD remains medically and surgically incurable. These patients are faced with a lifetime of recurrent disease flare-ups and remission and thus the management strategies for CD must be targeted towards lifelong management, taking into consideration both short- and long-term aspects of the disease.

The current standard medical practice is guided by the disease location, severity, associated complications and concurrent therapy taken by patients. It consists of a sequential ('step-up') approach to conservative use of immunomodulators and biological therapy with the ultimate goal of inducing and maintaining clinical remission. While the usage of the first-line agents (aminosalicylates [5-ASA], antibiotics and corticosteroids) and immunomodulators has, somewhat successfully, treated the acute disease and maintained remission, these agents have not been able to alter the long-term course of CD. The question of whether it is possible to alter the natural history of CD by an early introduction of therapies currently reserved for the 'top' of the treatment pyramid has been the subject of much discussion (i.e., 'top-down' approach).

In this review, we aim to provide an evidence-based discussion on the controversy and rationale for the use of 'top-down' versus 'step-up' therapy for the treatment of CD.

Natural History of CD

The clinical course of CD is characterized by intermittent exacerbation of symptoms alternating with periods of quiescence. An inceptive cohort study from Scandinavia by Munkholm et al. demonstrated that overall, 13% of patients will achieve complete remission, 20% of patients will experience annual relapse and 67% will have a combination of relapse and remission within the first 8 years after initial diagnosis.[2] Less than 5% of patients will have a continuous course of active disease. These patients were treated with 5-ASA agents and corticosteroids (prednisolone 60–80 mg daily) during periods of disease activity. 5-ASA agents were used continuously for at least 2 years and corticosteroids were tapered down to a maintenance dose, which was withheld for no more than 2–3 months. In Silverstein et al.'s population-based cohort study, conducted prior to the routine use of anti-TNF-α, it was found that a representative patient with CD would be expected to spend 24% of the time in medical remission without medications, 41% of the time in postsurgical remission without medications, 27% of the time in medical treatment with 5-ASA derivatives and 7% of the time having disease activity mandating treatment with corticosteroids or immunomodulators.[3]

A population-based study from Olmsted County, MN, USA by Schwartz et al. demonstrated the cumulative risk for the development of Crohn's fistulas was 33% at 10 years and 50% after 20 years.[4] The authors also showed that fistula formation preceded the diagnosis of CD in approximately half of the patients.[4] The majority (83%) of fistulae required a surgical approach.[4] The clinical course of fistulae is variable and depends on their location and complexity.[5] The majority of fistulae observed in CD are external fistulae.[4,5] Perianal fistulae (abnormal connections from an internal anal opening to the external surface of perianal skin) accounted for 55% of all fistulizing complications in CD patients, whereas entero–enteric fistulae accounted for 24% and recto–vaginal fistulae accounted for 9%.[4,5] Generally, it is more difficult to achieve a closure of internal fistulae (entero–vesical or entero–enteric) with medical therapy.[5]

After medical therapy the recurrence rate of perianal fistulae has been reported to be as high as 59–71% in the referral centers[6,7] compared with 34% in the population-based study.[4] Beaugerie et al. found that the presence of perianal disease, younger age of disease onset (≤40 years old) and need for corticosteroids, were risk factors for predicting a disabling course of CD.[8] Based on this study, which was conducted in a tertiary referral center and carried the risk of referral bias, 85% of patients developed a disabling course within 5 years of diagnosis.[8]

Our current ability to predict the course of CD is still rudimentary. Although CD has been recognized as having a chronic relapsing course, it is evident that the majority of patients remain in clinical remission at any particular time. Overall, the majority of patients would progress from inflammatory to complicated fistulizing or penetrating disease over time.

 

[David in Seattle]

What are the Current Available Therapies for Treatment of Patients with CD?

The first-line therapies are 5-ASA (not approved by the US FDA for treatment of CD), antibiotics (not FDA approved for treatment of CD) and the controlled-release corticosteroid budesonide (currently FDA approved for treatment of CD). These are used for mild-to-moderate disease. Oral prednisone is considered the second-line therapy. Immunomodulators, such as azathioprine (AZA), 6-mercaptopurine (6-MP) or methotrexate, represent third-line therapy for those patients who failed the previous therapy or who are steroid-dependent or steroid-refractory. Biologic agents, such as infliximab, adalimumab or certolizumab pegol, have traditionally been reserved for patients who failed the first three lines of drug therapy. Natalizumab, an anti-α4 integrin antibody, was recently approved by the FDA for moderate-to-severe Crohn's disease.[9,10] Owing to concern over the rare, but potentially disabling neurological side effect of progressive multifocal leukoencephalopathy (PML), natalizumab is only indicated for patients who did not respond to anti-TNF therapy and who are enrolled in a Tysabri Outreach Unified Commitment to Health (TOUCH) prescribing program.[10,11]
First-line Therapy (5-ASA, Antibiotics & Budesonide)

These medications are used in mild-to-moderate active CD. 5-ASA agents exert their therapeutic effect topically within the lumen of the intestine.[12] Since the oral route of drug administration results in rapid absorption in the proximal small bowel, different oral formulations have been developed to allow the release of the specific active moiety in different locations of the GI tract. These include the slow-release formulations (coated with an ethylcellulose), pH-dependent delayed release formulations (coated with Eudragit® L or S resins) and azo-bound prodrugs, such as olsalazine and balsalazide.[12,13] Mesalamine, when given as 3–6 g daily, was demonstrated to be effective in treating active CD.[14–16] However, recent randomized, double-blind, placebo controlled multicenter trials failed to show any evidence that 5-ASA formulations were more effective than placebo in maintaining medically induced remission in patients with CD[17–24] or any significant risk reductions in CD relapses.[17–19,21–23,25–28] The observed pooled risk difference between 5-ASA and controls was −4.7% (95% CI: −9.6–2.8).[26] A Cochrane systematic review of six randomized placebo controlled trials with 12-month follow-up and one placebo controlled study with 24-month follow-up demonstrated no superiority of 5-ASA over placebo in maintaining remission of CD with odds ratio (OR) of 1.00 (95% CI: 0.80–1.24) and 0.98 (95% CI: 0.51–1.90), respectively.[24] Therefore, there is currently insufficient evidence to recommend therapy with 5-ASA for maintaining medically achieved remission of CD.[29]

Luminal bacterial floras have been hypothesized to be a putative etiological factor in CD and this has led to the use of antibiotics for treating patients with mild-to-moderate luminal and perianal diseases.[30–33] Metronidazole and ciprofloxacin are the most widely used antibiotics. They can be used alone or in combination.[34] Metronidazole has been compared with placebo in a double-blinded randomized controlled trial and it was found that metronidazole was more effective in reducing clinical symptoms, especially in patients with diseases confined to the large intestine or both small and large intestines.[35] Metronidazole was also compared with sulfasalazine in a Scandinavian trial[36] and was found to be equally efficacious to sulfasalazine in the treatment of CD. Despite several clinical trials demonstrating the efficacy of metronidazole and/or ciprofloxacin for the treatment of active CD,[30,37–40] data are limited on the efficacy of antibiotics as maintenance therapy of nonsurgically[40,41] or surgically induced remission.[42,43] The potentially serious side effects (peripheral neuropathy[43,44] and tendinitis or tendon rupture[45,46]) associated with these drugs and the possibility of drug resistance also precluded their long-term use.

There has been speculation of a causative association between Mycobacterium avium and Mycobactrium paratuberculosis infections and CD. A meta-analysis of seven randomized placebo controlled trials observed no beneficial effect and produced insufficient evidence to support the use of antituberculosis therapy in patients with CD, with a pooled OR of 1.36 (95% CI: 0.87–2.13) and a number-needed-to-treat of 15.[47]

Controlled-release oral budesonide has high topical activity and low-systemic bioavailability (10%), and thus it has a reduced risk of systemic corticosteroid-related complications.[48,49] It is recommended for use in patients with mild-to-moderately active CD involving the ileum and/or right colon. The Cochrane systematic review of randomized trials assessing the efficacy of budesonide at a dose of 9 mg daily showed that it was more effective than placebo (relative risk [RR]: 1.96; 95% CI: 1.19–3.23) or mesalamine (RR: 1.63; 95% CI: 1.23–2.16) in inducing remission of mild-to-moderate active ileocecal CD after 8 weeks of treatment.[50] A predetermined pooled analysis of four randomized, placebo controlled trials evaluating the efficacy of budesonide in maintaining remission of CD found that budesonide administered at the daily dose of 6 mg was only effective in maintaining remission up to 9 months but did not prevent relapse over 9 months, whereas budesonide administered at lower daily dose of 3 mg was not superior to placebo at any time of the study period.[51] However, a recently published Cochrane meta-analysis of eight randomized placebo controlled trials has demonstrated that budesonide given at the daily dose of 6 mg was not more efficacious than placebo in maintaining remission of CD at 3 months (RR: 1.25; 95% CI: 1.00–1.58; p = 0.05), 6 months (RR: 1.15; 95% CI: 0.95–1.39; p = 0.14) or 12 months (RR: 1.13; 95% CI: 0.94–1.35; p = 0.19).[52] On the other hand, a lower maintenance dose of budesonide (3 mg daily) was shown to be superior to placebo only after 3 months of treatment (RR: 1.31; 95% CI: 1.03–1.67; p = 0.03) without sustained benefit after 6 and 12 months.[52]

Although some clinical trials demonstrated comparable efficacy in inducing clinical remission between budesonide and prednisolone,[53] the recent Cochrane systematic review of nine randomized controlled trials demonstrated that budesonide at a daily dose of 9 mg was inferior to conventional corticosteroids in inducing remission of CD (RR: 0.85; 95% CI: 0.75–0.97).[50] On the other hand, the safety analysis in six trials showed that treatment with budesonide was associated with significant reduction in adverse events related to corticosteroid use, with a RR: of 0.64 (95% CI: 0.54–0.76).[50] Rutgeerts et al. found that budesonide had fewer glucocorticoid-associated side effects and less suppression of the pituitary–adrenal function compared with prednisolone.[53] Despite these results, budesonide has a limited treatment population for active CD. It is not effective in approximately 20% of patients with active CD (in particular, patients with extensive diseases who do not have ileocecal involvement or those with left-sided colitis).[54] There is also no evidence for the use of budesonide in fistulizing disease. A comparison between budesonide 9 mg daily and weaning doses of prednisolone 40 mg daily in maintaining remission of CD performed by the authors of a recent Cochrane meta-analysis based on the results obtained by Schoon et al. [55] has shown no superiority of budesonide over a traditional corticosteroid at 3 (RR: 0.81; 95% CI: 0.60–1.09), 6 (RR: 0.79; 95% CI: 0.56–1.12) or 12 months (RR: 0.79; 95% CI: 0.55–1.13) of treatment.[52] Therefore, in light of the recent data, budesonide is not recommended as a maintenance treatment for CD.
Second-line Therapy (Systemic Corticosteroids)

 

[David in Seattle]

Second-line Therapy (Systemic Corticosteroids)

Corticosteroids are highly effective in achieving clinical remission in CD. Systemic corticosteroids (prednisone 40–60 mg daily) have remained the mainstay of treatment to control acute disease that has not responded to the first-line therapy. A population-based inception cohort study observed that among patients with CD who received corticosteroids, 84% of them had either complete or partial response and 16% of them did not respond to treatment over the first 30 days.[56] However, within 1 year of initial use of corticosteroids, 28% of patients with CD became corticosteroid-dependent and 38% of CD patients underwent surgery.[56] There are as yet no studies evaluating the optimal corticosteroid dosage or dose schedules for CD. However, it has been shown that approximately 50–70% of patients achieved clinical remission over 8–17 weeks in a dosage equivalent of prednisone 40 mg daily.[53,57,58] In addition, data from several clinical trials have clearly demonstrated that systemic corticosteroids in low doses are not an effective agent in maintaining remission of CD.[14,57] High-dose corticosteroids have not been evaluated as a potential maintenance treatment owing to increased risk of significant side effects, and long-term use of systemic corticosteroids is not recommended for the same reason.
Third-line Therapy (Immunomodulators & Methotrexate)

The immunomodulators AZA and 6-MP have been shown to be effective in maintaining clinical remission after corticosteroid-inductive therapy or surgery,[59] and in assisting corticosteroid dosage reduction. The corticosteroid-sparing effect was observed among 30 patients treated with AZA compared with placebo with a pooled Peto OR of 5.22 (95% CI: 1.06–25.68) and a number-needed-to-treat of three.[59] A meta-analysis of four controlled trials found that AZA/6-MP was significantly more efficacious than placebo in preventing clinical relapses in surgically induced remission, with a mean difference of 8% (p = 0.021) and 13% (p = 0.018) after 1 and 2 years, respectively.[60] In addition, when compared with placebo, AZA/6MP displayed an overall preventive effect on severe endoscopic recurrence, with a mean difference of 15% at 1 year post surgery (p = 0.026).[60] However, it needs to be emphasized that patients treated with AZA/6-MP experienced a nearly twofold increased rate of adverse events leading to withdrawal of the drug when compared with placebo recipients (17.2 vs 9.8%, respectively; p = 0.021).[60]

Among the rare but serious side effects[61–63] of immunomodulators is the fear of developing non-Hodgkin lymphoma[64–66] and hepatosplenic T-cell lymphoma[66–70] associated with the prolonged use of these medications. The slow onset of action of 3–6 months precludes their use as inductive agents. The genetic coding for thiopurine methyltransferase can now be identified prior to the use of 6-MP. This allows for a more tailored use of the drug and a decrease in toxicity for 0.3–11% of the population with a thiopurine methyltransferase genetic mutation.[71,72] Despite the risks of lymphoma, some of the authors claimed that the benefits of maintenance therapy with AZA outweigh the risks.[73] We need more evidence to better define the optimal duration of therapy, which will maximize the duration of clinical remission with minimal risks of potential lethal complications.

Methotrexate is a folic acid antagonist that inhibits purine synthesis, DNA and RNA formation, and suppresses inflammation in chronic inflammatory conditions through a complicated cascade.[74] There are fewer published articles on the use of methotrexate in CD compared with other medications. A recent Cochrane database meta-analysis of three randomized placebo-controlled trials has demonstrated that methotrexate, when administered intramusculary at the weekly dose of 15 mg, was three-times more efficacious than placebo in maintaining remission of CD.[75] Given the potential adverse events, such as liver fibrosis, pneumonitis and bone marrow suppression, the optimal duration of maintenance therapy with methotrexate remains unknown.[76,77] Among 20 patients with irritable bowel disease (IBD) who received methotrexate at a mean accumulated dose of 2633 mg over a mean period of 132 weeks, only one patient (5%), with an accompanying diagnosis of obesity and diabetes, had liver fibrosis.[78] Although these results may have implied that patients with IBD are not as high risk for liver fibrosis as patients with psoriasis or rheumatoid arthritis, more data are required on methotrexate-related liver toxicity in patients with IBD to validate these preliminary findings.
The Fourth-line Therapy: Anti-TNF (Infliximab, Adalimumab & Certolizumab Pegol)

The biological therapies for CD are designed to block or neutralize proinflammatory cytokines, which play a major role in the pathogenesis of CD. Infliximab is a murine chimeric antibody directed against TNF-α and it is administered intravenously. It was approved by the FDA[79] for induction and maintenance therapy in patients with moderate-to-severe CD refractory to conventional therapies (A Crohn's Disease Clinical Trial Evaluating Infliximab in a New Long-Term Treatment Regimen [ACCENT] I trial).[80] It is also effective in reducing the number of draining enterocutaneous and rectovaginal fistulae, and maintaining fistula closure in adult patients with fistulizing Crohn's disease.[81,82] The recommended maintenance dose of infliximab is 5 mg/kg every 8 weeks with an increase to 10 mg/kg in case of loss of response.[80] Studies have clearly demonstrated that maintenance therapy with infliximab in patients with CD is superior to episodic treatment.[80] Maintenance therapy was associated with higher clinical response and remission rates, significant reduction in hospitalizations and surgical procedures, prolonged mucosal healing, faster steroid weaning, decreased neutralizing antibody formation and better quality of life.[80,81, 83–86]

Recent preliminary 1-year data from the Study of Biologic and Immunomodulator Naive Patients in Crohn's Disease (SONIC) trial have indicated that monotherapy with infliximab or combination therapy consisting of infliximab and AZA are more likely to maintain long-term corticosteroid-free remission than monotherapy with AZA.[87] Immunomodulator-naive patients with active CD were enrolled and randomized into three treatment arms: monotherapy with infliximab given at 5 mg/kg (weeks 0, 2, 6 and then every 8 weeks), montherapy with oral AZA given at 2.5 mg/kg/day or combination therapy of infliximab and AZA at the dose mentioned earlier. It was found that the combination therapy and infliximab monotherapy had a significantly higher proportion of patients who were in corticosteroid-free remissions (46 and 35%, respectively). This was compared with AZA montherapy (24%) at week 50. However, final data from the SONIC trial[87] would be necessary to further assess the efficacy, safety and risk–benefit of infliximab and AZA combination therapy given the recent reports of hepatosplenic natural killer T-cell lymphomas observed in young males receiving the combination therapy.[67,70,88,89]

Adalimumab is an Ig-G1 monoclonal anti-TNF antibody of fully human origin that is administered subcutaneously and binds with high affinity and specificity to the soluble TNF. It was approved by the FDA in 2007[90] as an induction agent (Clinical Assessment of Adalimumab Safety and Efficacy Studied as Induction Therapy in Crohn's Disease [CLASSIC] I trial[91]) and a maintenance agent (CLASSIC II and Crohn's Trial of the Fully Human Antibody Adalimumab for Remission Maintenance [CHARM] trials[92,93]) for moderately to severely active CD in adult patients unresponsive to conventional therapy and in those who are intolerant to or lost response to infliximab (Gauging Adalimumab Effectiveness in Infliximab Nonresponders [GAIN] trial[94]). In the CHARM trial, patients with fistulizing CD treated with adalimumab had a significantly decreased number of draining fistulae per day compared with placebo (1.34 vs 0.88; p = 0.002) during a 56-week period.[95] An open-label extension Additional Long-Term Dosing with Humira to Evaluate Sustained Remission and Efficacy in Crohn's Disease (ADHERE) study of the aforementioned subgroup of patients treated with adalimumab observed that 90% of patients with healed fistulas at the end of the CHARM trial maintained their remissions for an additional year with the treatment of adalimumab.[95] The side effects of adalimumab are similar to those of infliximab.[92,93]

Certolizumab pegol is a humanized Fab' fragment attached to two polyethylene glycol molecules with a high binding affinity for TNF-α. Pegylation is thought to increase the half-life and improve the bioavailability of the drug, allowing it to be administered as a subcutaneous injection once every 4 weeks.[96] Certolizumab pegol was shown to be effective in both inducing (Pegylated Antibody Fragment Evaluation in Crohn's Disease Safety and Efficacy [PRECISE] I trial[97]) and maintaining (PRECISE II trial[98]) clinical response and remission. However, certolizumab was not found to be more efficacious than placebo on fistula closure in either of the aforementioned trials.[97,98] In 2008, this drug received FDA approval as an alternative treatment to reduce signs and symptoms of CD and to maintain clinical responses in adult patients presenting with moderately to severely active disease who had inadequate responses to the conventional therapy.[99]

 

[David in Seattle]

A recent meta-analysis of placebo controlled trials demonstrated that all three anti-TNF agents were safe in patients with CD refractory to standard medical therapy.[100] Although treatment with infiximab, adalimumab and certoliuzmab pegol is overall well tolerated, administration of these agents was associated with the occurrence of various adverse events.[5] These can manifest acutely as headaches, dizziness, nausea, injection-site erythema, flushing, fever, chills, chest pain, cough, dyspnea and pruritis; or as delayed reactions, such as myalgias, arthralgias, fever, rash, pruritis, dysphagia, urticaria and headaches. Hypersensitivity infusion reactions, development of antibodies to infliximab and anti-dsDNA antibodies were the most frequently observed adverse events after intravenous administration of infliximab.[5] Owing to the fact that adalimumab and certoliuzmab are administered subcutaneously, neither acute nor delayed infusion reactions have been reported.[5] On the other hand, injection-site reactions were observed.[5] All three agents are associated with increased risk of infectious complications, particularly with intracellular pathogens.[5] Physicians should also monitor meticulously for the potential development of lymphoma or other malignancies associated with the use of anti-TNF agents.
The Alternative Medical Therapy for the Nonresponders: Selective Adhesion Molecule Inhibitors (Natalizumab)



Natalizumab is a humanized monoclonal antibody targeted against the α4 subunit of integrin molecules and it belongs to a new class of biologic agents called selective adhesion molecule inhibitors.[101] By binding to the α4 subunit, it reduces inflammation and blocking adhesion and migration of leukocytes in the gut. It was approved by the FDA in 2008 as the treatment to induce (Efficacy of Natalizumab in Crohn's Disease Response and Remission [ENCORE] trial[102]) and maintain (Evaluation of Natalizumab as Continuous Therapy [ENACT] 2 trial[103]) clinical response and remission in adult patients with moderately to severely active CD who had inadequate response or intolerance to conventional CD therapies, including the anti-TNF-α agents.[104]

Owing to an underlying risk of PML, natalizumab is available only to patients enrolled in the risk management program (TOUCH Prescribing Program).[201] This agent is approved for use only as a monotherapy owing to the fact that there were three patients who developed PML while being treated with either IFN-β-1a or AZA.[10]

In the ENCORE trials, 509 patients with moderately to severely active CD were randomized into receiving natalizumab or placebo and their responses were assessed at weeks 4, 8 and 12.[102] It was shown that natalizumab had a higher response rate at week 4 (51 vs 37% in placebo; p = 0.01) and better remission rate than placebo at weeks 4, 8 and 12 (p ≤ 009).[102] The authors reported a similar frequency and types of adverse events between the treatment and placebo groups.[102]

So What are the Long-term Considerations for Patients with CD?

Mucosal ulcerations in CD lead to fistula formation, translocation of microbes, toxic megacolon, perforation and bleeding. It thus seems logical that effective treatment should imply complete mucosal healing in parallel with clinical remission. Cosnes et al. have shown that most patients with CD will eventually develop stricturing or perforating complications, with a proportion of 40 and 70% at 5 and 20 years after the initial diagnosis, respectively.[105] A retrospective study from Belgium assessed the 25-year course of CD according to the Vienna classification, and observed that there are statistically significant changes in disease behavior, from nonstricturing and nonpenetrating to structuring or penetrating in 27 and 29.4% of patients after a median duration of 5.5 and 6 years, respectively.[106]

With these results in mind, researchers attempted to advance the treatment options over the past years and have made our treatment goals more ambitious with modification of the natural course of the disease as the ultimate end point. The current potential medical therapy for CD modification consists of corticosteroids, immunomodulators and biological therapy.

Corticosteroids are effective induction agents, but they do not modify the natural course of disease. Modigliani et al. demonstrated that, in patients with CD who were treated with prednisolone (1 mg/kg/day) for up to 7 weeks, 92% of patients underwent clinical remissions within 7 weeks of treatment.[107] However, only 29% of patients in clinical remissions were also in endoscopic remission. In the National Cooperative Crohn's Disease Study (NCCDS) assessing patients receiving prednisone as an induction therapy, nine patients were excluded from further participation because of worsening diseases on their barium radiographs, suggesting disease progression despite clinical improvement in patients who received corticosteroids.[57] A small study from Sweden also demonstrated that early clinical remission in patients treated with prednisone (20–30 mg daily for 6–9 weeks) was poorly correlated with improvement of endoscopic ileal inflammation.[108] Corticosteroids may effectively downregulate mucosal inflammation, but their inability to heal the deep ulcers may be due to their deleterious effects on tissue restitution.[109]

Beaugerie et al. highlighted that among the predictors of disabling disease, patients who required an initial corticosteroid treatment were associated with increased risks of subsequent 5-year disabling clinical course.[8] Faubion et al. demonstrated in a population-based study that 38% of patients with CD who initiated therapy with corticosteroids required operation within 1 year.[56] It was reported that only approximately one third of patients have prolonged response 1 year after their first course.[110] These studies highlighted that the need for corticosteroid treatment is a marker of poor prognosis. Thus, it can be concluded that in addition to the undesirable toxicity and potential for dependency in long-term use, corticosteroids are not beneficial in maintaining remission or preventing new flares and it does not alter the natural course of CD.

The use of immunomodulators as induction and remission agents to treat CD has been well recognized. Candy et al. demonstrated in double-blind randomized control trials that AZA had a therapeutic advantage over placebo in the maintenance of corticosteroid-induced clinical remission in CD.[111] They showed that over a period of 15 months, 42% of patients who received AZA were in remission compared with 7% of patients who received placebo. A similar trial was performed in the pediatric population and it demonstrated that early introduction of immunomodulators was associated with a longer duration of remission and lower corticosteroid dosage requirement.[112] In total, 55 children were randomized to receive 6-MP or placebo in addition to prednisone. It was found that the addition of 6-MP to a regimen of corticosteroids resulted in significantly less need for prednisone and a higher rate of maintenance of remission (9% of patient relapse on AZA compared with 47% in placebo group).[112]

A double-blind noninferiority study comparing the use of placebo and AZA demonstrated that there were more CD relapses associated with placebo than AZA within 18 months of the study period in patients who were in clinical remission on AZA for more than 3.5 years.[113] In addition, a recent prospective cohort study showed that AZA withdrawal is associated with a high risk of clinical relapse (up to 62.7%) within 5 years of cessation.[114] These data suggest that if AZA is well tolerated, it should not be interrupted. In contrast to corticosteroids, the long-lasting clinical remission maintained with immunomodulators may be associated with mucosal healing.[113,115] D'Haens et al. found that in patients who were treated with AZA for a mean duration of 2 years complete mucosal healing was seen in up to 70% in the colon and 54% in the ileum, accompanied by the disappearance of the inflammatory infiltrate.[115] However, despite these encouraging findings, Cosnes et al. failed to demonstrate a decrease in the cumulative risk of intestinal resection associated with the use of immunomodulators (AZA and methotrexate) in a 25-year retrospective study.[116] Of the 565 patients enrolled in the study, 190 (34%) were operated on at least once. It may be argued that, since it was a retrospective study, it may not accurately reflect and may have over-reported the need for surgery, especially considering that the study was conducted in a tertiary referral center, treating, in general, more severe disease with delayed initiation of the medication. This also raises the point that perhaps early potent inflammatory suppressive agents are needed to change the outcome of the disease.[116]

Methotrexate has been shown to induce histological remission and mucosal healing.[76] It is also effective in maintaining remission,[117] and in some of the retrospective studies it was reported to have up to 90% maintenance of remission rate after 1 year.[118–120]

There is currently not enough evidence that immunomodulators change the natural history of CD, and prospective studies are necessary to answer this important question.

Infliximab has been shown to be a rapid induction and long-term maintenance agent with the ability to heal mucosal ulceration and reduce fistulae.

 

[David in Seattle]

In the ACCENT l trial, 573 patients with active CD were randomly assigned to receive placebo, infliximab 5 mg/kg or infliximab 10 mg/kg with scheduled repeat infusions.[80] This study successfully demonstrated that infliximab is efficacious in inducing early remission with 58% of patients responding to a single infusion of infliximab within 2 weeks.[80] The clinical remission sustainability rate was also higher in the infliximab-treated group, with 39% for lower and 45% for higher maintenance dose of infliximab compared with 21% of the placebo-treated group (p = 0.003 and p = 0.0002, respectively).[80] It was also observed that patients who responded to the initial infliximab treatment were more likely to discontinue corticosteroids (29% in combined infliximab group vs 9% in placebo group; p = 0.004) and maintain their response for a longer period of time if treatment with infliximab is administered every 8 weeks.[80] A multicenter trial conducted in Europe demonstrated that patients with active CD who were treated with infliximab, irrespective of the dosage, had clinical improvement that was accompanied by significant healing of endoscopic lesions and disappearance of the mucosal inflammatory infiltrate.[121] Present et al. found that 68 and 56% of patients who received infliximab 5 or 10 mg/kg, respectively, achieved a significantly greater reduction (p = 0.002 and p = 0.02, respectively) in the number of draining fistulae from baseline compared with the placebo group (26%).[82] Among patients treated with infliximab 5 and 10 mg/kg, complete fistula closure was observed in 55 and 38% of them, respectively, compared with 13% of the patients assigned to placebo (p = 0.001 and p = 0.04, respectively).[82] It was concluded that infliximab is an efficacious treatment for fistulas in patients with Crohn's disease.[82]

In the ACCENT 2 trial, 306 patients with active CD and draining fistulae were treated with infliximab and those who had a response by week 14 were then randomly assigned to receive placebo or infliximab 5 mg/kg every 8 weeks and to be followed to week 54.[81] The time to loss of response (≥40 weeks vs 14 weeks; p ≤ 0.001) and complete fistula healing at week 54 (36 vs 19%; p = 0.009) was significantly higher for patients who received infliximab maintenance therapy than for those who received placebo maintenance.[81] It was concluded that patients with fistulizing CD who have a response to induction therapy with infliximab have an increased likelihood of a sustained response over a 54-week period if infliximab treatment is continued every 8 weeks.[81]

A study comparing scheduled and episodic infliximab treatment strategies found that the efficacy of scheduled infliximab therapy (infusions at week 2 and 6 followed by infusions every 8 weeks) was superior to episodic infusions (infusions at week 2 and 6 followed by infusions every 8 weeks through to week 46).[122] Patients treated with a scheduled program had significantly lower Crohn's Disease Activity Index (CDAI) scores, higher responses and remission rates between weeks 10 and 30, significant rates of mucosal healing (44 vs 18%; p = 0.041) and fewer hospitalizations (p = 0.014) and surgical interventions (p = 0.01) than those receiving episodic treatment.[122] A strong correlation between clinical improvement and improvement of endoscopically viewed bowel ulcerations was successfully demonstrated.[121] The notion that mucosal healing predicts a better long-term outcome was further supported by a study conducted by Schnitzler et al..[84] The authors analyzed mucosal healing during long-term treatment with infliximab in 214 CD patients and assessed whether it had a better outcome in terms of the need for major abdominal surgery.[84] In their study, endoscopic mucosal healing was found in 67.8% of the 183 initial responders to induction with infliximab, with 83 patients having complete healing (45.4%) and 41 having partial healing (22.4%).[84] This was associated with a significantly lower need for major abdominal surgery during long-term median follow-up of 22 months (14.1% of patients with mucosal healing compared with 38.4% of patients without mucosal healing; p ≤ 0.0001).[84]

What is the Rationale for Early Use of Biological Therapy in CD?

Anti-TNF-α agents have been shown to be highly effective for the management of fistulas.[80,81,83–85] If a treatment induces profound and long-lasting mucosal healing, which in turn reduces complications and the need for surgical interventions, it could potentially slow down or even stop the progression and change the natural course of the disease.

Early treatment was shown to be associated with longer-sustained remission in children with early CD[123,124] and recent advancement in rheumatology (Behandel Strategieen [BeST] trial[125]) demonstrated that early aggressive treatment in patients with rheumatoid arthritis slowed down the disease progression, with earlier functional improvement and less radiographic damage after 1 year. AZA, despite its ability to induce mucosal healing, did not change the outcome of the disease.[116] This was in contrast to the trials on infliximab, with early mucosal healing associated with a better outcome. These data support the notion that time of initiation of therapy is of crucial importance if one takes into consideration that longer disease duration inevitably leads to more irreversible damage.

Several clinical trials on adalimumab have demonstrated the efficacy of this drug as an induction, remission and mucosal healing agent.[91,93,95] The CLASSIC I trial evaluating the efficacy of adalimumab induction therapy in patients with CD showed that the rates of remission at week 4 in the adalimumab group were as high as 36% in patients who received 160 mg compared with 12% in the placebo group (p = 0.001).[91] The extension study in the CLASSIC II trial showed that adalimumab administered weekly or biweekly was superior to placebo (79 vs 44%; p ≤ 0.05 and 83 vs 44%; p ≤ 0.05, respectively) in maintaining remission (83 vs 44% for placebo; p ≤ 0.05). A study performed by Colombel et al. showed that patients who received adalimumab had significantly lower numbers of draining fistulas than the placebo group during the treatment period of 56 weeks.[95] Of the patients with healed fistulas, 90% had sustained fistula healing for up to an additional year of open-label adalimumab.[95]

 

[David in Seattle]

Efficacy of certolizumab pegol as a maintenance agent in CD was assessed in a randomized double-blind placebo controlled trial – the PRECISE II trial.[98] The patients who responded to certolizumab pegol as induction therapy (i.e., reduction in CDAI ≥100 points from baseline) were randomized to receive either certolizumab pegol 400 mg or placebo administered every 4 weeks through to week 26.[98] The sustained clinical remission (CDAI ≤150) rates and clinical response maintenance rate were significantly higher in patients treated with certolizumab pegol when compared with the placebo arm at week 26 (48 vs 29%; p ≤ 0.001 and 63 vs 36%; p ≤ 0.001, respectively).[98] From this study, certolizumab pegol was shown to be more efficacious than placebo in maintaining clinical remission (RR: 1.68; 95%CI: 1.30–2.16) and clinical response (RR: 1.74; 95%CI: 1.41–2.13) through to the end of the PRECISE II trial.[98] A similar approach to the BeST Trial, investigating the early biological treatment effect on CD, was undertaken by D'Haens et al., comparing top-down and step-up therapy in a controlled, randomized fashion.[126] The study population consisted of 133 patients with CD, who were treatment-naive to glucocorticoids, immunomodulators or infliximab, had a CD diagnosis of less than 4 years and had active disease (as indicated by CDAI ≥220 points). They were randomized into receiving either early combination immunosuppression (top-down) or conventional (step-up) treatment. The conventional therapy consisted of an initial treatment with budesonide or methylprednisolone, followed by AZA if patients became steroid-dependant or steroid-refractory, followed by infliximab if immunosuppression failed to control the symptoms. The early combination immunosuppression therapy consists of initial treatment of infliximab and AZA, with repeat infliximab infusion as needed (episodic) for patients with disease relapse and failure to respond to corticosteroids or infliximab. They were able to demonstrate that patients who received early combination therapy (top-down) had a significantly higher proportion in early induction of remission, a lower relapse rate, a lower mean number of days of corticosteroid use and complete mucosal healing in 75% of the early combination immunosuppression (top-down) group, compared with 21% in the conventional (step-up) treatment group at 2 years. By assessing some of the proposed surrogate end points, the top-down therapy could potentially alter the natural history of CD. We may be able to prevent stricturing and penetrating disease or extraintestinal complications, avoid corticosteroid and related complications, decrease hospitalization and surgery and ultimately decrease the healthcare cost.

So Which One is Better? Step-up versus Top-down
Step-up Therapy

The current clinical practice and recommended treatment for CD[127] groups the therapeutic agents in a step-up manner according to the different CD severity levels,[57,128] with an ultimate goal to maintain clinical remission (Figure 1). The term 'step-up' refers to a sequential treatment strategy that often begins with a less effective, potentially less toxic treatment strategy, such as aminosalicylates, antibiotics or budesonide, with escalation to the highly effective but potentially more toxic treatment strategies, such as prednisone, immunomodulators and biological therapy, in patients who failed each line of therapy. In this strategy, one would avoid overtreating and unnecessary exposure to the risk of developing adverse events, especially in a subgroup of patients who may do well with the standard paradigm. For the same reason of toxicity, physicians are often reluctant to advance therapy resulting in patients not being adequately treated and developing tissue damage with the prolonged period of uncontrolled inflammation.

Figure 1.

Step-up versus top-down treatment approach for patients with Crohn's disease.
ASA: Aminosalicylate; AZA: Azathioprine; MTX: Methotrexate; SPS: Sulfasalazine.
Modified from [127] with permission from John Wiley & Sons, Inc.

 

[David in Seattle]

Top-down Therapy

Studies have shown that most patients treated with the conventional step-up therapy go on to develop stricturing or penetrating disease.[2,3,81] Ideas of using highly effective but potentially more toxic treatment strategies early in the course of a chronic illness to prevent disease progression and disability are now the center of focus in the treatment of patients with CD. Data from CD-related medical claims (October 1994–September 1995) in a 1994 integrated claims database showed that CD requiring hospitalization accounts for greater than 50% of healthcare costs.[129] Jewell et al. presented data looking at the influence of anti-TNF-α (infliximab) on resources in CD in the UK, comparing 6 months pre- and post-infliximab treatment and found that there were 1093 fewer bed days, fewer investigations and an unchanged number of out-patient standard follow-up visits.[130] The number of abdominal operations was halved, with 33 fewer examinations under anesthesia. This finding was consistent with some of our own trials.[80,81] It is estimated that approximately 80% of patients will require at least one surgical resection over a lifetime and that by 20 years following the current treatment standard paradigm, rates of surgical intervention will remain high despite earlier and increasing use of immunomodulators,[116] so it may not be unreasonable to administer these highly effective but potentially more toxic treatment strategies early in the course of a chronic illness.

D'Haens et al. evaluated the efficacy of early combination therapy versus conventional therapy, and the authors were able to demonstrate significant mucosal healing in 73% of patients treated with early immunosuppressive therapy compared with 30% in the conventional treatment group at the end of 104 weeks (p = 0.0028).[126] Since the data from the endoscopic substudy the of ACCENT I trial have demonstrated a better outcome with mucosal healing associated with the scheduled rather than episodic use of infliximab,[122,131] it could be hypothesized that this therapy could potentially alter the natural history of the disease. However, when assessing the actual number of analyzed patients for whom an endoscopic evaluation was performed it was relatively low (58 patients[122] and 40 patients[131]), which makes the data difficult to interpret.

There was a greater proportion of patients who achieved early clinical remission at week 14 (p = 0.0001) and week 26 (60 vs 36%; p = 0.0062)[126] in the early combined immunosuppression therapy group. This was consistent with previous studies.[80,92,98] They were also able to show a significant difference with respect to the number of patients in remission without corticosteroids and without surgery at weeks 26 and 52. A sustained clinical benefit was also observed in the early combination therapy group. Patients assigned to combination immunosuppression had a more rapid drop in CDAI scores and IBD questionnaire compared with patients receiving conventional therapy.[126] In their study, there were no important differences in the occurrence of adverse events between the two groups. All of these factors could argue favorably for the early initiation of combination therapy.

Corticosteroids are ineffective in maintaining remission, preventing new flares or inducing mucosal healing.[110] Their use has also been demonstrated as a predictor for poor outcome.[8,132] During the D'Haens study, patients assigned to early immunosuppression therapy had a reduced need of corticosteroids in the early phase of the disease compared with those in the conventional group.[126] However, this must be interpreted in the context that patients in the step-up group received multiple doses (>2) of corticosteroids before the initiation of immunomodulators, while patients in the top-down group received corticosteroids only if the flare was refractory to infliximab. Many clinicians would commonly introduce an immunomodulator with the need for a second course of corticosteroids instead of waiting for a third course, and this could lead to the step-up patients receiving more corticosteroids than desired.

We have good evidence that the use of other anti-TNF therapies in CD suggest that earlier introduction is associated with improved clinical outcomes.[98,133] However, aside from evaluating efficacy, the long-term safety and pharmacoeconomics are crucial factors to consider when initiating early combination versus sequential immunosuppressive therapy. There is mounting evidence that combination therapy may not be any more effective, nor as safe, as sequential monotherapy[134] and thus safety issues remain a major concern in the top-down approach. The combination of immunomodulator and biologics reduces antibody formation, infusion reaction and loss of response.[135] However, it is used at the expense of increased risk of TB, opportunistic infections and malignancy. The risks of lymphoma and hepatosplenic T-cell lymphoma have been found to be associated with long-term immunomodulator use.[62,136] More importantly, even if we concede that some form of 'top-down' therapy is better for sicker patients with a more ominous prognosis, a great proportion of patients with mild disease would be overtreated. These are some of the considerations that must be factored into our decision-making, and the benefits of aggressive medical therapy may not outweigh the risks. On the contrary, clinicians may be inclined to delay aggressive treatment owing to the concern that potential rare, but serious adverse effects despite the fact that a meta-analysis of 21 placebo controlled trials that enrolled a total of 5356 individuals has shown that anti-TNF therapy was not found to be associated with an increased risk of death (0.21 vs 0.05%; 95% CI: 0.21–0.29), malignancy (0.24 vs 0.39%; 95% CI: −0.45–0.18) or serious infection (2.09 vs 2.13%; 95% CI: 0.45–0.65) when compared with placebo controls[100] and that at the end of D'Haens' study, 76% of patients in the conventional treatment group were receiving an antimetabolite.[126] Delaying treatment could lead to increased and prolonged mucosal damage. The cost for initiating treatment may be higher in patients receiving early combination therapy compared with the sequential step-up therapy, but when taking into account the difficulty of measuring indirect costs, such as cost of lost productivity, quality of life, hospitalization and surgery rate, it may be more costly in the long term.

Although there is encouraging evidence showing benefit from early aggressive treatment in patients with 'early' rheumatoid arthritis, in our CD patient population, 'early' disease is not as clearly defined as in rheumatoid arthritis. We need a more appropriate definition to guide us on the initiation of therapy. When D'Haens et al. designed their trial, infliximab was recommended for use as an episodic agent.[126] With recent studies showing that scheduled dosing is better than episodic therapy, it may underestimate the potential benefits of early combination therapy.[122,137] The final critique on the D'Haens' study was the fact that it was not blinded, which may be necessary for medication dosage adjustment, but may also have influenced the reports of disease status. It appears that the ideal treatment strategy for CD remains uncertain. A longer duration of follow-up is required before it will be possible to evaluate whether infliximab is a disease-modifying anti-CD drug. However, the key may not be the agent, but when the agent is introduced.

Whom & When to Treat?

If the effectiveness of a top-down approach is established, the real challenge lies in the development of an improved classification system that would allow for the identification of particular subgroups with differing disease phenotypes and different prognoses in order to maximize the treatment benefit–risk profile. There are no simple answers. It is likely that only certain subgroups of patients with CD would benefit from early aggressive therapy. In a recent population-based study from Norway, the cumulative relapse rate during the first 10 years was 90%.[138] However, the cumulative probability of surgery was 37.9% and a large proportion of patients (44%) were in clinical remission during the last 5 years of follow-up,[138] indicating that the indiscriminate use of infliximab as a first-line therapy would represent an overtreatment in the majority of CD patients.

In patients of 40 years of age, the presence of perianal disease at diagnosis and an initial requirement for corticosteroids were identified as factors predictive of a subsequent 5-year disabling course of CD.[8] Such criteria may be considered in future clinical trials that evaluate therapeutics and have the potential to alter the natural course of CD. Despite promising results suggesting that serologic and pharmacogenetic markers, such as ASCA and NOD2 variants, which may aid in the determination of the clinical course and severity of CD, they are not yet recommended for use in clinical practice to predict the course of disease.[139] A second retrospective cohort study of 83 patients who underwent surgery within the first 3 years of CD diagnosis, found, by univariate analysis, that oral corticosteroid use within the first 6 months of diagnosis was associated with almost fourfold increased risk of surgery (unadjusted OR: 3.79; 95% CI: 1.90–7.55),[140] along with smoking, nausea and vomiting, abdominal pain and isolated ileal involvement.[140] However, multivariate regression analysis determined that only smoking was associated with increased risk of early surgery (OR: 3.42; 95% CI: 1.54–6.35).[140]

 

[David in Seattle]

In addition to the identified clinical factors associated with a disabling course, one could argue that top-down therapy should be considered in patients with a large burden of disease (extensive small bowel disease, small bowel and colon disease, additional rectal involvement), foregut CD and patients with multiple previous surgeries or large resections who cannot be adequately maintained with the traditional postoperative therapies. Certain genetic and serologic profiles may also be included in the consideration for a more aggressive therapy.[202]

There is a growing body of evidence to suggest the effectiveness of the top-down therapy (Figure 1); however, our ability to risk stratify patients remains rudimentary. There is an urgent need to improve our ability to assess prognosis at the time of diagnosis, to personalize treatment and target the patients who are at greatest risk for complicated disease with earlier, more potent anti-inflammatory therapy before the standard step-up approach is altered.

Expert Commentary: The Current & Future Therapeutic Paradigms in CD

Under the current therapeutic paradigm, low-risk disease progression is defined as patients with mild presentation, inflammatory disease, absence of perianal disease or extraintestinal manifestations and nonsmokers. Treatment is selected according to the disease location. In colonic CD, treatment is initiated with a 5-ASA agent with or without antibiotics. If the patient responds, 5-ASA agents should be continued with follow-up visits. If the patient does not respond, or if the patient has small intestine involvement, then budesonide or prednisone is the next step-up in treatment. If the patient responds to budesonide or prednisone, it is crucial that the dose is tapered with follow-up visits. If the patient does not respond, then immunomodulators (AZA, 6-MP or methotrexate) should be used. Patients should also be evaluated for the need of surgery. If a patient relapses or remains nonrespondant, then anti-TNF-α should be used. Intermittent-to-high risk progression is defined as patients with a young age at onset (≤18 years), noninflammatory disease behavior, extensive diseases involving small and large bowels, early steroid use, extraintestinal manifestations and those who are active smokers. These patients are initially treated with budesonide or prednisone with immunomodulators (AZA, 6-MP or methotrexate). If a patient shows a response, corticosteroids should be tapered and stopped while continuing on the immunosuppressants. If there is no response, then the patient should be started with an anti-TNF-α agent. If the patient responds to an anti-TNF-α agent, maintenance therapy should be continued. If there is no response, they should be switched to another anti-TNF-α agent (although the data for primary nonresponders are very limited) or natalizumab and surgery may be considered.

The current treatment pyramid uses a step-up approach with conservative use of immunomodulators and biological agents aiming to induce remission, maintain remission, prevent complications, optimize surgical outcomes and improve quality of life. In the future, we hope to invert the treatment pyramid with a top-down approach and earlier use of immunomodulators and biological agents, with additional goals of disease modification, mucosal healing, reduced pharmacoeconomics, disease prevention and improved quality-of-life in selected target populations of those patients who are most at risk for poor outcomes in the absence of aggressive therapy.

Five-year View

Current management recommendations for patients with CD are evolving. The focus of treatment will switch from maintaining clinical remission to complete mucosal healing, with halting the progression of the disease as the end point. Research is ongoing in the search for evidence for the benefit of early combination therapy. Reversal of the pyramids (the top-down approach) may be the future treatment direction and it will need to be guided by better definite timing and candidates, which may include an individual's genetic and serologic profiles.

 

[David in Seattle]

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[David in Seattle]

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• A meta-analysis of placebo controlled trials providing evidence-based summary of efficacy and safety of infliximab use in CD.

 

[David in Seattle]

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•• Recent randomized trial providing evidence that early introduction of combined immunosupression (azathioprine and infliximab) is more efficacious than conventional therapy ('step up' approach) in patients with CD.
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Websites
201. TOUCH Prescribing Program www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationfor PatientsandProviders/ucm199872.htm Accessed 17 March 2010


Papers of special note have been highlighted as:
• of interest
•• of considerable interest

 

[Zalanicht]

I did step up therapy and 2 months later i was in emerg getting a surgery.
I bet if i did the top down therapy starting with Remicade I'd have gone through ALOT less.

 

[peggy26]

Lots of good info. I wouldn't mind some Clarithromycin therapy. I think there are somme good connections being made about Crohn's being caused by bacteria, but I'm thinking folks may certainly have a predisposition to autoimmune diseases too.

I just started back on pasteurized milk and am finishing( I hope) a crummy flare.
I'm also starting raw milk and coconut oil.

Raw milk because it's a good whole food and coconut oil because it many have anti inflammatory properties.

 

[DustyKat]

Bump

 

[susie]

David, you´re SO great. Finding the good science among tons of vague crap, building up this amazing resource. Participatory medicine indeed!
Hats off to you.
And this .
Love,
susie