Infliximab Compared to Adalimumab -Which is Better?

Posted on June 5, 2014 by gutsandgrowth

Pharmaceutical companies are not motivated to provide a definitive answer on the title question. A recent study (Clin Gastroenterol Hepatol 2014; 12: 811-17) states that “head-to-head clinical trials of anti-TNF therapies are unlikely to ever be undertaken because of the extreme cost to conduct such studies and the financial risk that such trials would entail for the manufacturers.” The two most popular biologics, infliximab (IFX) and adalimumab (ADA), for inflammatory bowel disease have been incredibly successful (Multi-billion dollar biologics | gutsandgrowth).

The current study is “one of the first to directly compare the effectiveness” of IFX and ADA for Crohn’s disease. The authors retrospectively examined a U.S. Medicare data cohort from 2006-2010 and identified new users with 1459 IFX and 871 ADA patients. While 94% of Medicare enrollees are >65 years, this study had a range of patient ages due to those who received Medicare due to disability. In fact, in the ADA group, ~60% were between 30-60 years and in the IFX group, ~44% were in this age group.

Key result:

After 26 weeks of treatment, 49% of patients receiving IFX remained on drug compared with 47% of those receiving ADA.
Fewer patients with IFX underwent surgery (5.5 vs 6.9 surgeries per 100 person-years) but this did not reach statistical significance.
Rates of hospitalization did not differ among the two groups

While persistence is an imperfect measure of effectiveness, the fact that surgeries and hospitalizations were similar indicates that the medications are likely to have similar clinical effectiveness, at least in this population. Data on mucosal healing, more direct measures of effectiveness, and longer followup certainly would strengthen this conclusion.

My First Take: It is Hard to Save $$$ at a Rolls-Royce Dealership

Posted on June 4, 2014 by gutsandgrowth

A recent article looked at a crucial issue –trying to deliver “best care at lower cost” (Inflamm Bowel Dis 2014; 20: 946-51). “The goal of this report is to answer the primary question: What are implementable strategies and exploratory considerations for cost-efficient anti-TNF use while maintaining the highest quality of IBD care?”

The strategies that are discussed include the following:

Reduce costs of avoidable dose intensification of class switching by eliminating episodic anti-TNF use and improving patient education
Reduce over-utilization costs by accurately determining indication for escalating anti-TNF use
Reduce nondrug infliximab costs through shortened infusion times after initial safety is clearly established

Exploratory considerations:

Self-injectable anti-TNFs
Combination therapy
Monitoring anti-TNF drug levels and autoantibodies
Assessing mucosal healing as a clinical endpoint

The authors discuss both the exploratory issues and the strategies. Some of each could easily increase costs, at least in the short-term, rather than reduce them. The authors also make note of the development of an infliximab biosimilar (Inflecta) which could be approved in U.S. by 2015.

While the review article is a good read, in my opinion the authors fail to address in a meaningful way the larger context. The costs for hospital-based care are enormous; pediatric hospitals are like Rolls-Royce dealerships; and by the way, if you have to ask how much it costs, you probably cannot afford it. With regard to charges/costs, there is little transparency, high variability, and little accountability. Understanding health care costs and trying to get a good deal is much harder than buying a car.

For IBD care, as an example, the authors make note of the cost of infliximab at one pediatric tertiary care center. At this institution, “77% of the total health care cost for each infusion encounter” was for non-drug costs. Given how expensive the drug cost is, the expense for an infusion is very high, but probably similar to many other pediatric hospitals.

If one is interested in reducing the costs of infliximab and other infusions, the first practical step would be to consider infusion outside of a hospital-based setting, such as an infusion center. In such a setting, the patient safety would still be excellent but the costs would be less.

In Atlanta, there have been some high-profile hospital acquisitions that have increased health care costs (When doctors sell out, hospitals cash in | www.myajc.com). In many circumstances, when a hospital acquires a physician practice, infusion center, or endoscopy center, the charges and reimbursement increase despite no change in clinical care. In this way and many others, the current system promotes cost-inefficient care.

Related blog entries:

Marriage, Divorce and Separation with Anti-TNF Therapy

Posted on May 12, 2014 by gutsandgrowth

This review article (Inflamm Bowel Dis 2014; 20: 757-66) examines the question of whether and when anti-tumor necrosis factor (anti-TNF) agents can be stopped in Crohn’s disease (CD) patients in remission. This topic is particularly helpful since this comes up frequently in clinical practice.

As recently as a few years ago, one expert advised me that starting an anti-TNF agent (like infliximab or adalimumab) was like getting married. Once you committed, you stayed in that relationship indefinitely. Of course, it is well-known that individuals get divorced. In medical terms, I guess that would be the equivalent of developing antibodies to the anti-TNF agent or other adverse reactions. Switching from one anti-TNF to another would be equivalent to marital infidelity.

So what does this review article say about all of this? The article examines nine studies with a little more than 500 patients. “Current evidence suggests that a group of CD patients, possibly 30% to 40% in clinical remission while on IM (immunomodulators) and infliximab can stop the latter and maintain clinical remission for a relatively long interval. It seems that, if followed long enough, virtually all patients (including those on IM) will eventually develop clinical recurrence.”

If tempted to separate but not divorce anti-TNF therapy, the authors recommend, in addition to clinical remission, “normal colonoscopy (and/or normal surrogate markers of disease activity) should be adopted as a criterion when stopping therapy and during follow-up….As of today, many authors do not recommend to routinely stop anti-TNF agents in patients responding to this therapy and in the absence of other issues. Others propose to stop them after a minimum of 2 years of clinical and endoscopic remission or longer if only clinical remission can be documented…

If costs or other issues are present, we suggest to cautiously stop anti-TNF agents only in patients on combination therapy with profound (clinical, biochemical, and endoscopic) and long lasting (>1 year) remission and continuing the IM. Such patients should be closely followed by serial determinations of fecal calprotectin and inflammatory indices, and the medication immediately restarted in the presence of a flare. When in doubt, colonoscopy should be performed.”

Take-home message: Most patients are better off staying married to their anti-TNF therapy.

Also noted: Inflamm Bowel Dis 2014; 20: 742-56. Clinical Utility of Fecal Biomarkers for the Diagnosis and Management of Inflammatory Bowel Disease. This is a useful review with 103 references.

Superiority of Anti-TNF Therapy (Part 2)

Posted on May 10, 2014 by gutsandgrowth

A recent blog (Superiority of Anti-TNF Therapy in Children | gutsandgrowth) described a recent article showing that kids treated with anti-TNF therapy at the time of diagnosis had improved outcomes compared to children who were treated with other medications. In this day of multimedia, there is a video explaining the study which may be helpful for families and clinicians alike –here’s the link: Dr. Michael Stephens discusses the research findings: http://ow.ly/vW0Mk.

An excerpt from the explanation with the video:

The current research study looks at outcomes and compares three different types of treatments. The first group receives anti-TNF therapy. The second group received immune modulating therapy. The third group received no treatment within the first three months. This study was an observational study and the choice of treatment was at the discretion of the physician. In order to correct for this factor, a statistical technique was used. Patients with similar characteristics were paired within the three groups . The results showed that patients who received the anti-TNF therapy had an improved outcome, such as a higher remission rate and some indications of improved growth, at one year. All three groups had improvements in weight and body mass index but only the anti-TNF group had improvements in linear growth.

How Long Will Infliximab Work?

Posted on May 8, 2014 by gutsandgrowth

Given the limited therapeutic options, the question of infliximab (IFX) durability in pediatrics is quite important. One center has published its 10-year retrospective experience (Inflamm Bowel Dis 2014; 20: 606-13).

Inclusion criteria for the 188 patients included initiating IFX prior to age 21 years and patients who had a minimum of 1-year followup.

Demographics: Median age at diagnosis was 11 years for Crohn’s disease (CD) and 12 years for ulcerative colitis (UC). Indication for IFX due to steroid refractory disease was present in 42% of UC patients compared with 14% of CD patients. Monotherapy was more common in UC patients, 65%, compared to 35% of CD patients.

Methotrexate was administered in 69 (44%) of CD patients at time of IFX with the majority (n=56) as oral treatment (low-dose <10 mg every week). In addition, MTX was initiated after IFX induction in another 38 (24%). Only 36 (23%) remained on IFX mono therapy throughout the duration of treatment in CD patients.

Key findings:

88% of CD patients remained on IFX at 1 year, 80% at 2 years, and 72% at 5 years.
Only 7 of 157 CD patients were primary nonresponders.
65 of 89 CD patients who did not achieve a sustained durable remission underwent dose escalation. 40 of 65 responded to dose escalation.
Of those who lost response to IFX, the majority were transitioned to adalimumab (ADA) and among this group, 82% remained on ADA treatment at last followup.
Among UC patients (n=31), 9 were primary nonresponders. At last followup, 41% (9) remained in a durable sustained response at last followup.
While the authors used MTX due to favorable effects on IFX pharmacokinetics (Arthritis Rheum 1998; 41: 1552-63), there was “not a significant difference in IFX durability or efficacy between this group and patients with CD on IFX monotherapy”
Availability of antibodies to infliximab (ATIs) and IFX trough levels were only assessed in a subset. However, “we did see a significant difference in those that responded to dose intensification when ATIs were undetectable.”

Bottomline: The majority of CD patients can remain on IFX for >5 years. Among those who lose response, adalimumab was a durable alternative. A much lower durable response was evident with the subset of patients with UC.

Related blog post:

Digging into the COMMIT Study | gutsandgrowth

Also noted:

Inflamm Bowel Dis 2014; 20: 614-21. In this study of 78 youth with IBD, depressive symptoms warranting additional evaluation were present in 13% which was lower than in the community comparison group. Disease severity was noted to be inactive in 63% and mild in another 18%.

Inflamm Bowel Dis 2014; 20: 495-501. This study showed that 25 children exposed to anti-TNFs prenatally for maternal IBD seemed to show good safety. Immunologic investigation undertaken in 17 of the children was normal. No control group limited the ability to determine if increased infections were present.

And, here’s a link to Mar-April Circle Newsletter from ImproveCareNow -topics include group medical appointments, parent working group, dieting with IBD, and includes link to self management handbook.

Digging into the COMMIT Study

Posted on April 4, 2014 by gutsandgrowth

“Lies, damned lies, and statistics” –Mark Twain (who attributed this quote to Benjamin Disraeli)

Using statistics, the recent COMMIT study (Gastroenterol 2014; 146: 681-88) showed that the combination therapy of methotrexate (MTX) and infliximab (IFX) was not more effective than IFX alone. Does this result makes sense? No.

Before getting back to that question, here’s the background: this 50-week study was a randomized, double-blind, placebo-controlled trial with patients assigned to either methotrexate at dose escalated gradually to 25 mg/week (n=63) or placebo (n=62); both groups received a prednisone induction (with tapering starting at week 1) along with IFX (5 mg/kg) at weeks 1, 3, 7, 14, 22, 30, 38, and 46. Remission was considered to be a CD Activity Index (CDAI) of <150 in individuals off prednisone. The patients enrolled in this study were on average about 40 years of age and had similar baseline characteristics, including disease duration of more 9 years.

Amazing to me was the fact that nearly 40% of both the treatment and control group included current smokers (since smoking clearly worsens CD).

Key Results:

Combination therapy resulted in fewer antibodies to IFX (ATIs): 4% vs. 20% (P=.01)
Combination therapy resulted in higher IFX trough levels: 6.35 mcg/mL vs. 3.75 mcg/mL (P=.08); the proportion with detectable trough levels was also higher in the combination group: 52% compared with 46%.
Safety was similar. “No clinically relevant hepatotoxicity was identified.” However, 14 patients did experience an increase in liver enzymes. Infusion-related reactions were infrequent: 1 in combination group, and 3 in IFX monotherapy.
At week 14, 76% of combination group achieved prednisone-free remission and 78% of IFX monotherapy. At week 50, these numbers were 56% and 57% respectively.

Getting back to the question about why this does not add up as a negative study –the combination group had lower ATIs and better IFX drug levels, this usually translates into better response. As such, the limitations of this study deserve to be scrutinized:

Relatively small numbers of patients
Objective markers like colonoscopy were not included
Short duration of study period. While a 1 year study is not really all that short, some benefits of medications can take a longer time to appreciate
Prednisone induction may have obscured MTX benefit
Treatment group had long duration of disease. Those with shorter disease duration may have a more inflammatory component to their disease and respond more favorably.

Bottomline: this study showed that the combination of MTX/IFX was not statistically-superior to IFX alone. Given the favorable benefit on ATIs and IFX drug levels, MTX combination may still be useful, particularly in those with more recent onset of IBD.

Plus One More Reference:

Clin Gastroenterol Hepatol 2014; 12: 434-42. This retrospective study of 425 patients (1975-2012) examined features associated with failure of medical treatment. “Patients prescribed thiopurine or anti-TNF therapy when they have a complicated stage of CD are more likely to require surgery. Better patient outcomes are achieved by treating CD at early inflammation stages.”

Related blog entries:

CCFA Conference Notes 2014 (part 1)

Posted on March 27, 2014 by gutsandgrowth

Each year our local CCFA chapter holds a one day seminar with separate lectures for health care providers and families. Overall, it is a good opportunity to hear ‘cutting edge’ material. I did not pick up as much at this year’s seminar as in previous years, but will highlight what I thought was most important.

Key points:

Symptoms are not accurate at determining effectiveness of IBD therapy.
More frequent use of objective markers are needed to optimize treatment. Mucosal healing is starting to be a target in clinical practice, but limited by number of medications available.
Stricture classification and operative techniques were reviewed.
IBD frequently results in psychological problems: anxiety, depression, pain, sleep. 15% of kids and 25% of adults are having thoughts of death on screening tool intake.
Fecal microbiota transplantation (FMT) –not enough data to recommend for IBD. Clinical trials ongoing.

Debate: What should be the End Points in Therapy?

Tanvi Dhere (Emory): Goal: clinical symptoms
Cary Sauer (Emory Pediatrics): Goal: mucosal healing and normal bloodwork

In my opinion, this was the most thought-provoking and best presentation

Mucosal healing (MH) consensus definition –normal mucosa after previously abnormal with complete absence of ulceration, macroscopic and histologic signs of inflammation. In practice MH = absence of ulcerations.

Reasons why mucosal healing as a target is problematic:

Problems with MH –not validated. No long-term data utilizing endoscopic scoring indices of MH.
MH relies on a binomial endpoint –Yes or no, but there may be intermediate endpoints.
How likely is MH (different definitions in these studies)? SONIC –MH in 43.9% of combination Rx (30.1% in those with infliximab monotherapy); EXTEND (Adalimumab) 27% and 24.2% 12/52 weeks; MUSIC (certolizumab at 10/54 weeks) 11.5% and 18.9%.

In practice, Mayo Score 0-1 both considered to have MH.

Images above online at www.nature.com

In small study, MH at 1 year were not associated with improved outcomes at 5 years. Risks of MH: more procedures, more costs of treatment, and potential for more complications.

Dr. Sauer’s reply. Three simple questions –why should I try to target MH, is it possible, what is needed to get this done?

If the goal were only an asymptomatic patient – why do screening colonoscopy in the general population, much less in IBD?
In IBD, long-term evolution of IBD (Cosnes J et al. Inflamm Bowel Dis. 2002 Jul;8(4):244-50) is toward structuring and penetrating disease. CD Evolution This needs to be modified if possible.

Why MH? Improved symptoms, better quality of life, less likely to develop colon cancer, and it is an objective measure of treatment response.

In MH patients, less steroids and fewer flares over 2 year period.
MH healing patients have sustained clinical benefit over 96 months.
With MH, there is a decreased colectomy in UC. In one study, there was a lower colectomy rate at 8 years if colonic CD (62% vs 8%), decreased steroids in CD, decreased hospitalizations, & decreased fistulae.

Is MH possible in clinical practice? The accuracy of CDAI to detect endoscopic healing is low in patients with CD. (Bouguen G et al Clin Gastrohep 2014). More frequent adjustments in medical therapy –could lead to MH in up to 80% over 80 week study period. Same story in UC (Bouguen G et al IBD 2014).

What do I need to do to obtain MH? Endoscopy (or MRE), maximize medications (checking levels), change medications, and most important –set a target. “Adjusting infliximab dose alone could lead to MH in up to 60%.”

When to assess for MH? Consider endoscopy at 6 months into treatment if symptoms and at 12 months if in clinical remission.

Other viewpoints on MH from panel:

Dr. Loftus –“I think of this like oncology.” He agreed with using the best evaluating tool 6 months into treatment. Cross-sectional imaging is often more helpful, but may need more than one tool.

Dr. Long—“Are we going to check every 6 months?” No. She stated that she does not do this and tries to avoid repeated endoscopic procedures if this will not change treatment. Goal is to make sure patient is headed in right direction, often after starting therapy. Dr. Long stated that stool biomarkers most useful for colonic disease.

Dr. Dhere—documenting MH is important for deescalating treatment.

Millie Long “Quality of Care in IBD”

75% of Crohn disease patients will need surgery, 10% in 1^st year
“One way to gauge quality of care is to examine the degree of consistency in care”
High variability in care in IBD (Aliment Pham Ther 2007; 26: 1005-18)
“Over half of institutions with worst quality have mortality in normal range.” Outcomes may not occur until several years after treatment, thus more useful to measure process measures

PQRS IBD Quality Measures in Adults: 10 Measures

#1 Establishing/documenting IBD type, anatomic location, and activity
#2 Preventive care: corticosteroid sparing. Steroids associated with mortality (OR 2.1 in TREAT registry)
#3 Preventive care: Preventing bone loss. Limiting steroid use. Recommend weight-bearing exercise, Quit Smoking, Measure DEXA, added Calicum/Vit D/Bisphosphonates
#4: Vaccination –pneumococcal vaccine. Avoid live virus vaccines
#5 Vaccination –influenza vaccine, zoster vaccine
#6 Testing for latent TB prior to anti-TNF
#7 Testing for hepatitis B virus
#8 Testing for C diff with patients hospitalized with IBD
#9 VTE prophylaxis in adult IBD patients. Risk assessment on admission to hospital is recommended. IBD patients have 1.5-3.5-fold higher risk of VTE àwhich can increase mortality risk
#10 Screening for tobacco. Tobacco use after surgery increases recurrence by 2.5-fold. It also increases risk for reoperation.

Last year’s notes:

Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician. This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.

UC SUCCESS

Posted on February 27, 2014 by gutsandgrowth

The results of the “UC SUCCESS” trial show that combination therapy with infliximab and azathioprine is more effective than either medication as monotherapy in ulcerative colitis (UC) (Gastroenterol 2014; 146: 392-400). This study findings are similar to the SONIC trial in Crohn’s disease (CD).

Study Design: randomized, double-blind trial with evaluation at 16 weeks with a total of 239 patients. In patients assigned to infliximab (IFX) alone, they were given daily oral placebo pills. In patients with azathioprine monotherapy (AZA), dosed at 2.5 mg/kg/day, they also received placebo infusions. Patients had moderate to severe UC as defined by Mayo scores at baseline and had not responded adequately to a course of corticosteroids. All patients were naive to tumor necrosis factor α antagonists (anti-TNFα). Mean age was approximately 40 years.

Results:

IFX/AZA had a 39.7% corticosteroid-free remission at week 16 compared with 22.1% with IFX monotherapy and 23.8% with AZA monotherapy.
Mucosal healing at week 16 was evident in 62.8% of combination group compared with 54.6% IFX monotherapy and 36.8% with AZA monotherapy.
Serious adverse events were noted more frequently in the AZA monotherapy group, though this did not reach statistical significance.
A subset of patients had antibodies to infliximab (ATIs) measured. ATI-positivity was more common with IFX monotherapy (19%, 7 of 37) than for IFX/AZA combination (3%, 1 of 31)

While this study indicates that for moderate to severe UC combination therapy with IFX/AZA was superior in this age group, there were several limitations. Given the slow onset of action of azathioprine, more patients may have responded to this therapy if longer treatment duration was studied.

Take-home message: Combination therapy for UC, like CD, is more effective. In this small study population, the adverse events were not increased. In the pediatric population, particularly males, the concern for malignancy in patients (especially males) treated with combination therapy may limit the frequency of combination therapy.

Related blog posts:

Superiority of Anti-TNF Therapy in Children

Posted on February 6, 2014 by gutsandgrowth

This study’s conclusion comes as no surprise:

“In children newly diagnosed with comparably severe CD, early monotherapy with anti-TNFα produced better overall clinical and growth outcomes at 1 year than early monotherapy with an immunomodulator. Further data will be required to best identify children most likely to benefit from early treatment with anti-TNFα therapy.”

Here’s the reference:

Gastroenterology Volume 146, Issue 2 , Pages 383-391, February 2014

Here’s a link to the full text article: Increased Effectiveness of Early Therapy with Anti-Tumor Necrosis Factor-α Versus an Immunomodulator in Children with Crohn’s Disease

Methods: “From 2008 through 2012 at 28 pediatric gastroenterology centers in North America. Patients were managed by physician dictate. From 552 children (median age, 11.8 y; 61% male; 63% with pediatric CD activity index scores >30; and median C-reactive protein level 5.6-fold the upper limit of normal), we used propensity score methodology to identify 68 triads of patients matched for baseline characteristics who were treated with early anti-TNFα therapy, early immunomodulator, or no early immunotherapy.”

Another reference/link from same issue:

Accuracy of Magnetic Resonance Enterography in Assessing Response to Therapy and Mucosal Healing in Patients with Crohn’s Disease

What you might not know about anti-TNF monitoring…

Posted on January 11, 2014 by gutsandgrowth

At a recent group dinner meeting, we had the opportunity to review therapeutic anti-TNF monitoring. In addition, we discussed emerging treatments for inflammatory bowel disease, like golimumab, tofacintinib and vedolizumab.

As noted in previous blog entries (see below), therapeutic anti-TNF monitoring can help adjust treatment. Namely, if a patient loses response to therapy and has low trough levels of anti-TNF (Infliximab ❤ μg/mL, Adalimumab <8 μg/mL, or certolizumab <27.5 μg/mL) without antidrug antibodies (ADAs), then increasing the dose is likely to be effective. However, if a patient has a therapeutic level and is not responding, changing to another agent and/or further investigation is worthwhile.

So, what information is new?

Only about 20% of patients who lose clinical response develop ADAs. So, drug level, rather than ADAs, is most helpful.
For infliximab, adjusting dose 14 weeks into therapy to achieve a target trough level between 3-7 mcg/mL may be helpful.
Severe colitis patients may need higher initial doses (?as high as 20 mg/kg) due to potential for ‘antigen sink.’ This is due to notably higher clearance in the presence of low albumin, and high CRP. Other factors that increase clearance include higher BMI and male gender.
About 1/2 of patients who receive higher doses due to severe disease may be able to deescalate dosage when improved. (?which half)
Currently, a reactive approach to checking levels is common in U.S. in part due to costs associated with checking trough levels and ADAs (as much as $2500). That is, most commonly checking levels is undertaken in patients with suboptimal clinical response. A proactive approach to achieve target levels may be shown to be helpful.
While studies have not shown higher adverse reactions with higher trough levels, there are a few clinical situations in which lower trough levels can be important. In patients with psoriatic skin lesions and arthralgias, if trough levels are elevated, lowering the dose may be helpful.

Outstanding questions?

Should patients have drug levels checked when they are asymptomatic?
How does a practitioner account for variability among different laboratory assays?
What is the optimal target level for each anti-TNF agent? Is this different in Crohn disease compared with ulcerative colitis? Is the trough target level different in adults than children?
Is there a toxic level?
If a rapid test response were available, would checking drug levels be needed for hospitalized patients to assess anti-TNF rescue therapy?

Related blog links:

gutsandgrowth

Pediatric Gastroenterology

Tag Archives: infliximab