Tag Archives: adalimumab

Surgical Reset for Anti-TNF Therapy with Crohn’s Disease

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A recent study (A Assa et al. Inflamm Bowel Dis 2017; 23: 791-97) indicates that after surgery, anti-TNFα treatment is worth another try.

In this retrospective study with 53 children, 18 had “pharmacodynamic failure” with anti-TNFα medications (PK group) and 35 were controls. “Phamacocynamic failure is characterized by either a lack of improvement of CD symptoms or  loss of response after initial improvement in the setting of adequate serum drug levels without ADAs” [antidrug antibodies].

Key findings:

  • Mean age at time of intestinal resection was 14.8 years
  • Median time from resection to anti-TNF initiation was 8 months
  • Compared to the control group, the PK group had similar response to anti-TNF therapy.   “Similar proportions of patients from both groups were in clinical remission on anti-TNF treatment after 12 months and at the end of follow-up (1.8 years)”
  • At 12 months, remission rates were 89% (PK) versus 88.5% (control)

The authors propose an explanation: “A plausible explanation for this finding is that in severely inflamed tissue with high inflammatory burden, local high levels of TNFα serves as a sink for anti-TNFα antibodies and that tissue injury and local hypoxia might further limit drug penetrance to its target.”

My take: This information is useful.  Many patients who have surgery may respond to anti-TNFα therapy subsequently.  The unanswered question: Could more frequent dosing of anti-TNFα therapy have averted surgery in some patients by overcoming areas of intense disease?

 

Safety of Long-term Adalimumab in Pediatrics; Weighted PCDAI

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A recent study (W Faubion et al. Inflamm Bowel Dis 2017; 23: 453-60) reports on the long-term safety/effectiveness of Adalimumab in pediatric patients entering the IMAgINE 2 trial (& who completed the 52 week IMAgINE 1 trial).

Patients with a PCDAI <10 were considered to be in remission and those who had a drop in PCDAI of 15 or more were considered to have had a treatment response.

Key findings:

  • Of the 100 patients enrolled in IMAgINE 2, 41% achieved remission and 48% had a treatment response at week 240.
  • >80% of patients were “able to discontinue use of corticosteroids.”
  • Adalimumab treatment was associated with growth normalization.
  • No new safety signals were identified.

While this study provides some reassurance regarding long-term adalimumab use, it should be noted that the instruments used to assess efficacy in this trial (& many others) are suboptimal.

A recent study (D Turner et al. JPGN 2017; 64: 254-60) showed that PCDAI (and several similar versions) had “poor correlation with calprotectin” and none of the PCDAI versions “can give a valid assessment of mucosal healing.”  This study had used prospectively collected data from the ImageKids study of 100 children with Crohn’s disease.  For the weighted PCDAI, the “best cut-off to identify endoscopic mucosal healing was <12.5 points” with a sensitivity of 58% and specificity of 84%.\

wPCDAI:

History: (recall 1 week):

  • Abdominal Pain  0=None, 10=Mild (does not interfere with activities, brief), 20=Moderate/Severe
  • Patient functioning 0=No limitations, 10=Occn difficulty with activities (below par), 20=frequent limitations
  • Stools per day 0=0-1 liquid stools, no blood, 7.5=up to 2 semiformed stools with blood or 2-5 liquid nonblood, 15=Gross bleeding or ≥6 liquid stools or nocturnal diarrhea

Laboratory

  • ESR 0 points if <20, 7.5 points if 20-50, 15 points if >50
  • Albumin 0 points if ≥3.5 g/dL, 10 points if 3.1-3.4 g/dL, and 20 points if ≤3.0 g/dL

Examination

  • Weight 0= Weight gain or stable or voluntary weight loss, 5=involuntary weight loss 1-9% or involuntary weight stable, 10= weight loss ≥10%
  • Perirectal Disease 0=None or asymptomatic tags, 7.5= 1-2 indolent fistula, scant drainage, no tenderness, 15=active fistula, drainage, tenderness or abscess

Extraintestinal Manifestatons: Fever for 3 days (≥38.5), definite arthritis, uveitis, erythema nodosum, or pyoderma gangrenosum

  • Points: 0=None, 10 ≥1

Total Score 0-125: ______________________

As compared with PCDAI, the weighted PCDAI drops height velocity, abdominal examination, and hematocrit.  Turner et al note “their exclusion does not mean that they have no role in reflecting disease activity, but that the other included items, as a whole, are inclusive of the contribution of the 3 items.” Also, the weighted PCDAI simplifies the “extraintestinal manifestation” into a simple choice; overall, this affects few scores due to the low frequency of these manifestations.

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FDA approves Amjevita (Humira biosimilar)

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On 9/23/16: FDA approved Amjevita (Humira biosimilar)

Excerpt:

The U.S. Food and Drug Administration today approved Amjevita (adalimumab-atto) as a biosimilar to Humira (adalimumab) for multiple inflammatory diseases.

Amjevita is approved for the following indications in adult patients:

  • moderately to severely active rheumatoid arthritis;
  • active psoriatic arthritis;
  • active ankylosing spondylitis (an arthritis that affects the spine);
  • moderately to severely active Crohn’s disease;
  • moderately to severely active ulcerative colitis; and
  • moderate to severe plaque psoriasis.

…Amjevita is biosimilar to Humira. It has been approved as a biosimilar, not as an interchangeable product.

Fort Knox, Maine

Fort Knox, Maine

Safer Than You Think: Biologic Therapies for IBD and Risk of Infection and Malignancy

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While there have been a number of studies which have highlighted the potential risks of biologic agents, many studies have NOT identified any risk of infection or malignancy.

Another recent systematic review/meta-analysis (S Bonovas et al. Clin Gastroenterol Hepatol 2016; 14: 1385-97) provides reassuring data regarding the following biologics: infliximab, adalimumab, certolizumab, golimumab, natalizumab, and vedolizumab.

The authors identified 49 randomized placebo-controlled studies with 14,590 participants.

Key findings:

  • There was a moderate infection risk with odds ratio of 1.19 (19% increase in odds of developing an infection) and significant increase in opportunistic infections (eg. tuberculosis) OR 1.90
  • Risk of serious infections was NOT increased in patients treated with biologics with OR 0.89.  In studies with low risk of bias, the risk of serious infections had OR of 0.56.
  • No increase in malignancy risk was identified with OR 0.90 but the authors note that data was insufficient in terms of exposure and follow-up to be conclusive.

The authors note that the studies including in this review challenge some of the findings of observational studies. “However, observational studies lack the experimental random allocation of participants…the discrepancies between observational studies and randomized trial evidence might be explained by the inability of observational designs to fully address the complex and important differences between the IBD patients receiving and those not receiving biologics.”

Study limitations include “sponsorship bias -because the trials were supported by pharmaceutical companies and limited followup of 24 months. In addition, most of the trials in the meta-analysis were judged to be at high or unclear risk of bias because of their methodological characteristics.

My take: This study indicates that biologic therapies do not appear to increase the risk of serious infections and may not increase the overall risk of malignancy.

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Portland Fish Market

Portland Fish Market

 

 

Changes in the Use of IBD Biologic Therapy

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A recent study (W-J Lee et al. Inflamm Bowel Dis 2016; 22: 2410-17) offers a great deal of insight into changes in the use anti-Tumor Necrosis Factor Alpha (ant-TNF) therapy from 2009-2013 in patients ≤24 years.  The authors utilized databases with about 180 million people and identified 11,962 patients with inflammatory bowel disease (IBD).

Key findings:

  • 3300 of the 11,962 (27.6%) patients were treated with anti-TNF therapy.
  • Top-down treatment: 1298 of 3300 (39.3%) were treated with top-down therapy which was defined as usage of anti-TNF therapy within 30 days of first IBD medication prescription.  Interestingly, over the course of the study, there was a trend towards more top-down (versus step-up) therapy and shorter time to initiation of anti-TNF therapy. In 2009, 31.4% used a top-down approach compared with 49.8% in 2013.
  • Top-down therapy is associated with lower rates of corticosteroid use.
  • Infliximab dominant anti-TNF: infliximab was the anti-TNF in 89.2% of patients less than 12, 82.3% of patients 12-17, and 55.1% of patients 18-24.  Adalimumab accounted for the vast majority of the other TNF users. Though, the authors note a trend towards increasing use of adalimumab in both adult and pediatric patients in a separate study (Park KT et al. Inflamm Bowel Dis 2014; 20: 1242-49)
  • Cotherapy: thiopurines and methotrexate were used as cotherapy in 13.5% and 7.2% of top-down group compared with 54.8% and 14.6% respectively in step-up strategy.
  • Drug therapy among non-TNF users: 25.4% (2199) received a thiopurine, 79.3% (6871) received a 5-aminosalicylate, and 2.3% (201) received methotrexate.
  • Anti-TNF therapy discontinuation: Using top-down strategy 69.2% persisted on infliximab at 12 months and 56.8% persisted at 24 months.  In comparison, using step-up approach with infliximab, it was 72.7% at 12 months and 64.0% at 24 months.  The numbers were quite similar with all the anti-TNF agents indicating that step-up approach had significantly lower rate of anti-TNF discontinuation. The authors speculate that one factor could be use of cotherapy or possibly other adverse reactions.

The authors explain some of the limitations of their study in its reliance on databases, particularly with regard to misclassification.  However, in my opinion, these limitations do not affect any of the trends that the authors are able to document.

My take: For most of my patients, I have preferred to continue to utilize cotherapy  and/or step-up therapy because I think there is likely to be a more durable anti-TNF response.  The fairly small differences in anti-TNF durability have huge implications for those  who lose anti-TNF responsiveness given the limited treatment options.

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Hidden Lake and Bear Mountain, Glacier National Park

Hidden Lake and Bear Mountain, Glacier National Park

 

Biologic Exposure Prenatally and Perinatally

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The widespread use of anti-TNF therapy for inflammatory bowel disease has improved clinical outcomes including fewer surgeries, hospitalizations, and complications.  One consequence of this usage has been the exposure of infants to biologics due to their usage by their mothers during pregnancy.  A recent study (M Julsgaard et al. Gastroenterol 2016; 151: 110-19) explores this topic further.

In this study, the authors prospectively followed 80 pregnant women: 36 received adalimumab & 44 infliximab. In addition, 39 received concomitant thiopurine therapy.

Key findings:

  • The time from last exposure to anti-TNF agent correlated inversely with the concentration of these drugs in the umbilical cord and in mothers at the time of birth.
  • Median ratio for infant: mother drug concentration at birth was 1.21 for adalimumab and 1.97 for infliximab.
  • Mean time for drug clearance: 4.0 months for adalimumab and 7.3 months for infliximab. Drugs were not detected after 9 months of life for adalimumab and after 12 months of life for infliximab.
  • No increased risk of adverse pregnancy outcomes were identified; preterm birth was low (n=3 or 3.8%). 48% of women experienced a disease relapse during pregnancy.
  • In this small study, the relative risk for infection was 2.7 in infants exposed to combination therapy.  Benign courses of viral infections were noted in 16 (20%) of the entire cohort and of bacterial infections in 4 (5%).

The authors recommend avoidance of live virus vaccines in biologically-exposed infants for up to 1 year unless drug clearance has been documented. Currently, this would affect only rotavirus vaccination.

My take (borrowed from editorial pgs 25-26): “For now, the sum of evidence seems to support continued use of anti-TNF therapy in pregnancy when clinically indicated and, despite measureable levels in offspring, there does not seem to be a significant clinical consequence.”

Related study: “Adverse Pregnancy Outcomes among women with inflammatory bowel disease: a population-basd study from England” Inflamm Bowel Dis 2016; 22: 1621-30. The authors identified 1969 pregnancies from a total of 364,363 singleton pregnancies.  Women with Crohn’s had increased preterm births with an Odd ratio of 1.42, babies with low birth weight (OR 1.39); women with ulcerative colitis had only a small increase risk in preterm birth (absolute risk <2.7%).

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Art at Big Creek Greenway, Alpharetta

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Gold Medal Winner: Infliximab (anti-TNF competition)

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According to a recent retrospective study, (S Singh et al. Clin Gastroenterol Hepatol 2016; 14: 1120-29), infliximab outperformed its rivals.  In the spirit of the recent olympics, we’ll give infliximab a gold medal in the anti-TNF category.

Here’s the play-by-play:

This study used an administrative claims database with more than 100 million US enrollees.  In total, there were 3205 biologic-naive patients with Crohn’s disease (CD) with a mean age of 41 years.  All of the participants had not received a biologic agent for at least 12 months prior to their first study dose (between 2006-2014). In addition, the authors excluded patients who had a concomitant diagnosis which could necessitate a biologic, including rheumatoid arthritis, ankylosing spondylitis, and psoriasis.

Race details:

  • Compared to adalimumab-treated patients, inlfiximab-treated patients had a lower risk of CD-related hospitalization (aHR [adjusted Hazard Ratio] 0.80), abdominal surgery (aHR 0.76), and corticosteroid use (aHR 0.85)
  • Compared to certolizumab pegol-treated patients, infliximab-treated patients had a lower risk of hospitalization (all-cause) (aHR 0.70), and CD-related hospitalization (aHR 0.59).
  • All agents had comparable risk of serious infections

Post-race analysis:

Was this a fair race (ie study)? Definitely.  If anything, this study may have underestimated the benefit of infliximab.  Due to trouble with confounders across retrospective studies, it may be that infliximab was chosen preferentially among sicker patients.

My take: There is limited data on comparative effectiveness of anti-TNF agents.  This retrospective study  indicates that infliximab is likely superior to its competitors.  Definitive proof would necessitate a head-to-head live-action (prospective) competition.

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Screen Shot 2016-08-14 at 11.46.48 AM

‘Don’t Believe Our Study’

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The message I inferred from a recent study (CA Siegel et al. Clin Gastroenterol Hepatol 2015; 13: 2233-40) was to disregard their results which generally showed a lack of benefit of combination therapy (aka “concomitant immunomodulator” or dual therapy) compared with anti-tumor necrosis factor (anti-TNF) monotherapy for Crohn’s disease.

Specifically, the authors state the following in their discussion:

Although our results challenge the clinical importance of combination therapy in this specific scenario, it is hard to ignore the preponderance of data to date relating to the pharmacokinetics of anti-TNF medications that support the approach of combination therapy over monotherapy.

Here’s the background for this study.  The authors performed a meta-analysis of placebo-controlled trials (n=1601 subjects) to examine the question of whether continued use of immunomodulators (IMs) would be of benefit in patients who had failed monotherapy with IMs (“IM-experienced”).  The authors note that the SONIC study showed that combination therapy (infliximab and azathioprine) was more beneficial in patients who were IM-naive than monotherapy.  This meta-analysis included data from 3 anti-TNF agents: infliximab, adalimumab, and certolizumab.

Key findings:

  • Combination therapy was no more effective than monotherapy in inducing 6-month remission (odds ratio 1.02) or in maintaining a response (OR 1.53).
  • In subgroup analysis, there was a statistically-significant protective effect of baseline IM exposure versus no baseline IM exposure among those treated with infliximab.
  • Generally, combination therapy was not associated with any change in adverse reactions; however, combination therapy with infliximab had lower adverse events, which was driven by infusion reactions.

My take: This study indicates that combination therapy is likely helpful in IM-experienced patients who are starting infliximab and possibly not effective with the other anti-TNF agents.  The authors emphasize the need for well-designed, prospective, randomized, placebo-controlled trial for a definitive answer.  Until then, don’t believe their study.

Of interest: Recently I became aware of a college scholarship opportunity for young adults with IBD: Abbvie Scholarship Program.

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Clever Marketing or Truth in Advertising?

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Yosemite National Park

Yosemite National Park

Anti-TNF Therapy: Rapid Reduction in Pain in Crohn’s Disease

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A pretty cool use of technology provides strong evidence that decreased pain perception in the brain of patient’s with Crohn’s disease (CD) occurs well before anti-inflammatory effects like mucosal healing (A Hess et al. Gastroenterol 2015; 149: 864-66). In this study, the authors prospectively identified 4 patients with CD and performed functional MRI on day -1, day 1, and day 27. Key findings:

  • In three patients, who responded with a decrease in Harvey-Bradshaw Index by ≥2 points 14 weeks after anti-TNF initiation, the pain signal induced by either finger tapping or compression (see cover below) was markedly improved 1 day after anti-TNF initiation.
  • In the CD non responder, there was only slight reduction in signals at 24 hours and no improvement from baseline at day 27.

My take: This study explains why so many patients with severe symptoms can be managed quickly as outpatients.  The effects of anti-TNF therapy on pain occur within 24 hrs!  Pretty cool. Screen Shot 2015-10-11 at 5.56.36 PM

Another Look at “Step-up” IBD Therapy

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Whether and how long to continue immunomodulators in patients who have undergone a “step-up” treatment to anti-tumor necrosis factor (anti-TNF) therapy remains murky.  This is due to conflicting data from different patient cohorts, changing treatment trends, (e.g. use of drug monitoring to enhance anti-TNF therapy), and different endpoints. With regard to the latter, dual therapy has been clearly more effective in some landmark studies (eg. SONIC, UC SUCCESS); however, there have been ongoing concerns regarding long-term outcomes and adverse effects.

Will more studies help resolve this question? Perhaps, but not today.

A recent study (MT Osterman et al. Clin Gastroenterol Hepatol 2015; 13: 1293-1301) examined a retrospective cohort of new users of anti-TNF therapy for Crohn’s disease in Medicare recipients.  The authors matched 381 combination with infliximab (ie. dual therapy) with 912 users of monotherapy. In addition, the authors did the same with adalimumab with 196 combination users and 505 monotherapy users. In their cohort, combination therapy occurred primarily as a “step-up” treatment after institution of thiopurine therapy.

Results:

  • Key outcome measures were unchanged: rates of surgery (hazard ratio [HR] 1.2, hospitalization HR 0.82, discontinuation of anti-TNF therapy or surgery HR 1.09, and serious infection HR 0.93
  • Opportunistic infections were increased in combination therapy with HR 2.64 and herpes zoster infection was increased with HR 3.16

Take-home message: This study suggests, at least in this elderly population, that once remission is achieved with anti-TNF therapy, discontinuation of thiopurine therapy or use of an alternative immunomodulator therapy may be worthwhile.  At the same time, definitive answers to these type of questions await carefully designed randomized trials.

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