Another Look at “Step-up” IBD Therapy

Posted on September 9, 2015 by gutsandgrowth

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.

Related blog posts:

What HBV Testing is Needed Before Tumor Necrosis Factor Inhibitor Therapy

Posted on July 29, 2015 by gutsandgrowth

As noted in a previous blog post (What’s Going on with Hepatitis A and Hepatitis B?):

Hepatitis B Reactivation risk & recommendation: (For all of the specifics — Full text article link)

High risk of reactivation (>10%): B cell depleting agents (eg. rituximab, ofatumumab), anthracycline derivatives (eg. doxorubicin, epirubicin), and daily moderate to high dose steroids (>10 mg) for at least 4 weeks. Recommendation: Use HBV prophylaxis
Moderate risk of reactivation (1-10%): anti-TNF therapy, integrin inhibitors (eg. ustekinimab, vedolizumab), tyrosine kinase inhibitors, low-dose steroids daily (<10 mg/day) for at least 4 weeks. Recommendation: Use HBV prophylaxis if HBsAg-positive but not if only anti-HBc-positive
Low risk of reactivation (<1%): azathiopurine, 6-mercaptopurine, methotrexate. Recommendation: No antiviral prophylaxis required.

For those interested in a more detailed summary of the recommendations: AGA Website HBV Reactivation Recommendations

In line with the reactivation risk, a new study (and editorial) (M Barone et al. Hepatology 2015; 62: 40-6; editorial BP Perillo. Hepatology 2105; 62: 16-8) indicates that for those receiving tumor necrosis inhibitor (anti-TNF) monotherapy, hepatitis B screening requires only checking HBsAg. The study examined a total of 1218 Caucasian rheumatologic patients (receiving biologic agents) between 2001-12. In this cohort, the authors identified 179 patients who had a previously resolved HBV infection; 146 treated with anti-TNF, 14 with rituximab, and 19 with other biologic therapy. Key finding: HBV reactivation was not seen in these patients.

Bottomline: For most pediatric patients receiving anti-TNF monotherapy (eg. infliximab, adalimumab), screening with HBsAg alone should suffice.

Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications/diets (along with potential adverse effects) should be confirmed by prescribing physician/nutritionist. 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.

Grand Tetons from Jackson Lodge

How High Can You Go with Adalimumab?

Posted on July 15, 2015 by gutsandgrowth

A recent study (Inflamm Bowel Dis 2015; 21: 1047-53) explored the “Efficacy and Safety of Adalimumab 80 mg Weekly in Luminal Crohn’s Disease.”

Methods: Between 2011-2012, 42 adults with active Crohn’s disease, defined by CDAI > 150 and an objective marker of inflammation, had a dose escalation of adalimumab to 80 mg weekly in prospective multi center study.

Objective markers could include CRP >0.5 mg/dL, fecal calprotectin >300 mcg/g, radiologic evidence or endoscopic evidence
Only 4 patients were receiving concomitant immunomodulators (& none were started)
There were no reports of adalimumab drug levels

Findings: At 14 weeks, 33.3% achieved a clinical remission (CDAI <150) and 23 (54.8%) had a clinical response. These patients had associated improvements in CRP. The authors do not report on serious adverse events; all AEs “were consistent with previous experience with this drug.”

Take-home point: The authors do not recommend this approach in routine clinical practice at this time. However, it would seem that some patients with low adalimumab trough levels (and no anti-drug antibodies) may benefit from high doses of adalimumab

Briefly noted:

Fumery M, et al. JPGN 2015; 60: 744-48. This retrospective study identified 27 children who received adalimumab (ADA) after infliximab failure. Though ADA was well-tolerated, 8 (30%) had primary nonresponse to ADA and an additional 5 (26%) had ADA failure by 1 year.

Huang EY, et al. Inflamm Bowel Dis 2015; 21: 963-72. “Exposure to dexamethasone in mice led to substantial shifts in gut microbiota over a 4-week period.” Take-home point: Corticosteroids may have both direct and indirect impacts on the microbiome as one mechanism of influencing disease response

Related blog posts:

Zoo Atlanta

New Target Drug Levels in Inflammatory Bowel Disease

Posted on July 1, 2015 by gutsandgrowth

According to a recent review (Vaughn BP, Sandborn WJ, Cheifetz AS. Inflamm Bowel Dis 2015; 21: 1435-42), higher target levels of infliximab should be considered.

After reviewing the relevant studies which are summarized in Table 1, the authors state that in their experience infliximab (IFX) levels of 5 to 10 mcg/mL are desirable. Using this standard, they note in a retrospective review that proactive testing identifies only 29% of patients in this range.

Similarly, the TAXIT study (Casteele NV et al. Gastroenterol 2015; 148: 1320-29) identified 44% of patients with a trough concentration of 3-7 mcg/mL at baseline screening. In this study, after achieving an adequate trough concentration, they found that patients had ~70% clinical remission at 1 year. TAXIT acronym = the Trough Concentration Adapted Infliximab Treatment trial. The TAXIT study was a 1-year randomized control trial with 263 adults (178 with CD and 85 with UC).

Recommendations from this review:

When therapeutic drug monitoring is used to react to symptomatic patients (Figure 1), if they test negative for antibodies to infliximab (ATIs) and have a low IFX level, then increasing the dose is recommended. In those with therapeutic IFX and negative ATIs, then consider change in drug class or surgery (rather than dose escalation).
When therapeutic drug monitoring is used to react to symptomatic patients, if they test positive for ATIs, if there is a low level ATI (<15 mcg/mL for the referenced assay), then increasing the dose is recommended, otherwise consider change in drug class or surgery (rather than dose escalation).
For proactive monitoring, if negative ATI, and IFX trough level is >10 mcg/mL consider extending interval. If the IFX level is low, increase dose. If IFX is therapeutic, continue same dose and consider re-check in 6-12 months.
For proactive monitoring (Figure 3), if positive ATI, the authors recommend increasing dose if faced with low level ATI and consider change in drug class or surgery (rather than dose escalation). [If someone is doing well, I would not agree with this recommendation. I would not stop a therapy based on a single blood test.]

One more useful point:

The authors note that combination therapy improves IFX levels and lessens the likelihood of ATIs. “Current evidence suggests that combination of an anti-TNF with an immunomodulator is the most efficacious treatment for new-onset IBD.” They speculate that proactive monitoring may allow IFX monotherapy without the need for combination therapy or allow de-escalation of combination therapy.

Bottomline: Consider a higher infliximab target level (5-10 mcg/mL) and using proactive monitoring to achieve higher remission rates.

Related blog posts:

Cumberland Island

Briefly noted:

Casen C, et al. Aliment Pharmacol There 2015; 42: 71-83. (Thanks to Ben Gold for this reference). After studying the stool of 165 healthy controls, the authors used 54 DNA probes targeting >300 bacteria. This genetic analysis-map dysbiosis test, subsequently analyzed 330 more patients; it confirmed dysbiosis in 73% of IBS patients, 70% of treatment-naive IBD patients and 80% of IBD patients in remission compared with 16% of healthy individuals. Take-home point: Ultimately stool analysis could lead to more accurate evaluation and monitoring of individuals with suspected IBS or IBD.

IBD Shorts -Skin, Adalimumab Kinetics

Posted on May 23, 2015 by gutsandgrowth

From the IMAgINE study with 192 pediatric patients (Sharma S et al. Inflamm Bowel Dis 2015; 21: 783-92), the authors determined levels for adalimumab, that at week 52, were associated with remission and response. A cutoff level of 3.6 mcg/mL had a sensitivity of 32.7% and specificity of 88.6% for predicting remission; the same cutoff had a sensitivity of 46.2% and specificity of 83% for predicting a response. Overall, the authors noted dose proportionality with patients who received higher (or more frequent) doses with higher serum levels.

“Concomitant Use of Azathioprine/6-Mercaptopurine Decreases the Risk of Anti-TNF-Induced Skin Lesions” (Soh JS et al. Inflamm Bowel Dis 2015; 21: 832-9). Among a cohort of 500 Korean patients, the incidence of psoriaform and eczematiform lesions was 6.2%. Concomitant use of a thiopurine was associated with a hazard ratio of 0.452 (lower risk) for developing these adverse skin reactions.

More on Adalimumab (Humira) in Pediatrics

Posted on March 28, 2015 by gutsandgrowth

A recent ‘observational cohort’ study (Cozijnsen M, et al. JPGN 2015; 60: 205-10) provides more information regarding the use of adalimumab in pediatrics. The authors attempted to identify all Dutch patients <18 years of age with Crohn’s disease who received adalimumab after infliximab therapy. Excluded patients were those with “bad treatment adherence,” conflicting comorbidity, and previous participation in prospective study by Hyams et al Gastroenterol 2012; 143: 365-74 (Related blog post: Adalimumab for children with Crohn’s disease | gutsandgrowth).

Key findings:

53 patients met the inclusion criteria. 12 received monotherapy with adalimumab; cotherapy in 21 with thiopurines, 11 with methotrexate, 7 with steroids, and 2 with enteral nutrition.
Median followup was only 12 months.
Remission noted in 34 (64%) patients based on either wPCDAI or PGA (physician global assessment) after a median of 3.3 months. Remission was durable in 50% of these patients for 2 years.
Adalimumab failure was noted in 18 (34%). Only 3 patients in this study were primary infliximab nonresponders and only 1/3 responded to adalimumab.
One serious adverse event (infection) was reported.

One weakness of this study (& many others) is its reliance on clinical disease activity indices rather than more precise measures of mucosal healing.

Take-home point: This small study provides some information about the utility of adalimumab in clinical practice in pediatrics. As noted in other studies, those with a loss of response to infliximab, rather than primary nonresponders, appear to have a more favorable response to adalimumab. In addition, the glaring weakness in this study (i.e. small number of participants) validates the rationale behind efforts like ImproveCareNow which can generate information quickly from a large patient population.

Related study: “Levels of Drug and Antidrug Antibodies are Associated with Outcome of Interventions After Loss of Response to Infliximab or Adalimumab.” Yanai H, et al. Clin Gastroenterol Hepatol 2015; 13: 522-30. Retrospective study of 247 adult and pediatric patients. Key findings:

Patients with adequate trough levels (>4.5 mcg/mL for adalimumab, >3.8 mcg/mL for infliximab) “identified patients who failed to respond to an increase in dosage or a switch to another anti-TNF agent with 90% specificity.”
“Levels of antibody against adalimumab >4 mcg/mL-eq or antibodies against infliximab >9 mcg/mL-eq identified patients who did not respond to an increased drug dosage with 90% specificity.” These patients were likely to benefit by switching to an alternative anti-TNF.

Related study: Clin Gastroenterol Hepatol 2015; 13: 539-47. Trough levels of infliximab (>3 mcg/mL) at week 30 was associated with improved outcomes, including mucosal healing and corticosteroid-free remission.

Briefly noted from ImproveCareNow: Dotson JL et al. “Feasibility and Validity of the Pediatric Ulcerative Colitis Activity Index in Routine Clinical Practice.” JPGN 2015; 60: 200-04. This study, with 2503 patients, found that the PUCAI was completed in 96% if visits. The PUCAI correlated with PGA chain scores.

Related blog posts:

Withdrawing Therapy Leads To Relapse, Even if in Deep Remission

Posted on March 16, 2015 by gutsandgrowth

A recent study, presented as an oral abstract (thanks to Jeff Lewis for forwarding this reference), indicates that even in patients in deep remission, withdrawal of anti-TNF therapy leads to relapse in about 50% even when thiopurines are continued; this is in agreement with previous posts (see below).

Full abstract: OP007 Relapse after Deep Remission in Crohn’s disease. Here are the results and conclusion from the abstract:

Results

Sixty one patients were included and followed-up for a median of 28 months (range 7-47). After withdrawal of anti- TNFa therapy (44 infliximab and 17 adalimumab) 47 (77%) patients continued thiopurines. 32 (52.5%) patients relapsed until the end of follow-up with a median time to relapse of 8 months (range 1-25). The cumulative probability of maintaining remission was 82% at 6 months, 59% at 1 year and 51% at 2 years. Analysis of 28 patients who were in deep remission (endoscopic healing; faecal calprotectin <150mg/kg; CRP <5mg/l) revealed no better survival (82%, 64% and 40% at 6 months, 1 and 2 years, respectively). Four (8%) of relapsing CD patients required surgery 5 to 19 months after anti-TNFa cessation (2 for new stricture development, 1 for medically refractory flare and 1 for high grade dysplasia). In multivariate model only disease localization was risk factor of disease relapse (colonic vs. ileal/ileocolonic: OR 0.16, 95%CI: 0.03-0.72; p=0.02). Type of anti- TNFa preparation, smoking, disease behaviour, corticosteroid or thiopurine therapy, biological markers and anti-TNFa trough levels did not impact disease relapse.

Conclusion

Approximately half of CD patients relapsed within 2 years after anti- TNFa discontinuation despite being in endoscopic remission when anti-TNFa was stopped. The highest relapse rate was observed during the 1st year. Ileal disease increased the risk of disease flare, while no other risk factor was identified.

Related blog posts:

Bryce Canyon

What We Know Now: Therapeutic Drug Monitoring for Inflammatory Bowel Disease

Posted on February 4, 2015 by gutsandgrowth

This blog has discussed the utility of obtaining drug levels for both biologic agents and thiopurines. A recent article (Inflamm Bowel Dis 2015; 21: 182-97) provides a concise up-to-date review.

Here are the key points:

Primary nonresponse to anti-TNF therapy (PNR) “is most commonly defined as lack of improvement of clinical signs and symptoms after the induction phase leading to discontinuation of the drug.”
“We think that patients who respond but fail to achieve remission…are likely almost all due to insufficient drug.”
Table 2 provides a list of predicting factors, both negative and positive, for PNR. This list includes genetic mutations (e.g.. IL23R, NOD2/CARD15 variant), mucosal gene expression, clinical factors (e.g. young age, isolated colitis, smoking, nonstricturing disease, concomitant immunomodulators) and serologic (eg. CRP, hemoglobin, and presence of pANCA).
Patients with PNR to a TNF antagonist, “despite therapeutic concentrations of drug and no anti-drug antibodies (ADA), would likely benefit from a switch to an alternative drug with a different mechanism of action.”
“Patients with a high baseline inflammatory load…and increased clearance of drug because of a high turnover would likely benefit from higher induction doses.” This hypothesis has been proven in rheumatoid arthritis patients in which patients with high TNF concentrations had a clinical response to 10 mg/kg that was “significantly better than the response to 3 and 6 mg/kg of infliximab.”
Patients (with ADA) with an “early immunogenic response against the TNF antagonist are unlikely to respond to dose escalation and thus should be switched to another TNF antagonist, and it should be considered to give higher induction doses in combination with an IMM [immunomodulator] to reduce the risk of immunogenicity.”

Take-home message: New definition of primary nonresponse to anti-TNF agent: “a lack of improvement of objectively assessed signs of active inflammation at baseline, after the induction phase despite the presence of adequate concentrations of drug and the absence of anti drug antibodies.”

Also noted: “Surgical management of ulcerative colitis in the era of biologicals” Inflamm Bowel Dis 2015; 21: 208-10. Key point: “Sacrificing the non responsive diseased colon is an underused or unnecessarily delayed chance to normalize ..health and life.” “Deconditioning of patient with unreasonably long escalations of ineffective medications adds to the morbidity of surgical intervention.”

“Automimmune Features are Associated with Chronic Antibiotic-refractory Pouchitis”Inflamm Bowel Dis 2015; 21: 110-20. Key point: “Microsomal antibody expression and elevated IgG4-positive plasma cell infiltration were independent risk factors” for chronic antibiotic-refractory pouchitis.”

Update on MOC (recent blog:Resistance to Maintenance of Certification | gutsandgrowth) American Board of Internal Medicine “We Got It Wrong” “We launched programs that weren’t ready and we didn’t deliver an MOC program that physicians found meaningful. We want to change that.”

Related blog posts:

IBD Update January 2015 (Part 2)

Posted on January 8, 2015 by gutsandgrowth

1. A retrospective study (Inflamm Bowel Dis 2014; 20: 2292-98) of 217 patients with inflammatory bowel disease(108 infliximab-treated, 109 adalimumab-treated) provides data which indicates that combination therapy (mainly with thiopurines) resulted in higher trough levels and lower antibodies to infliximab (ATI) than monotherapy in patients treated with infliximab (IFX). This was not evident in the adalimumab (ADA)-treated patients. Overall, approximately 90% of study population had Crohn’s disease.

Key points from this study:

The majority of trough level/antidrug antibody levels were drawn due to loss of response. This is a major limitation of this study.
Among IFX-treated patients, those with combination therapy had trough level of 7.5 mcg/mL compared with 4.6 mcg/mL. In combination therapy patients, the incidence of ATIs was 5.7% compared with 29.8% in monotherapy patients.
According to this study, the dose of the immunomodulator (IM) did not significantly influence the infliximab trough level or antibody formation; that is, more than half of patients were receiving “suboptimal dosed IM” and their infliximab levels/ATIs were similar to those who were optimally-dosed.
Among those who were receiving combination therapy, the incidence of antibody formation was lower in IFX-treated patients who started IM concurrently with IFX compared with those in which IM was added subsequently.
There were many other limitations in this study, including the finding that 94% of monotherapy patients had received previous immunomodulator therapy.

Bottomline: This study suggests that combination therapy is beneficial for patients receiving infliximab (in agreement with the previous SONIC study) and may not be beneficial for patients receiving adalimumab; however, only a well-designed prospective study

2. Inflamm Bowel Dis 2014; 20: 2266-70. This study with 749 patients from Sweden showed that a large number of inflammatory bowel disease patients did not receive with iron supplementation: “Only 46% of patients with anemia were treated with iron supplementation or blood transfusion.” This study showed frequent persistence of anemia one year after diagnosis, especially in children. At time of diagnosis, 55% of children and 27% of adults had anemia and 28% and 16% at one year followup, respectively.

My take: Treatment of the underlying IBD, often helps anemia. However, in some patients treating the anemia with iron may help improve symptoms as much or more than other aspects of treatment.

3. Inflamm Bowel Dis 2014; 20: 2433-49. Reviews pain management approaches for patients with IBD. The article emphasizes how pain can be multifactoral and that opiod-induced hyperalgesia may worsen pain.

Anti-Tumor Necrosis Factor Therapies and Cochrane Reviews

Posted on December 4, 2014 by gutsandgrowth

A recent article (Inflamm Bowel Dis 2014; 20: 2132-41) reviews the best available evidence on anti-TNF therapies. This article emerged from a Cochrane collaboration session at Digestive Diseases Week (DDW) in 2013.

Key points:

“There is insufficient evidence to recommend ECI (early combined immunosuppression)) for every newly diagnosed patient, although it may be justifiable in some “high-risk” patients.”
With Crohn’s disease, combination of infliximab and azathioprine significantly improved remission, steroid-free remission, and mucosal healing rates compared with infliximab alone.
“A recent Cochrane review has shown that infliximab, adalimumab, and certolizumab are all effective…The choice of TNF-α antagonist depends on adherence, patient preference, mode of delivery, and cost.“
Elective switching of TNF-α antagonists: in patients who are doing well, elective switching “may be associated with loss of both tolerance and efficacy.” “Dose intensification or early treatment termination was observed in 47% of patients who switched to adalimumab after an ongoing response to scheduled maintenance infliximab therapy compared with 16% of patients who remained on infliximab maintenance therapy.” 28% of ADA patients discontinued therapy compared with 2% of IFX patients.
When to stop therapy: among patients in deep remission >6 months who stopped, relapse occurred in 43.9% over 1 year.
Patients who take thiopurines or biologics (IFX or ADA) have an increased risk of nonmelanoma skin cancer. Odds ratio, compared to controls, as high as 6.75 for combination therapy (>365 days).
Lymphoma: the Cochrane review “found no statistically significant difference in the incidence of lymphoma between biologics and control treatment…and data from the TREAT registry also demonstrated no apparent signal for TNF-α antagonist (i.e. infliximab)-related lymphoma or overall malignancy.”
There has been incremental risk of Non-Hodgkin’s lymphoma and hepatosplenic T-cell lymphoma with azathioprine (thiopurines).

Related blog posts:

gutsandgrowth

Pediatric Gastroenterology

Tag Archives: adalimumab

Another Look at “Step-up” IBD Therapy

What HBV Testing is Needed Before Tumor Necrosis Factor Inhibitor Therapy

How High Can You Go with Adalimumab?

New Target Drug Levels in Inflammatory Bowel Disease

IBD Shorts -Skin, Adalimumab Kinetics

More on Adalimumab (Humira) in Pediatrics

Withdrawing Therapy Leads To Relapse, Even if in Deep Remission

Conclusion

What We Know Now: Therapeutic Drug Monitoring for Inflammatory Bowel Disease

IBD Update January 2015 (Part 2)

Anti-Tumor Necrosis Factor Therapies and Cochrane Reviews