Citation: Gorelik Y, Freilich S, Gerassy-Vainberg S, et al Antibiotic use differentially affects the risk of anti-drug antibody formation during anti-TNFα therapy in inflammatory bowel disease patients: a report from the epi-IIRNGut Published Online First: 03 August 2021. doi: 10.1136/gutjnl-2021-325185
This study reviewed data from 1946 patients with 363 who developed anti-drug antibodies (ADA). Then, specific pathogen and germ-free C57BL mice were treated with respective antibiotics and challenged with infliximab. ADA were assessed after 14 days.
Cox proportional hazard model demonstrated an increased risk of ADA development in patients who used cephalosporins (HR=1.97, 95% CI 1.58 to 2.44), or penicillins with β-lactamase inhibitors (penicillin-BLI, HR=1.4, 95% CI 1.13 to 1.74), whereas a reduced risk was noted in patients treated with macrolides (HR=0.38, 95% CI 0.16 to 0.86) or fluoroquinolones (HR=0.20, 95% CI 0.12 to 0.35).
In mice exposed to infliximab, significantly increased ADA production was observed in cephalosporin as compared with macrolide pretreated mice. Germ-free mice produced no ADA.
My take: The combination of retrospective data and mouse studies suggests that taking some antibiotics (mainly penicillins and cephalosporins) could increase the risk of immunogenicity to infliximab and increase the risk of anti-drug antibodies.
A retrospective study (H Bar-Yoseph et al. Clin Gastroenterol Hepatol 2017; 15: 69-75) indicated that thiopurine use before infliximab (IFX) was associated with the prevention of antidrug antibody formation in patients with Crohn’s disease.
The authors had 207 eligible patients which included 93 who received IFX monotherapy, 52 who received combination therapy after response to thiopurine, 34 who received IFX after lack of response to thiopurines (but continued with combination treatment), and 28 who received de novo combination therapy. The total number of patients followed in these centers is much higher, but they excluded those with episodic infusions and for other reasons that could affect their conclusions.
Prior thiopurine therapy was associated with lower antidrug antibodies (ADA). At 1 year, past thiopurine responders had 19.3% ADA, past thiopurine failures had 16.1% ADA; both were much lower that the monotherapy rate of 46.6% The de novo combination group had a rate of 21.9% which did not reach significance.
Interestingly, after the first 5 months, the de novo combination group did not develop further ADA but during the first 5 months the rate of ADA was quite similar to the monotherapy rate. This could be related to the notion that thiopurines may take 3-6 months to achieve full effect.
Combination therapy (compiled) was associated with higher rates of clinical remission (58.8% vs 40.9%) and lower rates of active disease (8.8% vs. 21.5%).
Overall, this study showed high rates of ADA compared to many studies but the conclusions are similar to other published studies. It could be that many of those with positive ADA were lower antibody levels and that many of these levels may not be clinically significant. The study has limitations mainly related to being a retrospective study.
My take: This study supports the following:
Combination therapy is more effective than monotherapy
Using an immunomodulator before starting infliximab may reduce ADA formation more effectively than starting combination therapy de novo.
Disclaimer: These blog posts are for educational purposes only. Specific dosing/usage 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.
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).
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.
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.
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.
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?
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