Here are some selected slides and notes from this year’s NASPGHAN’s postrgraduate course. There may be errors in omission or transcription on my part.
Link to the full NASPGHAN PG Syllabus 2019 (Borrowed with permission)
– Intestinal Inflammation Session
192 David T. Rubin, MD, University of Chicago Positioning the new IBD therapies: Merging experience with evidence
Some key points:
- Ustekinumab escalation can increase response. Optimization in CD patients with loss of response led to recapture of response in 69% of patients
- Tofacitinib –given black warning, will likely be used in more refractory patients
- May be able retry a previous therapy (Chicago protocol in slide below)
As an aside, while Dr. Rubin is an excellent speaker, my view is that there are so many terrific pediatric IBD specialists, I would favor having a pediatric IBD specialist give this talk at our postgraduate course. (Some might argue that adult IBD specialists would have more experience with emerging therapies.)
204 Anne Griffiths, MD, FRCPC, Hospital for Sick Children Immunosuppressive therapy in IBD: Can we de-escalate therapy?
- High rate of relapse when biologic therapy is stopped. Use of an immunomodulator may reduce the relapse rate when stopping an anti-TNF agent
215 Stacy Kahn, MD, Boston Children’s Hospital When it is not IBD … rare forms of intestinal inflammation
- For patients with milder microscopic colitis, antidiarrheal agents can be given. For more severe disease, budesonide is effective.
223 Edaire Cheng, MD, UT Southwestern Medical Center Eosinophilic inflammation beyond the esophagus
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A recent study (LE Targownik, EI Benchimol, J Witt et al. Inflamm Bowel Dis 2019; 25: 1718-28) shows that direct health care costs are increased with anti-TNF therapy.
In this retrospective study using the Manitoba IBD Database, the authors examined the direct costs associated with anti-TNF therapy initiation in 928 patients (676 CD, 252 UC). Only 84 subjects were <18 years.
- The median costs for health care in the year of anti-TNF initiation increased compared to prior year. In year prior to initiation, median costs were $4698 for CD and $6364 for UC; in the first year of anti-TNF treatment, costs rose to $39,749 and $49,327 respectively.
- Costs remained elevated through 5 years of anti-TNF therapy for continuous users with total median of $210,956 and $245,260 respectively
- There were reductions in non-drug costs. Inpatient and outpatient costs decreased in the year after anti-TNF initiation by 12% and 7% respectively, when excluding the costs of anti-TNFs. These observed savings are considerably less than the medication expenditures.
- Costs for medications are likely to improve with the introduction of biosimilars. Currently these are being used mainly in persons with a new diagnosis due to reticence to switch from originator product in established patients.
- The authors note that costs were overall higher with infliximab (IFX) than adalimumab (ADA) though “it is possible that patients with higher-severity disease are channeled toward IFX over ADA.”
- Indirect costs like ability to go to work and achieve educational potential could offset some of the direct costs. In a prior study in the U.S., ADA treatment was estimated to reduce indirect costs of “nearly $11,000 per person treated.”
- Some costs were not measured in the study including emergency room visits, over the counter medications and alternative health care use.
- This was not a randomized study; thus, it is impossible to know what costs of persons with similar disease who were untreated would have been.
My take: This study shows that saving money is not the main reason to use anti-TNF therapies; rather, their effects on improved health and fewer complications.
Related blog posts:
- Do Anti-TNF Agents Reduce Surgeries and Hospitalizations?
- Top Anti-TNF for Ulcerative Colitis
- Gold Medal Winner: Infliximab (in the anti-TNF category) this post initially was during 2016 Olympics
- Comparing Biologics for Ulcerative Colitis | gutsandgrowth
- Head-to-Head: Nutritional Therapy versus Biological … – gutsandgrowth
- Adalimumab for children with Crohn’s disease | gutsandgrowth
- Should All Pediatric Patients with Crohn’s Disease … – gutsandgrowth
- What is Your Infliximab Adherence Rate? | gutsandgrowth
- Changes in the Use of IBD Biologic Therapy
Another large retrospective ‘real-world’ study (C Chen et al. Inflamm Bowel Dis 2019; 1417-27) examined persistence profiles of biologic therapies in newly diagnosed IBD patients. This study, based on Truven Health MarketScan data (2008-2015) included 5612 patients with Crohn’s disease (CD) and 3533 with ulcerative colitis (UC). There were 1156 persons (20.6%) in the pediatric age range (0-18)
- Less than half of the patients continued using their initial biologic treatment after 1 year (48.5% of CD cohort and 44.8% of UC cohort).
- For infliximab (IFX) in the CD cohort, the 1 year continued rate was 47.6% and the 5 year rate was 20.0%. In the UC cohort, the rates were 44.9% and 15.7% respectively.
- For adalimumab (ADA) in the CD cohort, the 1 year continued rate was 50.9% and the 5 year rate was 9.1%. In the UC cohort, the rates were 45.4% and 7.7% respectively.
- Combination therapy with immunomodulators (IMM) significantly decreased the risk of discontinuation, especially if IMM was started more than 30 days before the biologic agent (HR 0.22). Simultaneous starting had HR of 0.32.
- The major predictors for noncompliance included infection and hospitalization.
Why did combination therapy result in higher medication persistence rates?
- Potential reasons included improved efficacy by direct inflammatory effects and reduced drug antibodies to TNF antagonists. It is possible that patients receiving combination therapy had more severe disease and thus less likely to discontinue therapy.
Limitation: This study may overestimate drug discontinuation as some patients may simply have had a dosing delay.
My take: This study shows a higher-than-expected rate of drug discontinuation indicating dissatisfaction related to efficacy, cost or complications. Those receiving immunomodulators (combination therapy) were much less likely to discontinue treatment.
Related blog posts:
- Can Therapeutic Drug Monitoring with Monotherapy Achieve Similar Results as Combination Therapy in IBD?
- Digging into the COMMIT study
- Don’t be Fooled About Withdrawing Immunomodulator Cotherapy -Look Past the Headline
- Methotrexate –First Choice Immunomodulator? | gutsandgrowth
- Should All Pediatric Patients with Crohn’s Disease Continue Combination Therapy? | gutsandgrowth
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
A recent study (http://dx.doi.org/10.1136/gutjnl-2019-318440; SK Murthy et al. BMJ indicates that anti-TNF therapy has not been effective in significantly lowering CD-related hospitalizations or surgeries.
Full Text Link (from Eric Benchimol twitter feed): Introduction of anti-TNF therapy has not yielded expected declines in hospitalisation and intestinal resection rates in inflammatory bowel diseases: a population-based interrupted time series study)
My take: While big changes in the frequency of these outcomes were not demonstrated in this large study, prior studies, including the RISK study, have shown that anti-TNF therapy can be disease-modifying and reduce the risk of penetrating disease in Crohn’s disease.
Related blog post: CCFA Updates in IBD
A recent review provides some helpful advice: “A Practical Guide to the Safety and Monitoring of New IBD Therapies” (B Click, M Regueiro. Inflamm Bowel Dis 209; 25: 831-42).
This review discusses infection risk, malignancy risk, immunologic issues and other complications.
In terms of infection risk assessment, the authors describe a pyramid in which they stratify the risks of medications. The safest to least safe in their assessment: vedolizumab –>ustekinumab–>anti-TNF monotherapy–>thiopurine or tofacintinib–>thiopurine/anti-TNF combination–>steroids.
- Table 1 lists potential infections and vaccination recommendations
- Table 2 suggests management of active infections by IBD Medication Class
- For anti-TNF agents and for IL12/23 agents: the authors recommend continuation of agent if viral (eg EBV, VZV, HSV) or bacterial (eg. Strep/Staph)/C difficile infections (unless severe) but holding for opportunistic infections.
- For integrin agents, the authors recommend continuation of medications in the face of infections except “consider holding dose” during active C difficile infection
- For JAK agents, the authors recommend stopping during viral infections and with opportunistic infections. They recommend continuing with bacterial infections (hold if severe) and continuing with C difficile infection
- Table 3 suggests management in the setting of active malignancy
- Table 4 lists recommendations in the setting of immunologic complications. Theses categories include antidrug antibodies,lupus-like reactions, demyelinating conditions, and psoriasis.
- One of the points alluding to in this chart is that addition of methotrexate may help in patients receiving anti-TNF therapy with psoriasis.
- No psoriatic reactions have been reported with vedolizumab, ustekinumab or tofacitinib; ustekinumab is FDA-approved for use in psoriasis and tofacitinib is FDA-approved for psoriatic arthritis.
- Table 5 suggests recommendations in the setting of altered liver enzymes and altered lipids/creatine kinase
- Anti-TNF Agents in Pediatrics Have NOT Been Shown to Cause Lymphoma | gutsandgrowth
- Safer Than You Think: Biologic Therapies for IBD and Risk of Infection and Malignancy | gutsandgrowth
- TNF-α antagonists and infections
- Disease modifying treatment in IBD
- Only one chance to make first impression
- More on IBD Medicine Risks
A recent consensus report (AH Steinhart, R Panaccione et al. Inflamm Bowel Dis 2019; 1-13) provides updated guidelines for the management of perianal fistulizing Crohn’s disease (CD).
As an aside, the article starts off with an extremely lengthy disclosure (of financial interests) –more than 30 lines of extremely small font!
The scope of the problem:
- About 21% of CD patients have developed perianal fistulizing disease by 10 yrs and 26% after 20 years.
- This complication leads to significant morbidity/reduced quality of life and about 70% require surgical treatment during long-term followup.
The substance of the article are summarized in Table 4 and Figure 1. The recommendations all are considered to be based on either low quality of evidence or very low quality of evidence:
- In those with active fistulizing disease, the authors recommend imaging (EUS or MRI)
- In those with evidence of complicated fistulizing disease, “we suggest surgical consultation.”
- In those with active fistulizing CD, “we suggest the use of antibiotic therapy for initial management.”
- In those with active fistulizing CD, “we recommend the use of anti-TNF therapy” for induction and maintenance.
- In those with active fistulizing CD, “when starting anti-TNF therapy, we suggest it be combined with thiopurine or methotrexate over monotherapy to optimize pharmacokinetic parameters.”
- In those with active fistulizing CD, surgical management is recommended in those when there is an inadequate response to medical management.
Some additional pointers:
- Early surgical consultation is recommended in setting of suspected clinical abscess (eg. pain, fever, leukocytosis).
- The authors’ algorithm suggests that if early surgical intervention is not required, then patients should first receive antibiotics for initial symptom control, followed by imaging, and, if uncomplicated fistulizing disease on imaging, followed by anti-TNF therapy (with either MTX or thiopurine). If complicated fistulizing disease, then surgical intervention may be needed prior to institution of anti-TNF therapy.
- “The rate of fistula healing was 43% with medical therapy alone and 53% with combination surgical and medical therapy” based on a systematic review of 8 cohort studies.
My take: This article helps simplify/streamline the approach to this troubling complication.
Related blog posts:
- ADMIRE Study: Use of Stem Cells for Perianal Crohn’s Disease
- IPAA (Pouch) for Crohn’s Disease and Indeterminate Colitis
- Fecal diversion for Perianal Crohn’s Disease
- Tackling Crohn’s Perianal Fistulizing Disease | gutsandgrowth
- Pediatric Consensus Statement: Perianal Crohn Disease …
- Paris Classification of Pediatric Crohn’s Disease | gutsandgrowth
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.