Genetic Risk for Failing Infliximab

A recent study (A Wilson et al. AP&T 2019; https://doi.org/10.1111/apt.15563) noted that a HLADQA1*05A>G genotype predicts a high risk of developing anti-drug antibodies in patients receiving infliximab.

Here’s a link to the full article:  HLADQA1*05 genotype predicts anti‐drug antibody formation and loss of response during infliximab therapy for inflammatory bowel disease

Here’s the abstract (my highlights in bold):

Background

Anti‐drug antibodies (ADAs) are a leading contributor to infliximab loss of response and adverse drug events. It is not feasible to identify patients at risk of antibody formation before initiating infliximab. The genetic variation HLADQA1*05 (rs2097432) has been linked to infliximab antibody formation in Crohn’s disease (CD).

Aims

To evaluate the association between HLADQA1*05 and infliximab antibody formation, infliximab loss of response, treatment discontinuation and adverse drug events in patients with inflammatory bowel disease (IBD)

Methods

In a retrospective cohort study, infliximab‐exposed patients with IBD (n = 262) were screened for the genetic variation, HLADQA1*05A>G (rs2097432). Risk of infliximab ADA formation, infliximab loss of response, adverse events and discontinuation were assessed in wild‐type (GG) and variant‐carrying (AG or AA) individuals.

Results

Forty per cent of all participants were HLADQA1*05A>G variant carriers, with 79% of participants with infliximab antibodies carrying at least one variant allele. The risk of infliximab antibody formation was higher in HLADQA1*05A>G variant carriers (adjusted HR = 7.29, 95% confidence interval (CI) = 2.97‐17.191, P = 1.46 × 10−5) independent of age, sex, weight, dose and co‐immunosuppression with an immunomodulator. Variant carrier status was associated with an increased risk of infliximab loss of response (adjusted HR = 2.34, 95% CI = 1.41‐3.88, P = .001) and discontinuation (adjusted HR = 2.27, 95% CI = 1.46‐3.43, P = 2.53 × 10−4) although not with infliximab‐associated adverse drug events.

Conclusions

HLADQA1*05 is independently associated with a high risk of infliximab antibody formation in addition to infliximab loss of response and treatment discontinuation. There may be a role for genotype‐guided application of combination therapy in IBD.

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Immune-Mediated Reactions to Anti-TNFs and What to Do About Them

Statue

A recent review article (Feuerstein JD et al. Inflamm Bowel Dis 2015; 21: 1176-86) serves as a useful reference regarding immune-mediated reactions to anti-tumor necrosis factor (anti-TNF) medications used in inflammatory bowel disease (IBD).

Background:

  • All anti-TNF agents induce antidrug antibodies (ADAs).
  • With regard to infliximab (IFX) which has the most literature, it is well-recognized that combination therapy with an immunomodulator reduces the risk of antibodies to infliximab (ATIs).  For example, in the SONIC study, ATIs were noted in 0.9% of those with combination therapy compared with 14.6% of those receiving monotherapy with IFX.  With the UC-SUCCESS, the rates were 19% and 3% respectively.

Acute Infusion Reactions -Key points:

  • Acute infusion reactions (IRs) are more common in patients with ADAs.  IRs can be categorized as acute (w/in 24h) and chronic (2-14 d after infusion).
  • Acute IRs can be mild (dizziness, flushing, nausea, palpitation), moderate (chest pain, hypertension [SBP increase of more than 20], hypotension, fevers urticaria, mild dyspnea, chills, rash) or severe (severe hypertensions [SBP increase of more than 40] , severe hypotension, significant dyspnea with brochospasm, stridor, and rigors)
  • The authors provide a treatment algorithm (Figure 1) based on severity of acute IR.  All reactions are initially treated by stopping infusion, but many can be restarted at a low rate after administration of acetaminophen (mild & moderate), normal saline (mild & moderate), diphenhydramine (moderate), and possibly hydrocortisone (if needed in moderate cases).  While the algorithm suggests the possibility of restarting infusion reaction in severe cases without anaphylaxis, if this is considered, it may be worthwhile to attempt in a hospital setting.
  • Typically if infusions are restarted, the rates are 10 mL/hr x 15 minutes –>20 mL/hr x 15 minutes–> 40 mL/hr x 15 minutes –>80 mL/hr x 15 minutes –>100 mL/hr x 15 minutes–>125 mL/hr until completion.
  • Following an IR, the authors recommend checking for ATIs and for IFX level.
  • Prophylaxis for mild IRs includes the use of acetaminophen and antihistamines (2nd generation antihistamine daily for 5 days prior or first generation antihistamine an hour prior to infusion).  In addition, the infusion should be started at 10 mL/hr
  • Prophylaxis for moderate IRs includes the use of acetaminophen and antihistamines and steroids (prednisone 50 mg q12 hr x 3 doses prior or hydrocortisone 100 mg (or equivalent) 20 minutes prior to infusion).  In addition, the infusion should be started at 10 mL/hr
  • The authors recommend against premedication in those who have not had IRs. Use of premedication may cause a paradoxical increase in IRs due to symptoms induced by the antihistamine.

Autoimmune Complications:

  • Autoantibodies: anti-nuclear antibody (ANA), anti-double-stranded DNA antibody (anti-dsDNA), anti-cardiolipin antibody, antihistone antibody
  • Drug-Induced Lupus Erythematosus (DILE) -“the most frequently presenting symptoms, seen in 90% of cases, is symmetric arthralgias.”  Systemic involvement of the kidneys or central nervous system is rare. Treatment is cessation of the offending medication.
  • Vasculitis -likely due to the development of circulating immune complexes that deposits into smaller capillaries–>result in a type III hypersensitivity reaction.  The most common manifestation would be palpable purpura due to a leukocytoclastic vasculitis.
  • While autoimmune complications can be a class effect, many patients have been able to switch to a different anti-TNF.

Dermatologic Complications:

The authors review both anti-TNF induced psoriasis and eczema.  Treatment should be in conjunction with dermatology.  For psoriasis that involves >5% of body surface area, this could require changing to a different anti-TNF or a different drug class.  For severe cases, “anti-TNF therapy should be discontinued.”

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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.

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

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.”

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