- Email: [email protected]
Adverse reactions to infliximab and the outcome of desensitization
Ann Allergy Asthma Immunol xxx (2015) 1e4
Contents lists available at ScienceDirect
Adverse reactions to infliximab and the outcome of desensitization Ahmad A. Mourad, MD *; Moheb N. Boktor, MD y; Yesim Yilmaz-Demirdag, MD *; and Sami L. Bahna, MD, DrPH * * Allergy y
and Immunology Section, Louisiana State University Health, Shreveport, Louisiana Gastroenterology Section, Louisiana State University Health, Shreveport, Louisiana
A R T I C L E
I N F O
Article history: Received for publication March 23, 2015. Received in revised form June 3, 2015. Accepted for publication June 8, 2015.
A B S T R A C T
Background: Infliximab is a highly effective monoclonal antibody against tumor necrosis factor, which is a major inflammatory mediator in certain gastrointestinal, rheumatic, and skin diseases. In some patients, infliximab infusion causes systemic adverse reactions that often lead to discontinuation of therapy even in responsive patients. Objective: To investigate the frequency and characteristics of adverse reactions to infliximab at the authors’ institution and the outcome of their management, including desensitization. Methods: This was a single-center retrospective study of patients who were treated with infliximab, primarily for inflammatory bowel disease, from January 1, 2000 to March 31, 2014. Data included age, sex, underlying disease, infliximab therapy duration before the first reaction, manifestation of reaction, onset, and management. Results: There were 336 patients with inflammatory bowel disease who were treated with infliximab during the study period. Thirty patients (8.9%) developed a systemic adverse reaction to infliximab, which was discontinued in 15 patients (50%) and was continued in 3 patients after premedication and/or decreased infusion rate. Twelve patients (40%) underwent infliximab desensitization with gradually increasing doses starting at a dilution of 0.1 mg/mL to reach the full treatment dose over approximately 4 to 6 hours. It was successful in all 12 patients, who continued to receive up to 26 infliximab infusions, mostly without premedication. Conclusion: Infliximab can trigger systemic reactions that hinder its administration. The present desensitization protocol appears to be safe and effective and it can be considered in patients whose inflammatory bowel disease responds well to infliximab but who develop systemic adverse reactions. Ó 2015 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
Introduction Infliximab, a chimeric IgG1 monoclonal antibody (mAb) comprised of 75% human and 25% murine, has a high specificity against tumor necrosis factor, which is a major inflammatory mediator in certain gastrointestinal, rheumatic, and skin diseases with high efficacy.1e4 For many years, it has been used increasingly for inflammatory bowel diseases (IBDs), rheumatoid arthritis, and psoriatic arthritis. It is approved for patients at least 6 years old and is administered by intravenous infusion given at 0, 2, and 6 weeks and then every 8 weeks. In a large series, 9.7% of patients receiving infliximab developed acute infusion reactions that were serious in 1% and necessitated switching to other therapies.5 Reported reactions varied from headache, dizziness, nausea, flushing, and pruritus to more severe Reprints: Sami L. Bahna, MD, DrPH, Allergy and Immunology Section, Louisiana State University Health, 1501 Kings Highway, Shreveport, LA 71130-3932; E-mail: [email protected]. Disclosures: Authors have nothing to disclose.
symptoms of hypersensitivity reactions in the form of generalized urticaria, angioedema, dyspnea, and occasionally anaphylaxis. Mild reactions can be managed by decreasing the infusion rate and premedication with antihistamines with or without corticosteroids. Severe reactions often prevent the continuation of infliximab therapy unless desensitization is performed. Alternative medications could be more expensive, less effective, or more toxic.
Methods Patients This was a single-center retrospective study of patients at least 6 years of age who were treated with infliximab (Remicade, Janssen Biotech, Inc, Horsham, Pennsylvania) for IBD from January 1, 2000 to March 31, 2014. Every subject was given a unique “identifier” to maintain privacy and anonymity. Data included age, sex, underlying disease, infliximab therapy duration before the first reaction, manifestation of reaction, onset, and management. The study was
http://dx.doi.org/10.1016/j.anai.2015.06.004 1081-1206/Ó 2015 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
2
A.A. Mourad et al. / Ann Allergy Asthma Immunol xxx (2015) 1e4
Table 1 General desensitization protocol for infliximab Time (every 15 min) Step A: bag 1, infliximab concentration 0.1 mg/mL
Infusion Volume Dose number (mL) (mg)
1 2 3 4 5 6 7 8 Step B: bag 2, 9 infliximab concentration 10 11 1 mg/mL 12 13 Step C: bag 3, 14 infliximab 15 concentration 16 5 mg/mL 17a
0.1 0.2 0.5 1 5 10 25 5 10 12.5 17.5 20 30 8 16 32
Cumulative Pulse Respiratory BP Reaction dose (mg) rate rate
0.01 0.01 0.02 0.03 0.05 0.08 0.1 0.18 0.5 0.68 1 1.68 2.5 4.18 5 9.18 10 19.18 12.5 31.68 17.5 49.18 20 69.18 30 99.18 40 139.18 80 220 160 380
Abbreviation: BP, blood pressure. a The remaining dose until reaching the full therapeutic dose.
Table 2 Demographic data of 336 patients with IBD treated with infliximab and 30 patients who developed an adverse reaction Variable
All patients (N ¼ 336)
Female-to-male 1.11 ratio Age (y) <21 77/336 21e30 134/336 31e40 68/336 41e50 19/336 >50 38/336 IBD Crohn disease 275/336 Ulcerative colitis 61/336
Patients without Patients with P reaction (n ¼ 306) reaction (n ¼ 30) valuea 1.08
1.50
.40 .92
(22.9%) 72/306 (23.5%) (39.9%) 122/306 (39.9%) (20.2%) 61/306 (19.9%) (5.7%) 17/306 (5.6%) (11.3%) 34/306 (11.1%)
5/30 12/30 7/30 2/30 4/30
(16.7%) (40%) (23.3%) (6.7%) (13.3%)
(81.8%) 250/306 (81.7%) (18.2%) 56/306 (18.3%)
25/30 (83.3%) 5/30 (16.7%)
.82
Abbreviation: IBD, inflammatory bowel disease. a Patients without reactions vs patients with reactions.
Results
There was no adverse reaction to the first infliximab infusion. Twelve patients (40%) reacted to infliximab after 1 to 3 uneventful doses, 10 (33%) after 4 to 8 doses, and 8 (27%) after more than 8 doses (Fig 2). Subsequent management varied according to the severity of the reaction, disease control, and the patient’s preference. Infliximab was discontinued in 15 patients (50%) who were switched to another mAb medication (certolizumab or adalimumab) or continued on another medication such as azathioprine, sulfasalazine, or mesalamine. In contrast, infliximab was continued in 3 patients (10%) after premedication and/or decreasing the infusion rate and in 12 patients (40%) who underwent desensitization (Fig 3). The 12 desensitized patients underwent a total of 68 desensitizations and received the recommended therapeutic dose. Skin testing produced a positive reaction in only 1 patient (5 mg/mL intradermally). The number of desensitizations ranged from 1 to 26 per patient: 1 in 4 patients (33%), 2 in 3 (25%), 3 in 2 (17%), and 3 (25%) each received 12, 14, or 26. The procedure lasted 4 to 6 hours depending on the total dose administered or the occurrence of reactions that necessitated slowing the infusion rate. Some patients during desensitization developed mild adverse reactions that were treated by slowing the infusion rate and occasionally with antihistamines. None of these reactions required aborting the desensitization procedure or administering corticosteroid, albuterol, or epinephrine. The reactions during infliximab desensitization were mild respiratory symptoms, flushing, and chills each reported in 2 patients and angioedema at the infusion site, pruritus, nausea, and headache each reported in 1 patient. The desensitization protocol included no premedication before the first desensitization and
There were 336 patients with IBD treated with infliximab. Thirty patients (9%) developed systemic adverse reactions. Table 2 lists the characteristics of all 336 patients and of those who developed reactions. Upper and lower respiratory symptoms and urticaria or angioedema were the most common reported adverse reactions (37%). Other cutaneous reactions were flushing (23%) and pruritus (13%). Nausea and vomiting were reported in 17% and hypotension in 10%. Excluded from desensitization were 2 patients who developed opportunistic infections: 1 patient had pancytopenia and another had a serum sickness type of reaction (Fig 1). The rate of adverse reactions showed a trend (although not statistically significant) of increase by age: 8.6% for patients no older than 40 years vs 10.5% for patients older than 40 years (P ¼ .6), ie, the incidence of reactions in patients older than 40 years was 22% greater than in younger patients. Also, reactions were 34% greater in female than in male patients (10.2% vs 7.6%, P ¼ .4). The frequency of reactions in patients with Crohn disease was similar to that in patients with ulcerative colitis (9% and 8%, respectively).
Figure 1. Manifestations of adverse reactions to infliximab in 30 patients with inflammatory bowel disease. GI, gastrointestinal; Urt, urticaria.
approved by the institutional review board of Louisiana State University Health in Shreveport. Desensitization Protocol Before desensitization, skin prick testing was performed with the standard therapeutic concentration (5 mg/mL); if the reaction was negative, then the subject underwent intradermal testing with 1 mg/mL; if still negative, then it was repeated using 5 mg/mL. Published infliximab concentrations used for skin testing varied widely from 0.01 to 10 mg/mL for prick or intradermal testing.6e8 However, the optimal concentration that differentiates irritation from sensitization was not established. Table 1 presents the infliximab desensitization protocol with increasing dosage every 15 minutes. Three different infliximab dilutions were used. The first dilution, 0.1 mg/mL, was infused over 7 steps, starting at 0.1 mL. The second dilution, 1 mg/mL, was infused over 6 steps, starting at 5 mL. The third dilution, 5 mg/mL (standard concentration), was infused over 1 to 4 steps (depending on the total treatment dose), starting at 8 mL. To test the safety of the protocol, no premedication was given during the first desensitization procedure. The procedure was carried out in the hospital, and emergency medications (injectable epinephrine, methylprednisolone, diphenhydramine, famotidine, and nebulized albuterol) were available at the bedside.
A.A. Mourad et al. / Ann Allergy Asthma Immunol xxx (2015) 1e4
Figure 2. Distribution of 30 patients with inflammatory bowel disease who had reactions to infliximab according to the number of uneventful doses before the first reaction. No reaction occurred with the first infliximab dose.
premedication in 3 patients (antihistamine in 1 and prednisone in 2) who developed a reaction during their first desensitization. Discussion In this report, the authors describe their experience with 12 patients with IBD who received a total of 68 successful infliximab desensitizations. The protocol also was successful in 5 other patients: 2 with rheumatoid arthritis, 2 with psoriatic arthritis, and 1 with ankylosing spondylitis, for a total of 44 desensitizations. The adverse reactions during desensitization were mild (flushing and pruritus) and treated with diphenhydramine. No serious reactions were reported and those patients were able to continue infliximab treatment. The use of mAbs in modern medicine is a technologic advance that has enhanced treatment of several human diseases. By targeting specific proteins, mAbs provide an efficient means to maximize therapeutic efficacy. Infliximab is one of the chimeric mAbs that has proved effective for induction and maintenance therapy in Crohn disease and ulcerative colitis.1,2 Its administration has been associated in some patients with the occurrence of immediate or delayed adverse reactions that often limited its use. In the present series, acute reactions to infliximab occurred in 8.9%, which is similar to the 9.7% reported in another study.5 Most patients who developed reactions to infliximab benefited from desensitization and continued to receive their effective treatment without significant adverse effect. In 2001, Puchner et al9 first reported a successful desensitization protocol for infliximab in 2 patients with anaphylaxis. The procedure was carried out in an intensive care unit setting using an 11-step protocol with a 2-fold increase every 15 minutes starting at 1:100,000 of the treatment dose. In 2003, Cheifetz et al5 followed a protocol using a concentration of 5 mg/mL starting at 10 mL/h for 15 minutes. The rate of infusion
Figure 3. Subsequent management in 30 patients who developed adverse reactions to infliximab.
3
was increased every 15 minutes to 20, 40, 80, and 100 mL/h, after which the patient was continued at 150 mL/h for 30 minutes. If there was no reaction during this interval, then the rate was increased to 250 mL/h. In 2006, Duburque et al10 described 14 patients with Crohn disease who developed infliximab infusion reactions despite prophylactic administration of hydrocortisone. They successfully used an 11-step escalating-increments desensitization protocol, starting at a rate of 0.002 mg/mL/kg and gradually increasing to 0.2 mg/mL/kg for the next 7 steps. In 2009, Brennan et al11 reported on 6 patients who had immediate-type hypersensitivity reactions to infliximab and underwent a 12-step desensitization protocol. Although the desensitization procedure requires several hours, the studies cited earlier point to its advantage in allowing patients who respond well to infliximab but develop adverse reactions to continue the medication. It has been reported that changing to another medication carries the risk of relapse in more than 25% of patients.12 The desensitization procedure for infliximab should be performed by allergists with experience with drug desensitization and the treatment of anaphylaxis. The pathophysiology of these reactions is not known but is usually not mediated by IgE, although several cases of IgE reactions have been reported. The reactions in the present series do not seem to be mediated by IgE because skin testing showed a positive reaction in only 1 patient. IgG antibody and complement activation could be involved.13 Baert et al14 reported a positive correlation between IgG antibodies against infliximab and the risk of infusion reactions. The mechanism of desensitization is not clear. It has been postulated that the procedure could cause the formation of the univalent hapten carrier protein inhibiting IgE cross-linking on mast cells or possible intracellular signaling inhibition in the mast cell triggered by low-drug concentrations.15 In conclusion, effective infliximab therapy does not need to be discontinued in patients who develop systemic reactions. Desensitization can be successful in allowing the continuation of therapy, with only minor adverse reactions that can be easily managed or prevented. Application of the present desensitization protocol to a larger number of patients would further support its efficacy and safety. Acknowledgments The authors thank the allergy and immunology fellows and house staff who participated in the clinical care of these patients and Runhua Shi, MD, PhD, for assistance in statistical analysis. References [1] Kawalec P, Mikrut A, Wisniewska N, Pilc A. Tumor necrosis factor-a antibodies (infliximab, adalimumab and certolizumab) in Crohn’s disease: systematic review and meta-analysis. Arch Med Sci. 2013;9:765e779. [2] Rutgeerts P, Sandborn WJ, Feagan BG, et al. Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2005;353: 2462e2476. [3] Imagama T, Taguchi T. Efficacy and adverse reactions of the TNF alpha inhibitor infliximab in rheumatoid arthritis. Nihon Rinsho. 2013;71:1209e1213. [4] Rustin MH. Long-term safety of biologics in the treatment of moderate-tosevere plaque psoriasis: review of current data. Br J Dermatol. 2012; 167(suppl 3):3e11. [5] Cheifetz A, Smedley M, Martin S, et al. The incidence and management of infusion reactions to infliximab: a large center experience. Am J Gastroenterol. 2003;98:1315e1324. [6] Vultaggio A, Matucci A, Nencini F, Pratesi S, Maggi E. Skin testing and infliximab-specific antibodies detection as a combined strategy for preventing infusion reaction. Intern Emerg Med. 2012;7(suppl 2):S77eS79. [7] Matucci A, Pratesi S, Petroni G, et al. Allergological in vitro and in vivo evaluation of patients with hypersensitivity reactions to infliximab. Clin Exp Allergy. 2013;43:659e664. [8] Alvarez-Cuesta E, Madrigal-Burgaleta R, Angel-Pereira D, et al. Delving into cornerstones of hypersensitivity to antineoplastic and biological agents: value of diagnostic tools prior to desensitization [published online ahead of print March 31, 2015]. Allergy. http://dx.doi.org/10.1111/all.12620.
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[9] Puchner TC, Kugathasan S, Kelly KJ, Binion DG. Successful desensitization and therapeutic use of infliximab in adult and pediatric Crohn’s disease patients with prior anaphylactic reaction. Inflamm Bowel Dis. 2001;7: 34e37. [10] Duburque C, Lelong J, Iacob R, et al. Successful induction of tolerance to infliximab in patients with Crohn’s disease and prior severe infusion reactions. Aliment Pharmacol Ther. 2006;24:851e858. [11] Brennan PJ, Rodriguez Bouza T, Hsu FI, Sloane DE, Castells MC. Hypersensitivity reactions to mAbs: 105 desensitizations in 23 patients, from evaluation to treatment. J Allergy Clin Immunol. 2009;124:1259e1266.
[12] Hoentjen F, Haarhuis BJ, Drenth JP, de Jong DJ. Elective switching from infliximab to adalimumab in stable Crohn’s disease. Inflamm Bowel Dis. 2013; 19:761e766. [13] Khan DA, Solensky R. Drug allergy. J Allergy Clin Immunol. 2010;125(suppl 2): S126eS137. [14] Baert F, Noman M, Vermeire S, et al. Influence of immunogenicity on the longterm efficacy of infliximab in Crohn’s disease. N Engl J Med. 2003;348: 601e608. [15] deShazo RD, Kemp SF. Allergic reactions to drugs and biologic agents. JAMA. 1997;278:1895e1906.
Contents lists available at ScienceDirect
Adverse reactions to infliximab and the outcome of desensitization Ahmad A. Mourad, MD *; Moheb N. Boktor, MD y; Yesim Yilmaz-Demirdag, MD *; and Sami L. Bahna, MD, DrPH * * Allergy y
and Immunology Section, Louisiana State University Health, Shreveport, Louisiana Gastroenterology Section, Louisiana State University Health, Shreveport, Louisiana
A R T I C L E
I N F O
Article history: Received for publication March 23, 2015. Received in revised form June 3, 2015. Accepted for publication June 8, 2015.
A B S T R A C T
Background: Infliximab is a highly effective monoclonal antibody against tumor necrosis factor, which is a major inflammatory mediator in certain gastrointestinal, rheumatic, and skin diseases. In some patients, infliximab infusion causes systemic adverse reactions that often lead to discontinuation of therapy even in responsive patients. Objective: To investigate the frequency and characteristics of adverse reactions to infliximab at the authors’ institution and the outcome of their management, including desensitization. Methods: This was a single-center retrospective study of patients who were treated with infliximab, primarily for inflammatory bowel disease, from January 1, 2000 to March 31, 2014. Data included age, sex, underlying disease, infliximab therapy duration before the first reaction, manifestation of reaction, onset, and management. Results: There were 336 patients with inflammatory bowel disease who were treated with infliximab during the study period. Thirty patients (8.9%) developed a systemic adverse reaction to infliximab, which was discontinued in 15 patients (50%) and was continued in 3 patients after premedication and/or decreased infusion rate. Twelve patients (40%) underwent infliximab desensitization with gradually increasing doses starting at a dilution of 0.1 mg/mL to reach the full treatment dose over approximately 4 to 6 hours. It was successful in all 12 patients, who continued to receive up to 26 infliximab infusions, mostly without premedication. Conclusion: Infliximab can trigger systemic reactions that hinder its administration. The present desensitization protocol appears to be safe and effective and it can be considered in patients whose inflammatory bowel disease responds well to infliximab but who develop systemic adverse reactions. Ó 2015 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
Introduction Infliximab, a chimeric IgG1 monoclonal antibody (mAb) comprised of 75% human and 25% murine, has a high specificity against tumor necrosis factor, which is a major inflammatory mediator in certain gastrointestinal, rheumatic, and skin diseases with high efficacy.1e4 For many years, it has been used increasingly for inflammatory bowel diseases (IBDs), rheumatoid arthritis, and psoriatic arthritis. It is approved for patients at least 6 years old and is administered by intravenous infusion given at 0, 2, and 6 weeks and then every 8 weeks. In a large series, 9.7% of patients receiving infliximab developed acute infusion reactions that were serious in 1% and necessitated switching to other therapies.5 Reported reactions varied from headache, dizziness, nausea, flushing, and pruritus to more severe Reprints: Sami L. Bahna, MD, DrPH, Allergy and Immunology Section, Louisiana State University Health, 1501 Kings Highway, Shreveport, LA 71130-3932; E-mail: [email protected]. Disclosures: Authors have nothing to disclose.
symptoms of hypersensitivity reactions in the form of generalized urticaria, angioedema, dyspnea, and occasionally anaphylaxis. Mild reactions can be managed by decreasing the infusion rate and premedication with antihistamines with or without corticosteroids. Severe reactions often prevent the continuation of infliximab therapy unless desensitization is performed. Alternative medications could be more expensive, less effective, or more toxic.
Methods Patients This was a single-center retrospective study of patients at least 6 years of age who were treated with infliximab (Remicade, Janssen Biotech, Inc, Horsham, Pennsylvania) for IBD from January 1, 2000 to March 31, 2014. Every subject was given a unique “identifier” to maintain privacy and anonymity. Data included age, sex, underlying disease, infliximab therapy duration before the first reaction, manifestation of reaction, onset, and management. The study was
http://dx.doi.org/10.1016/j.anai.2015.06.004 1081-1206/Ó 2015 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
2
A.A. Mourad et al. / Ann Allergy Asthma Immunol xxx (2015) 1e4
Table 1 General desensitization protocol for infliximab Time (every 15 min) Step A: bag 1, infliximab concentration 0.1 mg/mL
Infusion Volume Dose number (mL) (mg)
1 2 3 4 5 6 7 8 Step B: bag 2, 9 infliximab concentration 10 11 1 mg/mL 12 13 Step C: bag 3, 14 infliximab 15 concentration 16 5 mg/mL 17a
0.1 0.2 0.5 1 5 10 25 5 10 12.5 17.5 20 30 8 16 32
Cumulative Pulse Respiratory BP Reaction dose (mg) rate rate
0.01 0.01 0.02 0.03 0.05 0.08 0.1 0.18 0.5 0.68 1 1.68 2.5 4.18 5 9.18 10 19.18 12.5 31.68 17.5 49.18 20 69.18 30 99.18 40 139.18 80 220 160 380
Abbreviation: BP, blood pressure. a The remaining dose until reaching the full therapeutic dose.
Table 2 Demographic data of 336 patients with IBD treated with infliximab and 30 patients who developed an adverse reaction Variable
All patients (N ¼ 336)
Female-to-male 1.11 ratio Age (y) <21 77/336 21e30 134/336 31e40 68/336 41e50 19/336 >50 38/336 IBD Crohn disease 275/336 Ulcerative colitis 61/336
Patients without Patients with P reaction (n ¼ 306) reaction (n ¼ 30) valuea 1.08
1.50
.40 .92
(22.9%) 72/306 (23.5%) (39.9%) 122/306 (39.9%) (20.2%) 61/306 (19.9%) (5.7%) 17/306 (5.6%) (11.3%) 34/306 (11.1%)
5/30 12/30 7/30 2/30 4/30
(16.7%) (40%) (23.3%) (6.7%) (13.3%)
(81.8%) 250/306 (81.7%) (18.2%) 56/306 (18.3%)
25/30 (83.3%) 5/30 (16.7%)
.82
Abbreviation: IBD, inflammatory bowel disease. a Patients without reactions vs patients with reactions.
Results
There was no adverse reaction to the first infliximab infusion. Twelve patients (40%) reacted to infliximab after 1 to 3 uneventful doses, 10 (33%) after 4 to 8 doses, and 8 (27%) after more than 8 doses (Fig 2). Subsequent management varied according to the severity of the reaction, disease control, and the patient’s preference. Infliximab was discontinued in 15 patients (50%) who were switched to another mAb medication (certolizumab or adalimumab) or continued on another medication such as azathioprine, sulfasalazine, or mesalamine. In contrast, infliximab was continued in 3 patients (10%) after premedication and/or decreasing the infusion rate and in 12 patients (40%) who underwent desensitization (Fig 3). The 12 desensitized patients underwent a total of 68 desensitizations and received the recommended therapeutic dose. Skin testing produced a positive reaction in only 1 patient (5 mg/mL intradermally). The number of desensitizations ranged from 1 to 26 per patient: 1 in 4 patients (33%), 2 in 3 (25%), 3 in 2 (17%), and 3 (25%) each received 12, 14, or 26. The procedure lasted 4 to 6 hours depending on the total dose administered or the occurrence of reactions that necessitated slowing the infusion rate. Some patients during desensitization developed mild adverse reactions that were treated by slowing the infusion rate and occasionally with antihistamines. None of these reactions required aborting the desensitization procedure or administering corticosteroid, albuterol, or epinephrine. The reactions during infliximab desensitization were mild respiratory symptoms, flushing, and chills each reported in 2 patients and angioedema at the infusion site, pruritus, nausea, and headache each reported in 1 patient. The desensitization protocol included no premedication before the first desensitization and
There were 336 patients with IBD treated with infliximab. Thirty patients (9%) developed systemic adverse reactions. Table 2 lists the characteristics of all 336 patients and of those who developed reactions. Upper and lower respiratory symptoms and urticaria or angioedema were the most common reported adverse reactions (37%). Other cutaneous reactions were flushing (23%) and pruritus (13%). Nausea and vomiting were reported in 17% and hypotension in 10%. Excluded from desensitization were 2 patients who developed opportunistic infections: 1 patient had pancytopenia and another had a serum sickness type of reaction (Fig 1). The rate of adverse reactions showed a trend (although not statistically significant) of increase by age: 8.6% for patients no older than 40 years vs 10.5% for patients older than 40 years (P ¼ .6), ie, the incidence of reactions in patients older than 40 years was 22% greater than in younger patients. Also, reactions were 34% greater in female than in male patients (10.2% vs 7.6%, P ¼ .4). The frequency of reactions in patients with Crohn disease was similar to that in patients with ulcerative colitis (9% and 8%, respectively).
Figure 1. Manifestations of adverse reactions to infliximab in 30 patients with inflammatory bowel disease. GI, gastrointestinal; Urt, urticaria.
approved by the institutional review board of Louisiana State University Health in Shreveport. Desensitization Protocol Before desensitization, skin prick testing was performed with the standard therapeutic concentration (5 mg/mL); if the reaction was negative, then the subject underwent intradermal testing with 1 mg/mL; if still negative, then it was repeated using 5 mg/mL. Published infliximab concentrations used for skin testing varied widely from 0.01 to 10 mg/mL for prick or intradermal testing.6e8 However, the optimal concentration that differentiates irritation from sensitization was not established. Table 1 presents the infliximab desensitization protocol with increasing dosage every 15 minutes. Three different infliximab dilutions were used. The first dilution, 0.1 mg/mL, was infused over 7 steps, starting at 0.1 mL. The second dilution, 1 mg/mL, was infused over 6 steps, starting at 5 mL. The third dilution, 5 mg/mL (standard concentration), was infused over 1 to 4 steps (depending on the total treatment dose), starting at 8 mL. To test the safety of the protocol, no premedication was given during the first desensitization procedure. The procedure was carried out in the hospital, and emergency medications (injectable epinephrine, methylprednisolone, diphenhydramine, famotidine, and nebulized albuterol) were available at the bedside.
A.A. Mourad et al. / Ann Allergy Asthma Immunol xxx (2015) 1e4
Figure 2. Distribution of 30 patients with inflammatory bowel disease who had reactions to infliximab according to the number of uneventful doses before the first reaction. No reaction occurred with the first infliximab dose.
premedication in 3 patients (antihistamine in 1 and prednisone in 2) who developed a reaction during their first desensitization. Discussion In this report, the authors describe their experience with 12 patients with IBD who received a total of 68 successful infliximab desensitizations. The protocol also was successful in 5 other patients: 2 with rheumatoid arthritis, 2 with psoriatic arthritis, and 1 with ankylosing spondylitis, for a total of 44 desensitizations. The adverse reactions during desensitization were mild (flushing and pruritus) and treated with diphenhydramine. No serious reactions were reported and those patients were able to continue infliximab treatment. The use of mAbs in modern medicine is a technologic advance that has enhanced treatment of several human diseases. By targeting specific proteins, mAbs provide an efficient means to maximize therapeutic efficacy. Infliximab is one of the chimeric mAbs that has proved effective for induction and maintenance therapy in Crohn disease and ulcerative colitis.1,2 Its administration has been associated in some patients with the occurrence of immediate or delayed adverse reactions that often limited its use. In the present series, acute reactions to infliximab occurred in 8.9%, which is similar to the 9.7% reported in another study.5 Most patients who developed reactions to infliximab benefited from desensitization and continued to receive their effective treatment without significant adverse effect. In 2001, Puchner et al9 first reported a successful desensitization protocol for infliximab in 2 patients with anaphylaxis. The procedure was carried out in an intensive care unit setting using an 11-step protocol with a 2-fold increase every 15 minutes starting at 1:100,000 of the treatment dose. In 2003, Cheifetz et al5 followed a protocol using a concentration of 5 mg/mL starting at 10 mL/h for 15 minutes. The rate of infusion
Figure 3. Subsequent management in 30 patients who developed adverse reactions to infliximab.
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was increased every 15 minutes to 20, 40, 80, and 100 mL/h, after which the patient was continued at 150 mL/h for 30 minutes. If there was no reaction during this interval, then the rate was increased to 250 mL/h. In 2006, Duburque et al10 described 14 patients with Crohn disease who developed infliximab infusion reactions despite prophylactic administration of hydrocortisone. They successfully used an 11-step escalating-increments desensitization protocol, starting at a rate of 0.002 mg/mL/kg and gradually increasing to 0.2 mg/mL/kg for the next 7 steps. In 2009, Brennan et al11 reported on 6 patients who had immediate-type hypersensitivity reactions to infliximab and underwent a 12-step desensitization protocol. Although the desensitization procedure requires several hours, the studies cited earlier point to its advantage in allowing patients who respond well to infliximab but develop adverse reactions to continue the medication. It has been reported that changing to another medication carries the risk of relapse in more than 25% of patients.12 The desensitization procedure for infliximab should be performed by allergists with experience with drug desensitization and the treatment of anaphylaxis. The pathophysiology of these reactions is not known but is usually not mediated by IgE, although several cases of IgE reactions have been reported. The reactions in the present series do not seem to be mediated by IgE because skin testing showed a positive reaction in only 1 patient. IgG antibody and complement activation could be involved.13 Baert et al14 reported a positive correlation between IgG antibodies against infliximab and the risk of infusion reactions. The mechanism of desensitization is not clear. It has been postulated that the procedure could cause the formation of the univalent hapten carrier protein inhibiting IgE cross-linking on mast cells or possible intracellular signaling inhibition in the mast cell triggered by low-drug concentrations.15 In conclusion, effective infliximab therapy does not need to be discontinued in patients who develop systemic reactions. Desensitization can be successful in allowing the continuation of therapy, with only minor adverse reactions that can be easily managed or prevented. Application of the present desensitization protocol to a larger number of patients would further support its efficacy and safety. Acknowledgments The authors thank the allergy and immunology fellows and house staff who participated in the clinical care of these patients and Runhua Shi, MD, PhD, for assistance in statistical analysis. References [1] Kawalec P, Mikrut A, Wisniewska N, Pilc A. Tumor necrosis factor-a antibodies (infliximab, adalimumab and certolizumab) in Crohn’s disease: systematic review and meta-analysis. Arch Med Sci. 2013;9:765e779. [2] Rutgeerts P, Sandborn WJ, Feagan BG, et al. Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2005;353: 2462e2476. [3] Imagama T, Taguchi T. Efficacy and adverse reactions of the TNF alpha inhibitor infliximab in rheumatoid arthritis. Nihon Rinsho. 2013;71:1209e1213. [4] Rustin MH. Long-term safety of biologics in the treatment of moderate-tosevere plaque psoriasis: review of current data. Br J Dermatol. 2012; 167(suppl 3):3e11. [5] Cheifetz A, Smedley M, Martin S, et al. The incidence and management of infusion reactions to infliximab: a large center experience. Am J Gastroenterol. 2003;98:1315e1324. [6] Vultaggio A, Matucci A, Nencini F, Pratesi S, Maggi E. Skin testing and infliximab-specific antibodies detection as a combined strategy for preventing infusion reaction. Intern Emerg Med. 2012;7(suppl 2):S77eS79. [7] Matucci A, Pratesi S, Petroni G, et al. Allergological in vitro and in vivo evaluation of patients with hypersensitivity reactions to infliximab. Clin Exp Allergy. 2013;43:659e664. [8] Alvarez-Cuesta E, Madrigal-Burgaleta R, Angel-Pereira D, et al. Delving into cornerstones of hypersensitivity to antineoplastic and biological agents: value of diagnostic tools prior to desensitization [published online ahead of print March 31, 2015]. Allergy. http://dx.doi.org/10.1111/all.12620.
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[12] Hoentjen F, Haarhuis BJ, Drenth JP, de Jong DJ. Elective switching from infliximab to adalimumab in stable Crohn’s disease. Inflamm Bowel Dis. 2013; 19:761e766. [13] Khan DA, Solensky R. Drug allergy. J Allergy Clin Immunol. 2010;125(suppl 2): S126eS137. [14] Baert F, Noman M, Vermeire S, et al. Influence of immunogenicity on the longterm efficacy of infliximab in Crohn’s disease. N Engl J Med. 2003;348: 601e608. [15] deShazo RD, Kemp SF. Allergic reactions to drugs and biologic agents. JAMA. 1997;278:1895e1906.