OBSERVATION Immediate Type I Hypersensitivity Response Implicated in Worsening Injection Site Reactions to Adalimumab Michael Paltiel, MD; Laura M. Gober, MD; April Deng, MD, PhD; Jamal Mikdashi, MD; Irena Alexeeva, MD; Sarbjit S. Saini, MD; Anthony A. Gaspari, MD Background: Tumor necrosis factor (TNF) inhibitors an immediate type I hypersensitivity reaction to adali- such as adalimumab, etanercept, and infliximab play an mumab. A histamine release assay performed on periph- increasingly important role in the management of a va- eral blood leukocytes from both patients demonstrated sig- riety of chronic inflammatory disorders. With their in- nificant histamine release on exposure to adalimumab. creasing use, a wide spectrum of dermatological adverse Furthermore, passive transfer of serum from one of the effects, including injection site reactions and the devel- allergic patients to basophils from a nonatopic, healthy do- opment of dermatitis, have been recognized. Previous nor sensitized those cells to release significant amounts studies have implicated the role of the delayed-type hy- of histamine with exposure to adalimumab. persensitivity reaction in mediation of injection site re- actions to etanercept. To our knowledge, there have been Conclusion: This study demonstrates that an IgE- no published studies on immunologic mechanism of in- mediated immediate type I hypersensitivity reaction plays jection site reactions to adalimumab to date. a role in the mediation of worsening injection site reac- tions in some patients receiving adalimumab. Observations: We describe 2 patients with a history of worsening injection site reactions to adalimumab. Find- ings from skin testing in both patients were suggestive of Arch Dermatol. 2008;144(9):1190-1194 HE ADVENT OF TUMOR rienced etanercept-induced ISRs by per- necrosis factor (TNF) forming an immunohistological analysis of inhibitors has dramatically reaction sites in 3 patients with rheuma- changed the therapeutic toid arthritis. The authors observed an in- approach to an increasing flammatory infiltrate composed largely of number of immune-mediated inflamma- T cells bearing an activated cytotoxic phe- T ϩ ϩ ϩ tory disorders including psoriasis notype (HLA-DR /CD3 /CD4−/CD8 ), 1 and psoriatic arthritis, rheumatoid with a minor contribution of cells bearing arthritis,2-4 juvenile idiopathic arthritis,5 6,7 an activated helper/inducer T-cell pheno- ankylosing spondylitis, ulcerative coli- ϩ ϩ ϩ − 8 9 type (HLA-DR /CD3 /CD4 /CD8 ), tis, and Crohn disease. Currently avail- CD14ϩ monocytes, CD1ϩ Langerhan cells, able anti-TNF agents include 1 soluble eosinophils, and neutrophils. The authors p75 TNF receptor (etanercept) and 2 speculated that their findings were most monoclonal anti-TNF antibodies (inflixi- consistent with a T-cell–mediated delayed mab and adalimumab). While generally hypersensitivity reaction, mediated by well tolerated and safe, a variety of ϩ 12 adverse effects including a wide spec- CD8 T cells. As with etanercept, pa- trum of dermatological conditions are tients receiving adalimumab therapy com- Author Affiliations: increasingly being recognized in the set- monly experience ISRs. To our knowl- Departments of Dermatology ting of TNF inhibitors. edge, however, no studies have been (Drs Paltiel, Deng, and In clinical trials, a variety of skin con- conducted to assess the immunologic Gaspari), Rheumatology ditions have been reported, including cu- mechanism of ISRs with adalimumab (Dr Mikdashi), and Neurology taneous eruptions and injection site reac- therapy to date. We describe 2 patients with (Dr Alexeeva), University of 4,10 prominent and worsening ISRs to adali- Maryland, and Department of tions (ISRs) during adalimumab therapy, Allergy and Clinical urticarial reactions and stomatitis during in- mumab and present evidence demonstrat- 11 Immunology, Johns Hopkins fliximab therapy, and ISRs during etaner- ing that immediate-type hypersensitivity re- University (Drs Gober and cept therapy.3 Zeltser et al12 conducted a action plays a role in the mediation of ISRs Saini), Baltimore, Maryland. retrospective study of patients who expe- in both patients. (REPRINTED) ARCH DERMATOL/ VOL 144 (NO. 9), SEP 2008 WWW.ARCHDERMATOL.COM 1190 ©2008 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/02/2021 REPORT OF CASES tients’ forearm, and skin was lightly pricked with a 27-gauge needle. A reading was performed 15 minutes after the pin prick. In addition, 0.1 mL (40 mg/0.8 mL) of adalimumab, 0.1 mL of CASE 1 vehicle, and 0.1 mL of normal saline were injected intrader- maly in the attempt to reproduce ISRs in both patients. Similar A 41-year-old Asian woman with a history of HLA-B27– testing was performed on 1 patient (patient 3), who had no his- positive spondyloarthropathy was treated with adali- tory of ISR to adalimumab after 9 months of therapy. mumab, 40 mg subcutaneously injected every other week, for arthritis involving both knees and the left ankle. The BASOPHIL ISOLATION patient’s arthritic symptoms improved considerably; how- AND HISTAMINE RELEASE ever, after 5 injections she began to develop ISRs consist- ing of prominent edema, erythema, and pruritus at the in- Venous blood samples for basophil studies were collected into jection sites on the abdomen and thighs. The initial syringes containing 5mM EDTA from 2 patients with a history reactions were localized to a small area within approxi- of ISRs to adalimumab, 1 patient (patient 3) with no history of mately 3 cm of injection site and appeared several hours ISRs to adalimumab, and 1 healthy, nonatopic control patient after an injection, and subsequent ISRs developed more with no history of exposure to adalimumab. Mixed blood leuko- cytes were isolated by dextran sedimentation and then stimu- rapidly (within minutes) and involved an increasingly lated for histamine release with adalimumab (0.5-50 000 ng/ greater area. Edema and erythema around the injection site mL) (Humira; Abbott Laboratories, Abbott Park, Illinois), human lasted 2 to 3 days after injection before gradual and com- ␥-globulin (50-50 000 µg/mL) (Sigma-Aldrich, St Louis, Mis- plete resolution. After 2 months of therapy, the patient de- souri), polyclonal goat antihuman IgE (0.1 µg/mL), and N- veloped multiple pruritic erythematous scaly patches in formyl-methionine-leucine-phenylalanine (1µM) at 37°C for a generalized distribution and discontinued the therapy. 45 minutes. Assays were performed in duplicate in standard buff- The dermatitis subsequently resolved with initiation of topi- ers containing calcium as previously described.13 Histamine was cal corticosteroids (clobetasol propionate, 0.05%, oint- quantified from supernatants using an automated fluorometric ment applied to the body and hydrocortisone, 2.5%, cream assay. Results are presented as the percentage of total histamine applied to the face) and narrow-band UV-B therapy. content minus the subject’s spontaneous histamine release. CASE 2 BASOPHIL SENSITIZATION A 60-year-old white woman with a history of irritable bowel In a separate experiment, basophils from the same nonatopic, healthy control patient were isolated by dextran sedimenta- syndrome, psoriasis, and psoriatic arthritis, attended our tion. Basophil surface IgE was stripped by incubating the cells dermatology clinic for treatment of persistent psoriasis and with lactic acid (pH 3.9) in normal saline for 3.5 minutes at psoriatic arthritis. The patient was being treated with etaner- room temperature.14,15 Following lactic acid stripping, serum cept, 25 mg every week for 4 years, with incomplete clear- from patient 1 was incubated with cells from the nonatopic do- ance of psoriasis and persistent arthritic symptoms. The nor at 37°C for 60 minutes in buffers containing heparin and patient had been previously treated with methotrexate and EDTA. Then the cells were stimulated for histamine release to phototherapy with limited success. Etanercept therapy was adalimumab (500-50 000 ng/mL) as described in the previous discontinued, and adalimumab therapy, 40 mg weekly for subsection. As a control to confirm removal of surface-bound the first 4 weeks, was initiated. The patient initially expe- IgE, cells were stimulated for histamine release by polyclonal rienced notable improvement of her arthritic symptoms goat antihuman IgE (0.1 µg/mL) and showed a 59% decrease in response after stripping (14%) vs before stripping (34%), with and psoriasis but developed edema and erythema around subsequent recovery of response (42%) following incubation the injection site within several hours after the second in- with serum from patient 1. jection. Gradually, each subsequent injection of adali- mumab resulted in a more prominent edema and ery- STATISTICAL ANALYSES thema around the injection site and developed more rapidly. Each ISR lasted 2 to 3 days before gradual resolution. The Quantitative data were analyzed for statistically significant dif- patient subsequently experienced decreased efficacy of the ferences between control and treatment groups using the Graph- drug in the treatment of psoriasis and psoriatic arthritis Pad Instat Software Program (GraphPad Software, San Diego, and discontinued the therapy. California). Because multiple comparisons were examined, a 1-way analysis of variance was applied to the quantitative data. PϽ.05 was considered statistically significant. METHODS RESULTS PIN-PRICK TESTING Pin-prick testing resulted in the development of wheal Pin-prick testing was used to