Allergy to monoclonal antibodies: cutting-edge

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Monoclonal antibodies are important therapeutic tools, but their usefulness is limited in patients ... This article reviews the current literature on desensitization and other .... Disclosure: David I Hong, MD, has disclosed no relevant financial relationships. .... Other reports describe antibodies to infliximab belonging to both the ...

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Allergy to monoclonal antibodies: cutting-edge desensitization methods for cutting-edge therapies Expert Rev. Clin. Immunol. 8(1), 43–54 (2012)

David I Hong, Lora Bankova, Katherine N Cahill, Timothy Kyin and Mariana C Castells* Harvard Medical School, 25 Shattuck Street, Boston, MA 02115, USA *Author for correspondence: [email protected]

Monoclonal antibodies are important therapeutic tools, but their usefulness is limited in patients who experience acute infusion reactions, most of which are consistent with type I hypersensitivity reactions including anaphylaxis. Patients who experience acute infusion reactions face the prospect of stopping treatment or switching to an alternative, and potentially more toxic or inferior treatment. Another option that overcomes the treatment hurdle of these reactions is rapid desensitization, a procedure in which the offending agent is re-administered in a stepwise, highly controlled fashion. While the risk of reactions is not completely eliminated, desensitization has proven to be a highly effective re-administration strategy for most patients who otherwise would not be able to tolerate their monoclonal antibody therapy owing to druginduced anaphylaxis. This article reviews the current literature on desensitization and other readministration protocols to monoclonal antibodies with an emphasis on four agents: rituximab, infliximab, cetuximab and trastuzumab. Keywords : allergy • anaphylaxis • cetuximab • drug desensitization • etanercept • infliximab • monoclonal antibody • rituximab • trastuzumab

Medscape: Continuing Medical Education Online This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of Medscape, LLC and Expert Reviews Ltd. Medscape, LLC is accredited by the ACCME to provide continuing medical education for physicians. Medscape, LLC designates this Journal-based CME activity for a maximum of 1 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. All other clinicians completing this activity will be issued a certificate of participation. To participate in this journal CME activity: (1) review the learning objectives and author disclosures; (2) study the education content; (3) take the post-test with a 70% minimum passing score and complete the evaluation at http://www.medscape.org/journal/expertimmunology; (4) view/ print certificate. Release date: 9 December 2011; Expiration date: 9 December 2012

Learning objectives Upon completion of this activity, participants should be able to: • Distinguish infusion-related reactions amenable to desensitization • Analyze infusion-related reactions to rituximab and their management • Analyze infusion-related reactions to infliximab and their management • Analyze infusion-related reactions to cetuximab and their management

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10.1586/ECI.11.75

© 2012 Expert Reviews Ltd

ISSN 1744-666X

43

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Hong, Bankova, Cahill, Kyin & Castells

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Financial & competing interests disclosure

Editor Elisa Manzotti, Editorial Director, Future Science Group Disclosure: Elisa Manzotti has disclosed no relevant financial relationships. CME Author Charles P Vega, MD, Health Sciences Clinical Professor; Residency Director, Department of Family Medicine, University of California, Irvine, CA, USA Disclosure: Charles P Vega, MD, has disclosed no relevant financial relationships. Authors David I Hong, MD, Harvard Medical School, Boston, MA, USA Disclosure: David I Hong, MD, has disclosed no relevant financial relationships. Lora Bankova, MD, Harvard Medical School, Boston, MA, USA Disclosure: Lora Bankova, MD, has disclosed no relevant financial relationships. Katherine N Cahill, MD, Harvard Medical School, Boston, MA, USA Disclosure: Katherine N Cahill, MD, has disclosed no relevant financial relationships. Timothy Kyin, MD, Harvard Medical School, Boston, MA, USA Disclosure: Timothy Kyin, MD, has disclosed no relevant financial relationships. Mariana C Castells, MD, PhD, Harvard Medical School, Boston, MA, USA Disclosure: Mariana C Castells, MD, PhD, has disclosed no relevant financial relationships.

The use of monoclonal antibodies (mAbs) in modern medicine is a technological advance that has revolutionized our approach to treating and thinking about a number of human diseases. By targeting specific proteins, mAbs provide an efficient means of exploiting our understanding of disease mechanisms to maximize therapeutic efficacy and, hopefully, minimize harm to the patient. The collective experience of using various mAbs over the years has uncovered data on hypersensitivity reactions to these drugs. Most reactions to mAbs occur acutely during the infusion, with symptoms ranging from mild rigors to systemic anaphylaxis. An extensive review of reactions to monoclonal treatments is beyond the scope of this review but can be found in the recently published review by Maggi et al. [1] . Reactions have been documented to occur with initial or repeated exposure, and skin testing to the offending agent can be negative, suggesting the mechanism of reaction is not necessarily IgE-dependent. The timing and type of symptoms patients experience during a reaction strongly suggest involvement by cells containing preformed inflammatory mediators (i.e., mast cells and basophils) since most reactions are responsive to immediate interventions such as stopping the infusion and treating symptoms of mast cell or basophil degranulation with epinephrine, antihistamine and/or albuterol. Hypersensitivity reactions, including most acute infusion reactions, represent a treatment impediment that in many cases can be circumvented by desensitization in which a patient is temporarily ‘tolerized’ to a medication that previously induced a hypersensitivity reaction. Since the first desensitization protocols to penicillins were conceived in the 1940s [2,3] , desensitizations have since been successfully performed against a variety of other medications eliciting acute hypersensitivity reactions. Our group’s experience desensitizing ovarian cancer patients to carboplatin and paclitaxel demonstrated that acute IgE-dependent (carboplatin) or -independent (paclitaxel) reactions are both amenable to desensitization protocols using serial log dilutions and careful step-wise dosing advancement [4] . While there is risk to re-administering a drug to which a patient has had a hypersensitivity reaction, this risk should be weighed against the benefit of using that drug when the offending agent is the best or only treatment option. Desensitization is 44

contraindicated in patients whose reaction suggests a history of Stevens–Johnson syndrome or toxic epidermal necrolysis. Nor is desensitization appropriate for reactions of serum sickness or hemolytic anemia [101] . Re-administration of the suspected offending agent in these patients is absolutely contraindicated. Other syndromes for which desensitization should be avoided include hypersensitivity pneumonitis, cytokine-release syndromes and direct adverse drug effects that are dose dependent. Desensitization is generally effective for IgE-dependent or -independent hypersensitivity reactions, including anaphylaxis [4] . Some reactions to mAbs occur on first exposure, and skin test data is generally not helpful [5] . While desensitization protocols may vary slightly from group to group, all start by giving the patient an extremely small dose, often 102 –103-fold lower than the full dose, and gradually increasing the rate of infusion in a step-wise fashion over fixed time intervals until the patient is ‘tolerized’ to the offending agent. The step-wise nature of desensitization protocols makes it unlikely that the patient will suffer a reaction as severe in magnitude as the initial reaction since the drug is typically infused in a slow, highly controlled fashion, and there are multiple built-in breakpoints for medical intervention if needed. Given the growing importance and utilization of monoclonal therapy in treating human diseases, the need to circumvent hypersensitivity reactions to deliver essential treatments is answered by desensitization techniques. This article covers the existing literature on monoclonal desensitizations focusing on four widely used agents: rituximab, infliximab, cetuximab and trastuzamab. Rituximab

Rituximab is a chimeric mouse–human anti-CD20 monoclonal antibody used in the treatment of non-Hodgkin’s lymphoma (NHL), chronic lymphocytic lymphoma (CLL) and in combination therapy for rheumatoid arthritis (RA), Wegener’s granulomatosis (WG) and microscopic polyangiitis (MPA) [6] . Infusion-related reactions described in the prescribing insert include urticaria, hypotension, angioedema, hypoxia, bronchospasm, pulmonary infiltrates, acute respiratory distress syndrome, Expert Rev. Clin. Immunol. 8(1), (2012)

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Allergy to monoclonal antibodies

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% of desensitizations

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% of desensitizations

myocardial infarction, ventricular fibrillation, cardiogenic shock, anaphylactoid 100 events,or death, which can occur within Rituximab 30–120 min of infusion [6] . The majority 80 Infliximab Trastuzumab of these infusion reactions were shown to 60 occur during the first infusion and decrease with each subsequent exposure. The rate 40 of occurrence of infusion reactions on first exposure also varies depending on the 20 treatment indication (12% for WG/MPA, 0 27% for RA, 77% for NHL) for reasons CVR RESP THROAT F/C GI N-M CUT that are unknown [6] . The first reported series of rapid desensitization for hypersensitivity reactions 100 Rituximab to rituximab was described by Castells 80 Infliximab et al. as part of a case series of 413 desenTrastuzumab 60 sitizations in 98  patients [4] . The paper described the efficacy of a three-solution, 40 12-step, rapid desensitization protocol for 20 cancer patients who experienced hyper0 sensitivity reactions to their first-line CUT CVR RESP THROAT F/C GI N-M chemo­t herapy agent. Desensitizations were performed for reactions to carboFigure 1. The prevalence of hypersensitivity reactions is reduced with rapid platin, cisplatin, oxaliplatin, paclitaxel, desensitization. (A) Breakdown of initial presenting reactions for which patients were liposomal doxorubicin, doxorubicin or referred for desensitization. (B) Prevalence of reactions with desensitization. CUT: Cutaneous; CVR: Cardiovascular; F/C: Fever/chills; GI: Gastrointestinal; rituximab. Three of the 98 patients had N-M: Neurologic/muscular; RESP: Respiratory; THROAT: Throat tightness. seven desensitizations performed for Adapted with permission from [5] . reactions to rituximab: two patients with severe pruritis and rash, and a third patient who had syncope. the infusion. Severe infusions were treated with methylpredA complete list of presenting symptoms can be found in Figure 1. nisolone and parenteral albuterol, oxygen or epinephrine, all of Just prior to desensitization, all patients received premedica- which were available at the patient bedside. The infusion was tion with H1-receptor blockers (diphenhydramine or hydroxy- then resumed once symptoms subsided. All patients receiving rituximab via desensitization were able to zine) and H2 blockers (famotidine or ranitidine). The predominant reason for substituting oral hydroxyzine for intravenous receive their full treatment dose over seven desensitizations with (iv.) diphenhydramine was a history of restless leg syndrome no severe reactions. Some patients did experience mild reaction with iv. diphenhydramine. Acetaminophen and/or glucocorti- (defined as any non-life-threatening reaction). It is notable that of coids were also administered at the discretion of the referring all 413 desensitizations studied, the majority of desensitizations physician. An example of the desensitization protocol for ritux- (67%) had no reaction and severe reactions occurred in only 6% imab is shown in Table 1. Three 250‑ml solutions with different of cases. Also, no patient experienced any reaction during desensiconcentrations were used in a 12-step protocol in which the tization that was more severe than the initial presenting reaction. Brennan et al. described a group of 14 additional patients dose was advanced over 15‑min intervals by increasing the rate and/or the concentration of drug being administered. Solutions who experienced hypersensitivity reactions to rituximab as part #1 and #2 were 100- and ten-fold dilutions, respectively, of of a review of 105 desensitizations to mAbs in 23 patients who the original drug concentration and were used for steps #1–4 had reactions to mAbs [5] . The protocol for infusions and treatand #5–8 of the protocol. The concentration of solution #3 ment of reactions was identical to that described in Castells was calculated based on the remaining dose of rituximab to be et al. but adapted to dosing of mAbs (rituximab, infliximab and delivered after the completion of step #8, diluted in 250 ml of trastuzumab) [4] . Eleven out of 14 rituximab-sensitive patients buffer solution. Steps #9–11 continued the incremental dose developed a reaction on their first exposure and had no known increase after which the patient was considered ‘desensitized’. prior exposure to any other mAb [5] . Data on rituximab skin The remainder of the dose to be infused was given in step #12 testing were collected, but the sensitivity and specificity could at a rate of 80 ml/h. This final step constituted approximately not be validated on a larger scale and a negative skin test did half of the total desensitization time and approximately 92% not preclude desensitization over a strong clinical history of of the total dose administered. Most reactions, if any, occurred hypersensitivity reaction. Interestingly, one patient in the study during this last step. Most reactions were mild and treated converted from a positive to a negative skin test and was able to with iv. diphenhydramine or oral hydroxyzine after pausing tolerate a subsequent rituximab infusion without desensitization. www.expert-reviews.com

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Table 1. Rituximab desensitization protocol: standard three-solution, 12-step protocol.

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Hong, Bankova, Cahill, Kyin & Castells

Infliximab

Infliximab is a chimeric mouse–human IgG1 mAb that binds TNF-a with high Step Solution Rate Time Volume Dose administered Cumulative affinity and specificity, and is used pri(ml/h) (min) infused per with this step (mg) dose (mg) marily in the treatment of inflammatory step (ml) bowel disease and rheumatoid arthritis. 1 1† 2.0 15 0.50 0.0221 0.0221 Other TNF-a inhibitors include etanercept, a TNF receptor–IgG fusion protein; 2 5.0 15 1.25 0.0553 0.0774 certolizumab, a humanized antibody; 3 10.0 15 2.50 0.1106 0.1880 and two fully human anti-TNF‑a mono4 20.0 15 5.00 0.2212 0.4092 clonals, adalimumab and golimumab. ‡ Infliximab is administered via iv. infusion 5 2 5.0 15 1.25 0.5530 0.9622 while etanercept, adalimumab, golim6 10.0 15 2.50 1.1060 2.0682 umab and certolizumab are administered 7 20.0 15 5.00 2.2120 4.2802 subcutaneously. 8 40.0 15 10.00 4.4240 8.7042 Acute reactions constitute the most com§ mon type of reaction observed with TNF-a 9 3 10.0 15 2.50 10.9730 19.6772 inhibitors. The majority of reports define 10 20.0 15 5.00 21.9459 41.6231 acute reactions as reactions occurring in 11 40.0 15 10.00 43.8918 85.5149 the first 24 h after infusion and range from 12 80.0 174.375 232.50 1020.4851 1106.0000 headache, dizziness, nausea, flushing and † Solution 1: 250 ml of 0.044 mg/ml (total per bag: 11.060 mg). pruritus to more systemic symptoms of ‡ Solution 2: 250 ml of 0.442 mg/ml (total per bag: 110.600 mg). hypersensitivity reaction like chest pain, § Solution 3: 250 ml of 4.389 mg/ml (total per bag: 1097.296 mg). Target dose: 1106.0 mg; standard volume per bag: 250 ml; final rate of infusion: 80 ml/h; calculated final dyspnea and sometimes full anaphylaxis [7,8] . concentration: 4.424 mg/ml; standard time of infusion: 187 min; total time: 339.375 min (5.66 h). The total Patients who develop antibodies against volume and dose dispensed are more than the final dose given to the patient because many of the solutions are not completely infused. infliximab (human antichimeric antibodAdapted with permission from [5]. ies) have an increased risk of having an To date, there are no published reports of detectable IgE specific acute infusion reaction than patients who did not develop antito rituximab. bodies against infliximab. In a study by Hanauer et al., 38% of Consistent with the findings of Castells et al., the majority of reac- patients who had an acute infusion reaction, defined as a reaction tions that occurred to rituximab desensitization occurred during occurring within 1 h of infusion initiation, were found to have the last step (#12) with the majority of reactions consisting of mild positive IgG antibodies to infliximab [7] . Similarly, Baert et al. cutaneous symptoms (i.e., flushing, hives) [4] . Again, all reactions showed a strong association between the concentration of antiwere less severe than the initial presenting hypersensitivity reaction. bodies against infliximab and the occurrence of an infusion reacWhen reactions did occur, the infusion would be paused and the tion [9] . Other reports describe antibodies to infliximab belonging symptoms treated with additional diphenhydramine or hydroxy- to both the IgE and IgM classes, and a high index of correlation zine. For severe or refractory symptoms, methylprednisolone was with infusion reactions [10] . The use of concomitant immuno­ usually administered as well. suppressive agents such as methotrexate [9] or daily oral steroids Because rapid desensitization is temporary, repeat desensi- [11] has been reported to reduce the incidence of infusion reactions tizations took into account the patient’s previous history with by inhibiting the development of antibodies to infliximab, sugdesensitizations by prescribing additional premedication(s), either gesting this is an important mechanism behind the development pre-infusion or at specific steps during the protocol depending of acute reactions to monoclonals in general. on the timing and type of reaction(s) encountered. In addition In addition to blocking antibody formation to infliximab, some to antihistamines, supplementary premedications also included groups suggest that slowing the infusion rate can be helpful in montelukast alone (for bronchospasm), montelukast plus aspirin some instances of acute infusion reactions [12] . Several groups (for flushing), and acetaminophen with or without glucocorti- have also developed protocols for infliximab administration with coids (for fever/chills). For example, a patient who experienced routine premedication with steroids, antihistamines and acethives, bronchospasm and flushing at the beginning of step 12 aminophen [12,13] . However, at least two open studies on adverse would receive premedication with diphenhydramine, ranitidine, drug reactions to infliximab suggest that there is no advantage montelukast and aspirin before the infusion and additional iv. of a routine premedication for patients who do not have a prior diphenhydramine just prior to step  12. Of all the rituximab history of infusion reactions [14,15] . desensitizations studied in this series, only one severe reaction For acute infusion reactions, several desensitization protocols (hypo­tension) occurred, but like all the other desensitizations have been successfully applied. Puchner et al. first reported successperformed in the study the reaction was treated to resolution and ful desensitization to TNF-a inhibitors for anaphylactic reactions the patient was able to receive the full prescribed dose. in 2001 [16] . They described two patients who were desensitized to 46

Expert Rev. Clin. Immunol. 8(1), (2012)

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Allergy to monoclonal antibodies

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infliximab in an intensive care unit setting using an 11-step proto- the dosage using a solution of 0.2 mg/ml/kg. The rate of dose col with a twofold increase at each step starting at 1/100,000 of the escalation is unfortunately not specified, but the total infusion final dose [16] . The dose was increased every 15 min and the infu- time was 2 h and 45 min in each case. Of the 14 patients studied, sion was completed in 4 h. Both desensitizations were successful all were able to receive at least one full infliximab treatment. Three with the patients able to receive the necessary dose of medication. patients had mild reactions which were easily managed during the Chiefetz et al. summarized their group’s experience for manag- desensitization, one patient had angioedema necessitating stoppage ing acute infusion reactions to infliximab based on the severity of the protocol, and one patient had a delayed reaction consisting (mild, moderate or severe) of a patient’s infusion reaction [8] . The of generalized arthralgias, myalgias, fever and headache requiring specific categorizations of reactions within the mild, moderate and treatment with corticosteroids. severe subcategories are too lengthy to describe for this review but Brennan et al. reported the experience from our center with correlated to the mortality risk of the respective reactions. The six patients who had immediate-type hypersensitivity reactions study was a retrospective analysis of 165 patients who received a to infliximab [5] . The patients were assessed for infliximab hypertotal of 479 infusions over a 2.5-year window. All patients received sensitivity by an allergist and offered desensitization if the patient initial infusions starting at 10 ml/h for 15 min. The rate of infu- had a mild or severe acute reaction defined by Brown’s criteria [18] sion was then doubled every 15 min to 20, 40, 80 and 100 ml/h, and/or a positive skin test to infliximab. Four patients (67%) had after which the patient was continued at 150 ml/h for 30 min. If a positive intradermal skin test at either 0.1 or 1.0 mg/ml concenthere was no reaction during this interval, the rate was increased tration and all patients undergoing desensitization had reactions to a top rate of 250 ml/h. If, and only if, patients suffered a reac- after several exposures to infliximab. The same protocol used for tion, they were given subsequent infliximab infusions by modi- rituximab desensitization was used successfully for infliximab fied infusion protocols including desensitization for a history of desensitization with the majority of reactions occurring during the moderate-to-severe reactions. In the study, there were 26 acute last step and consisting of mainly cutaneous symptoms of flushreactions of which 15 (58%) were mild, six (23%) were moderate ing, pruritis and/or hives. In addition to the premedication algoand five (19%) were severe. Patients with mild reactions received rithm used to treat and prevent reactions in patients undergoing standard premedication (diphenhydramine and acetaminophen) repeat desensitizations, another protocol modification that was before a test dose of 10 ml/h was given prior to uptitration of the occasionally employed was the insertion of one or more additional rate over 3 h. Six patients who had moderate reactions received steps in the protocol to decrease the slope of the dose–time curve standard premedication with uptitration of the rate from 10 ml/h at certain points in the protocol where reactions occurred despite to 125 ml/h over six steps of 15-min intervals. Patients with severe reactions received Table 2. Infliximab desensitization protocol for a patient who had standard premedication with the addition recurrent urticaria at step 11 refractory to additional antihistamine†. of steroids prior to infusion uptitration Step Solution Rate Time Volume Dose administered Cumulative from 10 ml/h to 100 ml/h over five steps (ml/h) (min) infused per with this step dose (mg) of 15-min intervals. All patients with mild step (ml) (mg) or moderate reactions were able to continue 1‡ 2.0 15 0.50 0.0118 0.0118 infliximab treatment. Of the four patients 1 5.0 15 1.25 0.0296 0.0414 who had severe reactions, two were able to 2 continue treatment with desensitization, 3 10.0 15 2.50 0.0591 0.1005 one had a breakthrough severe reaction 4 20.0 15 5.00 0.1182 0.2187 and one withdrew from further treatments. § 5 2 5.0 15 1.25 0.2956 0.5143 In 2006, Duburque et  al. reported 10.0 15 2.50 0.5912 1.1055 their experience with desensitization in 6 14 patients with Crohn’s disease who had 7 20.0 15 5.00 1.1824 2.2879 developed infusion reactions despite pro8 40.0 15 10.00 2.3648 4.6527 phylactic administration of hydro­cortisone ¶ 9 3 10.0 15 2.50 5.8655 10.5182 [17] . The protocol was specifically for patients 20.0 15 5.00 11.7309 22.2492 with severe infusion reactions for whom the 10 continuation of infliximab therapy was con- 11 40.0 15 10.00 23.4619 45.7111 sidered as the only therapeutic option. The 11a 60.0 15 15.00 35.1928 80.9039 authors used an 11-step protocol in which 80.0 174.375 232.50 545.4889 591.2000 the final target dose was 5 mg/kg. The first 12 four steps of the protocol represented dose †‡A three-solution, 13-step protocol was developed. Note the addition of step 11a. Solution 1: 250 ml of 0.024 mg/ml (total per bag: 5.912 mg). escalations using a solution of infliximab §Solution 2: 250 ml of 0.236 mg/ml (total per bag: 59.120 mg). ¶ Solution 3: 250 ml of 2.346 mg/ml (total per bag: 586.547 mg). diluted to 2 × 10-3 mg/ml/kg in which the Target dose: 591.2 mg; standard volume per bag: 250 ml; final rate of infusion: 80 ml/h; calculated final rate was increased in a step-wise manner concentration: 2.3648 mg/ml; standard time of infusion: 187.5 min; total time: 354.375 min (5.91 h). every 15 min. Steps #5–11 further increased Adapted with permission from [5]. www.expert-reviews.com

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Table 3. Etanercept desensitization protocol for a patient with hypersensitivity to both adalimumab and etanercept. Step

Time interval from previous step (min)

Dose (mg)

Dilution Volume administered (ml)

1

0

0.25

1:100

1

2

30

0.5

1:10

0.2

3

60

1

1:10

0.4

4

60

2

1:10

0.8

5

90

4

1:1

0.16

120

4.5

1:1

0.18

1

0

0.25

1:100

1

2

30

0.5

1:10

0.2

3

60

1

1:10

0.4

4

60

2

1:10

0.8

5

90

4

1:1

0.16

120

4.5

1:1

0.18

1

0

0.25

1:100

1

2

30

0.5

1:10

0.2

3

60

1

1:10

0.4

4

60

2

1:10

0.8

5

90

4

1:1

0.16

6

120

8

1:1

0.32

7

150

8.75

1:1

0.35

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Day 1†

6

Day 2



6

Day 3

§

Maintenance dosing (twice weekly) 1

NA

CME

Hong, Bankova, Cahill, Kyin & Castells

25

1:1

1

Total dose administered: 12.25 mg. ‡ Total dose administered: 12.25 mg. § Total dose administered: 25 mg. Etranercept desensitization standard dilution: 25 mg/ml. Data from [23].

performed a successful desensitization in a patient with plaque psoriasis who had poor responses to methotrexate and etancercept [21] . Infliximab was also tried but discontinued secondary to a cardiac dysrhythmia associated with its use. Adalimumab was very effective but induced generalized urticaria and rhinitis after six doses. The patient was skin-test positive to full strength adalimumab (50 mg/ml) as compared with ten negative control patients. In their protocol, no premedications were given and the adalimumab was given over six injections spaced 60 min apart starting with a 0.5-mg dose. Each subsequent injection was a rough doubling of the prior step. By the end of the 6-h desensitization, the patient had received her full dose of 44.25 mg. The administration of the early doses was made possible by 1:10 and 1:100 dilutions of full strength adalimumab in sterile water. Bavbek et al. very recently reported a successful desensitization to etanercept in a patient with ankylosing spondylitis who became sensitized to both adalimumab and etanercept [23] . The patient had developed local swelling, diffuse pruritus and shortness of breath after his 26th adalimumab injection and was then switched to etanercept. He developed a local reaction followed by a disseminated urticarial rash after his 22nd etanercept injection. The patient was positive on intradermal skin test to 1:100 dilution of etanercept as compared with two negative control patients. An attempt to prevent a reaction with antihistamines was unsuccessful secondary to a breakthrough disseminated urticarial rash. The patient was then desensitized following a 3-day protocol as shown in Table 3. The patient was premedicated with aspirin, monte­ lukast, H1 and H2 blockers, and received six to seven consecutive injections of gradually increasing etanercept doses on days one through three. Each injection was spaced by 30- to 150-min intervals starting at 1/100 dilution of the final dose and doubling the dose with each step. The cumulative dose on the first and second day was identical and equal to approximately half of the target dose (12.25 mg). On day three, the patient achieved the full target dose (25 mg) and desensitization was maintained by twice-weekly administrations of full-dose etanercept. Only small (

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