- Email: [email protected]
Year in review: urticaria and angioedema
Ann Allergy Asthma Immunol 114 (2015) 166e167
Contents lists available at ScienceDirect
Year in review: urticaria and angioedema Fred H. Hsieh, MD Allergy and Immunology, Respiratory Institute, Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio
A R T I C L E
I N F O
Article history: Received for publication November 4, 2014. Received in revised form November 25, 2014. Accepted for publication December 1, 2014.
Introduction Advances in the areas of urticaria, angioedema, and hereditary angioedema (HAE) were published in the Annals in 2014. These articles reflected unmet needs in urticaria pathogenesis, excitement over the use of new urticaria therapeutics, and increased activity and refinement in approaches to managing HAE. UrticariadPathogenesis Defects in filaggrin gene expression have been associated with skin epithelial barrier dysfunction and have been implicated in the pathogenesis of atopic dermatitis; Ye et al1 studied the expression of filaggrin in patients with chronic urticaria (CU). In skin biopsies from patients with CU, patients with atopic dermatitis, and normal controls, filaggrin expression was significantly increased only in patients with CU. This increase in filaggrin expression in CU was correlated with higher urticaria activity scores, increased transepidermal water loss, and decreased skin pH, suggesting that alterations in filaggrin expression in CU are associated with altered skin barrier function. Palikhe et al2 measured soluble P-selectin and the expression of P2Y12, a G-protein coupled purinergic receptor, on platelets derived from 14 aspirin-intolerant and 29 aspirin-tolerant patients with CU and 25 normal controls. P2Y12 expression was higher in patients with CU and soluble P-selectin levels were higher in aspirin-intolerant patients with CU compared with aspirin-tolerant patients. This preliminary study proposes a role for platelet activation in CU, although a direct mechanism by which platelet activation affects CU pathogenesis remains to be elucidated. Management of Chronic Urticaria Rorie et al3 enrolled 42 adult patients with CU in a prospective, double-blinded study of high-dose (4,000 IU/day) vs low-dose Reprints: Fred H. Hsieh, MD, Allergy and Immunology, Respiratory Institute, Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, A90, Cleveland, OH 44195; E-mail: [email protected]. Disclosure: Dr Hsieh receives research support from a Howard Hughes Medical Institute Early Career Grant.
(600 IU/day) oral vitamin D3 supplementation for 12 weeks to study the add-on benefit of vitamin D3 in the treatment of CU. All patients were instructed to take 10 mg of cetirizine twice daily, 150 mg of ranitidine twice daily, and 10 mg of montelukast daily in addition to their high-vs low-dose vitamin D supplement. The investigators found a statistically significant 40% decrease in total urticaria symptom scores in the high-dose vitamin D3 group only at 12 weeks, with a trend toward improved sleep quality and less pruritus. No adverse events were reported. Thus, high-dose vitamin D3 supplementation was found to be safe and potentially beneficial in treating CU. Orden et al4 retrospectively studied the efficacy of sulfasalazine in the treatment of CU in 31 patients treated with this immunomodulator during a 5-year period. Sulfasalazine was started in patients with poorly controlled CU at a dose of 500 mg/day and increased by 500 mg each week as tolerated to an initial target dose of 2,000 mg/day. This chart review found that 83% of patients reported an alleviation of symptoms at 3 months, with 51% of patient asymptomatic at 6 months. Thirty-five percent of patients tapered off sulfasalazine with no relapsing symptoms. Treatment failed in 16% of patients and 6% of patients developed a severe adverse event, which included leukopenia and rhabdomyolysis. The investigators concluded that sulfasalazine was roughly as effective as cyclosporine in the management of CU. Several studies focused on the use of omalizumab in CU. Sussman et al5 reported on the efficacy of omalizumab at 150 mg/month in a prospective, open-label study of 68 patients with severe, poorly controlled CU who had a 7-day urticaria activity score higher than 30 and a history of oral corticosteroid therapy. Patients were followed for up to 25 months. Treatment with omalizumab was associated with a substantial decrease in the 7-day urticaria activity score and a decrease in the use of concomitant medications, with 69% of patients achieving complete remission. No serious adverse events were reported during the observation period. Lang6 presented an evidenced-based appraisal of omalizumab in refractory urticaria and angioedema and concluded that the evidence of omalizumab efficacy is robust and with less potential for harm compared with other therapeutic alternatives, although costly. Kaplan7 delineated a straightforward and practical approach to CU
http://dx.doi.org/10.1016/j.anai.2014.12.001 1081-1206/Ó 2015 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
F.H. Hsieh / Ann Allergy Asthma Immunol 114 (2015) 166e167
treatment and proposed that omalizumab at 300 mg/month be considered as step 2 therapy after a trial of maximizing H1 antihistamines as step 1 therapy. Angioedema Wilson et al8 retrospectively studied 217 cases of angioedema attributed to angiotensin-converting enzyme inhibitor or angiotensin receptor blocker administration over a 3-year period but could not find any seasonal variation or association with daily temperature or pollen count. Hereditary AngioedemadClinical Aspects Walford and Zuraw9 presented a concise and updated review on the current cellular and molecular mechanisms of HAE, including a discussion of estrogen-associated angioedema. Xu et al10 retrospectively reviewed the clinical characteristics of 743 upper airway edema attacks in 43 Chinese patients with HAE and in this particular cohort found that dyspnea was the most frequent symptom of HAE attacks per episode and per patient. The mean age of onset was 27 years and the mean time for evolution of upper airway angioedema symptoms was 4.6 hours, although the interval to maximum symptoms could be as short as 30 minutes. Male patients comprised roughly half the cohort but had more asphyxiation attacks and required more tracheostomies. Nanda et al11 used a survey tool to query patients and medical providers on the use of short-term preprocedure prophylaxis medications for HAE. In the patient survey, 219 respondents reported their experience in aggregate for 66 invasive procedures. One hundred percent of patients received short-term prophylaxis, with anabolic steroids and plasma-derived C1 inhibitor (C1-INH) products most commonly used. However, short-term prophylaxis failed in 22% of patients. Thirty-seven physicians responded to the survey and reported their experience with 433 patients, with the physicians reporting a preference for plasma-derived C1-INH products vs anabolic steroids and with the physicians possibly overestimating the efficacy of short-term prophylaxis maneuvers. This variable approach to short-term prophylaxis, heterogeneous use of medications for short-term prophylaxis, and possible discordance between physician and patient experience of short-term prophylaxis efficacy demonstrate an important unmet need for future HAE clinical interventions. Hereditary AngioedemadTreatment Riedl et al12 reported on the results of a randomized, doubleblinded, placebo-controlled, multicenter trial of recombinant human (rh) C1-INH (derived from the milk of transgenic rabbits) for the treatment of angioedema attacks. Seventy-five patients who had oropharyngeal, facial, abdominal, or peripheral acute HAE attacks were randomized (3:2) to rhC1-INH or placebo, with efficacy measured using visual analog scale and treatment effect questionnaire (TEQ) scoring systems. The median time to symptom relief was 90 minutes in patients treated with rhC1-INH vs 152 minutes in those treated with placebo (TEQ) and the median time to minimal symptoms was 303 minutes in patients treated with rhC1-INH vs 483 minutes in those treated with placebo (TEQ); these findings were statistically significant. No thromboembolic events, anaphylaxis, or other serious adverse events related to rhC1-INH were reported. This study supports previous smaller
167
studies suggesting that rhC1-INH might be an additional therapeutic option for acute HAE attacks. Kuhlen et al13 reported on a retrospective experience of 1,177 home nursing visits to treat 158 patients with nonlaryngeal acute HAE attacks using the plasma kallikrein inhibitor ecallantide. Because ecallantide administered subcutaneously has a reported 2.7% anaphylaxis rate, according to the drug label it must be administered by a health care professional, typically in an emergency department or physician’s office. Patients were not eligible for home infusion by nursing personnel if they had a history of laryngeal attacks. The mean time to home nursing response was 64 minutes, most patients (75%) required only 1 dose of ecallantide, and the mean time to patient-reported symptom relief was 42 minutes. Three percent of patients developed laryngeal edema and 9 hypersensitivity reactions were reported, with 6 patients requiring epinephrine. The investigators concluded that home nursing infusion could be a reasonable solution for using ecallantide for the treatment of acute nonlaryngeal HAE attacks. Conclusions In 2014 the Annals published numerous articles on urticaria, angioedema, and HAE. This research explored novel aspects of disease pathogenesis, diagnosis, and treatment. These publications have significantly increased our knowledge of urticaria and angioedema and will improve the clinical care provided for these diseases. The coming year should bring even further advances built on these discoveries. References [1] Ye YM, Kim BE, Shin YS, Park HS, Leung DY. Increased epidermal filaggrin in chronic idiopathic urticaria is associated with severity of urticaria. Ann Allergy Asthma Immunol. 2014;112:533e538. [2] Palikhe S, Palikhe NS, Kim SH, et al. Elevated platelet activation in patients with chronic urticaria: a comparison between aspirin-intolerant and aspirintolerant groups. Ann Allergy Asthma Immunol. 2014;113:276e281. [3] Rorie A, Goldner WS, Lyden E, Poole JA. Beneficial role for supplemental vitamin D3 treatment in chronic urticaria: a randomized study. Ann Allergy Asthma Immunol. 2014;112:376e382. [4] Orden RA, Timble H, Saini SS. Efficacy and safety of sulfasalazine in patients with chronic idiopathic urticaria. Ann Allergy Asthma Immunol. 2014;112: 64e70. [5] Sussman G, Hebert J, Barron C, et al. Real-life experiences with omalizumab for the treatment of chronic urticaria. Ann Allergy Asthma Immunol. 2014;112: 170e174. [6] Lang DM. A critical appraisal of omalizumab as a therapeutic option for chronic refractory urticaria/angioedema. Ann Allergy Asthma Immunol. 2014; 112:276e279. [7] Kaplan AP. Therapy of chronic urticaria: a simple, modern approach. Ann Allergy Asthma Immunol. 2014;112:419e425. [8] Wilson M, Frohna W, Trent G, Sauter D. Evaluating for seasonal variation in angiotensin-converting enzyme inhibitor- and angiotensin receptor blockerinduced angioedema. Ann Allergy Asthma Immunol. 2014;112:178e179. [9] Walford HH, Zuraw BL. Current update on cellular and molecular mechanisms of hereditary angioedema. Ann Allergy Asthma Immunol. 2014;112:413e418. [10] Xu YY, Zhi YX, Liu RL, Craig T, Zhang HY. Upper airway edema in 43 patients with hereditary angioedema. Ann Allergy Asthma Immunol. 2014;112: 539e544. [11] Nanda MK, Singh U, Wilmot J, Bernstein JA. A cross-sectional questionnaire assessing patient and physician use of short-term prophylaxis for hereditary angioedema. Ann Allergy Asthma Immunol. 2014;113:198e203. [12] Riedl MA, Bernstein JA, Li H, et al. Recombinant human C1-esterase inhibitor relieves symptoms of hereditary angioedema attacks: phase 3, randomized, placebo-controlled trial. Ann Allergy Asthma Immunol. 2014;112:163e169. [13] Kuhlen J, Guyer A, Morphew T, Tachdjian R, Banerji A. Assessment of home infusion program for treating nonlaryngeal hereditary angioedema attacks. Ann Allergy Asthma Immunol. 2014;112:471e472.
Contents lists available at ScienceDirect
Year in review: urticaria and angioedema Fred H. Hsieh, MD Allergy and Immunology, Respiratory Institute, Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio
A R T I C L E
I N F O
Article history: Received for publication November 4, 2014. Received in revised form November 25, 2014. Accepted for publication December 1, 2014.
Introduction Advances in the areas of urticaria, angioedema, and hereditary angioedema (HAE) were published in the Annals in 2014. These articles reflected unmet needs in urticaria pathogenesis, excitement over the use of new urticaria therapeutics, and increased activity and refinement in approaches to managing HAE. UrticariadPathogenesis Defects in filaggrin gene expression have been associated with skin epithelial barrier dysfunction and have been implicated in the pathogenesis of atopic dermatitis; Ye et al1 studied the expression of filaggrin in patients with chronic urticaria (CU). In skin biopsies from patients with CU, patients with atopic dermatitis, and normal controls, filaggrin expression was significantly increased only in patients with CU. This increase in filaggrin expression in CU was correlated with higher urticaria activity scores, increased transepidermal water loss, and decreased skin pH, suggesting that alterations in filaggrin expression in CU are associated with altered skin barrier function. Palikhe et al2 measured soluble P-selectin and the expression of P2Y12, a G-protein coupled purinergic receptor, on platelets derived from 14 aspirin-intolerant and 29 aspirin-tolerant patients with CU and 25 normal controls. P2Y12 expression was higher in patients with CU and soluble P-selectin levels were higher in aspirin-intolerant patients with CU compared with aspirin-tolerant patients. This preliminary study proposes a role for platelet activation in CU, although a direct mechanism by which platelet activation affects CU pathogenesis remains to be elucidated. Management of Chronic Urticaria Rorie et al3 enrolled 42 adult patients with CU in a prospective, double-blinded study of high-dose (4,000 IU/day) vs low-dose Reprints: Fred H. Hsieh, MD, Allergy and Immunology, Respiratory Institute, Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, A90, Cleveland, OH 44195; E-mail: [email protected]. Disclosure: Dr Hsieh receives research support from a Howard Hughes Medical Institute Early Career Grant.
(600 IU/day) oral vitamin D3 supplementation for 12 weeks to study the add-on benefit of vitamin D3 in the treatment of CU. All patients were instructed to take 10 mg of cetirizine twice daily, 150 mg of ranitidine twice daily, and 10 mg of montelukast daily in addition to their high-vs low-dose vitamin D supplement. The investigators found a statistically significant 40% decrease in total urticaria symptom scores in the high-dose vitamin D3 group only at 12 weeks, with a trend toward improved sleep quality and less pruritus. No adverse events were reported. Thus, high-dose vitamin D3 supplementation was found to be safe and potentially beneficial in treating CU. Orden et al4 retrospectively studied the efficacy of sulfasalazine in the treatment of CU in 31 patients treated with this immunomodulator during a 5-year period. Sulfasalazine was started in patients with poorly controlled CU at a dose of 500 mg/day and increased by 500 mg each week as tolerated to an initial target dose of 2,000 mg/day. This chart review found that 83% of patients reported an alleviation of symptoms at 3 months, with 51% of patient asymptomatic at 6 months. Thirty-five percent of patients tapered off sulfasalazine with no relapsing symptoms. Treatment failed in 16% of patients and 6% of patients developed a severe adverse event, which included leukopenia and rhabdomyolysis. The investigators concluded that sulfasalazine was roughly as effective as cyclosporine in the management of CU. Several studies focused on the use of omalizumab in CU. Sussman et al5 reported on the efficacy of omalizumab at 150 mg/month in a prospective, open-label study of 68 patients with severe, poorly controlled CU who had a 7-day urticaria activity score higher than 30 and a history of oral corticosteroid therapy. Patients were followed for up to 25 months. Treatment with omalizumab was associated with a substantial decrease in the 7-day urticaria activity score and a decrease in the use of concomitant medications, with 69% of patients achieving complete remission. No serious adverse events were reported during the observation period. Lang6 presented an evidenced-based appraisal of omalizumab in refractory urticaria and angioedema and concluded that the evidence of omalizumab efficacy is robust and with less potential for harm compared with other therapeutic alternatives, although costly. Kaplan7 delineated a straightforward and practical approach to CU
http://dx.doi.org/10.1016/j.anai.2014.12.001 1081-1206/Ó 2015 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
F.H. Hsieh / Ann Allergy Asthma Immunol 114 (2015) 166e167
treatment and proposed that omalizumab at 300 mg/month be considered as step 2 therapy after a trial of maximizing H1 antihistamines as step 1 therapy. Angioedema Wilson et al8 retrospectively studied 217 cases of angioedema attributed to angiotensin-converting enzyme inhibitor or angiotensin receptor blocker administration over a 3-year period but could not find any seasonal variation or association with daily temperature or pollen count. Hereditary AngioedemadClinical Aspects Walford and Zuraw9 presented a concise and updated review on the current cellular and molecular mechanisms of HAE, including a discussion of estrogen-associated angioedema. Xu et al10 retrospectively reviewed the clinical characteristics of 743 upper airway edema attacks in 43 Chinese patients with HAE and in this particular cohort found that dyspnea was the most frequent symptom of HAE attacks per episode and per patient. The mean age of onset was 27 years and the mean time for evolution of upper airway angioedema symptoms was 4.6 hours, although the interval to maximum symptoms could be as short as 30 minutes. Male patients comprised roughly half the cohort but had more asphyxiation attacks and required more tracheostomies. Nanda et al11 used a survey tool to query patients and medical providers on the use of short-term preprocedure prophylaxis medications for HAE. In the patient survey, 219 respondents reported their experience in aggregate for 66 invasive procedures. One hundred percent of patients received short-term prophylaxis, with anabolic steroids and plasma-derived C1 inhibitor (C1-INH) products most commonly used. However, short-term prophylaxis failed in 22% of patients. Thirty-seven physicians responded to the survey and reported their experience with 433 patients, with the physicians reporting a preference for plasma-derived C1-INH products vs anabolic steroids and with the physicians possibly overestimating the efficacy of short-term prophylaxis maneuvers. This variable approach to short-term prophylaxis, heterogeneous use of medications for short-term prophylaxis, and possible discordance between physician and patient experience of short-term prophylaxis efficacy demonstrate an important unmet need for future HAE clinical interventions. Hereditary AngioedemadTreatment Riedl et al12 reported on the results of a randomized, doubleblinded, placebo-controlled, multicenter trial of recombinant human (rh) C1-INH (derived from the milk of transgenic rabbits) for the treatment of angioedema attacks. Seventy-five patients who had oropharyngeal, facial, abdominal, or peripheral acute HAE attacks were randomized (3:2) to rhC1-INH or placebo, with efficacy measured using visual analog scale and treatment effect questionnaire (TEQ) scoring systems. The median time to symptom relief was 90 minutes in patients treated with rhC1-INH vs 152 minutes in those treated with placebo (TEQ) and the median time to minimal symptoms was 303 minutes in patients treated with rhC1-INH vs 483 minutes in those treated with placebo (TEQ); these findings were statistically significant. No thromboembolic events, anaphylaxis, or other serious adverse events related to rhC1-INH were reported. This study supports previous smaller
167
studies suggesting that rhC1-INH might be an additional therapeutic option for acute HAE attacks. Kuhlen et al13 reported on a retrospective experience of 1,177 home nursing visits to treat 158 patients with nonlaryngeal acute HAE attacks using the plasma kallikrein inhibitor ecallantide. Because ecallantide administered subcutaneously has a reported 2.7% anaphylaxis rate, according to the drug label it must be administered by a health care professional, typically in an emergency department or physician’s office. Patients were not eligible for home infusion by nursing personnel if they had a history of laryngeal attacks. The mean time to home nursing response was 64 minutes, most patients (75%) required only 1 dose of ecallantide, and the mean time to patient-reported symptom relief was 42 minutes. Three percent of patients developed laryngeal edema and 9 hypersensitivity reactions were reported, with 6 patients requiring epinephrine. The investigators concluded that home nursing infusion could be a reasonable solution for using ecallantide for the treatment of acute nonlaryngeal HAE attacks. Conclusions In 2014 the Annals published numerous articles on urticaria, angioedema, and HAE. This research explored novel aspects of disease pathogenesis, diagnosis, and treatment. These publications have significantly increased our knowledge of urticaria and angioedema and will improve the clinical care provided for these diseases. The coming year should bring even further advances built on these discoveries. References [1] Ye YM, Kim BE, Shin YS, Park HS, Leung DY. Increased epidermal filaggrin in chronic idiopathic urticaria is associated with severity of urticaria. Ann Allergy Asthma Immunol. 2014;112:533e538. [2] Palikhe S, Palikhe NS, Kim SH, et al. Elevated platelet activation in patients with chronic urticaria: a comparison between aspirin-intolerant and aspirintolerant groups. Ann Allergy Asthma Immunol. 2014;113:276e281. [3] Rorie A, Goldner WS, Lyden E, Poole JA. Beneficial role for supplemental vitamin D3 treatment in chronic urticaria: a randomized study. Ann Allergy Asthma Immunol. 2014;112:376e382. [4] Orden RA, Timble H, Saini SS. Efficacy and safety of sulfasalazine in patients with chronic idiopathic urticaria. Ann Allergy Asthma Immunol. 2014;112: 64e70. [5] Sussman G, Hebert J, Barron C, et al. Real-life experiences with omalizumab for the treatment of chronic urticaria. Ann Allergy Asthma Immunol. 2014;112: 170e174. [6] Lang DM. A critical appraisal of omalizumab as a therapeutic option for chronic refractory urticaria/angioedema. Ann Allergy Asthma Immunol. 2014; 112:276e279. [7] Kaplan AP. Therapy of chronic urticaria: a simple, modern approach. Ann Allergy Asthma Immunol. 2014;112:419e425. [8] Wilson M, Frohna W, Trent G, Sauter D. Evaluating for seasonal variation in angiotensin-converting enzyme inhibitor- and angiotensin receptor blockerinduced angioedema. Ann Allergy Asthma Immunol. 2014;112:178e179. [9] Walford HH, Zuraw BL. Current update on cellular and molecular mechanisms of hereditary angioedema. Ann Allergy Asthma Immunol. 2014;112:413e418. [10] Xu YY, Zhi YX, Liu RL, Craig T, Zhang HY. Upper airway edema in 43 patients with hereditary angioedema. Ann Allergy Asthma Immunol. 2014;112: 539e544. [11] Nanda MK, Singh U, Wilmot J, Bernstein JA. A cross-sectional questionnaire assessing patient and physician use of short-term prophylaxis for hereditary angioedema. Ann Allergy Asthma Immunol. 2014;113:198e203. [12] Riedl MA, Bernstein JA, Li H, et al. Recombinant human C1-esterase inhibitor relieves symptoms of hereditary angioedema attacks: phase 3, randomized, placebo-controlled trial. Ann Allergy Asthma Immunol. 2014;112:163e169. [13] Kuhlen J, Guyer A, Morphew T, Tachdjian R, Banerji A. Assessment of home infusion program for treating nonlaryngeal hereditary angioedema attacks. Ann Allergy Asthma Immunol. 2014;112:471e472.