Urticaria

WASHINGTON – Patients with spontaneous chronic urticaria treated with the investigational anti-IgE monoclonal antibody ligelizumab experienced up to a year of symptom control in an open-label extension study, Diane Baker, MD, said at the annual meeting of the American Academy of Dermatology.

About 75% of the cohort experienced complete disease control at least once during the study. Novartis is developing ligelizumab (QGE031) as a treatment option for patients with spontaneous chronic urticaria (CSU) whose symptoms are inadequately controlled by H₁-antihistamines. Like omalizumab (Xolair), which is approved in the United States and Europe for treatment of CSU, ligelizumab is a humanized anti-IgE monoclonal antibody. But the investigational agent binds to IgE with greater affinity than omalizumab, said Dr. Baker, a dermatologist who practices in Portland, Ore.

The extension study was a follow-up to a 12-week, phase 2, dose-finding trial of 382 CSU patients. In the study, which was not powered for efficacy endpoints, 51% of those who received 72 mg subcutaneously every 4 weeks had a Hives Severity Score of 0 by week 12, compared with 42% of those who received 240 mg every 4 weeks and 26% of those taking the omalizumab comparator. Additionally, 47% of those in the 72-mg group and 46% of the 240-mg group achieved a score of 0 on another indicator, the Urticaria Activity Score, which measures symptoms over 7 days (UAS7).

The extension study, which evaluated the 240-mg dose, showed the durability of that response, with 52% of those in the 240-mg group maintained a UAS7 of 0 at 1 year, according to Dr. Baker. By the end of the year, most patients (75.8%) had experienced at least one period of complete symptom control, and 84.0% experienced a UAS of 6 or lower at least once.

Adverse events were common in the cohort, with 84% experiencing at least one. But most (78%) were mild or moderate, and there was no clear side effect pattern, Dr. Baker said. Eight patients discontinued treatment because of an adverse event, and another eight dropped out because of lack of efficacy. Other reasons for discontinuation were pregnancy, protocol deviation, and physician or patient decision.

Novartis has launched two 1-year, phase 3 trials randomizing patients to 72 mg or 240 mg of ligelizumab or 300 mg of omalizumab every 4 weeks in a similar patient population, Dr. Baker said. PEARL 1 and PEARL 2, the largest pivotal trials to date in CSU, will enroll more than 2,000 patients, according to a company press release.

Dr. Baker is a clinical trials investigator for Novartis.

msullivan@mdedge.com

SOURCE: Baker D et al. AAD 2019, Session S034.

WASHINGTON – Patients with spontaneous chronic urticaria treated with the investigational anti-IgE monoclonal antibody ligelizumab experienced up to a year of symptom control in an open-label extension study, Diane Baker, MD, said at the annual meeting of the American Academy of Dermatology.

About 75% of the cohort experienced complete disease control at least once during the study. Novartis is developing ligelizumab (QGE031) as a treatment option for patients with spontaneous chronic urticaria (CSU) whose symptoms are inadequately controlled by H₁-antihistamines. Like omalizumab (Xolair), which is approved in the United States and Europe for treatment of CSU, ligelizumab is a humanized anti-IgE monoclonal antibody. But the investigational agent binds to IgE with greater affinity than omalizumab, said Dr. Baker, a dermatologist who practices in Portland, Ore.

The extension study was a follow-up to a 12-week, phase 2, dose-finding trial of 382 CSU patients. In the study, which was not powered for efficacy endpoints, 51% of those who received 72 mg subcutaneously every 4 weeks had a Hives Severity Score of 0 by week 12, compared with 42% of those who received 240 mg every 4 weeks and 26% of those taking the omalizumab comparator. Additionally, 47% of those in the 72-mg group and 46% of the 240-mg group achieved a score of 0 on another indicator, the Urticaria Activity Score, which measures symptoms over 7 days (UAS7).

The extension study, which evaluated the 240-mg dose, showed the durability of that response, with 52% of those in the 240-mg group maintained a UAS7 of 0 at 1 year, according to Dr. Baker. By the end of the year, most patients (75.8%) had experienced at least one period of complete symptom control, and 84.0% experienced a UAS of 6 or lower at least once.

Adverse events were common in the cohort, with 84% experiencing at least one. But most (78%) were mild or moderate, and there was no clear side effect pattern, Dr. Baker said. Eight patients discontinued treatment because of an adverse event, and another eight dropped out because of lack of efficacy. Other reasons for discontinuation were pregnancy, protocol deviation, and physician or patient decision.

Novartis has launched two 1-year, phase 3 trials randomizing patients to 72 mg or 240 mg of ligelizumab or 300 mg of omalizumab every 4 weeks in a similar patient population, Dr. Baker said. PEARL 1 and PEARL 2, the largest pivotal trials to date in CSU, will enroll more than 2,000 patients, according to a company press release.

Dr. Baker is a clinical trials investigator for Novartis.

msullivan@mdedge.com

SOURCE: Baker D et al. AAD 2019, Session S034.

WASHINGTON – Patients with spontaneous chronic urticaria treated with the investigational anti-IgE monoclonal antibody ligelizumab experienced up to a year of symptom control in an open-label extension study, Diane Baker, MD, said at the annual meeting of the American Academy of Dermatology.

About 75% of the cohort experienced complete disease control at least once during the study. Novartis is developing ligelizumab (QGE031) as a treatment option for patients with spontaneous chronic urticaria (CSU) whose symptoms are inadequately controlled by H₁-antihistamines. Like omalizumab (Xolair), which is approved in the United States and Europe for treatment of CSU, ligelizumab is a humanized anti-IgE monoclonal antibody. But the investigational agent binds to IgE with greater affinity than omalizumab, said Dr. Baker, a dermatologist who practices in Portland, Ore.

The extension study was a follow-up to a 12-week, phase 2, dose-finding trial of 382 CSU patients. In the study, which was not powered for efficacy endpoints, 51% of those who received 72 mg subcutaneously every 4 weeks had a Hives Severity Score of 0 by week 12, compared with 42% of those who received 240 mg every 4 weeks and 26% of those taking the omalizumab comparator. Additionally, 47% of those in the 72-mg group and 46% of the 240-mg group achieved a score of 0 on another indicator, the Urticaria Activity Score, which measures symptoms over 7 days (UAS7).

The extension study, which evaluated the 240-mg dose, showed the durability of that response, with 52% of those in the 240-mg group maintained a UAS7 of 0 at 1 year, according to Dr. Baker. By the end of the year, most patients (75.8%) had experienced at least one period of complete symptom control, and 84.0% experienced a UAS of 6 or lower at least once.

Adverse events were common in the cohort, with 84% experiencing at least one. But most (78%) were mild or moderate, and there was no clear side effect pattern, Dr. Baker said. Eight patients discontinued treatment because of an adverse event, and another eight dropped out because of lack of efficacy. Other reasons for discontinuation were pregnancy, protocol deviation, and physician or patient decision.

Novartis has launched two 1-year, phase 3 trials randomizing patients to 72 mg or 240 mg of ligelizumab or 300 mg of omalizumab every 4 weeks in a similar patient population, Dr. Baker said. PEARL 1 and PEARL 2, the largest pivotal trials to date in CSU, will enroll more than 2,000 patients, according to a company press release.

Dr. Baker is a clinical trials investigator for Novartis.

msullivan@mdedge.com

SOURCE: Baker D et al. AAD 2019, Session S034.

WASHINGTON – During a session at the annual meeting of the American Academy of Dermatology, Adam Friedman, MD, presented on off-label use of immunomodulators for inflammatory skin diseases, the highlights of which he shared with fellow George Washington University dermatologist, A. Yasmine Kirkorian, MD, in an interview following the session.

Vidyard Video

Dr. Friedman, professor and interim chair of dermatology at George Washington University, Washington, provides his top list of immunomodulators, used off-label, ranging from dapsone and hydroxychloroquine, to pentoxifylline and low-dose naltrexone.

For example, as reflected in PubMed searches, low-dose naltrexone, which has to be compounded, is being used for such diseases as Hailey-Hailey and lichen planopilaris, said Dr. Friedman, who is using it for his mast cell activation syndrome patients. During the interview, he also describes his treatment approach for urticaria.

In his final remarks, Dr. Friedman encourages colleagues to “get creative,” publish, and talk about their experiences with off-label treatments in dermatology, citing the example of an article that mentioned using pioglitazone for lichen planopilaris. This article stimulated interest in using the type 2 diabetes agent pioglitazone to treat this skin disease, he notes.

Dr. Friedman and Dr. Kirkorian, a pediatric dermatologist at George Washington University and interim chief of pediatric dermatology at Children’s National in Washington had no relevant disclosures.

emechcatie@mdedge.com

WASHINGTON – During a session at the annual meeting of the American Academy of Dermatology, Adam Friedman, MD, presented on off-label use of immunomodulators for inflammatory skin diseases, the highlights of which he shared with fellow George Washington University dermatologist, A. Yasmine Kirkorian, MD, in an interview following the session.

Vidyard Video

Dr. Friedman, professor and interim chair of dermatology at George Washington University, Washington, provides his top list of immunomodulators, used off-label, ranging from dapsone and hydroxychloroquine, to pentoxifylline and low-dose naltrexone.

For example, as reflected in PubMed searches, low-dose naltrexone, which has to be compounded, is being used for such diseases as Hailey-Hailey and lichen planopilaris, said Dr. Friedman, who is using it for his mast cell activation syndrome patients. During the interview, he also describes his treatment approach for urticaria.

In his final remarks, Dr. Friedman encourages colleagues to “get creative,” publish, and talk about their experiences with off-label treatments in dermatology, citing the example of an article that mentioned using pioglitazone for lichen planopilaris. This article stimulated interest in using the type 2 diabetes agent pioglitazone to treat this skin disease, he notes.

Dr. Friedman and Dr. Kirkorian, a pediatric dermatologist at George Washington University and interim chief of pediatric dermatology at Children’s National in Washington had no relevant disclosures.

emechcatie@mdedge.com

WASHINGTON – During a session at the annual meeting of the American Academy of Dermatology, Adam Friedman, MD, presented on off-label use of immunomodulators for inflammatory skin diseases, the highlights of which he shared with fellow George Washington University dermatologist, A. Yasmine Kirkorian, MD, in an interview following the session.

Vidyard Video

Dr. Friedman, professor and interim chair of dermatology at George Washington University, Washington, provides his top list of immunomodulators, used off-label, ranging from dapsone and hydroxychloroquine, to pentoxifylline and low-dose naltrexone.

For example, as reflected in PubMed searches, low-dose naltrexone, which has to be compounded, is being used for such diseases as Hailey-Hailey and lichen planopilaris, said Dr. Friedman, who is using it for his mast cell activation syndrome patients. During the interview, he also describes his treatment approach for urticaria.

In his final remarks, Dr. Friedman encourages colleagues to “get creative,” publish, and talk about their experiences with off-label treatments in dermatology, citing the example of an article that mentioned using pioglitazone for lichen planopilaris. This article stimulated interest in using the type 2 diabetes agent pioglitazone to treat this skin disease, he notes.

Dr. Friedman and Dr. Kirkorian, a pediatric dermatologist at George Washington University and interim chief of pediatric dermatology at Children’s National in Washington had no relevant disclosures.

emechcatie@mdedge.com

GRAND CAYMAN, CAYMAN ISLANDS – Large doses of nonsedating second-generation antihistamines are at the heart of treating chronic urticaria and will adequately control symptoms in about half of patients.

Michele G. Sullivan/MDEdge News

But for those who don’t respond, treatment guidelines in both the United States and Europe outline a stepwise algorithm that should eventually control symptoms in about 95% of people, without continuous steroid use, Diane Baker, MD, said at the Caribbean Dermatology Symposium, provided by Global Academy for Medical Education.

The guidelines from the American Academy of Allergy, Asthma & Immunology/American College of Allergy, Asthma, and Immunology, and the European Academy of Allergy and Clinical Immunology [EAACI] and the American Academy of Allergy /Global Allergy are markedly similar, said Dr. Baker, a dermatologist in Portland, Ore.

The U.S. document offers a few more choices in its algorithm, while the European document sticks to a more straightforward progression of antihistamine progressing to omalizumab and then to cyclosporine.

“Both guidelines start with monotherapy of a second-generation antihistamine in the licensed dose. This has to be continuous monotherapy though. We still get patients who say, ‘My hives get better with the antihistamine, but they come back when I’m not taking it.’ Yes, patients need to understand that they have to stay on daily doses in order to control symptoms.”

Drug choice is largely physician preference. A 2014 Cochrane review examined 73 studies of H1-histamine blockers in 9,759 participants and found little difference between any of the drugs. “No single H1‐antihistamine stands out as most effective,” the authors concluded. “Cetirizine at 10 mg once daily in the short term and in the intermediate term was found to be effective in completely suppressing urticaria. Evidence is limited for desloratadine given at 5 mg once daily in the intermediate term and at 20 mg in the short term. Levocetirizine at 5 mg in the intermediate but not short term was effective for complete suppression. Levocetirizine 20 mg was effective in the short term, but 10 mg was not,” the study noted (Cochrane Database Syst Rev. 2014 Nov 14;[11]:CD006137).

“In my practice, we use cetirizine,” Dr. Baker said. “But if a patient is on fexofenadine, for example, and doing well, I wouldn’t change that.”

The treatment guidelines agree on the next step for unresponsive patients: Updosing the antihistamine. “You may have to jump up to four times the recommended dose,” she said. “Sometimes we do this gradually, but sometimes I go right ahead to that dose just to get the patient under control. And there’s good evidence that 50%-75% of our patients will be controlled on an updosing regimen. Just keep them on it until they are symptom free, and then you can try reducing it to see how they do.”

But even this can leave up to half of patients still itching. The next treatment step is where the guidelines diverge, Dr. Baker said. The U.S. document suggests trying several other options, including adding another second-generation antihistamine, adding an H2 agonist, a leukotriene receptor antagonist, or a sedating first-generation antihistamine.

“The European recommendation is to go straight to omalizumab,” Dr. Baker said. “They based this recommendation on the finding of insufficient evidence in the literature for any of these other things.”

Instead of recommending omalizumab to antihistamine-resistant patients, the U.S. guidelines suggest a dose-advancement trial of hydroxyzine or doxepin.

But there’s no arguing that omalizumab is highly effective for chronic urticaria, Dr. Baker noted. The 2015 ASTERIA trial perfectly illustrated the drug’s benefit for patients who were still symptomatic on optimal antihistamine treatment (J Invest Dermatol. 2015 Jan;135[1]:67-75).

The 40-week, randomized, double-blind placebo controlled study enrolled 319 patients, who received the injections as a monthly add-on therapy for 24 weeks in doses of 75 mg, 150 mg, or 300 mg or placebo. This was followed by 16 weeks of observation. The primary endpoint was change from baseline in weekly Itch Severity Score (ISS) at week 12.

The omalizumab 300-mg group had the best ISS scores at the end of the study. This group also met nine secondary endpoints, including a decreased time to reach the clinically important response of at least a 5-point ISS decrease.

The drug carries a low risk of adverse events, with just four patients (5%) in the omalizumab 300-mg group developing a serious side effect; none of these were judged to be related to the study drug. There is a very low risk of anaphylaxis associated with omalizumab – about 0.1% in clinical trials and 0.2% in postmarketing observational studies. A 2017 review of three omalizumab studies determined that asthma is the biggest risk factor for such a reaction.

The review found 132 patients with potential anaphylaxis associated with omalizumab. Asthma was the indication for omalizumab therapy in 80%; 43% of patients who provided an anaphylaxis history said that they had experienced a prior non–omalizumab-related reaction.

The U.S. guidelines don’t bring omalizumab into the picture until the final step, which recommends it, cyclosporine, or other unspecified biologics or immunosuppressive agents. At this point, however, the European guidelines move to a cyclosporine recommendation for the very small number of patients who were unresponsive to omalizumab.

Pivotal trials of omalizumab in urticaria used a once-monthly injection schedule, but more recent data suggest that patients who get the drug every 2 weeks may do better, Dr. Baker added. A chart review published in 2016 found a 100% response rate in patients who received twice monthly doses of 300 mg (J Am Acad Dermatol. 2016 Jun;74[6]:1274-6).

Dr. Baker disclosed that she has been a clinical trial investigator for Novartis.

Global Academy and this news organization are owned by the same parent company.

This article was updated 2/1/19.

msullivan@mdedge.com

GRAND CAYMAN, CAYMAN ISLANDS – Large doses of nonsedating second-generation antihistamines are at the heart of treating chronic urticaria and will adequately control symptoms in about half of patients.

Michele G. Sullivan/MDEdge News

But for those who don’t respond, treatment guidelines in both the United States and Europe outline a stepwise algorithm that should eventually control symptoms in about 95% of people, without continuous steroid use, Diane Baker, MD, said at the Caribbean Dermatology Symposium, provided by Global Academy for Medical Education.

The guidelines from the American Academy of Allergy, Asthma & Immunology/American College of Allergy, Asthma, and Immunology, and the European Academy of Allergy and Clinical Immunology [EAACI] and the American Academy of Allergy /Global Allergy are markedly similar, said Dr. Baker, a dermatologist in Portland, Ore.

The U.S. document offers a few more choices in its algorithm, while the European document sticks to a more straightforward progression of antihistamine progressing to omalizumab and then to cyclosporine.

“Both guidelines start with monotherapy of a second-generation antihistamine in the licensed dose. This has to be continuous monotherapy though. We still get patients who say, ‘My hives get better with the antihistamine, but they come back when I’m not taking it.’ Yes, patients need to understand that they have to stay on daily doses in order to control symptoms.”

Drug choice is largely physician preference. A 2014 Cochrane review examined 73 studies of H1-histamine blockers in 9,759 participants and found little difference between any of the drugs. “No single H1‐antihistamine stands out as most effective,” the authors concluded. “Cetirizine at 10 mg once daily in the short term and in the intermediate term was found to be effective in completely suppressing urticaria. Evidence is limited for desloratadine given at 5 mg once daily in the intermediate term and at 20 mg in the short term. Levocetirizine at 5 mg in the intermediate but not short term was effective for complete suppression. Levocetirizine 20 mg was effective in the short term, but 10 mg was not,” the study noted (Cochrane Database Syst Rev. 2014 Nov 14;[11]:CD006137).

“In my practice, we use cetirizine,” Dr. Baker said. “But if a patient is on fexofenadine, for example, and doing well, I wouldn’t change that.”

The treatment guidelines agree on the next step for unresponsive patients: Updosing the antihistamine. “You may have to jump up to four times the recommended dose,” she said. “Sometimes we do this gradually, but sometimes I go right ahead to that dose just to get the patient under control. And there’s good evidence that 50%-75% of our patients will be controlled on an updosing regimen. Just keep them on it until they are symptom free, and then you can try reducing it to see how they do.”

But even this can leave up to half of patients still itching. The next treatment step is where the guidelines diverge, Dr. Baker said. The U.S. document suggests trying several other options, including adding another second-generation antihistamine, adding an H2 agonist, a leukotriene receptor antagonist, or a sedating first-generation antihistamine.

“The European recommendation is to go straight to omalizumab,” Dr. Baker said. “They based this recommendation on the finding of insufficient evidence in the literature for any of these other things.”

Instead of recommending omalizumab to antihistamine-resistant patients, the U.S. guidelines suggest a dose-advancement trial of hydroxyzine or doxepin.

But there’s no arguing that omalizumab is highly effective for chronic urticaria, Dr. Baker noted. The 2015 ASTERIA trial perfectly illustrated the drug’s benefit for patients who were still symptomatic on optimal antihistamine treatment (J Invest Dermatol. 2015 Jan;135[1]:67-75).

The 40-week, randomized, double-blind placebo controlled study enrolled 319 patients, who received the injections as a monthly add-on therapy for 24 weeks in doses of 75 mg, 150 mg, or 300 mg or placebo. This was followed by 16 weeks of observation. The primary endpoint was change from baseline in weekly Itch Severity Score (ISS) at week 12.

The omalizumab 300-mg group had the best ISS scores at the end of the study. This group also met nine secondary endpoints, including a decreased time to reach the clinically important response of at least a 5-point ISS decrease.

The drug carries a low risk of adverse events, with just four patients (5%) in the omalizumab 300-mg group developing a serious side effect; none of these were judged to be related to the study drug. There is a very low risk of anaphylaxis associated with omalizumab – about 0.1% in clinical trials and 0.2% in postmarketing observational studies. A 2017 review of three omalizumab studies determined that asthma is the biggest risk factor for such a reaction.

The review found 132 patients with potential anaphylaxis associated with omalizumab. Asthma was the indication for omalizumab therapy in 80%; 43% of patients who provided an anaphylaxis history said that they had experienced a prior non–omalizumab-related reaction.

The U.S. guidelines don’t bring omalizumab into the picture until the final step, which recommends it, cyclosporine, or other unspecified biologics or immunosuppressive agents. At this point, however, the European guidelines move to a cyclosporine recommendation for the very small number of patients who were unresponsive to omalizumab.

Pivotal trials of omalizumab in urticaria used a once-monthly injection schedule, but more recent data suggest that patients who get the drug every 2 weeks may do better, Dr. Baker added. A chart review published in 2016 found a 100% response rate in patients who received twice monthly doses of 300 mg (J Am Acad Dermatol. 2016 Jun;74[6]:1274-6).

Dr. Baker disclosed that she has been a clinical trial investigator for Novartis.

Global Academy and this news organization are owned by the same parent company.

This article was updated 2/1/19.

msullivan@mdedge.com

GRAND CAYMAN, CAYMAN ISLANDS – Large doses of nonsedating second-generation antihistamines are at the heart of treating chronic urticaria and will adequately control symptoms in about half of patients.

Michele G. Sullivan/MDEdge News

But for those who don’t respond, treatment guidelines in both the United States and Europe outline a stepwise algorithm that should eventually control symptoms in about 95% of people, without continuous steroid use, Diane Baker, MD, said at the Caribbean Dermatology Symposium, provided by Global Academy for Medical Education.

The guidelines from the American Academy of Allergy, Asthma & Immunology/American College of Allergy, Asthma, and Immunology, and the European Academy of Allergy and Clinical Immunology [EAACI] and the American Academy of Allergy /Global Allergy are markedly similar, said Dr. Baker, a dermatologist in Portland, Ore.

The U.S. document offers a few more choices in its algorithm, while the European document sticks to a more straightforward progression of antihistamine progressing to omalizumab and then to cyclosporine.

“Both guidelines start with monotherapy of a second-generation antihistamine in the licensed dose. This has to be continuous monotherapy though. We still get patients who say, ‘My hives get better with the antihistamine, but they come back when I’m not taking it.’ Yes, patients need to understand that they have to stay on daily doses in order to control symptoms.”

Drug choice is largely physician preference. A 2014 Cochrane review examined 73 studies of H1-histamine blockers in 9,759 participants and found little difference between any of the drugs. “No single H1‐antihistamine stands out as most effective,” the authors concluded. “Cetirizine at 10 mg once daily in the short term and in the intermediate term was found to be effective in completely suppressing urticaria. Evidence is limited for desloratadine given at 5 mg once daily in the intermediate term and at 20 mg in the short term. Levocetirizine at 5 mg in the intermediate but not short term was effective for complete suppression. Levocetirizine 20 mg was effective in the short term, but 10 mg was not,” the study noted (Cochrane Database Syst Rev. 2014 Nov 14;[11]:CD006137).

“In my practice, we use cetirizine,” Dr. Baker said. “But if a patient is on fexofenadine, for example, and doing well, I wouldn’t change that.”

The treatment guidelines agree on the next step for unresponsive patients: Updosing the antihistamine. “You may have to jump up to four times the recommended dose,” she said. “Sometimes we do this gradually, but sometimes I go right ahead to that dose just to get the patient under control. And there’s good evidence that 50%-75% of our patients will be controlled on an updosing regimen. Just keep them on it until they are symptom free, and then you can try reducing it to see how they do.”

But even this can leave up to half of patients still itching. The next treatment step is where the guidelines diverge, Dr. Baker said. The U.S. document suggests trying several other options, including adding another second-generation antihistamine, adding an H2 agonist, a leukotriene receptor antagonist, or a sedating first-generation antihistamine.

“The European recommendation is to go straight to omalizumab,” Dr. Baker said. “They based this recommendation on the finding of insufficient evidence in the literature for any of these other things.”

Instead of recommending omalizumab to antihistamine-resistant patients, the U.S. guidelines suggest a dose-advancement trial of hydroxyzine or doxepin.

But there’s no arguing that omalizumab is highly effective for chronic urticaria, Dr. Baker noted. The 2015 ASTERIA trial perfectly illustrated the drug’s benefit for patients who were still symptomatic on optimal antihistamine treatment (J Invest Dermatol. 2015 Jan;135[1]:67-75).

The 40-week, randomized, double-blind placebo controlled study enrolled 319 patients, who received the injections as a monthly add-on therapy for 24 weeks in doses of 75 mg, 150 mg, or 300 mg or placebo. This was followed by 16 weeks of observation. The primary endpoint was change from baseline in weekly Itch Severity Score (ISS) at week 12.

The omalizumab 300-mg group had the best ISS scores at the end of the study. This group also met nine secondary endpoints, including a decreased time to reach the clinically important response of at least a 5-point ISS decrease.

The drug carries a low risk of adverse events, with just four patients (5%) in the omalizumab 300-mg group developing a serious side effect; none of these were judged to be related to the study drug. There is a very low risk of anaphylaxis associated with omalizumab – about 0.1% in clinical trials and 0.2% in postmarketing observational studies. A 2017 review of three omalizumab studies determined that asthma is the biggest risk factor for such a reaction.

The review found 132 patients with potential anaphylaxis associated with omalizumab. Asthma was the indication for omalizumab therapy in 80%; 43% of patients who provided an anaphylaxis history said that they had experienced a prior non–omalizumab-related reaction.

The U.S. guidelines don’t bring omalizumab into the picture until the final step, which recommends it, cyclosporine, or other unspecified biologics or immunosuppressive agents. At this point, however, the European guidelines move to a cyclosporine recommendation for the very small number of patients who were unresponsive to omalizumab.

Pivotal trials of omalizumab in urticaria used a once-monthly injection schedule, but more recent data suggest that patients who get the drug every 2 weeks may do better, Dr. Baker added. A chart review published in 2016 found a 100% response rate in patients who received twice monthly doses of 300 mg (J Am Acad Dermatol. 2016 Jun;74[6]:1274-6).

Dr. Baker disclosed that she has been a clinical trial investigator for Novartis.

Global Academy and this news organization are owned by the same parent company.

This article was updated 2/1/19.

msullivan@mdedge.com

Bedbugs are common pests causing several health and economic consequences. With increased travel, pesticide resistance, and a lack of awareness about prevention, bedbugs have become even more difficult to control, especially within large population centers.¹ The US Environmental Protection Agency considers bedbugs to be a considerable public health issue.² Typically, they are found in private residences; however, there have been more reports of bedbugs discovered in the workplace within the last 20 years.^3-5 Herein, we present a case of bedbugs presenting in this unusual environment.

Case Report

A 42-year-old man presented to our dermatology clinic with intensely itchy bumps over the bilateral posterior arms of 3 months’ duration. He had no other skin, hair, or nail concerns. Over the last 3 months prior to dermatologic evaluation, he was treated by an outside physician with topical steroids, systemic antibiotics, topical antifungals, and even systemic steroids with no improvement of the lesions or symptoms. On clinical examination at the current presentation, 8 to 10 pink dermal papules coalescing into 10-cm round patches were noted on the bilateral posterior arms (Figure 1). A punch biopsy of the posterior right arm was performed, and histologic analysis showed a dense superficial and deep infiltrate and a perivascular infiltrate of lymphocytes and eosinophils (Figure 2). No notable epidermal changes were observed.

At this time, the patient was counseled that the most likely cause was some unknown arthropod exposure. Given the chronicity of the patient’s disease course, bedbugs were favored; however, an extensive search of the patient’s home failed to uncover any arthropods, let alone bedbugs. A few weeks later, the patient discovered insects emanating from the mesh backing of his office chair while at work (Figure 3). The location of the intruders corresponded exactly with the lesions on the posterior arms. The occupational health office at his workplace collected samples of the arthropods and confirmed they were bedbugs. The patient’s lesions resolved with topical clobetasol once eradication of the workplace was complete.

Morphology and Epidemiology
Bedbugs are wingless arthropods that have flat, oval-shaped, reddish brown bodies. They are approximately 4.5-mm long and 2.5-mm wide (Figure 4). The 2 most common species of bedbugs that infect humans are Cimex lectularius and Cimex hemipterus. Bedbugs are most commonly found in hotels, apartments, and residential households near sleep locations. They reside in crevices, cracks, mattresses, cushions, dressers, and other structures proximal to the bed. During the day they remain hidden, but at night they emerge for a blood meal. The average lifespan of a bedbug is 6 to 12 months.⁶ Females lay more than 200 eggs that hatch in approximately 6 to 10 days.⁷ Bedbugs progress through 5 nymph stages before becoming adults; several blood meals are required to advance each stage.⁶

Although commonly attributed to the home, bedbugs are being increasingly seen in the office setting.^3-5 In a survey given to pest management professionals in 2015, more than 45% reported that they were contracted by corporations for bedbug infestations in office settings, an increase from 18% in 2010 and 36% in 2013.³ Bedbugs are brought into offices through clothing, luggage, books, and other personal items. Unable to find hosts at night, bedbugs adapt to daytime hours and spread to more unpredictable locations, including chairs, office equipment, desks, and computers.⁴ Additionally, they frequently move around to find a suitable host.⁵ As a result, the growth rate of bedbugs in an office setting is much slower than in the home, with fewer insects. Our patient did not have bedbugs at home, but it is possible that other employees transported them to the office over time.

Clinical Manifestations
Bedbugs cause pruritic and nonpruritic skin rashes, often of the arms, legs, neck, and face. A common reaction is an erythematous papule with a hemorrhagic punctum caused by one bite.⁸ Other presentations include purpuric macules, bullae, and papular urticaria.^8-10 Although bedbugs are suspected to transmit infectious diseases, no reports have substantiated that claim.¹¹

Our patient had several coalescing dermal papules on the arms indicating multiple bites around the same area. Due to the stationary aspect of his job—with the arms resting on his chair while typing at his desk—our patient was an easy target for consistent blood meals.

Detection
Due to an overall smaller population of insects in an office setting, detection of bedbugs in the workplace can be difficult. Infestations can be primarily identified on visual inspection by pest control.¹² The mesh backing on our patient’s chair was one site where bedbugs resided. It is important to check areas where employees congregate, such as lounges, lunch areas, conference rooms, and printers.⁴ It also is essential to examine coatracks and locker rooms, as employees may leave personal items that can serve as a source of transmission of the bugs from home. Additional detection tools provided by pest management professionals include canines, as well as devices that emit pheromones, carbon dioxide, or heat to ensnare the insects.¹²

Treatment
Treatment of bedbug bites is quite variable. For some patients, lesions may resolve on their own. Pruritic maculopapular eruptions can be treated with topical pramoxine or doxepin.⁸ Patients who develop allergic urticaria can use oral antihistamines. Systemic reactions such as anaphylaxis can be treated with a combination of intramuscular epinephrine, antihistamines, and corticosteroids.⁸ The etiology of our patient’s condition initially was unknown, and thus he was given unnecessary systemic steroids and antifungals until the source of the rash was identified and eradicated. Topical clobetasol was subsequently administered and was sufficient to resolve his symptoms.

Final Thoughts

Bedbugs continue to remain a nuisance in the home. This case provides an example of bedbugs in the office, a location that is not commonly associated with bedbug infestations. Bedbugs pose numerous psychological, economic, and health consequences.² Productivity can be reduced, as patients with symptomatic lesions will be unable to work effectively, and those who are unaffected may be unwilling to work knowing their office environment poses a health risk. In addition, employees may worry about bringing the bedbugs home. It is important that employees be educated on the signs of a bedbug infestation and take preventive measures to stop spreading or introducing them to the office space. Due to the scattered habitation of bedbugs in offices, pest control managers need to be vigilant to identify sources of infestation and eradicate accordingly. Clinical manifestations can be nonspecific, resembling autoimmune disorders, fungal infections, or bites from other various arthropods; thus, treatment is highly dependent on the patient’s history and occupational exposure.

Bedbugs have successfully adapted to a new environment in the office space. Dermatologists and other health care professionals can no longer exclusively associate bedbugs with the home. When the clinical and histological presentation suggests an arthropod assault, we must counsel our patients to surveil their homes and work settings alike. If necessary, they should seek the assistance of occupational health professionals.

Bedbugs are common pests causing several health and economic consequences. With increased travel, pesticide resistance, and a lack of awareness about prevention, bedbugs have become even more difficult to control, especially within large population centers.¹ The US Environmental Protection Agency considers bedbugs to be a considerable public health issue.² Typically, they are found in private residences; however, there have been more reports of bedbugs discovered in the workplace within the last 20 years.^3-5 Herein, we present a case of bedbugs presenting in this unusual environment.

Case Report

A 42-year-old man presented to our dermatology clinic with intensely itchy bumps over the bilateral posterior arms of 3 months’ duration. He had no other skin, hair, or nail concerns. Over the last 3 months prior to dermatologic evaluation, he was treated by an outside physician with topical steroids, systemic antibiotics, topical antifungals, and even systemic steroids with no improvement of the lesions or symptoms. On clinical examination at the current presentation, 8 to 10 pink dermal papules coalescing into 10-cm round patches were noted on the bilateral posterior arms (Figure 1). A punch biopsy of the posterior right arm was performed, and histologic analysis showed a dense superficial and deep infiltrate and a perivascular infiltrate of lymphocytes and eosinophils (Figure 2). No notable epidermal changes were observed.

At this time, the patient was counseled that the most likely cause was some unknown arthropod exposure. Given the chronicity of the patient’s disease course, bedbugs were favored; however, an extensive search of the patient’s home failed to uncover any arthropods, let alone bedbugs. A few weeks later, the patient discovered insects emanating from the mesh backing of his office chair while at work (Figure 3). The location of the intruders corresponded exactly with the lesions on the posterior arms. The occupational health office at his workplace collected samples of the arthropods and confirmed they were bedbugs. The patient’s lesions resolved with topical clobetasol once eradication of the workplace was complete.

Morphology and Epidemiology
Bedbugs are wingless arthropods that have flat, oval-shaped, reddish brown bodies. They are approximately 4.5-mm long and 2.5-mm wide (Figure 4). The 2 most common species of bedbugs that infect humans are Cimex lectularius and Cimex hemipterus. Bedbugs are most commonly found in hotels, apartments, and residential households near sleep locations. They reside in crevices, cracks, mattresses, cushions, dressers, and other structures proximal to the bed. During the day they remain hidden, but at night they emerge for a blood meal. The average lifespan of a bedbug is 6 to 12 months.⁶ Females lay more than 200 eggs that hatch in approximately 6 to 10 days.⁷ Bedbugs progress through 5 nymph stages before becoming adults; several blood meals are required to advance each stage.⁶

Although commonly attributed to the home, bedbugs are being increasingly seen in the office setting.^3-5 In a survey given to pest management professionals in 2015, more than 45% reported that they were contracted by corporations for bedbug infestations in office settings, an increase from 18% in 2010 and 36% in 2013.³ Bedbugs are brought into offices through clothing, luggage, books, and other personal items. Unable to find hosts at night, bedbugs adapt to daytime hours and spread to more unpredictable locations, including chairs, office equipment, desks, and computers.⁴ Additionally, they frequently move around to find a suitable host.⁵ As a result, the growth rate of bedbugs in an office setting is much slower than in the home, with fewer insects. Our patient did not have bedbugs at home, but it is possible that other employees transported them to the office over time.

Clinical Manifestations
Bedbugs cause pruritic and nonpruritic skin rashes, often of the arms, legs, neck, and face. A common reaction is an erythematous papule with a hemorrhagic punctum caused by one bite.⁸ Other presentations include purpuric macules, bullae, and papular urticaria.^8-10 Although bedbugs are suspected to transmit infectious diseases, no reports have substantiated that claim.¹¹

Our patient had several coalescing dermal papules on the arms indicating multiple bites around the same area. Due to the stationary aspect of his job—with the arms resting on his chair while typing at his desk—our patient was an easy target for consistent blood meals.

Detection
Due to an overall smaller population of insects in an office setting, detection of bedbugs in the workplace can be difficult. Infestations can be primarily identified on visual inspection by pest control.¹² The mesh backing on our patient’s chair was one site where bedbugs resided. It is important to check areas where employees congregate, such as lounges, lunch areas, conference rooms, and printers.⁴ It also is essential to examine coatracks and locker rooms, as employees may leave personal items that can serve as a source of transmission of the bugs from home. Additional detection tools provided by pest management professionals include canines, as well as devices that emit pheromones, carbon dioxide, or heat to ensnare the insects.¹²

Treatment
Treatment of bedbug bites is quite variable. For some patients, lesions may resolve on their own. Pruritic maculopapular eruptions can be treated with topical pramoxine or doxepin.⁸ Patients who develop allergic urticaria can use oral antihistamines. Systemic reactions such as anaphylaxis can be treated with a combination of intramuscular epinephrine, antihistamines, and corticosteroids.⁸ The etiology of our patient’s condition initially was unknown, and thus he was given unnecessary systemic steroids and antifungals until the source of the rash was identified and eradicated. Topical clobetasol was subsequently administered and was sufficient to resolve his symptoms.

Final Thoughts

Bedbugs continue to remain a nuisance in the home. This case provides an example of bedbugs in the office, a location that is not commonly associated with bedbug infestations. Bedbugs pose numerous psychological, economic, and health consequences.² Productivity can be reduced, as patients with symptomatic lesions will be unable to work effectively, and those who are unaffected may be unwilling to work knowing their office environment poses a health risk. In addition, employees may worry about bringing the bedbugs home. It is important that employees be educated on the signs of a bedbug infestation and take preventive measures to stop spreading or introducing them to the office space. Due to the scattered habitation of bedbugs in offices, pest control managers need to be vigilant to identify sources of infestation and eradicate accordingly. Clinical manifestations can be nonspecific, resembling autoimmune disorders, fungal infections, or bites from other various arthropods; thus, treatment is highly dependent on the patient’s history and occupational exposure.

Bedbugs have successfully adapted to a new environment in the office space. Dermatologists and other health care professionals can no longer exclusively associate bedbugs with the home. When the clinical and histological presentation suggests an arthropod assault, we must counsel our patients to surveil their homes and work settings alike. If necessary, they should seek the assistance of occupational health professionals.

Bedbugs are common pests causing several health and economic consequences. With increased travel, pesticide resistance, and a lack of awareness about prevention, bedbugs have become even more difficult to control, especially within large population centers.¹ The US Environmental Protection Agency considers bedbugs to be a considerable public health issue.² Typically, they are found in private residences; however, there have been more reports of bedbugs discovered in the workplace within the last 20 years.^3-5 Herein, we present a case of bedbugs presenting in this unusual environment.

Case Report

A 42-year-old man presented to our dermatology clinic with intensely itchy bumps over the bilateral posterior arms of 3 months’ duration. He had no other skin, hair, or nail concerns. Over the last 3 months prior to dermatologic evaluation, he was treated by an outside physician with topical steroids, systemic antibiotics, topical antifungals, and even systemic steroids with no improvement of the lesions or symptoms. On clinical examination at the current presentation, 8 to 10 pink dermal papules coalescing into 10-cm round patches were noted on the bilateral posterior arms (Figure 1). A punch biopsy of the posterior right arm was performed, and histologic analysis showed a dense superficial and deep infiltrate and a perivascular infiltrate of lymphocytes and eosinophils (Figure 2). No notable epidermal changes were observed.

At this time, the patient was counseled that the most likely cause was some unknown arthropod exposure. Given the chronicity of the patient’s disease course, bedbugs were favored; however, an extensive search of the patient’s home failed to uncover any arthropods, let alone bedbugs. A few weeks later, the patient discovered insects emanating from the mesh backing of his office chair while at work (Figure 3). The location of the intruders corresponded exactly with the lesions on the posterior arms. The occupational health office at his workplace collected samples of the arthropods and confirmed they were bedbugs. The patient’s lesions resolved with topical clobetasol once eradication of the workplace was complete.

Morphology and Epidemiology
Bedbugs are wingless arthropods that have flat, oval-shaped, reddish brown bodies. They are approximately 4.5-mm long and 2.5-mm wide (Figure 4). The 2 most common species of bedbugs that infect humans are Cimex lectularius and Cimex hemipterus. Bedbugs are most commonly found in hotels, apartments, and residential households near sleep locations. They reside in crevices, cracks, mattresses, cushions, dressers, and other structures proximal to the bed. During the day they remain hidden, but at night they emerge for a blood meal. The average lifespan of a bedbug is 6 to 12 months.⁶ Females lay more than 200 eggs that hatch in approximately 6 to 10 days.⁷ Bedbugs progress through 5 nymph stages before becoming adults; several blood meals are required to advance each stage.⁶

Although commonly attributed to the home, bedbugs are being increasingly seen in the office setting.^3-5 In a survey given to pest management professionals in 2015, more than 45% reported that they were contracted by corporations for bedbug infestations in office settings, an increase from 18% in 2010 and 36% in 2013.³ Bedbugs are brought into offices through clothing, luggage, books, and other personal items. Unable to find hosts at night, bedbugs adapt to daytime hours and spread to more unpredictable locations, including chairs, office equipment, desks, and computers.⁴ Additionally, they frequently move around to find a suitable host.⁵ As a result, the growth rate of bedbugs in an office setting is much slower than in the home, with fewer insects. Our patient did not have bedbugs at home, but it is possible that other employees transported them to the office over time.

Clinical Manifestations
Bedbugs cause pruritic and nonpruritic skin rashes, often of the arms, legs, neck, and face. A common reaction is an erythematous papule with a hemorrhagic punctum caused by one bite.⁸ Other presentations include purpuric macules, bullae, and papular urticaria.^8-10 Although bedbugs are suspected to transmit infectious diseases, no reports have substantiated that claim.¹¹

Our patient had several coalescing dermal papules on the arms indicating multiple bites around the same area. Due to the stationary aspect of his job—with the arms resting on his chair while typing at his desk—our patient was an easy target for consistent blood meals.

Detection
Due to an overall smaller population of insects in an office setting, detection of bedbugs in the workplace can be difficult. Infestations can be primarily identified on visual inspection by pest control.¹² The mesh backing on our patient’s chair was one site where bedbugs resided. It is important to check areas where employees congregate, such as lounges, lunch areas, conference rooms, and printers.⁴ It also is essential to examine coatracks and locker rooms, as employees may leave personal items that can serve as a source of transmission of the bugs from home. Additional detection tools provided by pest management professionals include canines, as well as devices that emit pheromones, carbon dioxide, or heat to ensnare the insects.¹²

Treatment
Treatment of bedbug bites is quite variable. For some patients, lesions may resolve on their own. Pruritic maculopapular eruptions can be treated with topical pramoxine or doxepin.⁸ Patients who develop allergic urticaria can use oral antihistamines. Systemic reactions such as anaphylaxis can be treated with a combination of intramuscular epinephrine, antihistamines, and corticosteroids.⁸ The etiology of our patient’s condition initially was unknown, and thus he was given unnecessary systemic steroids and antifungals until the source of the rash was identified and eradicated. Topical clobetasol was subsequently administered and was sufficient to resolve his symptoms.

Final Thoughts

Bedbugs continue to remain a nuisance in the home. This case provides an example of bedbugs in the office, a location that is not commonly associated with bedbug infestations. Bedbugs pose numerous psychological, economic, and health consequences.² Productivity can be reduced, as patients with symptomatic lesions will be unable to work effectively, and those who are unaffected may be unwilling to work knowing their office environment poses a health risk. In addition, employees may worry about bringing the bedbugs home. It is important that employees be educated on the signs of a bedbug infestation and take preventive measures to stop spreading or introducing them to the office space. Due to the scattered habitation of bedbugs in offices, pest control managers need to be vigilant to identify sources of infestation and eradicate accordingly. Clinical manifestations can be nonspecific, resembling autoimmune disorders, fungal infections, or bites from other various arthropods; thus, treatment is highly dependent on the patient’s history and occupational exposure.

Bedbugs have successfully adapted to a new environment in the office space. Dermatologists and other health care professionals can no longer exclusively associate bedbugs with the home. When the clinical and histological presentation suggests an arthropod assault, we must counsel our patients to surveil their homes and work settings alike. If necessary, they should seek the assistance of occupational health professionals.

Perniosis, or chilblain, is characterized by localized, tender, erythematous skin lesions that occur as an abnormal reaction to exposure to cold and damp conditions. Although the lesions favor the distal extremities, perniosis may present anywhere on the body. Lesions can develop within hours to days following exposure to temperature less than 10°C or damp environments with greater than 60% humidity.¹ Acute cases may lead to pruritus and tenderness, whereas chronic cases may involve lesions that blister or ulcerate and can take weeks to heal. We report an unusual case of erythematous plaques arising on the buttocks of a 73-year-old woman using ice pack treatments for chronic low back pain.

Case Report

A 73-year-old woman presented with recurrent tender lesions on the buttocks of 5 years’ duration. Her medical history was remarkable for hypertension, hypothyroidism, and lumbar spinal fusion surgery 5 years prior. Physical examination revealed indurated erythematous plaques with areas of erosions on the left buttock with some involvement of the right buttock (Figure 1).

After a trial of oral valacyclovir for presumed herpes simplex infection provided no relief, a punch biopsy of the left buttock was performed, which revealed a cell-poor interface dermatitis with superficial and deep perivascular and periadnexal lymphocytic infiltrates (Figure 2). Perieccrine lymphocytes were present in a small portion of the reticular dermis (Figure 3). The patient revealed she had been sitting on ice packs for several hours daily since the lumbar spinal fusion surgery 5 years prior to alleviate chronic low back pain.

Based on the clinicopathologic correlation, a diagnosis of perniosis secondary to ice pack therapy was made. An evaluation for concomitant or underlying connective tissue disease (CTD) including a complete blood cell count with sedimentation rate, antinuclear antibodies (ANAs), serum protein electrophoresis, and serum levels of cryoglobulins and complement components was unremarkable. Our patient was treated with simple analgesia and was encouraged to avoid direct contact with ice packs for extended periods of time. Because of her low back pain, she continued to use ice packs but readjusted them sporadically and decreased frequency of use. She had complete resolution of the lesions at 6-month follow-up.

Comment

Perniosis is a self-limited condition, manifesting as erythematous plaques or nodules following exposure to cold and damp conditions. It was first reported in 1902 by Hochsinger² as tender submental plaques occurring in children after exposure to cold weather. Since then, reports of perniosis have been described in equestrians and long-distance cyclists as well as in the context of other outdoor activities.^3-5 In all cases, patients developed perniosis at sites of exposure to cold or damp conditions.

Perniosis arising in patients using ice pack therapy is a rare and recent phenomenon, with only 3 other known reported cases.^6,7 In all cases, including ours, patients reported treating chronic low back pain with ice packs for more than 2 hours per day. Clinical presentations included erythematous to purpuric plaques with ulceration on the lower back or buttocks that reoccurred with subsequent use of ice packs. No concomitant CTD was reported.⁶

Much controversy exists as to whether idiopathic perniosis (IP) increases susceptibility to acquiring an autoimmune disease or if IP is a form of CTD that follows a more indolent course.⁸ In a prospective study of 33 patients with underlying IP, no patients developed lupus erythematosus (LE), with a median follow-up of 38 months.⁹ A study by Crowson and Magro⁸ revealed that 18 of 39 patients with perniotic lesions had an associated systemic disease including LE, human immunodeficiency virus, viral hepatitis, rheumatoid arthritis, cryofibrinogenemia, hypergammaglobulinemia, iritis, or Crohn disease. Of the 21 other patients who had no underlying CTD or systemic disease, 10 had a positive ANA test but no systemic symptoms; therefore, all 21 of these patients were classified as cases of IP.⁸

Cutaneous biopsy to distinguish between IP and autoimmune perniosis remains controversial; perniotic lesions and discoid LE share histopathologic features,⁹ as was evident with our case, which demonstrated overlapping findings of vacuolar change with superficial and deep perivascular and periadnexal lymphoid infiltrates. Typical features of IP include thrombosed capillaries in the papillary dermis and lymphocytic exocytosis localized to the acrosyringia, whereas secondary perniosis has superficial and deep perivascular and perieccrine lymphocytic infiltrates with vascular thrombosis in the reticular dermis. Vascular ectasia, dermal mucinosis, basement membrane zone thickening, and erythrocyte extravasation are not reliable and may be seen in both cases.⁸ One study revealed the only significant difference between both entities was the perieccrine distribution of lymphocytic infiltrate in cases of IP (P=.007), whereas an absence of perieccrine involvement was noted in autoimmune cases.⁹

Direct immunofluorescence (DIF) may help differentiate IP from autoimmune perniosis. In a prospective study by Viguier et al,⁹ 6 of 9 patients with IP had negative DIF and 3 had slight nonspecific C3 immunoreactivity of dermal vessels. Conversely, in patients with autoimmune perniosis, positive DIF with the lupus band test was seen in 3 of 7 patients, all who had a positive ANA test⁹; however, positive ANA levels also were reported in patients with autoimmune perniosis but negative DIF, suggesting that DIF lacks specificity in diagnosing autoimmune perniosis.

Although histopathologic findings bear similarities to LE, there are no guidelines to suggest for or against laboratory testing for CTD in patients presenting with perniosis. Some investigators have suggested that any patient with clinical features suggestive of perniosis should undergo laboratory evaluation including a complete blood cell count and assessment for antibodies to Ro, ANA, rheumatoid factor, cryofibrinogens, and antiphospholipid antibodies.⁹ Serum protein electrophoresis and immunofixation electrophoresis may be done to exclude monoclonal gammopathy.

For idiopathic cases, treatment is aimed at limiting or removing cold exposure. Patients should be advised regarding the use of long-term ice pack use and the potential development of perniosis. For chronic perniosis lasting beyond several weeks, a combination of a slow taper of oral prednisone, hydroxychloroquine, and quinacrine has been successful in patients with persistent lesions despite making environmental modifications.³ Intralesional triamcinolone acetonide and nifedipine also have been effective in perniotic hand lesions.¹⁰

Conclusion

We report a rare case of perniosis on the buttocks that arose in a patient who utilized ice packs for treatment of chronic low back pain. Ice pack–induced perniosis may be an underreported entity. Histopathologic examination is nondescript, as overlapping features of perniosis and LE have been observed with no underlying CTD present. Correlation with patient history and clinical examination is paramount in diagnosis and management.

Perniosis, or chilblain, is characterized by localized, tender, erythematous skin lesions that occur as an abnormal reaction to exposure to cold and damp conditions. Although the lesions favor the distal extremities, perniosis may present anywhere on the body. Lesions can develop within hours to days following exposure to temperature less than 10°C or damp environments with greater than 60% humidity.¹ Acute cases may lead to pruritus and tenderness, whereas chronic cases may involve lesions that blister or ulcerate and can take weeks to heal. We report an unusual case of erythematous plaques arising on the buttocks of a 73-year-old woman using ice pack treatments for chronic low back pain.

Case Report

A 73-year-old woman presented with recurrent tender lesions on the buttocks of 5 years’ duration. Her medical history was remarkable for hypertension, hypothyroidism, and lumbar spinal fusion surgery 5 years prior. Physical examination revealed indurated erythematous plaques with areas of erosions on the left buttock with some involvement of the right buttock (Figure 1).

After a trial of oral valacyclovir for presumed herpes simplex infection provided no relief, a punch biopsy of the left buttock was performed, which revealed a cell-poor interface dermatitis with superficial and deep perivascular and periadnexal lymphocytic infiltrates (Figure 2). Perieccrine lymphocytes were present in a small portion of the reticular dermis (Figure 3). The patient revealed she had been sitting on ice packs for several hours daily since the lumbar spinal fusion surgery 5 years prior to alleviate chronic low back pain.

Based on the clinicopathologic correlation, a diagnosis of perniosis secondary to ice pack therapy was made. An evaluation for concomitant or underlying connective tissue disease (CTD) including a complete blood cell count with sedimentation rate, antinuclear antibodies (ANAs), serum protein electrophoresis, and serum levels of cryoglobulins and complement components was unremarkable. Our patient was treated with simple analgesia and was encouraged to avoid direct contact with ice packs for extended periods of time. Because of her low back pain, she continued to use ice packs but readjusted them sporadically and decreased frequency of use. She had complete resolution of the lesions at 6-month follow-up.

Comment

Perniosis is a self-limited condition, manifesting as erythematous plaques or nodules following exposure to cold and damp conditions. It was first reported in 1902 by Hochsinger² as tender submental plaques occurring in children after exposure to cold weather. Since then, reports of perniosis have been described in equestrians and long-distance cyclists as well as in the context of other outdoor activities.^3-5 In all cases, patients developed perniosis at sites of exposure to cold or damp conditions.

Perniosis arising in patients using ice pack therapy is a rare and recent phenomenon, with only 3 other known reported cases.^6,7 In all cases, including ours, patients reported treating chronic low back pain with ice packs for more than 2 hours per day. Clinical presentations included erythematous to purpuric plaques with ulceration on the lower back or buttocks that reoccurred with subsequent use of ice packs. No concomitant CTD was reported.⁶

Much controversy exists as to whether idiopathic perniosis (IP) increases susceptibility to acquiring an autoimmune disease or if IP is a form of CTD that follows a more indolent course.⁸ In a prospective study of 33 patients with underlying IP, no patients developed lupus erythematosus (LE), with a median follow-up of 38 months.⁹ A study by Crowson and Magro⁸ revealed that 18 of 39 patients with perniotic lesions had an associated systemic disease including LE, human immunodeficiency virus, viral hepatitis, rheumatoid arthritis, cryofibrinogenemia, hypergammaglobulinemia, iritis, or Crohn disease. Of the 21 other patients who had no underlying CTD or systemic disease, 10 had a positive ANA test but no systemic symptoms; therefore, all 21 of these patients were classified as cases of IP.⁸

Cutaneous biopsy to distinguish between IP and autoimmune perniosis remains controversial; perniotic lesions and discoid LE share histopathologic features,⁹ as was evident with our case, which demonstrated overlapping findings of vacuolar change with superficial and deep perivascular and periadnexal lymphoid infiltrates. Typical features of IP include thrombosed capillaries in the papillary dermis and lymphocytic exocytosis localized to the acrosyringia, whereas secondary perniosis has superficial and deep perivascular and perieccrine lymphocytic infiltrates with vascular thrombosis in the reticular dermis. Vascular ectasia, dermal mucinosis, basement membrane zone thickening, and erythrocyte extravasation are not reliable and may be seen in both cases.⁸ One study revealed the only significant difference between both entities was the perieccrine distribution of lymphocytic infiltrate in cases of IP (P=.007), whereas an absence of perieccrine involvement was noted in autoimmune cases.⁹

Direct immunofluorescence (DIF) may help differentiate IP from autoimmune perniosis. In a prospective study by Viguier et al,⁹ 6 of 9 patients with IP had negative DIF and 3 had slight nonspecific C3 immunoreactivity of dermal vessels. Conversely, in patients with autoimmune perniosis, positive DIF with the lupus band test was seen in 3 of 7 patients, all who had a positive ANA test⁹; however, positive ANA levels also were reported in patients with autoimmune perniosis but negative DIF, suggesting that DIF lacks specificity in diagnosing autoimmune perniosis.

Although histopathologic findings bear similarities to LE, there are no guidelines to suggest for or against laboratory testing for CTD in patients presenting with perniosis. Some investigators have suggested that any patient with clinical features suggestive of perniosis should undergo laboratory evaluation including a complete blood cell count and assessment for antibodies to Ro, ANA, rheumatoid factor, cryofibrinogens, and antiphospholipid antibodies.⁹ Serum protein electrophoresis and immunofixation electrophoresis may be done to exclude monoclonal gammopathy.

For idiopathic cases, treatment is aimed at limiting or removing cold exposure. Patients should be advised regarding the use of long-term ice pack use and the potential development of perniosis. For chronic perniosis lasting beyond several weeks, a combination of a slow taper of oral prednisone, hydroxychloroquine, and quinacrine has been successful in patients with persistent lesions despite making environmental modifications.³ Intralesional triamcinolone acetonide and nifedipine also have been effective in perniotic hand lesions.¹⁰

Conclusion

We report a rare case of perniosis on the buttocks that arose in a patient who utilized ice packs for treatment of chronic low back pain. Ice pack–induced perniosis may be an underreported entity. Histopathologic examination is nondescript, as overlapping features of perniosis and LE have been observed with no underlying CTD present. Correlation with patient history and clinical examination is paramount in diagnosis and management.

Perniosis, or chilblain, is characterized by localized, tender, erythematous skin lesions that occur as an abnormal reaction to exposure to cold and damp conditions. Although the lesions favor the distal extremities, perniosis may present anywhere on the body. Lesions can develop within hours to days following exposure to temperature less than 10°C or damp environments with greater than 60% humidity.¹ Acute cases may lead to pruritus and tenderness, whereas chronic cases may involve lesions that blister or ulcerate and can take weeks to heal. We report an unusual case of erythematous plaques arising on the buttocks of a 73-year-old woman using ice pack treatments for chronic low back pain.

Case Report

A 73-year-old woman presented with recurrent tender lesions on the buttocks of 5 years’ duration. Her medical history was remarkable for hypertension, hypothyroidism, and lumbar spinal fusion surgery 5 years prior. Physical examination revealed indurated erythematous plaques with areas of erosions on the left buttock with some involvement of the right buttock (Figure 1).

After a trial of oral valacyclovir for presumed herpes simplex infection provided no relief, a punch biopsy of the left buttock was performed, which revealed a cell-poor interface dermatitis with superficial and deep perivascular and periadnexal lymphocytic infiltrates (Figure 2). Perieccrine lymphocytes were present in a small portion of the reticular dermis (Figure 3). The patient revealed she had been sitting on ice packs for several hours daily since the lumbar spinal fusion surgery 5 years prior to alleviate chronic low back pain.

Based on the clinicopathologic correlation, a diagnosis of perniosis secondary to ice pack therapy was made. An evaluation for concomitant or underlying connective tissue disease (CTD) including a complete blood cell count with sedimentation rate, antinuclear antibodies (ANAs), serum protein electrophoresis, and serum levels of cryoglobulins and complement components was unremarkable. Our patient was treated with simple analgesia and was encouraged to avoid direct contact with ice packs for extended periods of time. Because of her low back pain, she continued to use ice packs but readjusted them sporadically and decreased frequency of use. She had complete resolution of the lesions at 6-month follow-up.

Comment

Perniosis is a self-limited condition, manifesting as erythematous plaques or nodules following exposure to cold and damp conditions. It was first reported in 1902 by Hochsinger² as tender submental plaques occurring in children after exposure to cold weather. Since then, reports of perniosis have been described in equestrians and long-distance cyclists as well as in the context of other outdoor activities.^3-5 In all cases, patients developed perniosis at sites of exposure to cold or damp conditions.

Perniosis arising in patients using ice pack therapy is a rare and recent phenomenon, with only 3 other known reported cases.^6,7 In all cases, including ours, patients reported treating chronic low back pain with ice packs for more than 2 hours per day. Clinical presentations included erythematous to purpuric plaques with ulceration on the lower back or buttocks that reoccurred with subsequent use of ice packs. No concomitant CTD was reported.⁶

Much controversy exists as to whether idiopathic perniosis (IP) increases susceptibility to acquiring an autoimmune disease or if IP is a form of CTD that follows a more indolent course.⁸ In a prospective study of 33 patients with underlying IP, no patients developed lupus erythematosus (LE), with a median follow-up of 38 months.⁹ A study by Crowson and Magro⁸ revealed that 18 of 39 patients with perniotic lesions had an associated systemic disease including LE, human immunodeficiency virus, viral hepatitis, rheumatoid arthritis, cryofibrinogenemia, hypergammaglobulinemia, iritis, or Crohn disease. Of the 21 other patients who had no underlying CTD or systemic disease, 10 had a positive ANA test but no systemic symptoms; therefore, all 21 of these patients were classified as cases of IP.⁸

Cutaneous biopsy to distinguish between IP and autoimmune perniosis remains controversial; perniotic lesions and discoid LE share histopathologic features,⁹ as was evident with our case, which demonstrated overlapping findings of vacuolar change with superficial and deep perivascular and periadnexal lymphoid infiltrates. Typical features of IP include thrombosed capillaries in the papillary dermis and lymphocytic exocytosis localized to the acrosyringia, whereas secondary perniosis has superficial and deep perivascular and perieccrine lymphocytic infiltrates with vascular thrombosis in the reticular dermis. Vascular ectasia, dermal mucinosis, basement membrane zone thickening, and erythrocyte extravasation are not reliable and may be seen in both cases.⁸ One study revealed the only significant difference between both entities was the perieccrine distribution of lymphocytic infiltrate in cases of IP (P=.007), whereas an absence of perieccrine involvement was noted in autoimmune cases.⁹

Direct immunofluorescence (DIF) may help differentiate IP from autoimmune perniosis. In a prospective study by Viguier et al,⁹ 6 of 9 patients with IP had negative DIF and 3 had slight nonspecific C3 immunoreactivity of dermal vessels. Conversely, in patients with autoimmune perniosis, positive DIF with the lupus band test was seen in 3 of 7 patients, all who had a positive ANA test⁹; however, positive ANA levels also were reported in patients with autoimmune perniosis but negative DIF, suggesting that DIF lacks specificity in diagnosing autoimmune perniosis.

Although histopathologic findings bear similarities to LE, there are no guidelines to suggest for or against laboratory testing for CTD in patients presenting with perniosis. Some investigators have suggested that any patient with clinical features suggestive of perniosis should undergo laboratory evaluation including a complete blood cell count and assessment for antibodies to Ro, ANA, rheumatoid factor, cryofibrinogens, and antiphospholipid antibodies.⁹ Serum protein electrophoresis and immunofixation electrophoresis may be done to exclude monoclonal gammopathy.

For idiopathic cases, treatment is aimed at limiting or removing cold exposure. Patients should be advised regarding the use of long-term ice pack use and the potential development of perniosis. For chronic perniosis lasting beyond several weeks, a combination of a slow taper of oral prednisone, hydroxychloroquine, and quinacrine has been successful in patients with persistent lesions despite making environmental modifications.³ Intralesional triamcinolone acetonide and nifedipine also have been effective in perniotic hand lesions.¹⁰

Conclusion

We report a rare case of perniosis on the buttocks that arose in a patient who utilized ice packs for treatment of chronic low back pain. Ice pack–induced perniosis may be an underreported entity. Histopathologic examination is nondescript, as overlapping features of perniosis and LE have been observed with no underlying CTD present. Correlation with patient history and clinical examination is paramount in diagnosis and management.

To the Editor:

Gemcitabine is a nucleoside analogue used to treat a variety of solid and hematologic malignancies. Cutaneous toxicities include radiation recall dermatitis and erysipelaslike reactions that occur in areas not previously treated with radiation. Often referred to as pseudocellulitis, these reactions generally have been reported in areas of lymphedema in patients with solid malignancies.^1-6 Herein, we report a rare case of gemcitabine-induced pseudocellulitis on the legs in a patient with a history of hematologic malignancy and total body irradiation (TBI).

A 61-year-old woman with history of peripheral T-cell lymphoma presented to the emergency department at our institution with acute-onset redness, tenderness, and swelling of the legs that was concerning for cellulitis. The patient’s history was notable for receiving gemcitabine 1000 mg/m² for treatment of refractory lymphoma (12 and 4 days prior to presentation) as well as lymphedema of the legs. Her complete treatment course included multiple rounds of chemotherapy and matched unrelated donor nonmyeloablative allogeneic stem cell transplantation with a single dose of TBI at 200 cGy at our institution. Her transplant was complicated only by mild cutaneous graft-versus-host disease, which resolved with prednisone and tacrolimus.

On physical examination, the patient was afebrile with symmetric erythema and induration extending from the bilateral knees to the dorsal feet. A complete blood cell count was notable for a white blood cell count of 5400/µL (reference range, 4500–11,000/µL) and a platelet count of 96,000/µL (reference range, 150,000–400,000/µL). Plain film radiographs of the bilateral ankles were remarkable only for moderate subcutaneous edema. She received vancomycin in the emergency department and was admitted to the oncology service. Blood cultures drawn on admission were negative. Dermatology was consulted on admission, and a diagnosis of pseudocellulitis was made in conjunction with oncology (Figure). Antibiotics were held, and the patient was treated symptomatically with ibuprofen and was discharged 1 day after admission. The reaction resolved after 1 week with the use of diphenhydramine, nonsteroidal anti-inflammatory drugs, and compression. The patient was not rechallenged with gemcitabine.

Gemcitabine-induced pseudocellulitis is a rare cutaneous side effect of gemcitabine therapy. Reported cases have suggested key characteristics of pseudocellulitis (Table). The reaction is characterized by localized erythema, edema, and tenderness of the skin, with onset generally 48 hours to 1 week after receiving gemcitabine.^1-6 Lymphedema appears to be a risk factor.^1,3-5 Six cases (including the current case) demonstrated confinement of these findings to areas of prior lymphedema.^1,4,6 Infectious workup is negative, and rechallenging with gemcitabine likely will reproduce the reaction. Unlike radiation recall dermatitis, there is no prior localized radiation exposure.

Our patient had a history of hematologic malignancy and a one-time low-dose TBI of 200 cGy, unlike the other reported cases described in the Table. It is difficult to attribute our patient’s localized eruption to radiation recall given the history of TBI. The clinical examination, laboratory findings, and time frame of the reaction were consistent with gemcitabine-induced pseudocellulitis.

It is important to be aware of pseudocellulitis as a possible complication of gemcitabine therapy in patients without history of localized radiation. Early recognition of pseudocellulitis may prevent unnecessary exposure to broad-spectrum antibiotics. Patients’ temperature, white blood cell count, clinical examination, and potentially ancillary studies (eg, vascular studies, inflammatory markers) should be reviewed carefully to determine whether there is an infectious or alternate etiology. In patients with known prior lymphedema, it may be beneficial to educate clinicians and patients alike about this potential adverse effect of gemcitabine and the high likelihood of recurrence on re-exposure.

To the Editor:

Gemcitabine is a nucleoside analogue used to treat a variety of solid and hematologic malignancies. Cutaneous toxicities include radiation recall dermatitis and erysipelaslike reactions that occur in areas not previously treated with radiation. Often referred to as pseudocellulitis, these reactions generally have been reported in areas of lymphedema in patients with solid malignancies.^1-6 Herein, we report a rare case of gemcitabine-induced pseudocellulitis on the legs in a patient with a history of hematologic malignancy and total body irradiation (TBI).

A 61-year-old woman with history of peripheral T-cell lymphoma presented to the emergency department at our institution with acute-onset redness, tenderness, and swelling of the legs that was concerning for cellulitis. The patient’s history was notable for receiving gemcitabine 1000 mg/m² for treatment of refractory lymphoma (12 and 4 days prior to presentation) as well as lymphedema of the legs. Her complete treatment course included multiple rounds of chemotherapy and matched unrelated donor nonmyeloablative allogeneic stem cell transplantation with a single dose of TBI at 200 cGy at our institution. Her transplant was complicated only by mild cutaneous graft-versus-host disease, which resolved with prednisone and tacrolimus.

On physical examination, the patient was afebrile with symmetric erythema and induration extending from the bilateral knees to the dorsal feet. A complete blood cell count was notable for a white blood cell count of 5400/µL (reference range, 4500–11,000/µL) and a platelet count of 96,000/µL (reference range, 150,000–400,000/µL). Plain film radiographs of the bilateral ankles were remarkable only for moderate subcutaneous edema. She received vancomycin in the emergency department and was admitted to the oncology service. Blood cultures drawn on admission were negative. Dermatology was consulted on admission, and a diagnosis of pseudocellulitis was made in conjunction with oncology (Figure). Antibiotics were held, and the patient was treated symptomatically with ibuprofen and was discharged 1 day after admission. The reaction resolved after 1 week with the use of diphenhydramine, nonsteroidal anti-inflammatory drugs, and compression. The patient was not rechallenged with gemcitabine.

Gemcitabine-induced pseudocellulitis is a rare cutaneous side effect of gemcitabine therapy. Reported cases have suggested key characteristics of pseudocellulitis (Table). The reaction is characterized by localized erythema, edema, and tenderness of the skin, with onset generally 48 hours to 1 week after receiving gemcitabine.^1-6 Lymphedema appears to be a risk factor.^1,3-5 Six cases (including the current case) demonstrated confinement of these findings to areas of prior lymphedema.^1,4,6 Infectious workup is negative, and rechallenging with gemcitabine likely will reproduce the reaction. Unlike radiation recall dermatitis, there is no prior localized radiation exposure.

Our patient had a history of hematologic malignancy and a one-time low-dose TBI of 200 cGy, unlike the other reported cases described in the Table. It is difficult to attribute our patient’s localized eruption to radiation recall given the history of TBI. The clinical examination, laboratory findings, and time frame of the reaction were consistent with gemcitabine-induced pseudocellulitis.

It is important to be aware of pseudocellulitis as a possible complication of gemcitabine therapy in patients without history of localized radiation. Early recognition of pseudocellulitis may prevent unnecessary exposure to broad-spectrum antibiotics. Patients’ temperature, white blood cell count, clinical examination, and potentially ancillary studies (eg, vascular studies, inflammatory markers) should be reviewed carefully to determine whether there is an infectious or alternate etiology. In patients with known prior lymphedema, it may be beneficial to educate clinicians and patients alike about this potential adverse effect of gemcitabine and the high likelihood of recurrence on re-exposure.

To the Editor:

Gemcitabine is a nucleoside analogue used to treat a variety of solid and hematologic malignancies. Cutaneous toxicities include radiation recall dermatitis and erysipelaslike reactions that occur in areas not previously treated with radiation. Often referred to as pseudocellulitis, these reactions generally have been reported in areas of lymphedema in patients with solid malignancies.^1-6 Herein, we report a rare case of gemcitabine-induced pseudocellulitis on the legs in a patient with a history of hematologic malignancy and total body irradiation (TBI).

A 61-year-old woman with history of peripheral T-cell lymphoma presented to the emergency department at our institution with acute-onset redness, tenderness, and swelling of the legs that was concerning for cellulitis. The patient’s history was notable for receiving gemcitabine 1000 mg/m² for treatment of refractory lymphoma (12 and 4 days prior to presentation) as well as lymphedema of the legs. Her complete treatment course included multiple rounds of chemotherapy and matched unrelated donor nonmyeloablative allogeneic stem cell transplantation with a single dose of TBI at 200 cGy at our institution. Her transplant was complicated only by mild cutaneous graft-versus-host disease, which resolved with prednisone and tacrolimus.

On physical examination, the patient was afebrile with symmetric erythema and induration extending from the bilateral knees to the dorsal feet. A complete blood cell count was notable for a white blood cell count of 5400/µL (reference range, 4500–11,000/µL) and a platelet count of 96,000/µL (reference range, 150,000–400,000/µL). Plain film radiographs of the bilateral ankles were remarkable only for moderate subcutaneous edema. She received vancomycin in the emergency department and was admitted to the oncology service. Blood cultures drawn on admission were negative. Dermatology was consulted on admission, and a diagnosis of pseudocellulitis was made in conjunction with oncology (Figure). Antibiotics were held, and the patient was treated symptomatically with ibuprofen and was discharged 1 day after admission. The reaction resolved after 1 week with the use of diphenhydramine, nonsteroidal anti-inflammatory drugs, and compression. The patient was not rechallenged with gemcitabine.

Gemcitabine-induced pseudocellulitis is a rare cutaneous side effect of gemcitabine therapy. Reported cases have suggested key characteristics of pseudocellulitis (Table). The reaction is characterized by localized erythema, edema, and tenderness of the skin, with onset generally 48 hours to 1 week after receiving gemcitabine.^1-6 Lymphedema appears to be a risk factor.^1,3-5 Six cases (including the current case) demonstrated confinement of these findings to areas of prior lymphedema.^1,4,6 Infectious workup is negative, and rechallenging with gemcitabine likely will reproduce the reaction. Unlike radiation recall dermatitis, there is no prior localized radiation exposure.

Our patient had a history of hematologic malignancy and a one-time low-dose TBI of 200 cGy, unlike the other reported cases described in the Table. It is difficult to attribute our patient’s localized eruption to radiation recall given the history of TBI. The clinical examination, laboratory findings, and time frame of the reaction were consistent with gemcitabine-induced pseudocellulitis.

It is important to be aware of pseudocellulitis as a possible complication of gemcitabine therapy in patients without history of localized radiation. Early recognition of pseudocellulitis may prevent unnecessary exposure to broad-spectrum antibiotics. Patients’ temperature, white blood cell count, clinical examination, and potentially ancillary studies (eg, vascular studies, inflammatory markers) should be reviewed carefully to determine whether there is an infectious or alternate etiology. In patients with known prior lymphedema, it may be beneficial to educate clinicians and patients alike about this potential adverse effect of gemcitabine and the high likelihood of recurrence on re-exposure.

PARIS – Omalizumab is widely considered a breakthrough drug for treatment of chronic spontaneous urticaria (CSU) resistant to antihistamines, but ligelizumab leaves it in the dust, according to the results of a 382-patient phase 2b clinical trial.

“For sure, ligelizumab is the highlight of this year in urticariology,” Marcus Maurer, MD, declared at the annual congress of the European Academy of Dermatology and Venereology. An ongoing phase 3 trial will now compare more than 1,000 patients with CSU who will be randomized to ligelizumab, omalizumab, or placebo.

Like omalizumab (Xolair), which is approved in the United States and Europe for treatment of CSU, ligelizumab is a humanized anti-IgE monoclonal antibody. But the investigational agent binds to IgE with greater affinity than omalizumab, and this translated into greater therapeutic efficacy in the multicenter, double-blind, placebo-controlled clinical trial, explained Dr. Maurer, professor of dermatology and allergy at Charité University in Berlin.

Study participants, all refractory to histamine₁ antihistamines and in many cases to leukotriene receptor antagonists as well, were randomized to omalizumab at 300 mg, placebo, or to ligelizumab at 24 mg, 72 mg, or 240 mg administered by subcutaneous injection every 4 weeks for 20 weeks. The study showed that the effective dose of ligelizumab lies somewhere between 72 and 240 mg; the 24-mg dose won’t be pursued in further studies.

“Three things are important in the comparison between ligelizumab and omalizumab: First, ligelizumab works faster – and omalizumab is a fast-working drug in urticaria. As early as week 4 after initiation of treatment, ligelizumab resulted in a significantly higher response rate,” he said.

Second, a complete response rate as defined by an Urticaria Activity Score over the past 7 days (UAS7) of 0 was achieved by more than 50% of patients on ligelizumab at 240 mg, a rate twice that seen in the omalizumab group. Indeed, more patients were symptom-free on ligelizumab at 72 mg or 240 mg than on omalizumab throughout the 20-week study.

And third, time to relapse after treatment discontinuation was markedly longer with ligelizumab.

“Once you stop the treatment, we expect patients to come back because we didn’t cure the disease, we blocked the signs and symptoms by blocking mast cell degranulation. Relapse after the last injection occurred at about 4 weeks with omalizumab versus 10 weeks for ligelizumab on average. That’s amazing,” Dr. Maurer said.

At week 20, the mean reductions from baseline in UAS7 scores were 13.6 points with placebo, 15.2 points with the lowest dose of ligelizumab, 18.2 points with omalizumab, 23.1 points with ligelizumab at 72 mg, and 22.5 points for ligelizumab at 240 mg.

The side effect profiles for both biologics were essentially the same as for placebo with the exception of a 5.9% rate of mild injection site reactions with ligelizumab at the 240-mg dose versus 2.3% with placebo.

Many clinicians have noticed a significant limitation of omalizumab: It is less effective in patients with more complex CSU having an autoimmune overlay, type 2b angioedema, and/or long disease duration.

“This does not seem to be the case with ligelizumab. Even for the difficult-to-treat subpopulations of CSU, ligelizumab appears to be a drug that can protect against mast cell degranulation. We see a reduction in angioedema activity; we see a reduction in wheal size and number; we see a reduction in the itch – so across all the symptoms in the difficult subpopulations, this is the better drug. Now we have to make it work in the phase 3 trials to bring it to clinical practice,” he said.

Dr. Maurer reported receiving research funding from and serving as an advisor to and paid speaker for Novartis, which markets omalizumab and is developing ligelizumab.

bjancin@mdedge.com

PARIS – Omalizumab is widely considered a breakthrough drug for treatment of chronic spontaneous urticaria (CSU) resistant to antihistamines, but ligelizumab leaves it in the dust, according to the results of a 382-patient phase 2b clinical trial.

“For sure, ligelizumab is the highlight of this year in urticariology,” Marcus Maurer, MD, declared at the annual congress of the European Academy of Dermatology and Venereology. An ongoing phase 3 trial will now compare more than 1,000 patients with CSU who will be randomized to ligelizumab, omalizumab, or placebo.

Like omalizumab (Xolair), which is approved in the United States and Europe for treatment of CSU, ligelizumab is a humanized anti-IgE monoclonal antibody. But the investigational agent binds to IgE with greater affinity than omalizumab, and this translated into greater therapeutic efficacy in the multicenter, double-blind, placebo-controlled clinical trial, explained Dr. Maurer, professor of dermatology and allergy at Charité University in Berlin.

Study participants, all refractory to histamine₁ antihistamines and in many cases to leukotriene receptor antagonists as well, were randomized to omalizumab at 300 mg, placebo, or to ligelizumab at 24 mg, 72 mg, or 240 mg administered by subcutaneous injection every 4 weeks for 20 weeks. The study showed that the effective dose of ligelizumab lies somewhere between 72 and 240 mg; the 24-mg dose won’t be pursued in further studies.

“Three things are important in the comparison between ligelizumab and omalizumab: First, ligelizumab works faster – and omalizumab is a fast-working drug in urticaria. As early as week 4 after initiation of treatment, ligelizumab resulted in a significantly higher response rate,” he said.

Second, a complete response rate as defined by an Urticaria Activity Score over the past 7 days (UAS7) of 0 was achieved by more than 50% of patients on ligelizumab at 240 mg, a rate twice that seen in the omalizumab group. Indeed, more patients were symptom-free on ligelizumab at 72 mg or 240 mg than on omalizumab throughout the 20-week study.

And third, time to relapse after treatment discontinuation was markedly longer with ligelizumab.

“Once you stop the treatment, we expect patients to come back because we didn’t cure the disease, we blocked the signs and symptoms by blocking mast cell degranulation. Relapse after the last injection occurred at about 4 weeks with omalizumab versus 10 weeks for ligelizumab on average. That’s amazing,” Dr. Maurer said.

At week 20, the mean reductions from baseline in UAS7 scores were 13.6 points with placebo, 15.2 points with the lowest dose of ligelizumab, 18.2 points with omalizumab, 23.1 points with ligelizumab at 72 mg, and 22.5 points for ligelizumab at 240 mg.

The side effect profiles for both biologics were essentially the same as for placebo with the exception of a 5.9% rate of mild injection site reactions with ligelizumab at the 240-mg dose versus 2.3% with placebo.

Many clinicians have noticed a significant limitation of omalizumab: It is less effective in patients with more complex CSU having an autoimmune overlay, type 2b angioedema, and/or long disease duration.

“This does not seem to be the case with ligelizumab. Even for the difficult-to-treat subpopulations of CSU, ligelizumab appears to be a drug that can protect against mast cell degranulation. We see a reduction in angioedema activity; we see a reduction in wheal size and number; we see a reduction in the itch – so across all the symptoms in the difficult subpopulations, this is the better drug. Now we have to make it work in the phase 3 trials to bring it to clinical practice,” he said.

Dr. Maurer reported receiving research funding from and serving as an advisor to and paid speaker for Novartis, which markets omalizumab and is developing ligelizumab.

bjancin@mdedge.com

PARIS – Omalizumab is widely considered a breakthrough drug for treatment of chronic spontaneous urticaria (CSU) resistant to antihistamines, but ligelizumab leaves it in the dust, according to the results of a 382-patient phase 2b clinical trial.

“For sure, ligelizumab is the highlight of this year in urticariology,” Marcus Maurer, MD, declared at the annual congress of the European Academy of Dermatology and Venereology. An ongoing phase 3 trial will now compare more than 1,000 patients with CSU who will be randomized to ligelizumab, omalizumab, or placebo.

Like omalizumab (Xolair), which is approved in the United States and Europe for treatment of CSU, ligelizumab is a humanized anti-IgE monoclonal antibody. But the investigational agent binds to IgE with greater affinity than omalizumab, and this translated into greater therapeutic efficacy in the multicenter, double-blind, placebo-controlled clinical trial, explained Dr. Maurer, professor of dermatology and allergy at Charité University in Berlin.

Study participants, all refractory to histamine₁ antihistamines and in many cases to leukotriene receptor antagonists as well, were randomized to omalizumab at 300 mg, placebo, or to ligelizumab at 24 mg, 72 mg, or 240 mg administered by subcutaneous injection every 4 weeks for 20 weeks. The study showed that the effective dose of ligelizumab lies somewhere between 72 and 240 mg; the 24-mg dose won’t be pursued in further studies.

“Three things are important in the comparison between ligelizumab and omalizumab: First, ligelizumab works faster – and omalizumab is a fast-working drug in urticaria. As early as week 4 after initiation of treatment, ligelizumab resulted in a significantly higher response rate,” he said.

Second, a complete response rate as defined by an Urticaria Activity Score over the past 7 days (UAS7) of 0 was achieved by more than 50% of patients on ligelizumab at 240 mg, a rate twice that seen in the omalizumab group. Indeed, more patients were symptom-free on ligelizumab at 72 mg or 240 mg than on omalizumab throughout the 20-week study.

And third, time to relapse after treatment discontinuation was markedly longer with ligelizumab.

“Once you stop the treatment, we expect patients to come back because we didn’t cure the disease, we blocked the signs and symptoms by blocking mast cell degranulation. Relapse after the last injection occurred at about 4 weeks with omalizumab versus 10 weeks for ligelizumab on average. That’s amazing,” Dr. Maurer said.

At week 20, the mean reductions from baseline in UAS7 scores were 13.6 points with placebo, 15.2 points with the lowest dose of ligelizumab, 18.2 points with omalizumab, 23.1 points with ligelizumab at 72 mg, and 22.5 points for ligelizumab at 240 mg.

The side effect profiles for both biologics were essentially the same as for placebo with the exception of a 5.9% rate of mild injection site reactions with ligelizumab at the 240-mg dose versus 2.3% with placebo.

Many clinicians have noticed a significant limitation of omalizumab: It is less effective in patients with more complex CSU having an autoimmune overlay, type 2b angioedema, and/or long disease duration.

“This does not seem to be the case with ligelizumab. Even for the difficult-to-treat subpopulations of CSU, ligelizumab appears to be a drug that can protect against mast cell degranulation. We see a reduction in angioedema activity; we see a reduction in wheal size and number; we see a reduction in the itch – so across all the symptoms in the difficult subpopulations, this is the better drug. Now we have to make it work in the phase 3 trials to bring it to clinical practice,” he said.

Dr. Maurer reported receiving research funding from and serving as an advisor to and paid speaker for Novartis, which markets omalizumab and is developing ligelizumab.

bjancin@mdedge.com

To the Editor:

Autoimmune progesterone dermatitis (APD) is a rare dermatologic condition that can be challenging to diagnose. The associated skin lesions are not only variable in physical presentation but also in the timing of the outbreak. The skin disorder stems from an internal reaction to elevated levels of progesterone during the luteal phase of the menstrual cycle. Autoimmune progesterone dermatitis can be difficult to detect; although the typical menstrual cycle is 28 days, many women have longer or shorter hormonal phases, leading to cyclical irregularity that can cause the lesions to appear sporadic in nature when in fact they are not.¹

A 34-year-old woman with a history of endometriosis, psoriasis, and malignant melanoma presented to our dermatology clinic 2 days after a brief hospitalization during which she was diagnosed with a hypersensitivity reaction. Two days prior to her hospital admission, the patient developed a rash on the lower back with associated myalgia. The rash progressively worsened, spreading laterally to the flanks, which prompted her to seek medical attention. Blood work included a complete blood cell count with differential, complete metabolic panel, antinuclear antibody test, and erythrocyte sedimentation rate, which all were within reference range. A 4-mm punch biopsy from the left lateral flank was performed and was consistent with a neutrophilic dermatosis. The patient’s symptoms diminished and she was discharged the next day with instructions to follow up with a dermatologist.

Physical examination at our clinic revealed multiple minimally indurated, erythematous plaques with superficial scaling along the left lower back and upper buttock (Figure 1). No other skin lesions were present, and palpation of the cervical, axillary, and inguinal lymph nodes was unremarkable. A repeat 6-mm punch biopsy was performed and she was sent for fasting blood work.

Histologic examination of the punch biopsy revealed a superficial and deep perivascular and interstitial dermatitis with scattered neutrophils and eosinophils. Findings were described as nonspecific, possibly representing a dermal hypersensitivity or urticarial reaction.

Glucose-6-phosphate dehydrogenase testing was within reference range, and therapy was initiated with oral dapsone 50 mg once daily as well as fexofenadine 180 mg once daily. The patient initially responded well to the oral therapy, but she experienced recurrence of the skin eruption at infrequent intervals over the next few months, requiring escalating doses of dapsone to control the symptoms. After further questioning at a subsequent visit a few months later, it was discovered that the eruption occurred near the onset of the patient’s irregular menstrual cycle.

Approximately 1 year after her initial presentation, the patient returned for intradermal hormone injections to test for hormonally induced hypersensitivities. An injection of0.1 mL of a 50-mg/mL progesterone solution was administered in the right forearm as well as 0.1 mL of a 5-mg/mL estradiol solution and 0.1 mL of saline in the left forearm as a control. One hour after the injections, a strong positive reaction consisting of a 15-mm indurated plaque with surrounding wheal was noted at the site of the progesterone injection. The estradiol and saline control sites were clear of any dermal reaction (Figure 2). A diagnosis of APD was established, and the patient was referred to her gynecologist for treatment.

Due to the aggressive nature of her endometriosis, the gonadotropin-releasing hormone agonist leuprolide acetate was the first-line treatment prescribed by her gynecologist; however, after 8 months of therapy with leuprolide acetate, she was still experiencing breakthrough myalgia with her menstrual cycle and opted for a hysterectomy with a bilateral salpingo-oophorectomy. Within weeks of surgery, the myalgia ceased and the patient was completely asymptomatic.

Autoimmune progesterone dermatitis was first described in 1921.² In affected women, the body reacts to the progesterone hormone surge during the luteal phase of the menstrual cycle. Symptoms begin approximately 3 to 4 days prior to menses and resolve 2 to 3 days after onset of flow. These progesterone hypersensitivity reactions can present within a spectrum of morphologies and severities. The lesions can appear eczematous, urticarial, as an angioedemalike reaction, as an erythema multiforme–like reaction with targetoid lesions, or in other nonspecific ways.^1,3 Some patients experience a very mild, almost asymptomatic reaction, while others have a profound reaction progressing to anaphylaxis. Originally it was thought that exogenous exposure to progesterone led to a cross-reaction or hypersensitivity to the hormone; however, there have been cases reported in females as young as 12 years of age with no prior exposure.^3,4 Reactions also can vary during pregnancy. There have been reports of spontaneous abortion in some affected females, but symptoms may dissipate in others, possibly due to a slow rise in progesterone causing a desensitization reaction.^3,5

According to Bandino et al,⁶ there are 3 criteria for diagnosis of APD: (1) skin lesions related to the menstrual cycle, (2) positive response to intradermal testing with progesterone, and (3) symptomatic improvement after inhibiting progesterone secretions by suppressing ovulation.Areas checked with intradermal testing need to be evaluated 24 and 48 hours later for possible immediate or delayed-type hypersensitivity reactions. Biopsy typically is not helpful in this diagnosis because results usually are nonspecific.

Treatment of APD is targeted toward suppressing the internal hormonal surge. By suppressing the progesterone hormone, the symptoms are alleviated. The discomfort from the skin reaction typically is unresponsive to steroids or antihistamines. Oral contraceptives are first line in most cases because they suppress ovulation. Gonadotropin-releasing hormone analogues and tamoxifen also have been successful. For patients with severe disease that is recalcitrant to standard therapy or those who are postmenopausal, an oophorectemy is a curative option.^2,4,5,7

Autoimmune progesterone dermatitis is a rare cyclical dermatologic condition in which the body responds to a surge of the patient’s own progesterone hormone. The disorder is difficult to diagnose because it can present with differing morphologies and biopsy is nonspecific. It also can be increasingly difficult to diagnose in women who do not have a typical 28-day menstrual cycle. In our patient, her irregular menstrual cycle may have caused a delay in diagnosis. Although the condition is rare, APD should be included in the differential diagnosis in females with a recurrent, cyclical, or recalcitrant cutaneous eruption.

To the Editor:

Autoimmune progesterone dermatitis (APD) is a rare dermatologic condition that can be challenging to diagnose. The associated skin lesions are not only variable in physical presentation but also in the timing of the outbreak. The skin disorder stems from an internal reaction to elevated levels of progesterone during the luteal phase of the menstrual cycle. Autoimmune progesterone dermatitis can be difficult to detect; although the typical menstrual cycle is 28 days, many women have longer or shorter hormonal phases, leading to cyclical irregularity that can cause the lesions to appear sporadic in nature when in fact they are not.¹

A 34-year-old woman with a history of endometriosis, psoriasis, and malignant melanoma presented to our dermatology clinic 2 days after a brief hospitalization during which she was diagnosed with a hypersensitivity reaction. Two days prior to her hospital admission, the patient developed a rash on the lower back with associated myalgia. The rash progressively worsened, spreading laterally to the flanks, which prompted her to seek medical attention. Blood work included a complete blood cell count with differential, complete metabolic panel, antinuclear antibody test, and erythrocyte sedimentation rate, which all were within reference range. A 4-mm punch biopsy from the left lateral flank was performed and was consistent with a neutrophilic dermatosis. The patient’s symptoms diminished and she was discharged the next day with instructions to follow up with a dermatologist.

Physical examination at our clinic revealed multiple minimally indurated, erythematous plaques with superficial scaling along the left lower back and upper buttock (Figure 1). No other skin lesions were present, and palpation of the cervical, axillary, and inguinal lymph nodes was unremarkable. A repeat 6-mm punch biopsy was performed and she was sent for fasting blood work.

Histologic examination of the punch biopsy revealed a superficial and deep perivascular and interstitial dermatitis with scattered neutrophils and eosinophils. Findings were described as nonspecific, possibly representing a dermal hypersensitivity or urticarial reaction.

Glucose-6-phosphate dehydrogenase testing was within reference range, and therapy was initiated with oral dapsone 50 mg once daily as well as fexofenadine 180 mg once daily. The patient initially responded well to the oral therapy, but she experienced recurrence of the skin eruption at infrequent intervals over the next few months, requiring escalating doses of dapsone to control the symptoms. After further questioning at a subsequent visit a few months later, it was discovered that the eruption occurred near the onset of the patient’s irregular menstrual cycle.

Approximately 1 year after her initial presentation, the patient returned for intradermal hormone injections to test for hormonally induced hypersensitivities. An injection of0.1 mL of a 50-mg/mL progesterone solution was administered in the right forearm as well as 0.1 mL of a 5-mg/mL estradiol solution and 0.1 mL of saline in the left forearm as a control. One hour after the injections, a strong positive reaction consisting of a 15-mm indurated plaque with surrounding wheal was noted at the site of the progesterone injection. The estradiol and saline control sites were clear of any dermal reaction (Figure 2). A diagnosis of APD was established, and the patient was referred to her gynecologist for treatment.

Due to the aggressive nature of her endometriosis, the gonadotropin-releasing hormone agonist leuprolide acetate was the first-line treatment prescribed by her gynecologist; however, after 8 months of therapy with leuprolide acetate, she was still experiencing breakthrough myalgia with her menstrual cycle and opted for a hysterectomy with a bilateral salpingo-oophorectomy. Within weeks of surgery, the myalgia ceased and the patient was completely asymptomatic.

Autoimmune progesterone dermatitis was first described in 1921.² In affected women, the body reacts to the progesterone hormone surge during the luteal phase of the menstrual cycle. Symptoms begin approximately 3 to 4 days prior to menses and resolve 2 to 3 days after onset of flow. These progesterone hypersensitivity reactions can present within a spectrum of morphologies and severities. The lesions can appear eczematous, urticarial, as an angioedemalike reaction, as an erythema multiforme–like reaction with targetoid lesions, or in other nonspecific ways.^1,3 Some patients experience a very mild, almost asymptomatic reaction, while others have a profound reaction progressing to anaphylaxis. Originally it was thought that exogenous exposure to progesterone led to a cross-reaction or hypersensitivity to the hormone; however, there have been cases reported in females as young as 12 years of age with no prior exposure.^3,4 Reactions also can vary during pregnancy. There have been reports of spontaneous abortion in some affected females, but symptoms may dissipate in others, possibly due to a slow rise in progesterone causing a desensitization reaction.^3,5

According to Bandino et al,⁶ there are 3 criteria for diagnosis of APD: (1) skin lesions related to the menstrual cycle, (2) positive response to intradermal testing with progesterone, and (3) symptomatic improvement after inhibiting progesterone secretions by suppressing ovulation.Areas checked with intradermal testing need to be evaluated 24 and 48 hours later for possible immediate or delayed-type hypersensitivity reactions. Biopsy typically is not helpful in this diagnosis because results usually are nonspecific.

Treatment of APD is targeted toward suppressing the internal hormonal surge. By suppressing the progesterone hormone, the symptoms are alleviated. The discomfort from the skin reaction typically is unresponsive to steroids or antihistamines. Oral contraceptives are first line in most cases because they suppress ovulation. Gonadotropin-releasing hormone analogues and tamoxifen also have been successful. For patients with severe disease that is recalcitrant to standard therapy or those who are postmenopausal, an oophorectemy is a curative option.^2,4,5,7

Autoimmune progesterone dermatitis is a rare cyclical dermatologic condition in which the body responds to a surge of the patient’s own progesterone hormone. The disorder is difficult to diagnose because it can present with differing morphologies and biopsy is nonspecific. It also can be increasingly difficult to diagnose in women who do not have a typical 28-day menstrual cycle. In our patient, her irregular menstrual cycle may have caused a delay in diagnosis. Although the condition is rare, APD should be included in the differential diagnosis in females with a recurrent, cyclical, or recalcitrant cutaneous eruption.

To the Editor:

Autoimmune progesterone dermatitis (APD) is a rare dermatologic condition that can be challenging to diagnose. The associated skin lesions are not only variable in physical presentation but also in the timing of the outbreak. The skin disorder stems from an internal reaction to elevated levels of progesterone during the luteal phase of the menstrual cycle. Autoimmune progesterone dermatitis can be difficult to detect; although the typical menstrual cycle is 28 days, many women have longer or shorter hormonal phases, leading to cyclical irregularity that can cause the lesions to appear sporadic in nature when in fact they are not.¹

A 34-year-old woman with a history of endometriosis, psoriasis, and malignant melanoma presented to our dermatology clinic 2 days after a brief hospitalization during which she was diagnosed with a hypersensitivity reaction. Two days prior to her hospital admission, the patient developed a rash on the lower back with associated myalgia. The rash progressively worsened, spreading laterally to the flanks, which prompted her to seek medical attention. Blood work included a complete blood cell count with differential, complete metabolic panel, antinuclear antibody test, and erythrocyte sedimentation rate, which all were within reference range. A 4-mm punch biopsy from the left lateral flank was performed and was consistent with a neutrophilic dermatosis. The patient’s symptoms diminished and she was discharged the next day with instructions to follow up with a dermatologist.

Physical examination at our clinic revealed multiple minimally indurated, erythematous plaques with superficial scaling along the left lower back and upper buttock (Figure 1). No other skin lesions were present, and palpation of the cervical, axillary, and inguinal lymph nodes was unremarkable. A repeat 6-mm punch biopsy was performed and she was sent for fasting blood work.

Histologic examination of the punch biopsy revealed a superficial and deep perivascular and interstitial dermatitis with scattered neutrophils and eosinophils. Findings were described as nonspecific, possibly representing a dermal hypersensitivity or urticarial reaction.

Glucose-6-phosphate dehydrogenase testing was within reference range, and therapy was initiated with oral dapsone 50 mg once daily as well as fexofenadine 180 mg once daily. The patient initially responded well to the oral therapy, but she experienced recurrence of the skin eruption at infrequent intervals over the next few months, requiring escalating doses of dapsone to control the symptoms. After further questioning at a subsequent visit a few months later, it was discovered that the eruption occurred near the onset of the patient’s irregular menstrual cycle.

Approximately 1 year after her initial presentation, the patient returned for intradermal hormone injections to test for hormonally induced hypersensitivities. An injection of0.1 mL of a 50-mg/mL progesterone solution was administered in the right forearm as well as 0.1 mL of a 5-mg/mL estradiol solution and 0.1 mL of saline in the left forearm as a control. One hour after the injections, a strong positive reaction consisting of a 15-mm indurated plaque with surrounding wheal was noted at the site of the progesterone injection. The estradiol and saline control sites were clear of any dermal reaction (Figure 2). A diagnosis of APD was established, and the patient was referred to her gynecologist for treatment.

Due to the aggressive nature of her endometriosis, the gonadotropin-releasing hormone agonist leuprolide acetate was the first-line treatment prescribed by her gynecologist; however, after 8 months of therapy with leuprolide acetate, she was still experiencing breakthrough myalgia with her menstrual cycle and opted for a hysterectomy with a bilateral salpingo-oophorectomy. Within weeks of surgery, the myalgia ceased and the patient was completely asymptomatic.

Autoimmune progesterone dermatitis was first described in 1921.² In affected women, the body reacts to the progesterone hormone surge during the luteal phase of the menstrual cycle. Symptoms begin approximately 3 to 4 days prior to menses and resolve 2 to 3 days after onset of flow. These progesterone hypersensitivity reactions can present within a spectrum of morphologies and severities. The lesions can appear eczematous, urticarial, as an angioedemalike reaction, as an erythema multiforme–like reaction with targetoid lesions, or in other nonspecific ways.^1,3 Some patients experience a very mild, almost asymptomatic reaction, while others have a profound reaction progressing to anaphylaxis. Originally it was thought that exogenous exposure to progesterone led to a cross-reaction or hypersensitivity to the hormone; however, there have been cases reported in females as young as 12 years of age with no prior exposure.^3,4 Reactions also can vary during pregnancy. There have been reports of spontaneous abortion in some affected females, but symptoms may dissipate in others, possibly due to a slow rise in progesterone causing a desensitization reaction.^3,5

According to Bandino et al,⁶ there are 3 criteria for diagnosis of APD: (1) skin lesions related to the menstrual cycle, (2) positive response to intradermal testing with progesterone, and (3) symptomatic improvement after inhibiting progesterone secretions by suppressing ovulation.Areas checked with intradermal testing need to be evaluated 24 and 48 hours later for possible immediate or delayed-type hypersensitivity reactions. Biopsy typically is not helpful in this diagnosis because results usually are nonspecific.

Treatment of APD is targeted toward suppressing the internal hormonal surge. By suppressing the progesterone hormone, the symptoms are alleviated. The discomfort from the skin reaction typically is unresponsive to steroids or antihistamines. Oral contraceptives are first line in most cases because they suppress ovulation. Gonadotropin-releasing hormone analogues and tamoxifen also have been successful. For patients with severe disease that is recalcitrant to standard therapy or those who are postmenopausal, an oophorectemy is a curative option.^2,4,5,7

Autoimmune progesterone dermatitis is a rare cyclical dermatologic condition in which the body responds to a surge of the patient’s own progesterone hormone. The disorder is difficult to diagnose because it can present with differing morphologies and biopsy is nonspecific. It also can be increasingly difficult to diagnose in women who do not have a typical 28-day menstrual cycle. In our patient, her irregular menstrual cycle may have caused a delay in diagnosis. Although the condition is rare, APD should be included in the differential diagnosis in females with a recurrent, cyclical, or recalcitrant cutaneous eruption.

The cutaneous manifestations of Crohn disease (CD) are varied, including pyoderma gangrenosum, erythema nodosum, and metastatic CD (MCD). First described by Parks et al,¹ MCD is defined as the occurrence of granulomatous lesions at a skin site distant from the gastrointestinal tract.^1-20 Metastatic CD presents a diagnostic challenge because it is a rare component in the spectrum of inflammatory bowel disease complications, and many physicians are unaware of its existence. It may precede, coincide with, or develop after the diagnosis of intestinal disease.^2-5 Vulvoperineal involvement is particularly problematic because a multitude of other, more likely disease processes are considered first. Typically it is initially diagnosed as a presumed infection prompting reflexive treatment with antivirals, antifungals, and antibiotics. Patients may experience symptoms for years prior to correct diagnosis and institution of proper therapy. A variety of clinical presentations have been described, including nonspecific pain and swelling, erythematous papules and plaques, and nonhealing ulcers. Skin biopsy characteristically confirms the diagnosis and reveals dermal noncaseating granulomas. Multiple oral and parenteral therapies are available, with surgical intervention reserved for resistant cases. We present a case of vulvovaginal MCD in the setting of well-controlled intestinal disease. We also provide a review of the literature regarding genital CD and emphasize the need to keep MCD in the differential of vulvoperineal pathology.

Case Report

A 29-year-old woman was referred to the dermatology clinic with vulvar pain, swelling, and pruritus of 14 months’ duration. Her medical history was remarkable for CD following a colectomy with colostomy. Prior therapies included methotrexate with infliximab for 5 years followed by a 2-year regimen with adalimumab, which induced remission of the intestinal disease.

The patient previously had taken a variety of topical and oral antimicrobials based on treatment from a primary care physician because fungal, bacterial, and viral infections initially were suspected; however, the vulvar disease persisted, and drug-induced immunosuppression was considered to be an underlying factor. Thus, adalimumab was discontinued. Despite elimination of the biologic, the vulvar disease progressed, which prompted referral to the dermatology clinic.

Physical examination revealed diffuse vulvar edema with overlying erythema and scale (Figure 1A). Upon closer inspection, scattered violaceous papules atop a backdrop of lichenification were evident, imparting a cobblestone appearance (Figure 1B). Additionally, a fissure was present on the gluteal cleft. Biopsy from the left labia majora demonstrated well-formed granulomas within a fibrotic reticular dermis (Figures 2A and 2B). The granulomas consisted of both mononucleated and multinucleated histiocytes, rimmed peripherally by lymphocytes and plasma cells (Figure 2C). Periodic acid–Schiff–diastase and acid-fast bacilli stains as well as polarizing microscopy were negative.

Comment

Crohn disease is an idiopathic chronic inflammatory condition that primarily affects the gastrointestinal tract, anywhere from the mouth to the anus. It is characterized by transmural inflammation and fissures that can extend beyond the muscularis propria.^4,6 Extraintestinal manifestations are common.³

Cutaneous CD often presents as perianal, perifistular, or peristomal inflammation or ulceration.⁷ Other skin manifestations include pyoderma gangrenosum, erythema nodosum, erythema multiforme, epidermolysis bullosa acquisita, and palmar erythema.⁷ Metastatic CD involves skin noncontiguous with the gastrointestinal tract^1-20 and may involve any portion of the cutis. Although rare, MCD is the typical etiology underlying vulvar CD.⁸

Approximately 20% of MCD patients have cutaneous lesions without a history of gastrointestinal disease. More than half of cases in adults and approximately two-thirds in children involve the genitalia. Although more common in adults, vulvar involvement has been reported in children as young as 6 years of age.² Diagnosis is especially challenging when bowel symptoms are absent; those patients should be evaluated and followed for subsequent intestinal involvement.⁶

Clinically, symptoms may include general discomfort, pain, pruritus, and dyspareunia. Psychosocial and sexual dysfunction are prevalent and also should be addressed.⁹ Depending on the stage of the disease, physical examination may reveal erythema, edema, papules, pustules, nodules, condylomatous lesions, abscesses, fissures, fistulas, ulceration, acrochordons, and scarring.^2-6,10,11

A host of infections (ie, mycobacterial, actinomycosis, deep fungal, sexually transmitted, schistosomiasis), inflammatory conditions (ie, sarcoid, hidradenitis suppurativa), foreign body reactions, Melkersson-Rosenthal syndrome, and sexual abuse should be included in the differential diagnosis.^2,6,10-12 Once infection, sarcoid, and foreign body reaction have been ruled out, noncaseating granulomas in skin are highly suggestive of CD.⁷

Histopathologic findings of MCD reveal myriad morphological reaction patterns,^5,13 including high-grade dysplasia and carcinoma of the vulva; therefore, it may be imprudent to withhold diagnosis based on the absence of the historically pathognomonic noncaseating granulomas.⁵

The etiopathogenesis of MCD remains an enigma. Dermatopathologic examinations consistently reveal a vascular injury syndrome,¹³ implicating a possible circulatory system contribution via deposition of immune complexes or antigens in skin.⁷ Bacterial infection has been implicated in the intestinal manifestations of CD; however, failure to detect microbial ribosomal RNA in MCD biopsies refutes theories of hematogenous spread of microbes.¹³ Another plausible explanation is that antibodies are formed to conserved microbial epitopes following loss of tolerance to gut flora, which results in an excessive immunologic response at distinct sites in susceptible individuals.¹³ A T-lymphocyte–mediated type IV hypersensitivity reaction also has been proposed via cross-reactivity of lymphocytes, with skin antigens precipitating extraintestinal granuloma formation and vascular injury.³ Clearly, further investigation is needed.

Magnetic resonanance imaging can identify the extent and anatomy of intestinal and pelvic disease and can assist in the diagnosis of vulvar CD.^10,11,14 For these reasons, some experts propose that imaging should be instituted prior to therapy,^12,15,16 especially when direct extension is suspected.¹⁷

Treatment is challenging and often involves collaboration among several specialties.¹² Many treatment options exist because therapeutic responses vary and genital MCD is frequently recalcitrant to therapy.⁴ Medical therapy includes antibiotics such as metronidazole, corticosteroids (ie, topical, intralesional, systemic), and immune modulators (eg, azathioprine, 6-mercaptopurine, cyclosporine, methotrexate, mycophenolate mofetil, tumor necrosis factor α inhibitors).^{2,3,6,10,16,18} Thalidomide has been used for refractory cases.¹⁹ These treatments can be used alone or in combination. Patients should be monitored for side effects and informed that many treatment regimens may be required before a sustained response is achieved.^4,16,18 Surgery is reserved for the most resistant cases. Extensive radical excision of the involved area is the best approach, as limited local excision often is followed by recurrence.²⁰

Conclusion

Our case highlights that vulvar CD can develop in the setting of well-controlled intestinal disease. Vulvoperineal CD should be considered in the differential diagnosis of chronic vulvar pain, swelling, and pruritus, especially in cases resistant to standard therapies and regardless of whether or not gastrointestinal tract symptoms are present. Physicians must be cognizant that vulvar signs and symptoms may precede, coincide with, or follow the diagnosis of intestinal CD. Increased awareness of this entity may facilitate its early recognition and prompt more timely treatment among women with vulvar disease caused by MCD.

The cutaneous manifestations of Crohn disease (CD) are varied, including pyoderma gangrenosum, erythema nodosum, and metastatic CD (MCD). First described by Parks et al,¹ MCD is defined as the occurrence of granulomatous lesions at a skin site distant from the gastrointestinal tract.^1-20 Metastatic CD presents a diagnostic challenge because it is a rare component in the spectrum of inflammatory bowel disease complications, and many physicians are unaware of its existence. It may precede, coincide with, or develop after the diagnosis of intestinal disease.^2-5 Vulvoperineal involvement is particularly problematic because a multitude of other, more likely disease processes are considered first. Typically it is initially diagnosed as a presumed infection prompting reflexive treatment with antivirals, antifungals, and antibiotics. Patients may experience symptoms for years prior to correct diagnosis and institution of proper therapy. A variety of clinical presentations have been described, including nonspecific pain and swelling, erythematous papules and plaques, and nonhealing ulcers. Skin biopsy characteristically confirms the diagnosis and reveals dermal noncaseating granulomas. Multiple oral and parenteral therapies are available, with surgical intervention reserved for resistant cases. We present a case of vulvovaginal MCD in the setting of well-controlled intestinal disease. We also provide a review of the literature regarding genital CD and emphasize the need to keep MCD in the differential of vulvoperineal pathology.

Case Report

A 29-year-old woman was referred to the dermatology clinic with vulvar pain, swelling, and pruritus of 14 months’ duration. Her medical history was remarkable for CD following a colectomy with colostomy. Prior therapies included methotrexate with infliximab for 5 years followed by a 2-year regimen with adalimumab, which induced remission of the intestinal disease.

The patient previously had taken a variety of topical and oral antimicrobials based on treatment from a primary care physician because fungal, bacterial, and viral infections initially were suspected; however, the vulvar disease persisted, and drug-induced immunosuppression was considered to be an underlying factor. Thus, adalimumab was discontinued. Despite elimination of the biologic, the vulvar disease progressed, which prompted referral to the dermatology clinic.

Physical examination revealed diffuse vulvar edema with overlying erythema and scale (Figure 1A). Upon closer inspection, scattered violaceous papules atop a backdrop of lichenification were evident, imparting a cobblestone appearance (Figure 1B). Additionally, a fissure was present on the gluteal cleft. Biopsy from the left labia majora demonstrated well-formed granulomas within a fibrotic reticular dermis (Figures 2A and 2B). The granulomas consisted of both mononucleated and multinucleated histiocytes, rimmed peripherally by lymphocytes and plasma cells (Figure 2C). Periodic acid–Schiff–diastase and acid-fast bacilli stains as well as polarizing microscopy were negative.

Comment

Crohn disease is an idiopathic chronic inflammatory condition that primarily affects the gastrointestinal tract, anywhere from the mouth to the anus. It is characterized by transmural inflammation and fissures that can extend beyond the muscularis propria.^4,6 Extraintestinal manifestations are common.³

Cutaneous CD often presents as perianal, perifistular, or peristomal inflammation or ulceration.⁷ Other skin manifestations include pyoderma gangrenosum, erythema nodosum, erythema multiforme, epidermolysis bullosa acquisita, and palmar erythema.⁷ Metastatic CD involves skin noncontiguous with the gastrointestinal tract^1-20 and may involve any portion of the cutis. Although rare, MCD is the typical etiology underlying vulvar CD.⁸

Approximately 20% of MCD patients have cutaneous lesions without a history of gastrointestinal disease. More than half of cases in adults and approximately two-thirds in children involve the genitalia. Although more common in adults, vulvar involvement has been reported in children as young as 6 years of age.² Diagnosis is especially challenging when bowel symptoms are absent; those patients should be evaluated and followed for subsequent intestinal involvement.⁶

Clinically, symptoms may include general discomfort, pain, pruritus, and dyspareunia. Psychosocial and sexual dysfunction are prevalent and also should be addressed.⁹ Depending on the stage of the disease, physical examination may reveal erythema, edema, papules, pustules, nodules, condylomatous lesions, abscesses, fissures, fistulas, ulceration, acrochordons, and scarring.^2-6,10,11

A host of infections (ie, mycobacterial, actinomycosis, deep fungal, sexually transmitted, schistosomiasis), inflammatory conditions (ie, sarcoid, hidradenitis suppurativa), foreign body reactions, Melkersson-Rosenthal syndrome, and sexual abuse should be included in the differential diagnosis.^2,6,10-12 Once infection, sarcoid, and foreign body reaction have been ruled out, noncaseating granulomas in skin are highly suggestive of CD.⁷

Histopathologic findings of MCD reveal myriad morphological reaction patterns,^5,13 including high-grade dysplasia and carcinoma of the vulva; therefore, it may be imprudent to withhold diagnosis based on the absence of the historically pathognomonic noncaseating granulomas.⁵

The etiopathogenesis of MCD remains an enigma. Dermatopathologic examinations consistently reveal a vascular injury syndrome,¹³ implicating a possible circulatory system contribution via deposition of immune complexes or antigens in skin.⁷ Bacterial infection has been implicated in the intestinal manifestations of CD; however, failure to detect microbial ribosomal RNA in MCD biopsies refutes theories of hematogenous spread of microbes.¹³ Another plausible explanation is that antibodies are formed to conserved microbial epitopes following loss of tolerance to gut flora, which results in an excessive immunologic response at distinct sites in susceptible individuals.¹³ A T-lymphocyte–mediated type IV hypersensitivity reaction also has been proposed via cross-reactivity of lymphocytes, with skin antigens precipitating extraintestinal granuloma formation and vascular injury.³ Clearly, further investigation is needed.

Magnetic resonanance imaging can identify the extent and anatomy of intestinal and pelvic disease and can assist in the diagnosis of vulvar CD.^10,11,14 For these reasons, some experts propose that imaging should be instituted prior to therapy,^12,15,16 especially when direct extension is suspected.¹⁷

Treatment is challenging and often involves collaboration among several specialties.¹² Many treatment options exist because therapeutic responses vary and genital MCD is frequently recalcitrant to therapy.⁴ Medical therapy includes antibiotics such as metronidazole, corticosteroids (ie, topical, intralesional, systemic), and immune modulators (eg, azathioprine, 6-mercaptopurine, cyclosporine, methotrexate, mycophenolate mofetil, tumor necrosis factor α inhibitors).^{2,3,6,10,16,18} Thalidomide has been used for refractory cases.¹⁹ These treatments can be used alone or in combination. Patients should be monitored for side effects and informed that many treatment regimens may be required before a sustained response is achieved.^4,16,18 Surgery is reserved for the most resistant cases. Extensive radical excision of the involved area is the best approach, as limited local excision often is followed by recurrence.²⁰

Conclusion

Our case highlights that vulvar CD can develop in the setting of well-controlled intestinal disease. Vulvoperineal CD should be considered in the differential diagnosis of chronic vulvar pain, swelling, and pruritus, especially in cases resistant to standard therapies and regardless of whether or not gastrointestinal tract symptoms are present. Physicians must be cognizant that vulvar signs and symptoms may precede, coincide with, or follow the diagnosis of intestinal CD. Increased awareness of this entity may facilitate its early recognition and prompt more timely treatment among women with vulvar disease caused by MCD.

The cutaneous manifestations of Crohn disease (CD) are varied, including pyoderma gangrenosum, erythema nodosum, and metastatic CD (MCD). First described by Parks et al,¹ MCD is defined as the occurrence of granulomatous lesions at a skin site distant from the gastrointestinal tract.^1-20 Metastatic CD presents a diagnostic challenge because it is a rare component in the spectrum of inflammatory bowel disease complications, and many physicians are unaware of its existence. It may precede, coincide with, or develop after the diagnosis of intestinal disease.^2-5 Vulvoperineal involvement is particularly problematic because a multitude of other, more likely disease processes are considered first. Typically it is initially diagnosed as a presumed infection prompting reflexive treatment with antivirals, antifungals, and antibiotics. Patients may experience symptoms for years prior to correct diagnosis and institution of proper therapy. A variety of clinical presentations have been described, including nonspecific pain and swelling, erythematous papules and plaques, and nonhealing ulcers. Skin biopsy characteristically confirms the diagnosis and reveals dermal noncaseating granulomas. Multiple oral and parenteral therapies are available, with surgical intervention reserved for resistant cases. We present a case of vulvovaginal MCD in the setting of well-controlled intestinal disease. We also provide a review of the literature regarding genital CD and emphasize the need to keep MCD in the differential of vulvoperineal pathology.

Case Report

A 29-year-old woman was referred to the dermatology clinic with vulvar pain, swelling, and pruritus of 14 months’ duration. Her medical history was remarkable for CD following a colectomy with colostomy. Prior therapies included methotrexate with infliximab for 5 years followed by a 2-year regimen with adalimumab, which induced remission of the intestinal disease.

The patient previously had taken a variety of topical and oral antimicrobials based on treatment from a primary care physician because fungal, bacterial, and viral infections initially were suspected; however, the vulvar disease persisted, and drug-induced immunosuppression was considered to be an underlying factor. Thus, adalimumab was discontinued. Despite elimination of the biologic, the vulvar disease progressed, which prompted referral to the dermatology clinic.

Physical examination revealed diffuse vulvar edema with overlying erythema and scale (Figure 1A). Upon closer inspection, scattered violaceous papules atop a backdrop of lichenification were evident, imparting a cobblestone appearance (Figure 1B). Additionally, a fissure was present on the gluteal cleft. Biopsy from the left labia majora demonstrated well-formed granulomas within a fibrotic reticular dermis (Figures 2A and 2B). The granulomas consisted of both mononucleated and multinucleated histiocytes, rimmed peripherally by lymphocytes and plasma cells (Figure 2C). Periodic acid–Schiff–diastase and acid-fast bacilli stains as well as polarizing microscopy were negative.

Comment

Crohn disease is an idiopathic chronic inflammatory condition that primarily affects the gastrointestinal tract, anywhere from the mouth to the anus. It is characterized by transmural inflammation and fissures that can extend beyond the muscularis propria.^4,6 Extraintestinal manifestations are common.³

Cutaneous CD often presents as perianal, perifistular, or peristomal inflammation or ulceration.⁷ Other skin manifestations include pyoderma gangrenosum, erythema nodosum, erythema multiforme, epidermolysis bullosa acquisita, and palmar erythema.⁷ Metastatic CD involves skin noncontiguous with the gastrointestinal tract^1-20 and may involve any portion of the cutis. Although rare, MCD is the typical etiology underlying vulvar CD.⁸

Approximately 20% of MCD patients have cutaneous lesions without a history of gastrointestinal disease. More than half of cases in adults and approximately two-thirds in children involve the genitalia. Although more common in adults, vulvar involvement has been reported in children as young as 6 years of age.² Diagnosis is especially challenging when bowel symptoms are absent; those patients should be evaluated and followed for subsequent intestinal involvement.⁶

Clinically, symptoms may include general discomfort, pain, pruritus, and dyspareunia. Psychosocial and sexual dysfunction are prevalent and also should be addressed.⁹ Depending on the stage of the disease, physical examination may reveal erythema, edema, papules, pustules, nodules, condylomatous lesions, abscesses, fissures, fistulas, ulceration, acrochordons, and scarring.^2-6,10,11

A host of infections (ie, mycobacterial, actinomycosis, deep fungal, sexually transmitted, schistosomiasis), inflammatory conditions (ie, sarcoid, hidradenitis suppurativa), foreign body reactions, Melkersson-Rosenthal syndrome, and sexual abuse should be included in the differential diagnosis.^2,6,10-12 Once infection, sarcoid, and foreign body reaction have been ruled out, noncaseating granulomas in skin are highly suggestive of CD.⁷

Histopathologic findings of MCD reveal myriad morphological reaction patterns,^5,13 including high-grade dysplasia and carcinoma of the vulva; therefore, it may be imprudent to withhold diagnosis based on the absence of the historically pathognomonic noncaseating granulomas.⁵

The etiopathogenesis of MCD remains an enigma. Dermatopathologic examinations consistently reveal a vascular injury syndrome,¹³ implicating a possible circulatory system contribution via deposition of immune complexes or antigens in skin.⁷ Bacterial infection has been implicated in the intestinal manifestations of CD; however, failure to detect microbial ribosomal RNA in MCD biopsies refutes theories of hematogenous spread of microbes.¹³ Another plausible explanation is that antibodies are formed to conserved microbial epitopes following loss of tolerance to gut flora, which results in an excessive immunologic response at distinct sites in susceptible individuals.¹³ A T-lymphocyte–mediated type IV hypersensitivity reaction also has been proposed via cross-reactivity of lymphocytes, with skin antigens precipitating extraintestinal granuloma formation and vascular injury.³ Clearly, further investigation is needed.

Magnetic resonanance imaging can identify the extent and anatomy of intestinal and pelvic disease and can assist in the diagnosis of vulvar CD.^10,11,14 For these reasons, some experts propose that imaging should be instituted prior to therapy,^12,15,16 especially when direct extension is suspected.¹⁷

Treatment is challenging and often involves collaboration among several specialties.¹² Many treatment options exist because therapeutic responses vary and genital MCD is frequently recalcitrant to therapy.⁴ Medical therapy includes antibiotics such as metronidazole, corticosteroids (ie, topical, intralesional, systemic), and immune modulators (eg, azathioprine, 6-mercaptopurine, cyclosporine, methotrexate, mycophenolate mofetil, tumor necrosis factor α inhibitors).^{2,3,6,10,16,18} Thalidomide has been used for refractory cases.¹⁹ These treatments can be used alone or in combination. Patients should be monitored for side effects and informed that many treatment regimens may be required before a sustained response is achieved.^4,16,18 Surgery is reserved for the most resistant cases. Extensive radical excision of the involved area is the best approach, as limited local excision often is followed by recurrence.²⁰

Conclusion

Our case highlights that vulvar CD can develop in the setting of well-controlled intestinal disease. Vulvoperineal CD should be considered in the differential diagnosis of chronic vulvar pain, swelling, and pruritus, especially in cases resistant to standard therapies and regardless of whether or not gastrointestinal tract symptoms are present. Physicians must be cognizant that vulvar signs and symptoms may precede, coincide with, or follow the diagnosis of intestinal CD. Increased awareness of this entity may facilitate its early recognition and prompt more timely treatment among women with vulvar disease caused by MCD.