Psoriasis

KAUAI, HAWAII – When certolizumab pegol receives marketing approval for moderate to severe psoriasis – which experts say is a virtual lock – it will offer a singular advantage over current anti–tumor necrosis factor (anti-TNF) biologics: strong evidence of safety in pregnancy.

“Some believe this will make certolizumab the anti-TNF agent of choice in women of childbearing potential, ” Kenneth B. Gordon, MD, observed at the Hawaii Dermatology Seminar provided by the Global Academy for Medical Education/Skin Disease Education Foundation.

Bruce Jancin/Frontline Medical News

CRIB was a prospective postmarketing pharmacokinetic study that evaluated placental transfer of certolizumab from 16 pregnant women on the biologic to their infants. All of the mothers received their last dose of certolizumab for rheumatoid arthritis or other approved indications within 35 days of delivery. Blood samples were collected from mothers, newborns, and umbilical cords within 1 hour of delivery, and again from the infants at weeks 4 and 8 after delivery.

Only one infant had a detectable plasma level of certolizumab at birth, and it was barely measurable at 0.042 mcg/mL, as compared with 49.4 mcg/mL in the mother’s plasma. This is consistent with the fact that certolizumab’s pegylated arm allows only minimal or no placental transfer from mother to infant, so there is essentially no third trimester in utero fetal exposure. In contrast, as Dr. Kimball noted, other anti-TNF biologics lack a pegylated arm and thus preferentially cross the placenta, creating a theoretical increased risk of maternal pregnancy complications and/or congenital malformations.

Dr. Kimball, professor of dermatology at Harvard Medical School and chief executive officer of Harvard Medical Faculty Physicians at Beth Israel Deaconess Medical Center, both in Boston, also has been deeply involved in an ongoing registry (sponsored by certolizumab manufacturer UCB) of several hundred women on certolizumab in pregnancy. The data have reassuringly shown no increased risk of maternal pregnancy complications such as preeclampsia, gestational diabetes, or preterm birth, nor any increase in or pattern of congenital malformations, compared with background rates in the general population.

Dr. Gordon said that while he understands the concerns, he personally doesn’t think the class-wide safety of TNF inhibitors in pregnancy and lactation is a big issue.

“My argument is that anti-TNF agents have been used very frequently in women of childbearing age, and also in women who are pregnant or lactating. And there have not been any side effect signals from that,” he explained.

The prospects of gaining an expanded indication for certolizumab in psoriasis hinge in part on the impressive results of the pivotal phase 3, randomized, double-blind, placebo-controlled CIMPASI-1 and CIMPASI-2 trials. In CIMPASI-1, the week-48 Psoriasis Area and Severity Index (PASI) 75 and PASI 90 response rates were 87.1% and 60.2%, respectively, in patients on the biologic at 400 mg every 2 weeks; among those on certolizumab at 200 mg every 2 weeks, the rates were 67.2% and 42.8%. In CIMPASI-2, the PASI 75 and PASI 90 rates were 81.3% and 62.0% at 400 mg and 78.7% and 59.6% with 200 mg every 2 weeks.

There were no cases of tuberculosis or any other significant safety concerns through 48 weeks, Dr. Gordon said.

“Certolizumab is coming soon for psoriasis,” predicted Craig L. Leonardi, MD, a psoriasis researcher at Saint Louis University. “The data are very impressive. It’s a high-performance drug. There’s no reason why this drug shouldn’t be approved.”

Since Dr. Kimball’s presentation of the CRIB data at the 2017 annual meeting of the European Academy of Dermatology and Venereology, the study has been published (Ann Rheum Dis. 2018 Feb;77[2]:228-33).

Dr. Gordon reported receiving research support from and serving as a paid consultant to numerous pharmaceutical companies developing new psoriasis therapies.

SDEF/Global Academy for Medical Education and this news organization are owned by the same parent company.

[email protected]

KAUAI, HAWAII – When certolizumab pegol receives marketing approval for moderate to severe psoriasis – which experts say is a virtual lock – it will offer a singular advantage over current anti–tumor necrosis factor (anti-TNF) biologics: strong evidence of safety in pregnancy.

“Some believe this will make certolizumab the anti-TNF agent of choice in women of childbearing potential, ” Kenneth B. Gordon, MD, observed at the Hawaii Dermatology Seminar provided by the Global Academy for Medical Education/Skin Disease Education Foundation.

Bruce Jancin/Frontline Medical News

CRIB was a prospective postmarketing pharmacokinetic study that evaluated placental transfer of certolizumab from 16 pregnant women on the biologic to their infants. All of the mothers received their last dose of certolizumab for rheumatoid arthritis or other approved indications within 35 days of delivery. Blood samples were collected from mothers, newborns, and umbilical cords within 1 hour of delivery, and again from the infants at weeks 4 and 8 after delivery.

Only one infant had a detectable plasma level of certolizumab at birth, and it was barely measurable at 0.042 mcg/mL, as compared with 49.4 mcg/mL in the mother’s plasma. This is consistent with the fact that certolizumab’s pegylated arm allows only minimal or no placental transfer from mother to infant, so there is essentially no third trimester in utero fetal exposure. In contrast, as Dr. Kimball noted, other anti-TNF biologics lack a pegylated arm and thus preferentially cross the placenta, creating a theoretical increased risk of maternal pregnancy complications and/or congenital malformations.

Dr. Kimball, professor of dermatology at Harvard Medical School and chief executive officer of Harvard Medical Faculty Physicians at Beth Israel Deaconess Medical Center, both in Boston, also has been deeply involved in an ongoing registry (sponsored by certolizumab manufacturer UCB) of several hundred women on certolizumab in pregnancy. The data have reassuringly shown no increased risk of maternal pregnancy complications such as preeclampsia, gestational diabetes, or preterm birth, nor any increase in or pattern of congenital malformations, compared with background rates in the general population.

Dr. Gordon said that while he understands the concerns, he personally doesn’t think the class-wide safety of TNF inhibitors in pregnancy and lactation is a big issue.

“My argument is that anti-TNF agents have been used very frequently in women of childbearing age, and also in women who are pregnant or lactating. And there have not been any side effect signals from that,” he explained.

The prospects of gaining an expanded indication for certolizumab in psoriasis hinge in part on the impressive results of the pivotal phase 3, randomized, double-blind, placebo-controlled CIMPASI-1 and CIMPASI-2 trials. In CIMPASI-1, the week-48 Psoriasis Area and Severity Index (PASI) 75 and PASI 90 response rates were 87.1% and 60.2%, respectively, in patients on the biologic at 400 mg every 2 weeks; among those on certolizumab at 200 mg every 2 weeks, the rates were 67.2% and 42.8%. In CIMPASI-2, the PASI 75 and PASI 90 rates were 81.3% and 62.0% at 400 mg and 78.7% and 59.6% with 200 mg every 2 weeks.

There were no cases of tuberculosis or any other significant safety concerns through 48 weeks, Dr. Gordon said.

“Certolizumab is coming soon for psoriasis,” predicted Craig L. Leonardi, MD, a psoriasis researcher at Saint Louis University. “The data are very impressive. It’s a high-performance drug. There’s no reason why this drug shouldn’t be approved.”

Since Dr. Kimball’s presentation of the CRIB data at the 2017 annual meeting of the European Academy of Dermatology and Venereology, the study has been published (Ann Rheum Dis. 2018 Feb;77[2]:228-33).

Dr. Gordon reported receiving research support from and serving as a paid consultant to numerous pharmaceutical companies developing new psoriasis therapies.

SDEF/Global Academy for Medical Education and this news organization are owned by the same parent company.

[email protected]

KAUAI, HAWAII – When certolizumab pegol receives marketing approval for moderate to severe psoriasis – which experts say is a virtual lock – it will offer a singular advantage over current anti–tumor necrosis factor (anti-TNF) biologics: strong evidence of safety in pregnancy.

“Some believe this will make certolizumab the anti-TNF agent of choice in women of childbearing potential, ” Kenneth B. Gordon, MD, observed at the Hawaii Dermatology Seminar provided by the Global Academy for Medical Education/Skin Disease Education Foundation.

Bruce Jancin/Frontline Medical News

CRIB was a prospective postmarketing pharmacokinetic study that evaluated placental transfer of certolizumab from 16 pregnant women on the biologic to their infants. All of the mothers received their last dose of certolizumab for rheumatoid arthritis or other approved indications within 35 days of delivery. Blood samples were collected from mothers, newborns, and umbilical cords within 1 hour of delivery, and again from the infants at weeks 4 and 8 after delivery.

Only one infant had a detectable plasma level of certolizumab at birth, and it was barely measurable at 0.042 mcg/mL, as compared with 49.4 mcg/mL in the mother’s plasma. This is consistent with the fact that certolizumab’s pegylated arm allows only minimal or no placental transfer from mother to infant, so there is essentially no third trimester in utero fetal exposure. In contrast, as Dr. Kimball noted, other anti-TNF biologics lack a pegylated arm and thus preferentially cross the placenta, creating a theoretical increased risk of maternal pregnancy complications and/or congenital malformations.

Dr. Kimball, professor of dermatology at Harvard Medical School and chief executive officer of Harvard Medical Faculty Physicians at Beth Israel Deaconess Medical Center, both in Boston, also has been deeply involved in an ongoing registry (sponsored by certolizumab manufacturer UCB) of several hundred women on certolizumab in pregnancy. The data have reassuringly shown no increased risk of maternal pregnancy complications such as preeclampsia, gestational diabetes, or preterm birth, nor any increase in or pattern of congenital malformations, compared with background rates in the general population.

Dr. Gordon said that while he understands the concerns, he personally doesn’t think the class-wide safety of TNF inhibitors in pregnancy and lactation is a big issue.

“My argument is that anti-TNF agents have been used very frequently in women of childbearing age, and also in women who are pregnant or lactating. And there have not been any side effect signals from that,” he explained.

The prospects of gaining an expanded indication for certolizumab in psoriasis hinge in part on the impressive results of the pivotal phase 3, randomized, double-blind, placebo-controlled CIMPASI-1 and CIMPASI-2 trials. In CIMPASI-1, the week-48 Psoriasis Area and Severity Index (PASI) 75 and PASI 90 response rates were 87.1% and 60.2%, respectively, in patients on the biologic at 400 mg every 2 weeks; among those on certolizumab at 200 mg every 2 weeks, the rates were 67.2% and 42.8%. In CIMPASI-2, the PASI 75 and PASI 90 rates were 81.3% and 62.0% at 400 mg and 78.7% and 59.6% with 200 mg every 2 weeks.

There were no cases of tuberculosis or any other significant safety concerns through 48 weeks, Dr. Gordon said.

“Certolizumab is coming soon for psoriasis,” predicted Craig L. Leonardi, MD, a psoriasis researcher at Saint Louis University. “The data are very impressive. It’s a high-performance drug. There’s no reason why this drug shouldn’t be approved.”

Since Dr. Kimball’s presentation of the CRIB data at the 2017 annual meeting of the European Academy of Dermatology and Venereology, the study has been published (Ann Rheum Dis. 2018 Feb;77[2]:228-33).

Dr. Gordon reported receiving research support from and serving as a paid consultant to numerous pharmaceutical companies developing new psoriasis therapies.

SDEF/Global Academy for Medical Education and this news organization are owned by the same parent company.

[email protected]

A significant proportion of patients with psoriasis and psoriatic arthritis (PsA) are underdiagnosed and undertreated for cardiovascular risk factors (CVRF), according to Lihi Eder, MD, of the University of Toronto, and her associates.

In a cross-sectional analysis published in the Journal of Rheumatology, researchers examined 2,254 patients (58.9% with PsA, 41.1% with psoriasis only) from eight centers in Canada, the United States, and Israel. They found that 1,017 of the patients had hypertension (PsA: 48.5%, psoriasis: 40.2%), including 233 who were not previously diagnosed with hypertension and were not taking any blood pressure–lowering medications (PsA: 19.9%, psoriasis: 39.1%). Many patients had low adherence to hypertension treatment recommendations: A total of 602 (PsA: 55.9%, psoriasis: 64.8%) were untreated or undertreated. Undertreatment of hypertension occurred in 60.9% patients with cardiovascular disease or diabetes mellitus.

[email protected]

SOURCE: Eder L et al. J Rheumatol. 2018 Feb 1. doi: 10.3899/jrheum.170379.

A significant proportion of patients with psoriasis and psoriatic arthritis (PsA) are underdiagnosed and undertreated for cardiovascular risk factors (CVRF), according to Lihi Eder, MD, of the University of Toronto, and her associates.

In a cross-sectional analysis published in the Journal of Rheumatology, researchers examined 2,254 patients (58.9% with PsA, 41.1% with psoriasis only) from eight centers in Canada, the United States, and Israel. They found that 1,017 of the patients had hypertension (PsA: 48.5%, psoriasis: 40.2%), including 233 who were not previously diagnosed with hypertension and were not taking any blood pressure–lowering medications (PsA: 19.9%, psoriasis: 39.1%). Many patients had low adherence to hypertension treatment recommendations: A total of 602 (PsA: 55.9%, psoriasis: 64.8%) were untreated or undertreated. Undertreatment of hypertension occurred in 60.9% patients with cardiovascular disease or diabetes mellitus.

[email protected]

SOURCE: Eder L et al. J Rheumatol. 2018 Feb 1. doi: 10.3899/jrheum.170379.

A significant proportion of patients with psoriasis and psoriatic arthritis (PsA) are underdiagnosed and undertreated for cardiovascular risk factors (CVRF), according to Lihi Eder, MD, of the University of Toronto, and her associates.

In a cross-sectional analysis published in the Journal of Rheumatology, researchers examined 2,254 patients (58.9% with PsA, 41.1% with psoriasis only) from eight centers in Canada, the United States, and Israel. They found that 1,017 of the patients had hypertension (PsA: 48.5%, psoriasis: 40.2%), including 233 who were not previously diagnosed with hypertension and were not taking any blood pressure–lowering medications (PsA: 19.9%, psoriasis: 39.1%). Many patients had low adherence to hypertension treatment recommendations: A total of 602 (PsA: 55.9%, psoriasis: 64.8%) were untreated or undertreated. Undertreatment of hypertension occurred in 60.9% patients with cardiovascular disease or diabetes mellitus.

[email protected]

SOURCE: Eder L et al. J Rheumatol. 2018 Feb 1. doi: 10.3899/jrheum.170379.

KAUAI, HAWAII – All psoriasis patients not already known to have psoriatic arthritis should complete the brief Psoriasis Epidemiology Screening Tool (PEST) for the rheumatologic disease once per year, advised Jashin J. Wu, MD. The PEST is a simple, validated, five-question yes/no screening tool. It’s geared towards nonrheumatologists who may not feel competent to diagnose psoriatic arthritis or who just don’t have time to do so. Three or more “yes” answers is deemed a positive result warranting consideration of referral to a rheumatologist, explained Dr. Wu, the director of the psoriasis clinic and director of dermatology research at Kaiser Permanente Los Angeles Medical Center.

Bruce Jancin/Frontline Medical News

• Have you ever had a swollen joint (or joints)?
• Has a doctor ever told you that you have arthritis?
• Do your fingernails or toenails have holes or pits?
• Have you had pain in your heel?
• Have you had a finger or toe that was completely swollen and painful for no apparent reason?

The PEST has been shown to have 92% sensitivity and 78% specificity for diagnosis of psoriatic arthritis (Clin Exp Rheumatol. 2009 May-Jun;27[3]:469-74).

Dr. Wu’s call for regular screening for psoriatic arthritis resonated with another psoriasis expert at the meeting, Craig L. Leonardi, MD.

“It’s our moral obligation to be on the lookout for that disease. Remember that patients who develop psoriatic arthritis usually have their skin disease for 10 years before they develop their first signs and symptoms of psoriatic arthritis. So that means they should be in the dermatologist’s office getting their skin treated as they start to have problems with their joints,” observed Dr. Leonardi, of Saint Louis University.

Dr. Wu reported receiving research funding from AbbVie, Amgen, Eli Lilly, Janssen, Novartis, and Regeneron.

The SDEF and this news organization are owned by the same parent company.
 

[email protected]

KAUAI, HAWAII – All psoriasis patients not already known to have psoriatic arthritis should complete the brief Psoriasis Epidemiology Screening Tool (PEST) for the rheumatologic disease once per year, advised Jashin J. Wu, MD. The PEST is a simple, validated, five-question yes/no screening tool. It’s geared towards nonrheumatologists who may not feel competent to diagnose psoriatic arthritis or who just don’t have time to do so. Three or more “yes” answers is deemed a positive result warranting consideration of referral to a rheumatologist, explained Dr. Wu, the director of the psoriasis clinic and director of dermatology research at Kaiser Permanente Los Angeles Medical Center.

Bruce Jancin/Frontline Medical News

• Have you ever had a swollen joint (or joints)?
• Has a doctor ever told you that you have arthritis?
• Do your fingernails or toenails have holes or pits?
• Have you had pain in your heel?
• Have you had a finger or toe that was completely swollen and painful for no apparent reason?

The PEST has been shown to have 92% sensitivity and 78% specificity for diagnosis of psoriatic arthritis (Clin Exp Rheumatol. 2009 May-Jun;27[3]:469-74).

Dr. Wu’s call for regular screening for psoriatic arthritis resonated with another psoriasis expert at the meeting, Craig L. Leonardi, MD.

“It’s our moral obligation to be on the lookout for that disease. Remember that patients who develop psoriatic arthritis usually have their skin disease for 10 years before they develop their first signs and symptoms of psoriatic arthritis. So that means they should be in the dermatologist’s office getting their skin treated as they start to have problems with their joints,” observed Dr. Leonardi, of Saint Louis University.

Dr. Wu reported receiving research funding from AbbVie, Amgen, Eli Lilly, Janssen, Novartis, and Regeneron.

The SDEF and this news organization are owned by the same parent company.
 

[email protected]

KAUAI, HAWAII – All psoriasis patients not already known to have psoriatic arthritis should complete the brief Psoriasis Epidemiology Screening Tool (PEST) for the rheumatologic disease once per year, advised Jashin J. Wu, MD. The PEST is a simple, validated, five-question yes/no screening tool. It’s geared towards nonrheumatologists who may not feel competent to diagnose psoriatic arthritis or who just don’t have time to do so. Three or more “yes” answers is deemed a positive result warranting consideration of referral to a rheumatologist, explained Dr. Wu, the director of the psoriasis clinic and director of dermatology research at Kaiser Permanente Los Angeles Medical Center.

Bruce Jancin/Frontline Medical News

• Have you ever had a swollen joint (or joints)?
• Has a doctor ever told you that you have arthritis?
• Do your fingernails or toenails have holes or pits?
• Have you had pain in your heel?
• Have you had a finger or toe that was completely swollen and painful for no apparent reason?

The PEST has been shown to have 92% sensitivity and 78% specificity for diagnosis of psoriatic arthritis (Clin Exp Rheumatol. 2009 May-Jun;27[3]:469-74).

Dr. Wu’s call for regular screening for psoriatic arthritis resonated with another psoriasis expert at the meeting, Craig L. Leonardi, MD.

“It’s our moral obligation to be on the lookout for that disease. Remember that patients who develop psoriatic arthritis usually have their skin disease for 10 years before they develop their first signs and symptoms of psoriatic arthritis. So that means they should be in the dermatologist’s office getting their skin treated as they start to have problems with their joints,” observed Dr. Leonardi, of Saint Louis University.

Dr. Wu reported receiving research funding from AbbVie, Amgen, Eli Lilly, Janssen, Novartis, and Regeneron.

The SDEF and this news organization are owned by the same parent company.
 

[email protected]

Molluscum contagiosum (MC) is a double-stranded DNA virus of the Poxviridae family, which commonly infects human keratinocytes resulting in small, umbilicated, flesh-colored papules. The greatest incidence of MC is seen in the pediatric population and sexually active young adults, and it is considered a self-limited disease in immunocompetent individuals.¹ With the emergence of the human immunodeficiency virus (HIV) and subsequent AIDS epidemic in the 1980s, a new population of immunocompromised individuals has been observed to be increasingly susceptible to MC with an atypical clinical presentation and a recalcitrant disease course.² Although the increased prevalence of MC in the HIV population has been well-documented, it has been observed in other disease states or iatrogenically induced immunosuppression due to a deficiency in function or absolute number of T lymphocytes.

We present a case of a patient with long-standing psoriasis on biologic therapy who presented with MC with a subsequent workup that revealed AIDS. This case reiterates the importance of MC as a potential indicator of underlying immunosuppression. We review the literature to evaluate the occurrence of MC in immunosuppressed patients.

Case Report

A 33-year-old man initially presented for evaluation of severe plaque-type psoriasis associated with pain, erythema, and swelling of the joints of the hands of 10 years’ duration. He was started on methotrexate 5 mg weekly and topical corticosteroids but was unable to tolerate methotrexate due to headaches. He also had difficulty affording topical medications and adjunctive phototherapy. The patient was sporadically seen in follow-up with persistence of psoriatic plaques involving up to 60% body surface area (BSA) with the only treatment consisting of occasional topical steroids. Five years later, the patient was restarted on methotrexate 5 to 7.5 mg weekly, which resulted in moderate improvement. However, because of persistent elevation of liver enzymes, this treatment was stopped. Several months later he was evaluated for treatment with a biologic agent, and after a negative tuberculin skin test, he began treatment with etanercept 50 mg subcutaneous injection twice weekly, which provided notable improvement and allowed for reduction of dose frequency to once weekly.

At follow-up 1 year later, the patient had continued improvement of psoriasis with approximately 30% BSA on a treatment regimen of etanercept 50 mg weekly injection and topical corticosteroids. However, on physical examination, there were multiple small semitranslucent papules with telangiectases on the chest and upper back (Figure 1). Biopsy of a representative papule on the chest revealed MC (Figure 2). The patient was subsequently advised to stop etanercept and to return immediately to the clinic for HIV testing. He returned for follow-up 3 months later with pronounced worsening of disease and a new onset of blurred vision of the right eye. Cutaneous examination revealed numerous large erythematous plaques with superficial scale and cerebriform surface on the chest, back, abdomen, and upper and lower extremities involving 80% BSA (Figure 3). Biopsy of a plaque demonstrated psoriasiform dermatitis with neutrophils and parakeratosis consistent with psoriasis. Extensive blood work was notable for reactive HIV antibody and lymphopenia, CD4 lymphocyte count of 60 cells/mm³, and an HIV viral load of 247,000 copies/mL, meeting diagnostic criteria for AIDS. Additionally, ophthalmologic evaluation revealed toxoplasma retinitis. Upon initiation of highly active antiretroviral therapy (HAART) and continued use of topical corticosteroids, the patient experienced notable improvement of disease severity with approximately 20% BSA.

Comment

Molluscum contagiosum is a common skin infection. Among patients with HIV and other types of impaired cellular immunity, the prevalence of MC is estimated to be as high as 20%.³ The MC poxvirus survives and proliferates within the epidermis by interfering with tumor necrosis factor–induced apoptosis of virally infected cells; therefore, intact cell-mediated immunity is an important component of prevention and clearance of poxvirus infections. In immunocompromised patients, the presentation of MC varies widely, and the disease is often difficult to eradicate. This review will highlight the prevalence, presentation, and treatment of MC in the context of immunosuppressed states.

HIV/AIDS
Molluscum contagiosum in HIV-positive patients was first recognized in 1983,² and its prevalence is estimated to range from 5% to 18% in AIDS patients.³ Molluscum contagiosum is a clinical sign of HIV progression, and its incidence appears to increase with reduced immune function (ie, a CD4 cell count <200/mm³).³ In a study of 456 patients with HIV-associated skin disorders, the majority of patients with MC had notable immunosuppression with a median survival time of 12 months. Thus, MC was not an independent prognostic marker but a clinical indicator of markedly reduced immune status.⁴

Molluscum contagiosum is transmitted in both sexual and nonsexual patterns in HIV-positive individuals, with the distribution of the latter involving primarily the face and neck. Although it may present with typical umbilicated papules, MC has a wide range of atypical clinical presentations in patients with AIDS that can make it difficult to diagnose. Complicated cases of eyelid MC have been reported in advanced HIV in both adults and children, resulting in obstruction of vision due to large lesions (up to 2 cm) or hundreds of confluent lesions.⁵ Giant MC, which appears as large exophytic nodules, is another presentation that has been frequently described in patients with advanced HIV. In these patients, the lesions often are too voluminous for conservative therapy and require excision.⁶ Atypical MC lesions also can resemble other dermatologic conditions, including condyloma acuminatum,⁷ nevus sebaceous of Jadassohn, ecthyma,⁸ and cutaneous horns,^9,10 as well as other bacterial and fungal infections in HIV-positive patients, such as cutaneous Cryptococcus neoformans,^11,12 disseminated histoplasmosis,¹³ and infections caused by Penicillium marneffei¹⁴ and Bartonella henselae.¹⁵ In most cases of MC in HIV-positive patients, diagnosis is dependent on the examination of biopsy specimens, which maintain the same histopathologic features regardless of immune status.

The management of MC in patients with HIV/AIDS is difficult. Molluscum contagiosum has shown no evidence of spontaneous resolution in patients with HIV, and treatment with one modality is often insufficient. Treatment is most successful when a combination approach is utilized with destructive procedures (eg, curettage, cryosurgery) and adjunctive agents (eg, retinoids, cantharidin, trichloroacetic acid). Imiquimod and cidofovir have been used off label for MC in AIDS patients.¹⁶ Imiquimod, which is used to treat genital warts, another cutaneous viral infection seen in patients with HIV, has demonstrated efficacy in treating MC.¹⁶ In a randomized controlled trial comparing imiquimod cream 5% to cryotherapy for MC in healthy children, imiquimod was slow acting but better suited than cryotherapy for patients with eruptions of many small lesions.¹⁷ For HIV patients, numerous reports have described successful treatment of disseminated or recalcitrant MC with topical imiquimod.^18-20 Cidofovir, an antiviral used to treat cytomegalovirus retinitis in patients with AIDS, is a promising antiviral agent against the poxvirus family. In a study of viral DNA polymerase genes of MC virus, cidofovir inhibited MC virus DNA polymerase activity.²¹ It has been used in both topical (1% to 3%) and intravenous form to successfully treat recalcitrant and exuberant giant MC.^6,22 However, the use of cidofovir is limited by its high costs, especially when compounded into a topical formulation.²³

From a systemic standpoint, numerous reports have shown that treating the underlying HIV by optimizing HAART is the most important first step in clearing MC.^24-27 However, a special concern regarding the initiation of HAART in patients with MC as well as a markedly impaired immune function is the development of an inflammatory reaction called immune reconstitution inflammatory syndrome (IRIS). This reaction is thought to be a result of immune recovery in severely immunosuppressed patients. During the initial phase of reconstitution when CD4 lymphocyte counts rise and viral load decreases, IRIS occurs due to an inflammatory reaction to microbial and autoimmune antigens, leading to temporary clinical deterioration.²⁸ The incidence has been reported in up to 25% of patients starting HAART, and 52% to 78% of IRIS cases involve dermatologic manifestations such as varicella-zoster virus, cytomegalovirus infections, genital warts, and MC.^29,30 In a cohort study of 199 patients, 2% of patients developed MC within 6 months of initiating HAART.³¹ In a case of exuberant MC lesions after beginning HAART, the lesions spontaneously resolved with the progression of immune reconstitution.²⁸

Malignancies
Patients with hematologic malignancies such as lymphoma and leukemia comprise another subset of patients at risk for atypical presentations of MC. Molluscum contagiosum has been described in patients with hematologic malignancies such as adult T-cell leukemia/lymphoma, multiple myeloma, chronic myeloid leukemia, acute lymphoblastic leukemia, lymphomatoid papulosis, and non-Hodgkin lymphoma. In a review of MC in children with cancer, 0.5% were diagnosed with MC.^32,33 Reports also have documented eruptive MC in the presence of solid organ cancers, including lung cancer.³⁴

In patients with malignancies, the differential diagnosis should include other common dermatologic conditions such as varicella, herpes simplex, papillomas, pyoderma, and cutaneous cryptococcosis, as well as MC. Similar to HIV-positive patients, the lesions of MC described in patients with malignancies do not tend to spontaneously resolve. In a report of a pediatric patient with acute lymphoblastic leukemia, MC presented as an ulcerated lesion without any classic features, requiring biopsy for definitive diagnosis. Only partial resolution was achieved with cryotherapy and crusting of the lesion in an attempt to slow the progression.³⁵ In a series of 5 children with hematologic malignancies and MC, little improvement was noted after treatment with surgical scraping, liquid nitrogen, and salicylic acid ointment 5%. Similar to patients with HIV, improvement of immune status and function help clear the disease, and patients who reach remission and discontinue chemotherapeutic agents have a higher rate of spontaneous resolution of previously recalcitrant MC lesions.³⁶

Transplant Patients
Molluscum contagiosum in transplant patients has features similar to patients with HIV/AIDS. In organ transplant recipients, there is an increased risk for cutaneous disease from iatrogenic immunosuppression or immunosuppression through infectious or neoplastic processes.³⁷ As in other immunocompromised populations, MC often has an atypical presentation in transplant patients with more extensive involvement and recalcitrant, rapidly recurring lesions.

In a review of 145 pediatric organ transplant recipients, MC was the fourth most common skin infection after verruca vulgaris, tinea versicolor, and herpes simplex/zoster. Affecting 7% of patients, the majority of patients demonstrated clinically typical lesions; however, the disease was difficult to eradicate if multiple lesions were present.³⁷ In other reports in adults, fulminant and giant MC have been described after renal and other solid organ transplants.^38,39 Molluscum contagiosum also has been reported to mimic other skin diseases in transplant patients including tinea barbae⁴⁰ and nodular basal cell carcinomas.⁴¹

The standard treatments are identical to those used in patients with HIV, including ablative methods via liquid nitrogen, electrocautery, cantharidin, trichloroacetic acid, and topical retinoids. Similar to MC in other immunocompromised states, treatment can be difficult and usually requires multiple modalities. For children, imiquimod cream 5% has been recommended due to high clearance rates (up to 92%) and the painless nature of the treatment.^42,43

Other Iatrogenic Immunosuppressive States
Immunosuppression through the use of steroids, chemotherapeutic agents, and biologic drugs often is the result of treatment of various diseases. In patients with psoriasis treated with systemic immunosuppressive agents, there are numerous reports that describe the appearance of eruptive MC in association with methotrexate, cyclosporine, and biologics. Methotrexate acts as an immunosuppressive agent by binding to dihydrofolate reductase, which inhibits DNA synthesis in immunologically competent cells.⁴⁴ It also may block host defense mechanisms against MC by suppressing the expression of serum inflammatory cytokines such as tumor necrosis factor α (TNF-α) and IFN-γ and suppressing the activity of TNF-α inducing apoptosis of virus-infected cells. Cyclosporine used in conjunction with methotrexate may exacerbate the insult to the immune system by inhibiting the production of IFN-γ.⁴⁵ Biologics are an emerging class of drugs that have demonstrated efficacy in moderate to severe psoriasis by inhibiting TNF-α or other inflammatory molecules. Several published reports have described eruptive or atypical MC in patients on biologic medications. In one case, within 2 weeks after initiation of infliximab, a monoclonal antibody against TNF-α, a patient developed an eruption of MC involving the entire body.⁴⁶ In another report, an anti–TNF-α agent for rheumatoid arthritis was associated with atypical MC with eyelid lesions.⁴⁷

There are other skin disorders treated with immunosuppressive agents that also have been associated with MC. In a patient with pemphigus vulgaris treated with prednisolone, pimecrolimus, and azathioprine, MC lesions were observed on the face and within healed pemphigus vulgaris sites.⁴⁸ Pimecrolimus and tacrolimus, corticosteroid-sparing agents, suppress cell-mediated immunity and inhibit inflammatory cytokines such as IL-2. The infection resolved with a gradual tapering of immunosuppressive therapy and 10 sessions of cryotherapy.⁴⁸ In a case of topical pimecrolimus for pityriasis alba, the patient developed biopsy-proven MC within 2 weeks of initiating treatment in the areas that were treated with tacrolimus.⁴⁹

In nontransplant patients with iatrogenic immunosuppression, MC treatment has not been documented to be as challenging as in patients with inherent immunosuppression. Most patients respond to either withdrawal of the drug alone or to simple ablative treatments such as cryotherapy.^45,46,48 This important difference is most likely due to the presence of an otherwise intact immune system.

Conclusion

This case describes the appearance of MC in a patient with psoriasis treated with a TNF-α inhibitor who was ultimately diagnosed with AIDS. Although atypical MC infections have been documented in patients with psoriasis undergoing treatment with biologics, it is thought to be more common for MC to occur in more remarkably immunocompromised states such as AIDS. Thus, the persistence and progression of MC in our patient despite discontinuation of etanercept suggested a separate underlying process. Subsequent workup led to the diagnosis of AIDS along with the opportunistic ocular infection of toxoplasmosis retinitis. This clinical sequence consisting of psoriasis treated with a biologic agent, development of MC, and subsequent diagnosis of AIDS is unique and clinically significant to dermatologists. The presentation of psoriasis in patients with HIV can be diverse with different levels of severity and atypical clinical features. In many cases, HIV is known to exacerbate the classic clinical presentation of psoriasis. However, there are other particular presentations of psoriasis in HIV patients that have been observed, which include a predilection for scalp lesions, palmoplantar keratoderma, flexural involvement, and higher levels of immunodeficiency.⁵⁰ Although tuberculin skin tests are required prior to initiating biologic therapy due to the potential for disease reactivation, there are no requirements for HIV antibody testing. In cases of severe recalcitrant psoriasis, an HIV test should be ordered during the workup to establish an early diagnosis so that an HIV-positive patient can avoid poor outcomes from either the disease processes, the use of certain therapeutic agents, or both. Furthermore, the benefit of avoiding possible harm to the patient and potential legal action outweighs the cost of performing surveillance HIV testing in this subset of patients. Thus, due to the potential additive immunosuppressive effect of HIV with biologic therapy, providers should always assess for risk factors and consider testing for HIV in all patients before initiating treatment with immunosuppressive agents such as biologics.

Molluscum contagiosum (MC) is a double-stranded DNA virus of the Poxviridae family, which commonly infects human keratinocytes resulting in small, umbilicated, flesh-colored papules. The greatest incidence of MC is seen in the pediatric population and sexually active young adults, and it is considered a self-limited disease in immunocompetent individuals.¹ With the emergence of the human immunodeficiency virus (HIV) and subsequent AIDS epidemic in the 1980s, a new population of immunocompromised individuals has been observed to be increasingly susceptible to MC with an atypical clinical presentation and a recalcitrant disease course.² Although the increased prevalence of MC in the HIV population has been well-documented, it has been observed in other disease states or iatrogenically induced immunosuppression due to a deficiency in function or absolute number of T lymphocytes.

We present a case of a patient with long-standing psoriasis on biologic therapy who presented with MC with a subsequent workup that revealed AIDS. This case reiterates the importance of MC as a potential indicator of underlying immunosuppression. We review the literature to evaluate the occurrence of MC in immunosuppressed patients.

Case Report

A 33-year-old man initially presented for evaluation of severe plaque-type psoriasis associated with pain, erythema, and swelling of the joints of the hands of 10 years’ duration. He was started on methotrexate 5 mg weekly and topical corticosteroids but was unable to tolerate methotrexate due to headaches. He also had difficulty affording topical medications and adjunctive phototherapy. The patient was sporadically seen in follow-up with persistence of psoriatic plaques involving up to 60% body surface area (BSA) with the only treatment consisting of occasional topical steroids. Five years later, the patient was restarted on methotrexate 5 to 7.5 mg weekly, which resulted in moderate improvement. However, because of persistent elevation of liver enzymes, this treatment was stopped. Several months later he was evaluated for treatment with a biologic agent, and after a negative tuberculin skin test, he began treatment with etanercept 50 mg subcutaneous injection twice weekly, which provided notable improvement and allowed for reduction of dose frequency to once weekly.

At follow-up 1 year later, the patient had continued improvement of psoriasis with approximately 30% BSA on a treatment regimen of etanercept 50 mg weekly injection and topical corticosteroids. However, on physical examination, there were multiple small semitranslucent papules with telangiectases on the chest and upper back (Figure 1). Biopsy of a representative papule on the chest revealed MC (Figure 2). The patient was subsequently advised to stop etanercept and to return immediately to the clinic for HIV testing. He returned for follow-up 3 months later with pronounced worsening of disease and a new onset of blurred vision of the right eye. Cutaneous examination revealed numerous large erythematous plaques with superficial scale and cerebriform surface on the chest, back, abdomen, and upper and lower extremities involving 80% BSA (Figure 3). Biopsy of a plaque demonstrated psoriasiform dermatitis with neutrophils and parakeratosis consistent with psoriasis. Extensive blood work was notable for reactive HIV antibody and lymphopenia, CD4 lymphocyte count of 60 cells/mm³, and an HIV viral load of 247,000 copies/mL, meeting diagnostic criteria for AIDS. Additionally, ophthalmologic evaluation revealed toxoplasma retinitis. Upon initiation of highly active antiretroviral therapy (HAART) and continued use of topical corticosteroids, the patient experienced notable improvement of disease severity with approximately 20% BSA.

Comment

Molluscum contagiosum is a common skin infection. Among patients with HIV and other types of impaired cellular immunity, the prevalence of MC is estimated to be as high as 20%.³ The MC poxvirus survives and proliferates within the epidermis by interfering with tumor necrosis factor–induced apoptosis of virally infected cells; therefore, intact cell-mediated immunity is an important component of prevention and clearance of poxvirus infections. In immunocompromised patients, the presentation of MC varies widely, and the disease is often difficult to eradicate. This review will highlight the prevalence, presentation, and treatment of MC in the context of immunosuppressed states.

HIV/AIDS
Molluscum contagiosum in HIV-positive patients was first recognized in 1983,² and its prevalence is estimated to range from 5% to 18% in AIDS patients.³ Molluscum contagiosum is a clinical sign of HIV progression, and its incidence appears to increase with reduced immune function (ie, a CD4 cell count <200/mm³).³ In a study of 456 patients with HIV-associated skin disorders, the majority of patients with MC had notable immunosuppression with a median survival time of 12 months. Thus, MC was not an independent prognostic marker but a clinical indicator of markedly reduced immune status.⁴

Molluscum contagiosum is transmitted in both sexual and nonsexual patterns in HIV-positive individuals, with the distribution of the latter involving primarily the face and neck. Although it may present with typical umbilicated papules, MC has a wide range of atypical clinical presentations in patients with AIDS that can make it difficult to diagnose. Complicated cases of eyelid MC have been reported in advanced HIV in both adults and children, resulting in obstruction of vision due to large lesions (up to 2 cm) or hundreds of confluent lesions.⁵ Giant MC, which appears as large exophytic nodules, is another presentation that has been frequently described in patients with advanced HIV. In these patients, the lesions often are too voluminous for conservative therapy and require excision.⁶ Atypical MC lesions also can resemble other dermatologic conditions, including condyloma acuminatum,⁷ nevus sebaceous of Jadassohn, ecthyma,⁸ and cutaneous horns,^9,10 as well as other bacterial and fungal infections in HIV-positive patients, such as cutaneous Cryptococcus neoformans,^11,12 disseminated histoplasmosis,¹³ and infections caused by Penicillium marneffei¹⁴ and Bartonella henselae.¹⁵ In most cases of MC in HIV-positive patients, diagnosis is dependent on the examination of biopsy specimens, which maintain the same histopathologic features regardless of immune status.

The management of MC in patients with HIV/AIDS is difficult. Molluscum contagiosum has shown no evidence of spontaneous resolution in patients with HIV, and treatment with one modality is often insufficient. Treatment is most successful when a combination approach is utilized with destructive procedures (eg, curettage, cryosurgery) and adjunctive agents (eg, retinoids, cantharidin, trichloroacetic acid). Imiquimod and cidofovir have been used off label for MC in AIDS patients.¹⁶ Imiquimod, which is used to treat genital warts, another cutaneous viral infection seen in patients with HIV, has demonstrated efficacy in treating MC.¹⁶ In a randomized controlled trial comparing imiquimod cream 5% to cryotherapy for MC in healthy children, imiquimod was slow acting but better suited than cryotherapy for patients with eruptions of many small lesions.¹⁷ For HIV patients, numerous reports have described successful treatment of disseminated or recalcitrant MC with topical imiquimod.^18-20 Cidofovir, an antiviral used to treat cytomegalovirus retinitis in patients with AIDS, is a promising antiviral agent against the poxvirus family. In a study of viral DNA polymerase genes of MC virus, cidofovir inhibited MC virus DNA polymerase activity.²¹ It has been used in both topical (1% to 3%) and intravenous form to successfully treat recalcitrant and exuberant giant MC.^6,22 However, the use of cidofovir is limited by its high costs, especially when compounded into a topical formulation.²³

From a systemic standpoint, numerous reports have shown that treating the underlying HIV by optimizing HAART is the most important first step in clearing MC.^24-27 However, a special concern regarding the initiation of HAART in patients with MC as well as a markedly impaired immune function is the development of an inflammatory reaction called immune reconstitution inflammatory syndrome (IRIS). This reaction is thought to be a result of immune recovery in severely immunosuppressed patients. During the initial phase of reconstitution when CD4 lymphocyte counts rise and viral load decreases, IRIS occurs due to an inflammatory reaction to microbial and autoimmune antigens, leading to temporary clinical deterioration.²⁸ The incidence has been reported in up to 25% of patients starting HAART, and 52% to 78% of IRIS cases involve dermatologic manifestations such as varicella-zoster virus, cytomegalovirus infections, genital warts, and MC.^29,30 In a cohort study of 199 patients, 2% of patients developed MC within 6 months of initiating HAART.³¹ In a case of exuberant MC lesions after beginning HAART, the lesions spontaneously resolved with the progression of immune reconstitution.²⁸

Malignancies
Patients with hematologic malignancies such as lymphoma and leukemia comprise another subset of patients at risk for atypical presentations of MC. Molluscum contagiosum has been described in patients with hematologic malignancies such as adult T-cell leukemia/lymphoma, multiple myeloma, chronic myeloid leukemia, acute lymphoblastic leukemia, lymphomatoid papulosis, and non-Hodgkin lymphoma. In a review of MC in children with cancer, 0.5% were diagnosed with MC.^32,33 Reports also have documented eruptive MC in the presence of solid organ cancers, including lung cancer.³⁴

In patients with malignancies, the differential diagnosis should include other common dermatologic conditions such as varicella, herpes simplex, papillomas, pyoderma, and cutaneous cryptococcosis, as well as MC. Similar to HIV-positive patients, the lesions of MC described in patients with malignancies do not tend to spontaneously resolve. In a report of a pediatric patient with acute lymphoblastic leukemia, MC presented as an ulcerated lesion without any classic features, requiring biopsy for definitive diagnosis. Only partial resolution was achieved with cryotherapy and crusting of the lesion in an attempt to slow the progression.³⁵ In a series of 5 children with hematologic malignancies and MC, little improvement was noted after treatment with surgical scraping, liquid nitrogen, and salicylic acid ointment 5%. Similar to patients with HIV, improvement of immune status and function help clear the disease, and patients who reach remission and discontinue chemotherapeutic agents have a higher rate of spontaneous resolution of previously recalcitrant MC lesions.³⁶

Transplant Patients
Molluscum contagiosum in transplant patients has features similar to patients with HIV/AIDS. In organ transplant recipients, there is an increased risk for cutaneous disease from iatrogenic immunosuppression or immunosuppression through infectious or neoplastic processes.³⁷ As in other immunocompromised populations, MC often has an atypical presentation in transplant patients with more extensive involvement and recalcitrant, rapidly recurring lesions.

In a review of 145 pediatric organ transplant recipients, MC was the fourth most common skin infection after verruca vulgaris, tinea versicolor, and herpes simplex/zoster. Affecting 7% of patients, the majority of patients demonstrated clinically typical lesions; however, the disease was difficult to eradicate if multiple lesions were present.³⁷ In other reports in adults, fulminant and giant MC have been described after renal and other solid organ transplants.^38,39 Molluscum contagiosum also has been reported to mimic other skin diseases in transplant patients including tinea barbae⁴⁰ and nodular basal cell carcinomas.⁴¹

The standard treatments are identical to those used in patients with HIV, including ablative methods via liquid nitrogen, electrocautery, cantharidin, trichloroacetic acid, and topical retinoids. Similar to MC in other immunocompromised states, treatment can be difficult and usually requires multiple modalities. For children, imiquimod cream 5% has been recommended due to high clearance rates (up to 92%) and the painless nature of the treatment.^42,43

Other Iatrogenic Immunosuppressive States
Immunosuppression through the use of steroids, chemotherapeutic agents, and biologic drugs often is the result of treatment of various diseases. In patients with psoriasis treated with systemic immunosuppressive agents, there are numerous reports that describe the appearance of eruptive MC in association with methotrexate, cyclosporine, and biologics. Methotrexate acts as an immunosuppressive agent by binding to dihydrofolate reductase, which inhibits DNA synthesis in immunologically competent cells.⁴⁴ It also may block host defense mechanisms against MC by suppressing the expression of serum inflammatory cytokines such as tumor necrosis factor α (TNF-α) and IFN-γ and suppressing the activity of TNF-α inducing apoptosis of virus-infected cells. Cyclosporine used in conjunction with methotrexate may exacerbate the insult to the immune system by inhibiting the production of IFN-γ.⁴⁵ Biologics are an emerging class of drugs that have demonstrated efficacy in moderate to severe psoriasis by inhibiting TNF-α or other inflammatory molecules. Several published reports have described eruptive or atypical MC in patients on biologic medications. In one case, within 2 weeks after initiation of infliximab, a monoclonal antibody against TNF-α, a patient developed an eruption of MC involving the entire body.⁴⁶ In another report, an anti–TNF-α agent for rheumatoid arthritis was associated with atypical MC with eyelid lesions.⁴⁷

There are other skin disorders treated with immunosuppressive agents that also have been associated with MC. In a patient with pemphigus vulgaris treated with prednisolone, pimecrolimus, and azathioprine, MC lesions were observed on the face and within healed pemphigus vulgaris sites.⁴⁸ Pimecrolimus and tacrolimus, corticosteroid-sparing agents, suppress cell-mediated immunity and inhibit inflammatory cytokines such as IL-2. The infection resolved with a gradual tapering of immunosuppressive therapy and 10 sessions of cryotherapy.⁴⁸ In a case of topical pimecrolimus for pityriasis alba, the patient developed biopsy-proven MC within 2 weeks of initiating treatment in the areas that were treated with tacrolimus.⁴⁹

In nontransplant patients with iatrogenic immunosuppression, MC treatment has not been documented to be as challenging as in patients with inherent immunosuppression. Most patients respond to either withdrawal of the drug alone or to simple ablative treatments such as cryotherapy.^45,46,48 This important difference is most likely due to the presence of an otherwise intact immune system.

Conclusion

This case describes the appearance of MC in a patient with psoriasis treated with a TNF-α inhibitor who was ultimately diagnosed with AIDS. Although atypical MC infections have been documented in patients with psoriasis undergoing treatment with biologics, it is thought to be more common for MC to occur in more remarkably immunocompromised states such as AIDS. Thus, the persistence and progression of MC in our patient despite discontinuation of etanercept suggested a separate underlying process. Subsequent workup led to the diagnosis of AIDS along with the opportunistic ocular infection of toxoplasmosis retinitis. This clinical sequence consisting of psoriasis treated with a biologic agent, development of MC, and subsequent diagnosis of AIDS is unique and clinically significant to dermatologists. The presentation of psoriasis in patients with HIV can be diverse with different levels of severity and atypical clinical features. In many cases, HIV is known to exacerbate the classic clinical presentation of psoriasis. However, there are other particular presentations of psoriasis in HIV patients that have been observed, which include a predilection for scalp lesions, palmoplantar keratoderma, flexural involvement, and higher levels of immunodeficiency.⁵⁰ Although tuberculin skin tests are required prior to initiating biologic therapy due to the potential for disease reactivation, there are no requirements for HIV antibody testing. In cases of severe recalcitrant psoriasis, an HIV test should be ordered during the workup to establish an early diagnosis so that an HIV-positive patient can avoid poor outcomes from either the disease processes, the use of certain therapeutic agents, or both. Furthermore, the benefit of avoiding possible harm to the patient and potential legal action outweighs the cost of performing surveillance HIV testing in this subset of patients. Thus, due to the potential additive immunosuppressive effect of HIV with biologic therapy, providers should always assess for risk factors and consider testing for HIV in all patients before initiating treatment with immunosuppressive agents such as biologics.

Molluscum contagiosum (MC) is a double-stranded DNA virus of the Poxviridae family, which commonly infects human keratinocytes resulting in small, umbilicated, flesh-colored papules. The greatest incidence of MC is seen in the pediatric population and sexually active young adults, and it is considered a self-limited disease in immunocompetent individuals.¹ With the emergence of the human immunodeficiency virus (HIV) and subsequent AIDS epidemic in the 1980s, a new population of immunocompromised individuals has been observed to be increasingly susceptible to MC with an atypical clinical presentation and a recalcitrant disease course.² Although the increased prevalence of MC in the HIV population has been well-documented, it has been observed in other disease states or iatrogenically induced immunosuppression due to a deficiency in function or absolute number of T lymphocytes.

We present a case of a patient with long-standing psoriasis on biologic therapy who presented with MC with a subsequent workup that revealed AIDS. This case reiterates the importance of MC as a potential indicator of underlying immunosuppression. We review the literature to evaluate the occurrence of MC in immunosuppressed patients.

Case Report

A 33-year-old man initially presented for evaluation of severe plaque-type psoriasis associated with pain, erythema, and swelling of the joints of the hands of 10 years’ duration. He was started on methotrexate 5 mg weekly and topical corticosteroids but was unable to tolerate methotrexate due to headaches. He also had difficulty affording topical medications and adjunctive phototherapy. The patient was sporadically seen in follow-up with persistence of psoriatic plaques involving up to 60% body surface area (BSA) with the only treatment consisting of occasional topical steroids. Five years later, the patient was restarted on methotrexate 5 to 7.5 mg weekly, which resulted in moderate improvement. However, because of persistent elevation of liver enzymes, this treatment was stopped. Several months later he was evaluated for treatment with a biologic agent, and after a negative tuberculin skin test, he began treatment with etanercept 50 mg subcutaneous injection twice weekly, which provided notable improvement and allowed for reduction of dose frequency to once weekly.

At follow-up 1 year later, the patient had continued improvement of psoriasis with approximately 30% BSA on a treatment regimen of etanercept 50 mg weekly injection and topical corticosteroids. However, on physical examination, there were multiple small semitranslucent papules with telangiectases on the chest and upper back (Figure 1). Biopsy of a representative papule on the chest revealed MC (Figure 2). The patient was subsequently advised to stop etanercept and to return immediately to the clinic for HIV testing. He returned for follow-up 3 months later with pronounced worsening of disease and a new onset of blurred vision of the right eye. Cutaneous examination revealed numerous large erythematous plaques with superficial scale and cerebriform surface on the chest, back, abdomen, and upper and lower extremities involving 80% BSA (Figure 3). Biopsy of a plaque demonstrated psoriasiform dermatitis with neutrophils and parakeratosis consistent with psoriasis. Extensive blood work was notable for reactive HIV antibody and lymphopenia, CD4 lymphocyte count of 60 cells/mm³, and an HIV viral load of 247,000 copies/mL, meeting diagnostic criteria for AIDS. Additionally, ophthalmologic evaluation revealed toxoplasma retinitis. Upon initiation of highly active antiretroviral therapy (HAART) and continued use of topical corticosteroids, the patient experienced notable improvement of disease severity with approximately 20% BSA.

Comment

Molluscum contagiosum is a common skin infection. Among patients with HIV and other types of impaired cellular immunity, the prevalence of MC is estimated to be as high as 20%.³ The MC poxvirus survives and proliferates within the epidermis by interfering with tumor necrosis factor–induced apoptosis of virally infected cells; therefore, intact cell-mediated immunity is an important component of prevention and clearance of poxvirus infections. In immunocompromised patients, the presentation of MC varies widely, and the disease is often difficult to eradicate. This review will highlight the prevalence, presentation, and treatment of MC in the context of immunosuppressed states.

HIV/AIDS
Molluscum contagiosum in HIV-positive patients was first recognized in 1983,² and its prevalence is estimated to range from 5% to 18% in AIDS patients.³ Molluscum contagiosum is a clinical sign of HIV progression, and its incidence appears to increase with reduced immune function (ie, a CD4 cell count <200/mm³).³ In a study of 456 patients with HIV-associated skin disorders, the majority of patients with MC had notable immunosuppression with a median survival time of 12 months. Thus, MC was not an independent prognostic marker but a clinical indicator of markedly reduced immune status.⁴

Molluscum contagiosum is transmitted in both sexual and nonsexual patterns in HIV-positive individuals, with the distribution of the latter involving primarily the face and neck. Although it may present with typical umbilicated papules, MC has a wide range of atypical clinical presentations in patients with AIDS that can make it difficult to diagnose. Complicated cases of eyelid MC have been reported in advanced HIV in both adults and children, resulting in obstruction of vision due to large lesions (up to 2 cm) or hundreds of confluent lesions.⁵ Giant MC, which appears as large exophytic nodules, is another presentation that has been frequently described in patients with advanced HIV. In these patients, the lesions often are too voluminous for conservative therapy and require excision.⁶ Atypical MC lesions also can resemble other dermatologic conditions, including condyloma acuminatum,⁷ nevus sebaceous of Jadassohn, ecthyma,⁸ and cutaneous horns,^9,10 as well as other bacterial and fungal infections in HIV-positive patients, such as cutaneous Cryptococcus neoformans,^11,12 disseminated histoplasmosis,¹³ and infections caused by Penicillium marneffei¹⁴ and Bartonella henselae.¹⁵ In most cases of MC in HIV-positive patients, diagnosis is dependent on the examination of biopsy specimens, which maintain the same histopathologic features regardless of immune status.

The management of MC in patients with HIV/AIDS is difficult. Molluscum contagiosum has shown no evidence of spontaneous resolution in patients with HIV, and treatment with one modality is often insufficient. Treatment is most successful when a combination approach is utilized with destructive procedures (eg, curettage, cryosurgery) and adjunctive agents (eg, retinoids, cantharidin, trichloroacetic acid). Imiquimod and cidofovir have been used off label for MC in AIDS patients.¹⁶ Imiquimod, which is used to treat genital warts, another cutaneous viral infection seen in patients with HIV, has demonstrated efficacy in treating MC.¹⁶ In a randomized controlled trial comparing imiquimod cream 5% to cryotherapy for MC in healthy children, imiquimod was slow acting but better suited than cryotherapy for patients with eruptions of many small lesions.¹⁷ For HIV patients, numerous reports have described successful treatment of disseminated or recalcitrant MC with topical imiquimod.^18-20 Cidofovir, an antiviral used to treat cytomegalovirus retinitis in patients with AIDS, is a promising antiviral agent against the poxvirus family. In a study of viral DNA polymerase genes of MC virus, cidofovir inhibited MC virus DNA polymerase activity.²¹ It has been used in both topical (1% to 3%) and intravenous form to successfully treat recalcitrant and exuberant giant MC.^6,22 However, the use of cidofovir is limited by its high costs, especially when compounded into a topical formulation.²³

From a systemic standpoint, numerous reports have shown that treating the underlying HIV by optimizing HAART is the most important first step in clearing MC.^24-27 However, a special concern regarding the initiation of HAART in patients with MC as well as a markedly impaired immune function is the development of an inflammatory reaction called immune reconstitution inflammatory syndrome (IRIS). This reaction is thought to be a result of immune recovery in severely immunosuppressed patients. During the initial phase of reconstitution when CD4 lymphocyte counts rise and viral load decreases, IRIS occurs due to an inflammatory reaction to microbial and autoimmune antigens, leading to temporary clinical deterioration.²⁸ The incidence has been reported in up to 25% of patients starting HAART, and 52% to 78% of IRIS cases involve dermatologic manifestations such as varicella-zoster virus, cytomegalovirus infections, genital warts, and MC.^29,30 In a cohort study of 199 patients, 2% of patients developed MC within 6 months of initiating HAART.³¹ In a case of exuberant MC lesions after beginning HAART, the lesions spontaneously resolved with the progression of immune reconstitution.²⁸

Malignancies
Patients with hematologic malignancies such as lymphoma and leukemia comprise another subset of patients at risk for atypical presentations of MC. Molluscum contagiosum has been described in patients with hematologic malignancies such as adult T-cell leukemia/lymphoma, multiple myeloma, chronic myeloid leukemia, acute lymphoblastic leukemia, lymphomatoid papulosis, and non-Hodgkin lymphoma. In a review of MC in children with cancer, 0.5% were diagnosed with MC.^32,33 Reports also have documented eruptive MC in the presence of solid organ cancers, including lung cancer.³⁴

In patients with malignancies, the differential diagnosis should include other common dermatologic conditions such as varicella, herpes simplex, papillomas, pyoderma, and cutaneous cryptococcosis, as well as MC. Similar to HIV-positive patients, the lesions of MC described in patients with malignancies do not tend to spontaneously resolve. In a report of a pediatric patient with acute lymphoblastic leukemia, MC presented as an ulcerated lesion without any classic features, requiring biopsy for definitive diagnosis. Only partial resolution was achieved with cryotherapy and crusting of the lesion in an attempt to slow the progression.³⁵ In a series of 5 children with hematologic malignancies and MC, little improvement was noted after treatment with surgical scraping, liquid nitrogen, and salicylic acid ointment 5%. Similar to patients with HIV, improvement of immune status and function help clear the disease, and patients who reach remission and discontinue chemotherapeutic agents have a higher rate of spontaneous resolution of previously recalcitrant MC lesions.³⁶

Transplant Patients
Molluscum contagiosum in transplant patients has features similar to patients with HIV/AIDS. In organ transplant recipients, there is an increased risk for cutaneous disease from iatrogenic immunosuppression or immunosuppression through infectious or neoplastic processes.³⁷ As in other immunocompromised populations, MC often has an atypical presentation in transplant patients with more extensive involvement and recalcitrant, rapidly recurring lesions.

In a review of 145 pediatric organ transplant recipients, MC was the fourth most common skin infection after verruca vulgaris, tinea versicolor, and herpes simplex/zoster. Affecting 7% of patients, the majority of patients demonstrated clinically typical lesions; however, the disease was difficult to eradicate if multiple lesions were present.³⁷ In other reports in adults, fulminant and giant MC have been described after renal and other solid organ transplants.^38,39 Molluscum contagiosum also has been reported to mimic other skin diseases in transplant patients including tinea barbae⁴⁰ and nodular basal cell carcinomas.⁴¹

The standard treatments are identical to those used in patients with HIV, including ablative methods via liquid nitrogen, electrocautery, cantharidin, trichloroacetic acid, and topical retinoids. Similar to MC in other immunocompromised states, treatment can be difficult and usually requires multiple modalities. For children, imiquimod cream 5% has been recommended due to high clearance rates (up to 92%) and the painless nature of the treatment.^42,43

Other Iatrogenic Immunosuppressive States
Immunosuppression through the use of steroids, chemotherapeutic agents, and biologic drugs often is the result of treatment of various diseases. In patients with psoriasis treated with systemic immunosuppressive agents, there are numerous reports that describe the appearance of eruptive MC in association with methotrexate, cyclosporine, and biologics. Methotrexate acts as an immunosuppressive agent by binding to dihydrofolate reductase, which inhibits DNA synthesis in immunologically competent cells.⁴⁴ It also may block host defense mechanisms against MC by suppressing the expression of serum inflammatory cytokines such as tumor necrosis factor α (TNF-α) and IFN-γ and suppressing the activity of TNF-α inducing apoptosis of virus-infected cells. Cyclosporine used in conjunction with methotrexate may exacerbate the insult to the immune system by inhibiting the production of IFN-γ.⁴⁵ Biologics are an emerging class of drugs that have demonstrated efficacy in moderate to severe psoriasis by inhibiting TNF-α or other inflammatory molecules. Several published reports have described eruptive or atypical MC in patients on biologic medications. In one case, within 2 weeks after initiation of infliximab, a monoclonal antibody against TNF-α, a patient developed an eruption of MC involving the entire body.⁴⁶ In another report, an anti–TNF-α agent for rheumatoid arthritis was associated with atypical MC with eyelid lesions.⁴⁷

There are other skin disorders treated with immunosuppressive agents that also have been associated with MC. In a patient with pemphigus vulgaris treated with prednisolone, pimecrolimus, and azathioprine, MC lesions were observed on the face and within healed pemphigus vulgaris sites.⁴⁸ Pimecrolimus and tacrolimus, corticosteroid-sparing agents, suppress cell-mediated immunity and inhibit inflammatory cytokines such as IL-2. The infection resolved with a gradual tapering of immunosuppressive therapy and 10 sessions of cryotherapy.⁴⁸ In a case of topical pimecrolimus for pityriasis alba, the patient developed biopsy-proven MC within 2 weeks of initiating treatment in the areas that were treated with tacrolimus.⁴⁹

In nontransplant patients with iatrogenic immunosuppression, MC treatment has not been documented to be as challenging as in patients with inherent immunosuppression. Most patients respond to either withdrawal of the drug alone or to simple ablative treatments such as cryotherapy.^45,46,48 This important difference is most likely due to the presence of an otherwise intact immune system.

Conclusion

This case describes the appearance of MC in a patient with psoriasis treated with a TNF-α inhibitor who was ultimately diagnosed with AIDS. Although atypical MC infections have been documented in patients with psoriasis undergoing treatment with biologics, it is thought to be more common for MC to occur in more remarkably immunocompromised states such as AIDS. Thus, the persistence and progression of MC in our patient despite discontinuation of etanercept suggested a separate underlying process. Subsequent workup led to the diagnosis of AIDS along with the opportunistic ocular infection of toxoplasmosis retinitis. This clinical sequence consisting of psoriasis treated with a biologic agent, development of MC, and subsequent diagnosis of AIDS is unique and clinically significant to dermatologists. The presentation of psoriasis in patients with HIV can be diverse with different levels of severity and atypical clinical features. In many cases, HIV is known to exacerbate the classic clinical presentation of psoriasis. However, there are other particular presentations of psoriasis in HIV patients that have been observed, which include a predilection for scalp lesions, palmoplantar keratoderma, flexural involvement, and higher levels of immunodeficiency.⁵⁰ Although tuberculin skin tests are required prior to initiating biologic therapy due to the potential for disease reactivation, there are no requirements for HIV antibody testing. In cases of severe recalcitrant psoriasis, an HIV test should be ordered during the workup to establish an early diagnosis so that an HIV-positive patient can avoid poor outcomes from either the disease processes, the use of certain therapeutic agents, or both. Furthermore, the benefit of avoiding possible harm to the patient and potential legal action outweighs the cost of performing surveillance HIV testing in this subset of patients. Thus, due to the potential additive immunosuppressive effect of HIV with biologic therapy, providers should always assess for risk factors and consider testing for HIV in all patients before initiating treatment with immunosuppressive agents such as biologics.

Melkersson-Rosenthal syndrome (MRS) is a rare condition comprised of unilateral peripheral facial nerve palsy, episodic or progressive facial edema, and lingua plicata (also known as fissured tongue). Melkersson-Rosenthal syndrome is a subtype of orofacial granulomatosis and often is mistaken for angioedema or pseudoangioedema due to the swelling of the lips and eyelids. We present a case of MRS that cleared in response to adalimumab therapy.

Case Report

A 69-year-old woman presented to our dermatology clinic with facial edema and a fissured tongue of 4 years’ duration. These symptoms had failed to improve with doxycycline, tacrolimus ointment 0.1%, and cortisone injections of the upper lip, as well as a balsam-free diet, fragrance-free skin products, and flavor-free toothpaste prescribed by multiple physicians over 4 years. Two weeks prior to the current presentation the patient developed left facial nerve palsy that was diagnosed by an outside physician as Bell palsy, and the patient completed a 7-day course of prednisone 1 day prior to presentation. The patient’s medical history was remarkable for type 2 diabetes mellitus controlled with metformin, hyperlipidemia controlled with ezetimibe-simvastatin, and psoriasis. She reported no family history of autoimmune or dermatologic disorders and denied any fever, unintentional weight loss, nausea, vomiting, or diarrhea.

On physical examination, the patient had considerable perioral edema and erythema without warmth or tenderness (Figure 1A). The tongue was fissured with notable scalloping at the lateral margins (Figure 1B). There were no aphthous ulcers or lymphadenopathy, and the remainder of the neurologic examination was normal. The patient had erythematous plaques with scaling on the bilateral elbows. Cardiopulmonary, musculoskeletal, and abdominal examinations were otherwise normal.

Laboratory data revealed an elevated white blood cell count of 17,500/µL (reference range, 4500–11,000/µL), an elevated absolute neutrophil count of 14,018/µL (reference range, 0–700/µL), and an absolute eosinophil count of 0/µL (reference range, 0–450/µL), with the rest of the complete blood cell count within reference range. A basic metabolic panel showed an elevated glucose level of 326 mg/dL (reference range, 70–110 mg/dL), consistent with diabetes and most likely exacerbated by the recent steroid course. A lipid panel was consistent with diagnosed hyperlipidemia (total cholesterol, 236 mg/dL [reference range, <200 mg/dL]; low-density lipoprotein, 134 mg/dL [reference range, 10–30 mg/dL]; triglycerides, 188 mg/dL [reference range, <160 mg/dL]). Hepatitis B and C tests were negative. A punch biopsy of the buccal and labial mucosa was taken, revealing a parakeratinized stratified squamous epithelium with an unusual pattern of surface keratinization with foci of intracellular and extracellular edema in the spinous layer. The underlying fibrous connective tissue was edematous with infiltrates of lymphocytes, mast cells, macrophages, and a few plasma cells. The pathology report listed the diagnosis as nonspecific “chronic mucositis,” with a list of differential diagnoses that included angioedema, hypersensitivity reaction, or other possible autoimmune disorders.

On consideration of these differential diagnoses, it was felt most likely to be MRS, which remains a primarily clinical diagnosis characterized by the triad of symptoms seen in this patient. Treatment of this condition emphasizes inflammation, and steroid therapy often is utilized, as it was in our patient. After the diagnosis of MRS was made, the patient received adalimumab 80 mg subcutaneously on day 1 and 40 mg on day 8 as a loading dose; she subsequently began a course of subcutaneous injections of adalimumab 40 mg once every other week for treatment of psoriasis with the goal of simultaneously treating the MRS. The symptoms did not completely resolve at this dose, so it was increased to 40 mg once weekly. The patient reported that the facial edema, lingua plicata, and facial nerve palsy resolved concomitantly over approximately 3 months with greater improvement at 5 months (Figure 2). The patient has had no relapses as of the last follow-up at 11 months.

Comment

Melkersson-Rosenthal syndrome usually presents sporadically, though there are reports of familial association,^1-3 and only 8% to 25% of patients worldwide present with the complete triad of symptoms.⁴ The pathogenesis of the syndrome is controversial. Granulomatous changes have been found in patients experiencing chronic edema. However, according to Zimmer et al⁵ in a study of 42 MRS patients, only 46% (19/42) had granulomatous changes; 36% (15/42) had nonspecific inflammation, 11% (5/42) had incidental findings, and 7% (3/42) showed no histopathologic abnormalities. Granulomatous cheilitis is a subtype of orofacial granulomatosis, an idiopathic process that causes swelling of the face and lips as well as intraoral swelling and ulceration. Orofacial granulomatosis is referred to as granulomatous cheilitis when the lip is involved. Melkersson-Rosenthal syndrome is another subtype of orofacial granulomatosis that includes facial palsy and fissured tongue.^6,7

In a clinical study of 7 patients with MRS, Liu and Yu¹ found 3 (42%) patients to have dysarthria, dysphagia, and tongue muscle atrophy; 1 patient to have migrainelike headaches; 1 patient to have decreased vision and an ocular movement disorder; 1 patient to have ipsilateral hearing loss; and 1 patient to lack any other symptoms. Halevy et al⁸ suggested a possible association of MRS with psoriasis. In their review of 12 patients, 1 (8%) had psoriatic arthritis, 2 (17%) had skin biopsy–proven psoriasis, and 3 (25%) had a family history of psoriasis.⁸ Because the disease is quite rare, it is difficult to determine other symptoms that may be associated with the disease.

Tumor necrosis factor α (TNF-α) is needed for granuloma formation, and TNF-α antagonists have been used to treat a number of granulomatous conditions including Crohn disease and sarcoidosis.^9-11 Two case reports indicate that infliximab, a mouse/human chimeric monoclonal antibody to TNF-α, has been used successfully to clear MRS.^12,13 One report cited the use of adalimumab for maintenance therapy of MRS,¹² and more recently, adalimumab has been reported for refractory MRS.¹⁴ However, there currently are no known reports regarding the efficacy of adalimumab as a first-line treatment of MRS.

Adalimumab is a fully human monoclonal antibody to TNF-α, which is administered via subcutaneous injections. Infliximab must be administered at an infusion center, making treatment logistically more difficult for patients, and can be associated with the development of infusion reactions, though the exact data on infusion reactions are difficult to estimate due to variations in reporting.^15,16

In 2014, Stein et al¹⁴ reported a case of refractory MRS in a 29-year-old man associated with acute attacks of hearing loss. The patient’s symptoms were controlled with high-dose prednisolone but were unable to be maintained on methotrexate or azathioprine as steroid-sparing agents. The patient was loaded with adalimumab 80 mg subcutaneously once on day 1 and was continued on 40 mg subcutaneously once every 3 weeks, gradually extending to once every 4 weeks when symptoms improved. The patient was slowly weaned off prednisolone 16 months after starting adalimumab. After 20 months, adalimumab therapy was discontinued and the patient remained recurrence free at 4 years’ follow-up.¹⁴ In another case, adalimumab was utilized as maintenance therapy after initial improvement with infliximab.¹² Kakimoto et al¹² reported a previously healthy 19-year-old woman with edema of the bilateral eyelids and upper lip. The authors determined the patient had MRS despite the lack of fissured tongue or facial nerve palsy and started infliximab. The condition resolved after the patient’s second infusion of infliximab and completely cleared after the third infusion; however, she had logistical difficulties reaching the infusion center and disliked the flulike response she experienced with the treatment. She was started on once weekly subcutaneous injections of adalimumab 40 mg and did not relapse.¹² Another patient with granulomatous cheilitis responded to adalimumab after corticosteroids, intralesional injections of triamcinolone, topical tacrolimus, roxithromycin, and clofazimine failed.¹⁷ The patient received adalimumab 80 mg for the first week and 40 mg for the second week and every 2 weeks thereafter. The patient began improving after the third dose and remained relapse free for at least 6 months of follow-up.¹⁷

Conclusion

We present a case of a 69-year-old woman who presented with facial nerve palsy, facial edema, and a fissured tongue, which is the classic triad of MRS, and all 3 symptoms improved with adalimumab.

Melkersson-Rosenthal syndrome (MRS) is a rare condition comprised of unilateral peripheral facial nerve palsy, episodic or progressive facial edema, and lingua plicata (also known as fissured tongue). Melkersson-Rosenthal syndrome is a subtype of orofacial granulomatosis and often is mistaken for angioedema or pseudoangioedema due to the swelling of the lips and eyelids. We present a case of MRS that cleared in response to adalimumab therapy.

Case Report

A 69-year-old woman presented to our dermatology clinic with facial edema and a fissured tongue of 4 years’ duration. These symptoms had failed to improve with doxycycline, tacrolimus ointment 0.1%, and cortisone injections of the upper lip, as well as a balsam-free diet, fragrance-free skin products, and flavor-free toothpaste prescribed by multiple physicians over 4 years. Two weeks prior to the current presentation the patient developed left facial nerve palsy that was diagnosed by an outside physician as Bell palsy, and the patient completed a 7-day course of prednisone 1 day prior to presentation. The patient’s medical history was remarkable for type 2 diabetes mellitus controlled with metformin, hyperlipidemia controlled with ezetimibe-simvastatin, and psoriasis. She reported no family history of autoimmune or dermatologic disorders and denied any fever, unintentional weight loss, nausea, vomiting, or diarrhea.

On physical examination, the patient had considerable perioral edema and erythema without warmth or tenderness (Figure 1A). The tongue was fissured with notable scalloping at the lateral margins (Figure 1B). There were no aphthous ulcers or lymphadenopathy, and the remainder of the neurologic examination was normal. The patient had erythematous plaques with scaling on the bilateral elbows. Cardiopulmonary, musculoskeletal, and abdominal examinations were otherwise normal.

Laboratory data revealed an elevated white blood cell count of 17,500/µL (reference range, 4500–11,000/µL), an elevated absolute neutrophil count of 14,018/µL (reference range, 0–700/µL), and an absolute eosinophil count of 0/µL (reference range, 0–450/µL), with the rest of the complete blood cell count within reference range. A basic metabolic panel showed an elevated glucose level of 326 mg/dL (reference range, 70–110 mg/dL), consistent with diabetes and most likely exacerbated by the recent steroid course. A lipid panel was consistent with diagnosed hyperlipidemia (total cholesterol, 236 mg/dL [reference range, <200 mg/dL]; low-density lipoprotein, 134 mg/dL [reference range, 10–30 mg/dL]; triglycerides, 188 mg/dL [reference range, <160 mg/dL]). Hepatitis B and C tests were negative. A punch biopsy of the buccal and labial mucosa was taken, revealing a parakeratinized stratified squamous epithelium with an unusual pattern of surface keratinization with foci of intracellular and extracellular edema in the spinous layer. The underlying fibrous connective tissue was edematous with infiltrates of lymphocytes, mast cells, macrophages, and a few plasma cells. The pathology report listed the diagnosis as nonspecific “chronic mucositis,” with a list of differential diagnoses that included angioedema, hypersensitivity reaction, or other possible autoimmune disorders.

On consideration of these differential diagnoses, it was felt most likely to be MRS, which remains a primarily clinical diagnosis characterized by the triad of symptoms seen in this patient. Treatment of this condition emphasizes inflammation, and steroid therapy often is utilized, as it was in our patient. After the diagnosis of MRS was made, the patient received adalimumab 80 mg subcutaneously on day 1 and 40 mg on day 8 as a loading dose; she subsequently began a course of subcutaneous injections of adalimumab 40 mg once every other week for treatment of psoriasis with the goal of simultaneously treating the MRS. The symptoms did not completely resolve at this dose, so it was increased to 40 mg once weekly. The patient reported that the facial edema, lingua plicata, and facial nerve palsy resolved concomitantly over approximately 3 months with greater improvement at 5 months (Figure 2). The patient has had no relapses as of the last follow-up at 11 months.

Comment

Melkersson-Rosenthal syndrome usually presents sporadically, though there are reports of familial association,^1-3 and only 8% to 25% of patients worldwide present with the complete triad of symptoms.⁴ The pathogenesis of the syndrome is controversial. Granulomatous changes have been found in patients experiencing chronic edema. However, according to Zimmer et al⁵ in a study of 42 MRS patients, only 46% (19/42) had granulomatous changes; 36% (15/42) had nonspecific inflammation, 11% (5/42) had incidental findings, and 7% (3/42) showed no histopathologic abnormalities. Granulomatous cheilitis is a subtype of orofacial granulomatosis, an idiopathic process that causes swelling of the face and lips as well as intraoral swelling and ulceration. Orofacial granulomatosis is referred to as granulomatous cheilitis when the lip is involved. Melkersson-Rosenthal syndrome is another subtype of orofacial granulomatosis that includes facial palsy and fissured tongue.^6,7

In a clinical study of 7 patients with MRS, Liu and Yu¹ found 3 (42%) patients to have dysarthria, dysphagia, and tongue muscle atrophy; 1 patient to have migrainelike headaches; 1 patient to have decreased vision and an ocular movement disorder; 1 patient to have ipsilateral hearing loss; and 1 patient to lack any other symptoms. Halevy et al⁸ suggested a possible association of MRS with psoriasis. In their review of 12 patients, 1 (8%) had psoriatic arthritis, 2 (17%) had skin biopsy–proven psoriasis, and 3 (25%) had a family history of psoriasis.⁸ Because the disease is quite rare, it is difficult to determine other symptoms that may be associated with the disease.

Tumor necrosis factor α (TNF-α) is needed for granuloma formation, and TNF-α antagonists have been used to treat a number of granulomatous conditions including Crohn disease and sarcoidosis.^9-11 Two case reports indicate that infliximab, a mouse/human chimeric monoclonal antibody to TNF-α, has been used successfully to clear MRS.^12,13 One report cited the use of adalimumab for maintenance therapy of MRS,¹² and more recently, adalimumab has been reported for refractory MRS.¹⁴ However, there currently are no known reports regarding the efficacy of adalimumab as a first-line treatment of MRS.

Adalimumab is a fully human monoclonal antibody to TNF-α, which is administered via subcutaneous injections. Infliximab must be administered at an infusion center, making treatment logistically more difficult for patients, and can be associated with the development of infusion reactions, though the exact data on infusion reactions are difficult to estimate due to variations in reporting.^15,16

In 2014, Stein et al¹⁴ reported a case of refractory MRS in a 29-year-old man associated with acute attacks of hearing loss. The patient’s symptoms were controlled with high-dose prednisolone but were unable to be maintained on methotrexate or azathioprine as steroid-sparing agents. The patient was loaded with adalimumab 80 mg subcutaneously once on day 1 and was continued on 40 mg subcutaneously once every 3 weeks, gradually extending to once every 4 weeks when symptoms improved. The patient was slowly weaned off prednisolone 16 months after starting adalimumab. After 20 months, adalimumab therapy was discontinued and the patient remained recurrence free at 4 years’ follow-up.¹⁴ In another case, adalimumab was utilized as maintenance therapy after initial improvement with infliximab.¹² Kakimoto et al¹² reported a previously healthy 19-year-old woman with edema of the bilateral eyelids and upper lip. The authors determined the patient had MRS despite the lack of fissured tongue or facial nerve palsy and started infliximab. The condition resolved after the patient’s second infusion of infliximab and completely cleared after the third infusion; however, she had logistical difficulties reaching the infusion center and disliked the flulike response she experienced with the treatment. She was started on once weekly subcutaneous injections of adalimumab 40 mg and did not relapse.¹² Another patient with granulomatous cheilitis responded to adalimumab after corticosteroids, intralesional injections of triamcinolone, topical tacrolimus, roxithromycin, and clofazimine failed.¹⁷ The patient received adalimumab 80 mg for the first week and 40 mg for the second week and every 2 weeks thereafter. The patient began improving after the third dose and remained relapse free for at least 6 months of follow-up.¹⁷

Conclusion

We present a case of a 69-year-old woman who presented with facial nerve palsy, facial edema, and a fissured tongue, which is the classic triad of MRS, and all 3 symptoms improved with adalimumab.

Melkersson-Rosenthal syndrome (MRS) is a rare condition comprised of unilateral peripheral facial nerve palsy, episodic or progressive facial edema, and lingua plicata (also known as fissured tongue). Melkersson-Rosenthal syndrome is a subtype of orofacial granulomatosis and often is mistaken for angioedema or pseudoangioedema due to the swelling of the lips and eyelids. We present a case of MRS that cleared in response to adalimumab therapy.

Case Report

A 69-year-old woman presented to our dermatology clinic with facial edema and a fissured tongue of 4 years’ duration. These symptoms had failed to improve with doxycycline, tacrolimus ointment 0.1%, and cortisone injections of the upper lip, as well as a balsam-free diet, fragrance-free skin products, and flavor-free toothpaste prescribed by multiple physicians over 4 years. Two weeks prior to the current presentation the patient developed left facial nerve palsy that was diagnosed by an outside physician as Bell palsy, and the patient completed a 7-day course of prednisone 1 day prior to presentation. The patient’s medical history was remarkable for type 2 diabetes mellitus controlled with metformin, hyperlipidemia controlled with ezetimibe-simvastatin, and psoriasis. She reported no family history of autoimmune or dermatologic disorders and denied any fever, unintentional weight loss, nausea, vomiting, or diarrhea.

On physical examination, the patient had considerable perioral edema and erythema without warmth or tenderness (Figure 1A). The tongue was fissured with notable scalloping at the lateral margins (Figure 1B). There were no aphthous ulcers or lymphadenopathy, and the remainder of the neurologic examination was normal. The patient had erythematous plaques with scaling on the bilateral elbows. Cardiopulmonary, musculoskeletal, and abdominal examinations were otherwise normal.

Laboratory data revealed an elevated white blood cell count of 17,500/µL (reference range, 4500–11,000/µL), an elevated absolute neutrophil count of 14,018/µL (reference range, 0–700/µL), and an absolute eosinophil count of 0/µL (reference range, 0–450/µL), with the rest of the complete blood cell count within reference range. A basic metabolic panel showed an elevated glucose level of 326 mg/dL (reference range, 70–110 mg/dL), consistent with diabetes and most likely exacerbated by the recent steroid course. A lipid panel was consistent with diagnosed hyperlipidemia (total cholesterol, 236 mg/dL [reference range, <200 mg/dL]; low-density lipoprotein, 134 mg/dL [reference range, 10–30 mg/dL]; triglycerides, 188 mg/dL [reference range, <160 mg/dL]). Hepatitis B and C tests were negative. A punch biopsy of the buccal and labial mucosa was taken, revealing a parakeratinized stratified squamous epithelium with an unusual pattern of surface keratinization with foci of intracellular and extracellular edema in the spinous layer. The underlying fibrous connective tissue was edematous with infiltrates of lymphocytes, mast cells, macrophages, and a few plasma cells. The pathology report listed the diagnosis as nonspecific “chronic mucositis,” with a list of differential diagnoses that included angioedema, hypersensitivity reaction, or other possible autoimmune disorders.

On consideration of these differential diagnoses, it was felt most likely to be MRS, which remains a primarily clinical diagnosis characterized by the triad of symptoms seen in this patient. Treatment of this condition emphasizes inflammation, and steroid therapy often is utilized, as it was in our patient. After the diagnosis of MRS was made, the patient received adalimumab 80 mg subcutaneously on day 1 and 40 mg on day 8 as a loading dose; she subsequently began a course of subcutaneous injections of adalimumab 40 mg once every other week for treatment of psoriasis with the goal of simultaneously treating the MRS. The symptoms did not completely resolve at this dose, so it was increased to 40 mg once weekly. The patient reported that the facial edema, lingua plicata, and facial nerve palsy resolved concomitantly over approximately 3 months with greater improvement at 5 months (Figure 2). The patient has had no relapses as of the last follow-up at 11 months.

Comment

Melkersson-Rosenthal syndrome usually presents sporadically, though there are reports of familial association,^1-3 and only 8% to 25% of patients worldwide present with the complete triad of symptoms.⁴ The pathogenesis of the syndrome is controversial. Granulomatous changes have been found in patients experiencing chronic edema. However, according to Zimmer et al⁵ in a study of 42 MRS patients, only 46% (19/42) had granulomatous changes; 36% (15/42) had nonspecific inflammation, 11% (5/42) had incidental findings, and 7% (3/42) showed no histopathologic abnormalities. Granulomatous cheilitis is a subtype of orofacial granulomatosis, an idiopathic process that causes swelling of the face and lips as well as intraoral swelling and ulceration. Orofacial granulomatosis is referred to as granulomatous cheilitis when the lip is involved. Melkersson-Rosenthal syndrome is another subtype of orofacial granulomatosis that includes facial palsy and fissured tongue.^6,7

In a clinical study of 7 patients with MRS, Liu and Yu¹ found 3 (42%) patients to have dysarthria, dysphagia, and tongue muscle atrophy; 1 patient to have migrainelike headaches; 1 patient to have decreased vision and an ocular movement disorder; 1 patient to have ipsilateral hearing loss; and 1 patient to lack any other symptoms. Halevy et al⁸ suggested a possible association of MRS with psoriasis. In their review of 12 patients, 1 (8%) had psoriatic arthritis, 2 (17%) had skin biopsy–proven psoriasis, and 3 (25%) had a family history of psoriasis.⁸ Because the disease is quite rare, it is difficult to determine other symptoms that may be associated with the disease.

Tumor necrosis factor α (TNF-α) is needed for granuloma formation, and TNF-α antagonists have been used to treat a number of granulomatous conditions including Crohn disease and sarcoidosis.^9-11 Two case reports indicate that infliximab, a mouse/human chimeric monoclonal antibody to TNF-α, has been used successfully to clear MRS.^12,13 One report cited the use of adalimumab for maintenance therapy of MRS,¹² and more recently, adalimumab has been reported for refractory MRS.¹⁴ However, there currently are no known reports regarding the efficacy of adalimumab as a first-line treatment of MRS.

Adalimumab is a fully human monoclonal antibody to TNF-α, which is administered via subcutaneous injections. Infliximab must be administered at an infusion center, making treatment logistically more difficult for patients, and can be associated with the development of infusion reactions, though the exact data on infusion reactions are difficult to estimate due to variations in reporting.^15,16

In 2014, Stein et al¹⁴ reported a case of refractory MRS in a 29-year-old man associated with acute attacks of hearing loss. The patient’s symptoms were controlled with high-dose prednisolone but were unable to be maintained on methotrexate or azathioprine as steroid-sparing agents. The patient was loaded with adalimumab 80 mg subcutaneously once on day 1 and was continued on 40 mg subcutaneously once every 3 weeks, gradually extending to once every 4 weeks when symptoms improved. The patient was slowly weaned off prednisolone 16 months after starting adalimumab. After 20 months, adalimumab therapy was discontinued and the patient remained recurrence free at 4 years’ follow-up.¹⁴ In another case, adalimumab was utilized as maintenance therapy after initial improvement with infliximab.¹² Kakimoto et al¹² reported a previously healthy 19-year-old woman with edema of the bilateral eyelids and upper lip. The authors determined the patient had MRS despite the lack of fissured tongue or facial nerve palsy and started infliximab. The condition resolved after the patient’s second infusion of infliximab and completely cleared after the third infusion; however, she had logistical difficulties reaching the infusion center and disliked the flulike response she experienced with the treatment. She was started on once weekly subcutaneous injections of adalimumab 40 mg and did not relapse.¹² Another patient with granulomatous cheilitis responded to adalimumab after corticosteroids, intralesional injections of triamcinolone, topical tacrolimus, roxithromycin, and clofazimine failed.¹⁷ The patient received adalimumab 80 mg for the first week and 40 mg for the second week and every 2 weeks thereafter. The patient began improving after the third dose and remained relapse free for at least 6 months of follow-up.¹⁷

Conclusion

We present a case of a 69-year-old woman who presented with facial nerve palsy, facial edema, and a fissured tongue, which is the classic triad of MRS, and all 3 symptoms improved with adalimumab.

Myth: Biologics Work Slowly

Biologics have demonstrated efficacy in psoriasis and often are used in psoriasis patients who have not achieved desired results with other treatments, patients who have had intolerable side effects from other treatments, and patients with concurrent diseases that preclude the use of systemic therapies. Because of the quality-of-life impact of psoriasis, patients look for quick clearance of their symptoms, but can biologics deliver fast results or do they work slowly?

Biologics such as etanercept and adalimumab block tumor necrosis factor α signaling, while ustekinumab targets IL-12 and IL-23 and others target IL-17. Some patients may begin to see improvement in skin lesions within 1 month of initiating biologic therapies because they target specific proinflammatory pathways that are critical to the pathogenesis of psoriasis, but response time varies among patients and specific therapy used.

The psoriasis area and severity index (PASI) measures psoriasis treatment success. Based on the American Academy of Dermatology’s guidelines of care for the management of psoriasis and psoriatic arthritis published in 2008, short-term response was achieved in 10 to 14 weeks for the following biologics:

• Adalimumab: 80% of patients achieved PASI 75 at week 12
• Etanercept: 49% of patients given 50 mg twice weekly achieved PASI 75 at 12 weeks; 34% of patients given 25 mg twice weekly achieved PASI 75 at 12 weeks
• Infliximab: 80% of patients achieved PASI 75 at week 10

Of the newer biologics, Premier Research recently noted that PASI 75 was achieved after 12 weeks with the following biologics:

• Brodalumab: 83% after 12 weeks
• Ixekizumab: 90% after 12 weeks
• Secukinumab: 80% after 12 weeks
• Ustekinumab: 70% after 12 weeks

There are a variety of factors to consider when determining which biologic to use for a psoriasis patient. These data may help in the decision process. However, dermatologists must educate psoriasis patients with a high body mass index that their disease may take longer to respond and may need combination therapy for optimal clearance.

Expert Commentary

All of the biologics, especially the IL-17 inhibitors, work very quickly to clear psoriasis. The only way they work “slowly” is that it may take time (usually a few days) for the payers to approve biologic prescriptions. 

—Jashin J. Wu, MD (Los Angeles, California)

Myth: Biologics Work Slowly

Biologics have demonstrated efficacy in psoriasis and often are used in psoriasis patients who have not achieved desired results with other treatments, patients who have had intolerable side effects from other treatments, and patients with concurrent diseases that preclude the use of systemic therapies. Because of the quality-of-life impact of psoriasis, patients look for quick clearance of their symptoms, but can biologics deliver fast results or do they work slowly?

Biologics such as etanercept and adalimumab block tumor necrosis factor α signaling, while ustekinumab targets IL-12 and IL-23 and others target IL-17. Some patients may begin to see improvement in skin lesions within 1 month of initiating biologic therapies because they target specific proinflammatory pathways that are critical to the pathogenesis of psoriasis, but response time varies among patients and specific therapy used.

The psoriasis area and severity index (PASI) measures psoriasis treatment success. Based on the American Academy of Dermatology’s guidelines of care for the management of psoriasis and psoriatic arthritis published in 2008, short-term response was achieved in 10 to 14 weeks for the following biologics:

• Adalimumab: 80% of patients achieved PASI 75 at week 12
• Etanercept: 49% of patients given 50 mg twice weekly achieved PASI 75 at 12 weeks; 34% of patients given 25 mg twice weekly achieved PASI 75 at 12 weeks
• Infliximab: 80% of patients achieved PASI 75 at week 10

Of the newer biologics, Premier Research recently noted that PASI 75 was achieved after 12 weeks with the following biologics:

• Brodalumab: 83% after 12 weeks
• Ixekizumab: 90% after 12 weeks
• Secukinumab: 80% after 12 weeks
• Ustekinumab: 70% after 12 weeks

There are a variety of factors to consider when determining which biologic to use for a psoriasis patient. These data may help in the decision process. However, dermatologists must educate psoriasis patients with a high body mass index that their disease may take longer to respond and may need combination therapy for optimal clearance.

Expert Commentary

All of the biologics, especially the IL-17 inhibitors, work very quickly to clear psoriasis. The only way they work “slowly” is that it may take time (usually a few days) for the payers to approve biologic prescriptions. 

—Jashin J. Wu, MD (Los Angeles, California)

Myth: Biologics Work Slowly

Biologics have demonstrated efficacy in psoriasis and often are used in psoriasis patients who have not achieved desired results with other treatments, patients who have had intolerable side effects from other treatments, and patients with concurrent diseases that preclude the use of systemic therapies. Because of the quality-of-life impact of psoriasis, patients look for quick clearance of their symptoms, but can biologics deliver fast results or do they work slowly?

Biologics such as etanercept and adalimumab block tumor necrosis factor α signaling, while ustekinumab targets IL-12 and IL-23 and others target IL-17. Some patients may begin to see improvement in skin lesions within 1 month of initiating biologic therapies because they target specific proinflammatory pathways that are critical to the pathogenesis of psoriasis, but response time varies among patients and specific therapy used.

The psoriasis area and severity index (PASI) measures psoriasis treatment success. Based on the American Academy of Dermatology’s guidelines of care for the management of psoriasis and psoriatic arthritis published in 2008, short-term response was achieved in 10 to 14 weeks for the following biologics:

• Adalimumab: 80% of patients achieved PASI 75 at week 12
• Etanercept: 49% of patients given 50 mg twice weekly achieved PASI 75 at 12 weeks; 34% of patients given 25 mg twice weekly achieved PASI 75 at 12 weeks
• Infliximab: 80% of patients achieved PASI 75 at week 10

Of the newer biologics, Premier Research recently noted that PASI 75 was achieved after 12 weeks with the following biologics:

• Brodalumab: 83% after 12 weeks
• Ixekizumab: 90% after 12 weeks
• Secukinumab: 80% after 12 weeks
• Ustekinumab: 70% after 12 weeks

There are a variety of factors to consider when determining which biologic to use for a psoriasis patient. These data may help in the decision process. However, dermatologists must educate psoriasis patients with a high body mass index that their disease may take longer to respond and may need combination therapy for optimal clearance.

Expert Commentary

All of the biologics, especially the IL-17 inhibitors, work very quickly to clear psoriasis. The only way they work “slowly” is that it may take time (usually a few days) for the payers to approve biologic prescriptions. 

—Jashin J. Wu, MD (Los Angeles, California)

‌

According to industry estimates, roughly 64% of US adults were smartphone users in 2015.¹ Smartphones enable users to utilize mobile applications (apps) that can perform a variety of functions in many categories, including business, music, photography, entertainment, education, social networking, travel, and lifestyle. The widespread adoption and use of mobile apps has implications for medical practice. Mobile apps have the capability to serve as information sources for patients, educational tools for students, and diagnostic aids for physicians.² Consequently, a number of medical and health care–oriented apps have already been developed³ and are increasingly utilized by patients and providers.⁴

Given its visual nature, dermatology is particularly amenable to the integration of mobile medical apps. A study by Brewer et al⁵ identified more than 229 dermatology-related apps in categories ranging from general dermatology reference, self-surveillance and diagnosis, disease guides, educational aids, sunscreen and UV recommendations, and teledermatology. Patients served as the target audience and principal consumers of more than half of these dermatology apps.⁵

Mobile medical and health care apps demonstrate great potential for serving as valuable information sources for patients with dermatologic conditions; however, the content, functions, accuracy, and educational value of dermatology mobile apps are not well characterized, making it difficult for patients and health care providers to select and recommend appropriate apps.⁶ In this study, we created a rubric to objectively grade 44 publicly available mobile dermatology apps with the primary focus of patient education.

Methods

We conducted a search of dermatology-related educational mobile apps that were publicly available via the App Store (Apple Inc) from January 2016 to November 2016. (The pricing, availability, and other features of these apps may have changed since the study period.) The following search terms were used: dermatology, dermoscopy, melanoma, skin cancer, psoriasis, rosacea, acne, eczema, dermal fillers, and Mohs surgery. We excluded apps that were not in English; had a solely commercial focus; were mobile textbooks or scientific journals; were used to provide teledermatology services with no educational purpose; were solely focused on homeopathic, alternative, and/or complementary medicine; or were intended primarily as a reference for students or health care professionals. Our search yielded 44 apps with patient education as a primary objective. The apps were divided into 6 categories based on their focus: general dermatology, cosmetic dermatology, acne, eczema, psoriasis, and skin cancer.

Each app was reviewed using a quantified grading rubric developed by the researchers. In a prior evaluation, Handel⁷ reviewed 35 health and wellness mobile apps utilizing the categories of ease of use, reliability, quality, scope of information, and aesthetics.⁴ These criteria were modified and adapted for the purposes of this study, and a 4-point scale was applied to each criterion. The final criteria were (1) educational objectives, (2) content, (3) accuracy, (4) design, and (5) conflict of interest. The quantified grading rubric is described in Table 1.

Results

The possible range of scores based on the grading rubric was 5 to 20. The actual range of scores was 8 to 19 (Table 2). The 44 reviewed apps were categorized by topic as acne, cosmetic dermatology, eczema, general dermatology, psoriasis, or skin cancer. A sample of 15 apps selected to represent the distribution of scores and their grading on the rubric are presented in Table 3.

Comment

The number of dermatology-related apps available to mobile users continues to grow at an increasing rate.⁸ The apps vary in many aspects, including their purpose, scope, intended audience, and goals of the app publisher. In turn, more individuals are turning to mobile apps for medical information,⁴ especially in dermatology, thus it is necessary to create a systematic way to evaluate the quality and utility of each app to assist users in making informed decisions about which apps will best meet their needs in the midst of a wide array of choices.

For the purpose of this study, an objective rubric was created that can be used to evaluate the quality of medical apps for patient education in dermatology. An app’s adequacy and usefulness for patient education was thought to depend on 3 possible score ranges into which the app could fall based on the grading rubric. An app with a total score in the range of 5 to 10 was not thought to be useful and may even be detrimental to patients. An app with a total score in the range of 11 to 15 may be used for patient education with some reservations based on shortcomings for certain criteria. An app with a score in the range of 16 to 20 was thought to be valuable and adequate for patient education. For example, the How to Treat Acne app received a total score of 8 and therefore would not be recommended to patients based on the grading rubric used in this study. This particular app provided sparse and sometimes inaccurate information, had a confusing user interface, and contained many obstructive advertisements. In contrast, the Eczema Doc app received a total score of 19, which indicates a quality app deemed to be useful for patient information based on the established rubric. This app met all the objectives that it advertised, contained accurate information with verified citation of sources, and was very easy for users to navigate.

Of the 44 graded apps, only 9 (20.5%) received scores in the highest range of 16 to 20, which indicates a need for improvements in mobile dermatology apps intended for patient education. Adopting the grading rubric developed in this study as a standard in the creation of medical apps could have beneficial implications in disseminating accurate, safe, unbiased, and easy-to-understand information to patients.

‌

According to industry estimates, roughly 64% of US adults were smartphone users in 2015.¹ Smartphones enable users to utilize mobile applications (apps) that can perform a variety of functions in many categories, including business, music, photography, entertainment, education, social networking, travel, and lifestyle. The widespread adoption and use of mobile apps has implications for medical practice. Mobile apps have the capability to serve as information sources for patients, educational tools for students, and diagnostic aids for physicians.² Consequently, a number of medical and health care–oriented apps have already been developed³ and are increasingly utilized by patients and providers.⁴

Given its visual nature, dermatology is particularly amenable to the integration of mobile medical apps. A study by Brewer et al⁵ identified more than 229 dermatology-related apps in categories ranging from general dermatology reference, self-surveillance and diagnosis, disease guides, educational aids, sunscreen and UV recommendations, and teledermatology. Patients served as the target audience and principal consumers of more than half of these dermatology apps.⁵

Mobile medical and health care apps demonstrate great potential for serving as valuable information sources for patients with dermatologic conditions; however, the content, functions, accuracy, and educational value of dermatology mobile apps are not well characterized, making it difficult for patients and health care providers to select and recommend appropriate apps.⁶ In this study, we created a rubric to objectively grade 44 publicly available mobile dermatology apps with the primary focus of patient education.

Methods

We conducted a search of dermatology-related educational mobile apps that were publicly available via the App Store (Apple Inc) from January 2016 to November 2016. (The pricing, availability, and other features of these apps may have changed since the study period.) The following search terms were used: dermatology, dermoscopy, melanoma, skin cancer, psoriasis, rosacea, acne, eczema, dermal fillers, and Mohs surgery. We excluded apps that were not in English; had a solely commercial focus; were mobile textbooks or scientific journals; were used to provide teledermatology services with no educational purpose; were solely focused on homeopathic, alternative, and/or complementary medicine; or were intended primarily as a reference for students or health care professionals. Our search yielded 44 apps with patient education as a primary objective. The apps were divided into 6 categories based on their focus: general dermatology, cosmetic dermatology, acne, eczema, psoriasis, and skin cancer.

Each app was reviewed using a quantified grading rubric developed by the researchers. In a prior evaluation, Handel⁷ reviewed 35 health and wellness mobile apps utilizing the categories of ease of use, reliability, quality, scope of information, and aesthetics.⁴ These criteria were modified and adapted for the purposes of this study, and a 4-point scale was applied to each criterion. The final criteria were (1) educational objectives, (2) content, (3) accuracy, (4) design, and (5) conflict of interest. The quantified grading rubric is described in Table 1.

Results

The possible range of scores based on the grading rubric was 5 to 20. The actual range of scores was 8 to 19 (Table 2). The 44 reviewed apps were categorized by topic as acne, cosmetic dermatology, eczema, general dermatology, psoriasis, or skin cancer. A sample of 15 apps selected to represent the distribution of scores and their grading on the rubric are presented in Table 3.

Comment

The number of dermatology-related apps available to mobile users continues to grow at an increasing rate.⁸ The apps vary in many aspects, including their purpose, scope, intended audience, and goals of the app publisher. In turn, more individuals are turning to mobile apps for medical information,⁴ especially in dermatology, thus it is necessary to create a systematic way to evaluate the quality and utility of each app to assist users in making informed decisions about which apps will best meet their needs in the midst of a wide array of choices.

For the purpose of this study, an objective rubric was created that can be used to evaluate the quality of medical apps for patient education in dermatology. An app’s adequacy and usefulness for patient education was thought to depend on 3 possible score ranges into which the app could fall based on the grading rubric. An app with a total score in the range of 5 to 10 was not thought to be useful and may even be detrimental to patients. An app with a total score in the range of 11 to 15 may be used for patient education with some reservations based on shortcomings for certain criteria. An app with a score in the range of 16 to 20 was thought to be valuable and adequate for patient education. For example, the How to Treat Acne app received a total score of 8 and therefore would not be recommended to patients based on the grading rubric used in this study. This particular app provided sparse and sometimes inaccurate information, had a confusing user interface, and contained many obstructive advertisements. In contrast, the Eczema Doc app received a total score of 19, which indicates a quality app deemed to be useful for patient information based on the established rubric. This app met all the objectives that it advertised, contained accurate information with verified citation of sources, and was very easy for users to navigate.

Of the 44 graded apps, only 9 (20.5%) received scores in the highest range of 16 to 20, which indicates a need for improvements in mobile dermatology apps intended for patient education. Adopting the grading rubric developed in this study as a standard in the creation of medical apps could have beneficial implications in disseminating accurate, safe, unbiased, and easy-to-understand information to patients.

‌

According to industry estimates, roughly 64% of US adults were smartphone users in 2015.¹ Smartphones enable users to utilize mobile applications (apps) that can perform a variety of functions in many categories, including business, music, photography, entertainment, education, social networking, travel, and lifestyle. The widespread adoption and use of mobile apps has implications for medical practice. Mobile apps have the capability to serve as information sources for patients, educational tools for students, and diagnostic aids for physicians.² Consequently, a number of medical and health care–oriented apps have already been developed³ and are increasingly utilized by patients and providers.⁴

Given its visual nature, dermatology is particularly amenable to the integration of mobile medical apps. A study by Brewer et al⁵ identified more than 229 dermatology-related apps in categories ranging from general dermatology reference, self-surveillance and diagnosis, disease guides, educational aids, sunscreen and UV recommendations, and teledermatology. Patients served as the target audience and principal consumers of more than half of these dermatology apps.⁵

Mobile medical and health care apps demonstrate great potential for serving as valuable information sources for patients with dermatologic conditions; however, the content, functions, accuracy, and educational value of dermatology mobile apps are not well characterized, making it difficult for patients and health care providers to select and recommend appropriate apps.⁶ In this study, we created a rubric to objectively grade 44 publicly available mobile dermatology apps with the primary focus of patient education.

Methods

We conducted a search of dermatology-related educational mobile apps that were publicly available via the App Store (Apple Inc) from January 2016 to November 2016. (The pricing, availability, and other features of these apps may have changed since the study period.) The following search terms were used: dermatology, dermoscopy, melanoma, skin cancer, psoriasis, rosacea, acne, eczema, dermal fillers, and Mohs surgery. We excluded apps that were not in English; had a solely commercial focus; were mobile textbooks or scientific journals; were used to provide teledermatology services with no educational purpose; were solely focused on homeopathic, alternative, and/or complementary medicine; or were intended primarily as a reference for students or health care professionals. Our search yielded 44 apps with patient education as a primary objective. The apps were divided into 6 categories based on their focus: general dermatology, cosmetic dermatology, acne, eczema, psoriasis, and skin cancer.

Each app was reviewed using a quantified grading rubric developed by the researchers. In a prior evaluation, Handel⁷ reviewed 35 health and wellness mobile apps utilizing the categories of ease of use, reliability, quality, scope of information, and aesthetics.⁴ These criteria were modified and adapted for the purposes of this study, and a 4-point scale was applied to each criterion. The final criteria were (1) educational objectives, (2) content, (3) accuracy, (4) design, and (5) conflict of interest. The quantified grading rubric is described in Table 1.

Results

The possible range of scores based on the grading rubric was 5 to 20. The actual range of scores was 8 to 19 (Table 2). The 44 reviewed apps were categorized by topic as acne, cosmetic dermatology, eczema, general dermatology, psoriasis, or skin cancer. A sample of 15 apps selected to represent the distribution of scores and their grading on the rubric are presented in Table 3.

Comment

The number of dermatology-related apps available to mobile users continues to grow at an increasing rate.⁸ The apps vary in many aspects, including their purpose, scope, intended audience, and goals of the app publisher. In turn, more individuals are turning to mobile apps for medical information,⁴ especially in dermatology, thus it is necessary to create a systematic way to evaluate the quality and utility of each app to assist users in making informed decisions about which apps will best meet their needs in the midst of a wide array of choices.

For the purpose of this study, an objective rubric was created that can be used to evaluate the quality of medical apps for patient education in dermatology. An app’s adequacy and usefulness for patient education was thought to depend on 3 possible score ranges into which the app could fall based on the grading rubric. An app with a total score in the range of 5 to 10 was not thought to be useful and may even be detrimental to patients. An app with a total score in the range of 11 to 15 may be used for patient education with some reservations based on shortcomings for certain criteria. An app with a score in the range of 16 to 20 was thought to be valuable and adequate for patient education. For example, the How to Treat Acne app received a total score of 8 and therefore would not be recommended to patients based on the grading rubric used in this study. This particular app provided sparse and sometimes inaccurate information, had a confusing user interface, and contained many obstructive advertisements. In contrast, the Eczema Doc app received a total score of 19, which indicates a quality app deemed to be useful for patient information based on the established rubric. This app met all the objectives that it advertised, contained accurate information with verified citation of sources, and was very easy for users to navigate.

Of the 44 graded apps, only 9 (20.5%) received scores in the highest range of 16 to 20, which indicates a need for improvements in mobile dermatology apps intended for patient education. Adopting the grading rubric developed in this study as a standard in the creation of medical apps could have beneficial implications in disseminating accurate, safe, unbiased, and easy-to-understand information to patients.

To the Editor:

A 69-year-old white man presented with a skin lesion on the back of 1 to 2 weeks’ duration. The patient stated he was unaware of it, but his wife had recently noticed the new spot. He denied any bleeding, pain, pruritus, or other associated symptoms with the lesion. He also denied any prior treatment to the area. The patient’s medical history was remarkable for severe psoriasis involving more than 80% body surface area, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, coronary artery disease, squamous cell carcinoma, and actinic keratoses. He had been on multiple treatment regimens over the last 20 years for control of psoriasis including topical corticosteroids, psoralen plus UVA and UVB phototherapy, gold injections, acitretin, prednisone, efalizumab, ustekinumab, and alefacept upon evaluation of this new skin lesion. Utilization of immunosuppressive agents also provided an additional benefit of controlling the patient’s inflammatory arthritic disease.

On physical examination a 0.6×0.7-cm, pink to erythematous, pearly papule with superficial telangiectases was noted on the right side of the dorsal thorax (Figure 1). Multiple well-demarcated erythematous plaques with silvery scale and areas of secondary excoriation were noted on the trunk and both legs consistent with the patient’s history of psoriasis.

A shave biopsy was performed on the skin lesion on the right side of the dorsal thorax with a suspected clinical diagnosis of basal cell carcinoma. Two weeks later the patient returned for a discussion of the pathology report, which revealed nodules of basaloid cells with tightly packed vesicular nuclei and scant cytoplasm in sheets within the superficial dermis, as well as areas of nuclear molding, numerous mitotic figures, and areas of focal necrosis (Figure 2). In addition, immunostaining was positive for cytokeratin (CK) 20 antibodies with a characteristic paranuclear dot uptake of the antibody. These findings were consistent with a diagnosis of Merkel cell carcinoma (MCC). At that time, alefacept was discontinued and he was referred to a tertiary referral center for further evaluation and treatment.

The patient subsequently underwent wide excision with 1-cm margins of the MCC, with intraoperative lymphatic mapping/sentinel lymph node biopsy (SLNB) of the right axillary nodal basin 1 month later, which he tolerated well without any associated complications. Further histopathologic examination revealed the deep, medial, and lateral surgical margins to be negative of residual neoplasm. However, one sentinel lymph node indicated positivity for micrometastatic MCC, consistent with stage IIIA disease progression.

He underwent a second procedure the following month for complete right axillary lymph node dissection. Histopathologic examination of the right axillary contents included 28 lymph nodes, which were negative for carcinoma. He continued to do well without any signs of clinical recurrence or distant metastasis at subsequent follow-up visits.

Approximately 2.5 years after the second procedure, the patient began to develop right upper quadrant abdominal pain of an unclear etiology. Computed tomography of the abdomen and pelvis was performed, revealing areas of calcification and findings consistent with malignant lymphadenopathy. Multiple hepatic lesions also were noted including a 9-cm lesion in the posterior right hepatic lobe. Computed tomography–guided biopsy of the liver lesion was performed and the findings were consistent with metastatic MCC, indicating progression to stage IV disease.

The patient was subsequently started on combination chemotherapeutic treatment with carboplatin and VP-16, with a planned treatment course of 4 to 6 cycles. He was able to complete a total of 6 cycles over a 4-month period, tolerating the treatment regimen fairly well. Follow-up positron emission tomography–computed tomography was within normal limits with no evidence of any hypermetabolic activity noted, indicating a complete radiographic remission of MCC. He was seen approximately 1 month after completion of treatment for clinical follow-up and monthly thereafter.

While on chemotherapy, the patient experienced a notable improvement in the psoriasis and psoriatic joint disease. Upon completion of chemotherapy, he was restarted on the same treatment plan that was utilized prior to surgery including topical corticosteroids, calcitriol, intramuscular steroid injections, and UVB phototherapy, which provided substantial control of psoriasis and arthritic joint disease. The patient later died, likely due to his multiple comorbidities.

Merkel cells are slow-responding mechanoreceptors located within the basal layer of the epidermis and are the source of a rare aggressive cutaneous malignancy.¹ Merkel cell carcinoma was first noted in 1972 and termed trabecular carcinoma of the skin, and it accounts for less than 1% of all nonmelanoma skin cancer.^2,3 This primary neuroendocrine carcinoma has remarkable metastatic potential (34%–75%) and can invade regional lymph nodes, as well as distant metastasis most commonly to the liver, lungs, bones, and brain.² Approximately 25% of patients present with palpable lymphadenopathy and 5% with distant metastasis at the time of diagnosis. This frequency of metastasis at diagnosis as well as the recurrence after treatment contributes to the poor prognosis of MCC. Local recurrence rates have been reported at 25% with lymph node involvement in 52% and metastasis in 34%, with most recurrences occurring within 2 years of diagnosis. Patient mortality is dependent on the aggressiveness of the tumor, with 5-year survival rates of 83.3% without lymph node involvement, 58.3% with lymph node involvement, and 31.3% in those with metastatic disease.⁴

The tumor classically presents as a red to violaceous, painless nodule with a smooth shiny surface most often on the head and neck region.^4-6 Approximately 50% of MCC cases present in the head and neck region, 32% to 38% on the extremities, and 12% to 14% on the trunk.¹ This nonspecific presentation may lead to diagnostic uncertainty and a consequent delay in treatment. Definitive diagnosis of MCC is achieved with a skin biopsy and allows for distinction from other clinically similar–appearing neoplasms. Merkel cell carcinoma presents histologically as small round basophilic cells penetrating through the dermis in 3 histologic patterns: the trabecular, intermediate (80% of cases), and small cell type.⁵ It may be differentiated immunohistochemically from other neoplasms, as it displays CK20 positivity (showing paranuclear dotlike depositions in the cytoplasm or cell membrane) and is negative for CK7. Chromagranin and synaptophysin positivity also may provide further histologic confirmation. In addition, absence of peripheral palisading, retraction artifact, and a fibromyxoid stroma allow for distinction from cutaneous basal cell carcinoma, which may display these features histologically. Other immunohistochemical markers that may be of value include thyroid transcription factor 1, which is typically positive in cutaneous metastasis of neuroendocrine carcinoma of the lung; S-100 and human melanoma black 45, which are positive in melanoma; and leukocyte common antigen (CD45), which can be positive in lymphoma. These stains are classically negative in MCC.³

Merkel cell carcinoma is commonly associated with the presence of Merkel cell polyomavirus (MCPyV) in tumor specimens, with a prevalence of 70% to 80% in all cases. Merkel cell polyomavirus is a class 2A carcinogen (ie, a probable carcinogen to humans) and is classified among a group of viruses that encode T antigens (ie, an antigen coded by a viral genome associated with transformation of infected cells by tumor viruses), which can lead to initiation of tumorigenesis through interference with cellular tumor suppressing proteins such as p53.⁵ In addition, several risk factors have been associated with the development of MCC including immunosuppression, older age (>50 years), and UV-exposed fair skin.⁷ One explanation for this phenomenon is the increase in MCPyV small T antigen transcripts induced by UV irradiation.⁵ In addition, as with other cancers induced by viruses, host immunity can impede tumor progression and development. Therefore, impairment of normal immune function likely creates a higher risk for MCC development and potential for a worse prognosis.³Although the exact incidence of MCC in immunosuppressed patients appears unclear, chronic immunosuppressive therapy may play a notable role in the pathogenesis of the tumor.³

Although each of these factors was observed in our patient, it also was possible that his associated comorbidities further contributed to disease presentation. In particular, rheumatoid arthritis has been shown to carry an increased risk for the development of MCC.⁸ In addition, inflammatory monocytes infected with MCPyV, as evidenced in a patient with a history of chronic psoriasis prior to diagnosis of MCC, also may contribute to the pathogenesis of MCC by traveling to inflammatory skin lesions, such as those seen in psoriasis, releasing MCPyV locally and infecting Merkel cells.⁹ Although MCPyV testing was never performed in our patient, it certainly would be prudent as well as further studies determining the correlation of MCC to these disease processes.

Although regression is rare, multiple cases have documented spontaneous regression of MCC after biopsy of these lesions.^4,6,10 The exact mechanism is unclear, but apoptosis induced by T-cell immunity is suspected to play a role. Programmed cell death 1 protein (PD-1)–positive cells play a role. The PD-1 receptor is an inhibitory receptor expressed by T cells and in approximately half of tumor-infiltrating cells in MCC. It was found that in a regressed case of MCC there was a notably lower percentage of PD-1 positivity compared to cases with no apparent regression, suggesting that PD-1–positive cells suppress tumor immunity to MCC and that significant reduction in these cells may induce clinical regression.¹⁰ Additional investigation would be beneficial to examine the relationship of this phenomenon to tumor regression.

Initial evaluation of these patients should include a meticulous clinical examination with an emphasis on detection of cutaneous, lymph node, and distant metastasis. Due to the risk of metastatic potential, regional lymph node ultrasonography and computed tomography of the chest, abdomen, and pelvis typically are recommended at baseline. Other imaging modalities may be warranted based on clinical findings.³ Treatment modalities include various approaches, with surgical excision of the primary tumor with more than 1-cm margin to the fascial plane being the primary modality for uncomplicated cases.^1,3,7 In addition, SLNB also should be performed at the time of the procedure. In the case of a positive SLNB or suspected regional lymph node involvement upon initial examination, radical regional lymph node dissection also is recommended.³ Although some authorities advocate postsurgical radiation therapy to minimize the risk of local recurrence, there does not appear to be a clear benefit in survival rate.^3,5 However, radiation treatment as monotherapy has been advocated in certain instances, particularly in cases of unresectable tumors or patients who are poor surgical candidates.^5,7 Cases of distant metastasis (stage IV disease) may include management with surgery, radiation, and/or chemotherapy. Although none of these modalities have consistently shown to improve survival, there appears to be up to a 60% response with chemotherapy in these patients.³

Because MCC tends to affect an older population, often with other notable comorbidities, important considerations involving a treatment plan include the cost, side effects, and convenience for patients. The combination of carboplatin and VP-16 (etoposide) was utilized and tolerated well in our patient, and it has been successful in achieving complete radiologic and clinical remission of his metastatic disease. This combination appears to prolong survival in patients with distant metastasis, as compared to those patients not receiving chemotherapy.¹ Our patient has since died, but in these high-risk patients, close clinical monitoring is essential to help optimize their prognosis.

Merkel cell carcinoma is a rare aggressive cutaneous neoplasm that most commonly affects the elderly, immunosuppressed, and those with chronic UV sun damage. An association between the oncogenesis of MCC and infection with MCPyV has been documented, but other underlying diseases also may play a role in this process including rheumatoid arthritis and psoriasis. Although these risk factors were associated with our patient, his history of chronic immunosuppressive therapy for treatment of his psoriasis and inflammatory joint disease likely played a role in the pathogenesis of the tumor and should be an important point of discussion with any patient requiring this type of long-term management for disease control. Our unique clinical case highlights a patient with substantial comorbidities who developed metastatic MCC and achieved complete clinical and radiologic remission after treatment with surgery and chemotherapy.

To the Editor:

A 69-year-old white man presented with a skin lesion on the back of 1 to 2 weeks’ duration. The patient stated he was unaware of it, but his wife had recently noticed the new spot. He denied any bleeding, pain, pruritus, or other associated symptoms with the lesion. He also denied any prior treatment to the area. The patient’s medical history was remarkable for severe psoriasis involving more than 80% body surface area, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, coronary artery disease, squamous cell carcinoma, and actinic keratoses. He had been on multiple treatment regimens over the last 20 years for control of psoriasis including topical corticosteroids, psoralen plus UVA and UVB phototherapy, gold injections, acitretin, prednisone, efalizumab, ustekinumab, and alefacept upon evaluation of this new skin lesion. Utilization of immunosuppressive agents also provided an additional benefit of controlling the patient’s inflammatory arthritic disease.

On physical examination a 0.6×0.7-cm, pink to erythematous, pearly papule with superficial telangiectases was noted on the right side of the dorsal thorax (Figure 1). Multiple well-demarcated erythematous plaques with silvery scale and areas of secondary excoriation were noted on the trunk and both legs consistent with the patient’s history of psoriasis.

A shave biopsy was performed on the skin lesion on the right side of the dorsal thorax with a suspected clinical diagnosis of basal cell carcinoma. Two weeks later the patient returned for a discussion of the pathology report, which revealed nodules of basaloid cells with tightly packed vesicular nuclei and scant cytoplasm in sheets within the superficial dermis, as well as areas of nuclear molding, numerous mitotic figures, and areas of focal necrosis (Figure 2). In addition, immunostaining was positive for cytokeratin (CK) 20 antibodies with a characteristic paranuclear dot uptake of the antibody. These findings were consistent with a diagnosis of Merkel cell carcinoma (MCC). At that time, alefacept was discontinued and he was referred to a tertiary referral center for further evaluation and treatment.

The patient subsequently underwent wide excision with 1-cm margins of the MCC, with intraoperative lymphatic mapping/sentinel lymph node biopsy (SLNB) of the right axillary nodal basin 1 month later, which he tolerated well without any associated complications. Further histopathologic examination revealed the deep, medial, and lateral surgical margins to be negative of residual neoplasm. However, one sentinel lymph node indicated positivity for micrometastatic MCC, consistent with stage IIIA disease progression.

He underwent a second procedure the following month for complete right axillary lymph node dissection. Histopathologic examination of the right axillary contents included 28 lymph nodes, which were negative for carcinoma. He continued to do well without any signs of clinical recurrence or distant metastasis at subsequent follow-up visits.

Approximately 2.5 years after the second procedure, the patient began to develop right upper quadrant abdominal pain of an unclear etiology. Computed tomography of the abdomen and pelvis was performed, revealing areas of calcification and findings consistent with malignant lymphadenopathy. Multiple hepatic lesions also were noted including a 9-cm lesion in the posterior right hepatic lobe. Computed tomography–guided biopsy of the liver lesion was performed and the findings were consistent with metastatic MCC, indicating progression to stage IV disease.

The patient was subsequently started on combination chemotherapeutic treatment with carboplatin and VP-16, with a planned treatment course of 4 to 6 cycles. He was able to complete a total of 6 cycles over a 4-month period, tolerating the treatment regimen fairly well. Follow-up positron emission tomography–computed tomography was within normal limits with no evidence of any hypermetabolic activity noted, indicating a complete radiographic remission of MCC. He was seen approximately 1 month after completion of treatment for clinical follow-up and monthly thereafter.

While on chemotherapy, the patient experienced a notable improvement in the psoriasis and psoriatic joint disease. Upon completion of chemotherapy, he was restarted on the same treatment plan that was utilized prior to surgery including topical corticosteroids, calcitriol, intramuscular steroid injections, and UVB phototherapy, which provided substantial control of psoriasis and arthritic joint disease. The patient later died, likely due to his multiple comorbidities.

Merkel cells are slow-responding mechanoreceptors located within the basal layer of the epidermis and are the source of a rare aggressive cutaneous malignancy.¹ Merkel cell carcinoma was first noted in 1972 and termed trabecular carcinoma of the skin, and it accounts for less than 1% of all nonmelanoma skin cancer.^2,3 This primary neuroendocrine carcinoma has remarkable metastatic potential (34%–75%) and can invade regional lymph nodes, as well as distant metastasis most commonly to the liver, lungs, bones, and brain.² Approximately 25% of patients present with palpable lymphadenopathy and 5% with distant metastasis at the time of diagnosis. This frequency of metastasis at diagnosis as well as the recurrence after treatment contributes to the poor prognosis of MCC. Local recurrence rates have been reported at 25% with lymph node involvement in 52% and metastasis in 34%, with most recurrences occurring within 2 years of diagnosis. Patient mortality is dependent on the aggressiveness of the tumor, with 5-year survival rates of 83.3% without lymph node involvement, 58.3% with lymph node involvement, and 31.3% in those with metastatic disease.⁴

The tumor classically presents as a red to violaceous, painless nodule with a smooth shiny surface most often on the head and neck region.^4-6 Approximately 50% of MCC cases present in the head and neck region, 32% to 38% on the extremities, and 12% to 14% on the trunk.¹ This nonspecific presentation may lead to diagnostic uncertainty and a consequent delay in treatment. Definitive diagnosis of MCC is achieved with a skin biopsy and allows for distinction from other clinically similar–appearing neoplasms. Merkel cell carcinoma presents histologically as small round basophilic cells penetrating through the dermis in 3 histologic patterns: the trabecular, intermediate (80% of cases), and small cell type.⁵ It may be differentiated immunohistochemically from other neoplasms, as it displays CK20 positivity (showing paranuclear dotlike depositions in the cytoplasm or cell membrane) and is negative for CK7. Chromagranin and synaptophysin positivity also may provide further histologic confirmation. In addition, absence of peripheral palisading, retraction artifact, and a fibromyxoid stroma allow for distinction from cutaneous basal cell carcinoma, which may display these features histologically. Other immunohistochemical markers that may be of value include thyroid transcription factor 1, which is typically positive in cutaneous metastasis of neuroendocrine carcinoma of the lung; S-100 and human melanoma black 45, which are positive in melanoma; and leukocyte common antigen (CD45), which can be positive in lymphoma. These stains are classically negative in MCC.³

Merkel cell carcinoma is commonly associated with the presence of Merkel cell polyomavirus (MCPyV) in tumor specimens, with a prevalence of 70% to 80% in all cases. Merkel cell polyomavirus is a class 2A carcinogen (ie, a probable carcinogen to humans) and is classified among a group of viruses that encode T antigens (ie, an antigen coded by a viral genome associated with transformation of infected cells by tumor viruses), which can lead to initiation of tumorigenesis through interference with cellular tumor suppressing proteins such as p53.⁵ In addition, several risk factors have been associated with the development of MCC including immunosuppression, older age (>50 years), and UV-exposed fair skin.⁷ One explanation for this phenomenon is the increase in MCPyV small T antigen transcripts induced by UV irradiation.⁵ In addition, as with other cancers induced by viruses, host immunity can impede tumor progression and development. Therefore, impairment of normal immune function likely creates a higher risk for MCC development and potential for a worse prognosis.³Although the exact incidence of MCC in immunosuppressed patients appears unclear, chronic immunosuppressive therapy may play a notable role in the pathogenesis of the tumor.³

Although each of these factors was observed in our patient, it also was possible that his associated comorbidities further contributed to disease presentation. In particular, rheumatoid arthritis has been shown to carry an increased risk for the development of MCC.⁸ In addition, inflammatory monocytes infected with MCPyV, as evidenced in a patient with a history of chronic psoriasis prior to diagnosis of MCC, also may contribute to the pathogenesis of MCC by traveling to inflammatory skin lesions, such as those seen in psoriasis, releasing MCPyV locally and infecting Merkel cells.⁹ Although MCPyV testing was never performed in our patient, it certainly would be prudent as well as further studies determining the correlation of MCC to these disease processes.

Although regression is rare, multiple cases have documented spontaneous regression of MCC after biopsy of these lesions.^4,6,10 The exact mechanism is unclear, but apoptosis induced by T-cell immunity is suspected to play a role. Programmed cell death 1 protein (PD-1)–positive cells play a role. The PD-1 receptor is an inhibitory receptor expressed by T cells and in approximately half of tumor-infiltrating cells in MCC. It was found that in a regressed case of MCC there was a notably lower percentage of PD-1 positivity compared to cases with no apparent regression, suggesting that PD-1–positive cells suppress tumor immunity to MCC and that significant reduction in these cells may induce clinical regression.¹⁰ Additional investigation would be beneficial to examine the relationship of this phenomenon to tumor regression.

Initial evaluation of these patients should include a meticulous clinical examination with an emphasis on detection of cutaneous, lymph node, and distant metastasis. Due to the risk of metastatic potential, regional lymph node ultrasonography and computed tomography of the chest, abdomen, and pelvis typically are recommended at baseline. Other imaging modalities may be warranted based on clinical findings.³ Treatment modalities include various approaches, with surgical excision of the primary tumor with more than 1-cm margin to the fascial plane being the primary modality for uncomplicated cases.^1,3,7 In addition, SLNB also should be performed at the time of the procedure. In the case of a positive SLNB or suspected regional lymph node involvement upon initial examination, radical regional lymph node dissection also is recommended.³ Although some authorities advocate postsurgical radiation therapy to minimize the risk of local recurrence, there does not appear to be a clear benefit in survival rate.^3,5 However, radiation treatment as monotherapy has been advocated in certain instances, particularly in cases of unresectable tumors or patients who are poor surgical candidates.^5,7 Cases of distant metastasis (stage IV disease) may include management with surgery, radiation, and/or chemotherapy. Although none of these modalities have consistently shown to improve survival, there appears to be up to a 60% response with chemotherapy in these patients.³

Because MCC tends to affect an older population, often with other notable comorbidities, important considerations involving a treatment plan include the cost, side effects, and convenience for patients. The combination of carboplatin and VP-16 (etoposide) was utilized and tolerated well in our patient, and it has been successful in achieving complete radiologic and clinical remission of his metastatic disease. This combination appears to prolong survival in patients with distant metastasis, as compared to those patients not receiving chemotherapy.¹ Our patient has since died, but in these high-risk patients, close clinical monitoring is essential to help optimize their prognosis.

Merkel cell carcinoma is a rare aggressive cutaneous neoplasm that most commonly affects the elderly, immunosuppressed, and those with chronic UV sun damage. An association between the oncogenesis of MCC and infection with MCPyV has been documented, but other underlying diseases also may play a role in this process including rheumatoid arthritis and psoriasis. Although these risk factors were associated with our patient, his history of chronic immunosuppressive therapy for treatment of his psoriasis and inflammatory joint disease likely played a role in the pathogenesis of the tumor and should be an important point of discussion with any patient requiring this type of long-term management for disease control. Our unique clinical case highlights a patient with substantial comorbidities who developed metastatic MCC and achieved complete clinical and radiologic remission after treatment with surgery and chemotherapy.

To the Editor:

A 69-year-old white man presented with a skin lesion on the back of 1 to 2 weeks’ duration. The patient stated he was unaware of it, but his wife had recently noticed the new spot. He denied any bleeding, pain, pruritus, or other associated symptoms with the lesion. He also denied any prior treatment to the area. The patient’s medical history was remarkable for severe psoriasis involving more than 80% body surface area, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, coronary artery disease, squamous cell carcinoma, and actinic keratoses. He had been on multiple treatment regimens over the last 20 years for control of psoriasis including topical corticosteroids, psoralen plus UVA and UVB phototherapy, gold injections, acitretin, prednisone, efalizumab, ustekinumab, and alefacept upon evaluation of this new skin lesion. Utilization of immunosuppressive agents also provided an additional benefit of controlling the patient’s inflammatory arthritic disease.

On physical examination a 0.6×0.7-cm, pink to erythematous, pearly papule with superficial telangiectases was noted on the right side of the dorsal thorax (Figure 1). Multiple well-demarcated erythematous plaques with silvery scale and areas of secondary excoriation were noted on the trunk and both legs consistent with the patient’s history of psoriasis.

A shave biopsy was performed on the skin lesion on the right side of the dorsal thorax with a suspected clinical diagnosis of basal cell carcinoma. Two weeks later the patient returned for a discussion of the pathology report, which revealed nodules of basaloid cells with tightly packed vesicular nuclei and scant cytoplasm in sheets within the superficial dermis, as well as areas of nuclear molding, numerous mitotic figures, and areas of focal necrosis (Figure 2). In addition, immunostaining was positive for cytokeratin (CK) 20 antibodies with a characteristic paranuclear dot uptake of the antibody. These findings were consistent with a diagnosis of Merkel cell carcinoma (MCC). At that time, alefacept was discontinued and he was referred to a tertiary referral center for further evaluation and treatment.

The patient subsequently underwent wide excision with 1-cm margins of the MCC, with intraoperative lymphatic mapping/sentinel lymph node biopsy (SLNB) of the right axillary nodal basin 1 month later, which he tolerated well without any associated complications. Further histopathologic examination revealed the deep, medial, and lateral surgical margins to be negative of residual neoplasm. However, one sentinel lymph node indicated positivity for micrometastatic MCC, consistent with stage IIIA disease progression.

He underwent a second procedure the following month for complete right axillary lymph node dissection. Histopathologic examination of the right axillary contents included 28 lymph nodes, which were negative for carcinoma. He continued to do well without any signs of clinical recurrence or distant metastasis at subsequent follow-up visits.

Approximately 2.5 years after the second procedure, the patient began to develop right upper quadrant abdominal pain of an unclear etiology. Computed tomography of the abdomen and pelvis was performed, revealing areas of calcification and findings consistent with malignant lymphadenopathy. Multiple hepatic lesions also were noted including a 9-cm lesion in the posterior right hepatic lobe. Computed tomography–guided biopsy of the liver lesion was performed and the findings were consistent with metastatic MCC, indicating progression to stage IV disease.

The patient was subsequently started on combination chemotherapeutic treatment with carboplatin and VP-16, with a planned treatment course of 4 to 6 cycles. He was able to complete a total of 6 cycles over a 4-month period, tolerating the treatment regimen fairly well. Follow-up positron emission tomography–computed tomography was within normal limits with no evidence of any hypermetabolic activity noted, indicating a complete radiographic remission of MCC. He was seen approximately 1 month after completion of treatment for clinical follow-up and monthly thereafter.

While on chemotherapy, the patient experienced a notable improvement in the psoriasis and psoriatic joint disease. Upon completion of chemotherapy, he was restarted on the same treatment plan that was utilized prior to surgery including topical corticosteroids, calcitriol, intramuscular steroid injections, and UVB phototherapy, which provided substantial control of psoriasis and arthritic joint disease. The patient later died, likely due to his multiple comorbidities.

Merkel cells are slow-responding mechanoreceptors located within the basal layer of the epidermis and are the source of a rare aggressive cutaneous malignancy.¹ Merkel cell carcinoma was first noted in 1972 and termed trabecular carcinoma of the skin, and it accounts for less than 1% of all nonmelanoma skin cancer.^2,3 This primary neuroendocrine carcinoma has remarkable metastatic potential (34%–75%) and can invade regional lymph nodes, as well as distant metastasis most commonly to the liver, lungs, bones, and brain.² Approximately 25% of patients present with palpable lymphadenopathy and 5% with distant metastasis at the time of diagnosis. This frequency of metastasis at diagnosis as well as the recurrence after treatment contributes to the poor prognosis of MCC. Local recurrence rates have been reported at 25% with lymph node involvement in 52% and metastasis in 34%, with most recurrences occurring within 2 years of diagnosis. Patient mortality is dependent on the aggressiveness of the tumor, with 5-year survival rates of 83.3% without lymph node involvement, 58.3% with lymph node involvement, and 31.3% in those with metastatic disease.⁴

The tumor classically presents as a red to violaceous, painless nodule with a smooth shiny surface most often on the head and neck region.^4-6 Approximately 50% of MCC cases present in the head and neck region, 32% to 38% on the extremities, and 12% to 14% on the trunk.¹ This nonspecific presentation may lead to diagnostic uncertainty and a consequent delay in treatment. Definitive diagnosis of MCC is achieved with a skin biopsy and allows for distinction from other clinically similar–appearing neoplasms. Merkel cell carcinoma presents histologically as small round basophilic cells penetrating through the dermis in 3 histologic patterns: the trabecular, intermediate (80% of cases), and small cell type.⁵ It may be differentiated immunohistochemically from other neoplasms, as it displays CK20 positivity (showing paranuclear dotlike depositions in the cytoplasm or cell membrane) and is negative for CK7. Chromagranin and synaptophysin positivity also may provide further histologic confirmation. In addition, absence of peripheral palisading, retraction artifact, and a fibromyxoid stroma allow for distinction from cutaneous basal cell carcinoma, which may display these features histologically. Other immunohistochemical markers that may be of value include thyroid transcription factor 1, which is typically positive in cutaneous metastasis of neuroendocrine carcinoma of the lung; S-100 and human melanoma black 45, which are positive in melanoma; and leukocyte common antigen (CD45), which can be positive in lymphoma. These stains are classically negative in MCC.³

Merkel cell carcinoma is commonly associated with the presence of Merkel cell polyomavirus (MCPyV) in tumor specimens, with a prevalence of 70% to 80% in all cases. Merkel cell polyomavirus is a class 2A carcinogen (ie, a probable carcinogen to humans) and is classified among a group of viruses that encode T antigens (ie, an antigen coded by a viral genome associated with transformation of infected cells by tumor viruses), which can lead to initiation of tumorigenesis through interference with cellular tumor suppressing proteins such as p53.⁵ In addition, several risk factors have been associated with the development of MCC including immunosuppression, older age (>50 years), and UV-exposed fair skin.⁷ One explanation for this phenomenon is the increase in MCPyV small T antigen transcripts induced by UV irradiation.⁵ In addition, as with other cancers induced by viruses, host immunity can impede tumor progression and development. Therefore, impairment of normal immune function likely creates a higher risk for MCC development and potential for a worse prognosis.³Although the exact incidence of MCC in immunosuppressed patients appears unclear, chronic immunosuppressive therapy may play a notable role in the pathogenesis of the tumor.³

Although each of these factors was observed in our patient, it also was possible that his associated comorbidities further contributed to disease presentation. In particular, rheumatoid arthritis has been shown to carry an increased risk for the development of MCC.⁸ In addition, inflammatory monocytes infected with MCPyV, as evidenced in a patient with a history of chronic psoriasis prior to diagnosis of MCC, also may contribute to the pathogenesis of MCC by traveling to inflammatory skin lesions, such as those seen in psoriasis, releasing MCPyV locally and infecting Merkel cells.⁹ Although MCPyV testing was never performed in our patient, it certainly would be prudent as well as further studies determining the correlation of MCC to these disease processes.

Although regression is rare, multiple cases have documented spontaneous regression of MCC after biopsy of these lesions.^4,6,10 The exact mechanism is unclear, but apoptosis induced by T-cell immunity is suspected to play a role. Programmed cell death 1 protein (PD-1)–positive cells play a role. The PD-1 receptor is an inhibitory receptor expressed by T cells and in approximately half of tumor-infiltrating cells in MCC. It was found that in a regressed case of MCC there was a notably lower percentage of PD-1 positivity compared to cases with no apparent regression, suggesting that PD-1–positive cells suppress tumor immunity to MCC and that significant reduction in these cells may induce clinical regression.¹⁰ Additional investigation would be beneficial to examine the relationship of this phenomenon to tumor regression.

Initial evaluation of these patients should include a meticulous clinical examination with an emphasis on detection of cutaneous, lymph node, and distant metastasis. Due to the risk of metastatic potential, regional lymph node ultrasonography and computed tomography of the chest, abdomen, and pelvis typically are recommended at baseline. Other imaging modalities may be warranted based on clinical findings.³ Treatment modalities include various approaches, with surgical excision of the primary tumor with more than 1-cm margin to the fascial plane being the primary modality for uncomplicated cases.^1,3,7 In addition, SLNB also should be performed at the time of the procedure. In the case of a positive SLNB or suspected regional lymph node involvement upon initial examination, radical regional lymph node dissection also is recommended.³ Although some authorities advocate postsurgical radiation therapy to minimize the risk of local recurrence, there does not appear to be a clear benefit in survival rate.^3,5 However, radiation treatment as monotherapy has been advocated in certain instances, particularly in cases of unresectable tumors or patients who are poor surgical candidates.^5,7 Cases of distant metastasis (stage IV disease) may include management with surgery, radiation, and/or chemotherapy. Although none of these modalities have consistently shown to improve survival, there appears to be up to a 60% response with chemotherapy in these patients.³

Because MCC tends to affect an older population, often with other notable comorbidities, important considerations involving a treatment plan include the cost, side effects, and convenience for patients. The combination of carboplatin and VP-16 (etoposide) was utilized and tolerated well in our patient, and it has been successful in achieving complete radiologic and clinical remission of his metastatic disease. This combination appears to prolong survival in patients with distant metastasis, as compared to those patients not receiving chemotherapy.¹ Our patient has since died, but in these high-risk patients, close clinical monitoring is essential to help optimize their prognosis.

Merkel cell carcinoma is a rare aggressive cutaneous neoplasm that most commonly affects the elderly, immunosuppressed, and those with chronic UV sun damage. An association between the oncogenesis of MCC and infection with MCPyV has been documented, but other underlying diseases also may play a role in this process including rheumatoid arthritis and psoriasis. Although these risk factors were associated with our patient, his history of chronic immunosuppressive therapy for treatment of his psoriasis and inflammatory joint disease likely played a role in the pathogenesis of the tumor and should be an important point of discussion with any patient requiring this type of long-term management for disease control. Our unique clinical case highlights a patient with substantial comorbidities who developed metastatic MCC and achieved complete clinical and radiologic remission after treatment with surgery and chemotherapy.

GENEVA – Healthy lifestyle changes produce significant improvement in both psoriasis severity and Dermatologic Life Quality Index scores in obese psoriasis patients, according to a systematic review and meta-analysis presented by Ching-Chi Chi, MD, at the annual congress of the European Academy of Dermatology and Venereology.

A plausible mechanism of benefit exists for these findings: “Fat tissue is known to be an endocrine organ that produces inflammatory cytokines, such as tumor necrosis factor. Reduce the amount of fat tissue and you reduce inflammation,” explained Dr. Chi, professor of dermatology at Chang Gung University in Taoyuan, Taiwan.

jancin

Also, participants in the dietary intervention studies averaged a 14.4-point improvement from baseline in Dermatologic Life Quality Index (DLQI) scores at week 24 versus a 2.2-point improvement in controls. Researchers consider a 5-point or greater improvement in the DLQI clinically meaningful.

A combined diet and exercise program resulted in a 45% increased likelihood that obese psoriasis patients would achieve a PASI 50 response at week 16, with a number needed to treat of 7. There was a trend in the active treatment arm for higher PASI 75 and PASI 100 responses than in controls as well, but it wasn’t statistically significant.

The one randomized trial of a walking exercise program coupled with continuous health education demonstrated a significant reduction in the rate of psoriasis flares, compared with controls, over a 3-year period.

In contrast, the studies of educational programs promoting a healthy lifestyle without an associated dietary or physical activity intervention failed to show a reduction in PASI scores.

Dr. Chi reported no financial conflicts of interest regarding his study, which was funded by Chang Gung Memorial Hospital.

[email protected]

SOURCE: Chi C. EADV 2017.

GENEVA – Healthy lifestyle changes produce significant improvement in both psoriasis severity and Dermatologic Life Quality Index scores in obese psoriasis patients, according to a systematic review and meta-analysis presented by Ching-Chi Chi, MD, at the annual congress of the European Academy of Dermatology and Venereology.

A plausible mechanism of benefit exists for these findings: “Fat tissue is known to be an endocrine organ that produces inflammatory cytokines, such as tumor necrosis factor. Reduce the amount of fat tissue and you reduce inflammation,” explained Dr. Chi, professor of dermatology at Chang Gung University in Taoyuan, Taiwan.

jancin

Also, participants in the dietary intervention studies averaged a 14.4-point improvement from baseline in Dermatologic Life Quality Index (DLQI) scores at week 24 versus a 2.2-point improvement in controls. Researchers consider a 5-point or greater improvement in the DLQI clinically meaningful.

A combined diet and exercise program resulted in a 45% increased likelihood that obese psoriasis patients would achieve a PASI 50 response at week 16, with a number needed to treat of 7. There was a trend in the active treatment arm for higher PASI 75 and PASI 100 responses than in controls as well, but it wasn’t statistically significant.

The one randomized trial of a walking exercise program coupled with continuous health education demonstrated a significant reduction in the rate of psoriasis flares, compared with controls, over a 3-year period.

In contrast, the studies of educational programs promoting a healthy lifestyle without an associated dietary or physical activity intervention failed to show a reduction in PASI scores.

Dr. Chi reported no financial conflicts of interest regarding his study, which was funded by Chang Gung Memorial Hospital.

[email protected]

SOURCE: Chi C. EADV 2017.

GENEVA – Healthy lifestyle changes produce significant improvement in both psoriasis severity and Dermatologic Life Quality Index scores in obese psoriasis patients, according to a systematic review and meta-analysis presented by Ching-Chi Chi, MD, at the annual congress of the European Academy of Dermatology and Venereology.

A plausible mechanism of benefit exists for these findings: “Fat tissue is known to be an endocrine organ that produces inflammatory cytokines, such as tumor necrosis factor. Reduce the amount of fat tissue and you reduce inflammation,” explained Dr. Chi, professor of dermatology at Chang Gung University in Taoyuan, Taiwan.

jancin

Also, participants in the dietary intervention studies averaged a 14.4-point improvement from baseline in Dermatologic Life Quality Index (DLQI) scores at week 24 versus a 2.2-point improvement in controls. Researchers consider a 5-point or greater improvement in the DLQI clinically meaningful.

A combined diet and exercise program resulted in a 45% increased likelihood that obese psoriasis patients would achieve a PASI 50 response at week 16, with a number needed to treat of 7. There was a trend in the active treatment arm for higher PASI 75 and PASI 100 responses than in controls as well, but it wasn’t statistically significant.

The one randomized trial of a walking exercise program coupled with continuous health education demonstrated a significant reduction in the rate of psoriasis flares, compared with controls, over a 3-year period.

In contrast, the studies of educational programs promoting a healthy lifestyle without an associated dietary or physical activity intervention failed to show a reduction in PASI scores.

Dr. Chi reported no financial conflicts of interest regarding his study, which was funded by Chang Gung Memorial Hospital.

[email protected]

SOURCE: Chi C. EADV 2017.

GENEVA – Ixekizumab improved fingernail psoriasis significantly faster and with a higher complete nail clearance rate by week 24 compared with ustekinumab in a head-to-head phase 3b randomized trial, Yves Dutronc, MD, reported at the annual congress of the European Academy of Dermatology and Venereology.

This is a clinically important finding because – as dermatologists and psoriasis patients well know – nail and skin psoriasis are two different animals.

Bruce Jancin/Frontline Medical News

[email protected]

SOURCE: Dutronc Y. https://eadvgeneva2017.org/

GENEVA – Ixekizumab improved fingernail psoriasis significantly faster and with a higher complete nail clearance rate by week 24 compared with ustekinumab in a head-to-head phase 3b randomized trial, Yves Dutronc, MD, reported at the annual congress of the European Academy of Dermatology and Venereology.

This is a clinically important finding because – as dermatologists and psoriasis patients well know – nail and skin psoriasis are two different animals.

Bruce Jancin/Frontline Medical News

[email protected]

SOURCE: Dutronc Y. https://eadvgeneva2017.org/

GENEVA – Ixekizumab improved fingernail psoriasis significantly faster and with a higher complete nail clearance rate by week 24 compared with ustekinumab in a head-to-head phase 3b randomized trial, Yves Dutronc, MD, reported at the annual congress of the European Academy of Dermatology and Venereology.

This is a clinically important finding because – as dermatologists and psoriasis patients well know – nail and skin psoriasis are two different animals.

Bruce Jancin/Frontline Medical News

[email protected]

SOURCE: Dutronc Y. https://eadvgeneva2017.org/