The prevalence of psoriasis among human immunodeficiency virus (HIV)–positive patients in the United States is reported to be approximately 1% to 3%, which is similar to the rates reported for the general population.¹ Recalcitrant cases of psoriasis in patients with no history of the condition can be the initial manifestation of HIV infection. In patients with preexisting psoriasis, a flare of their disease can be seen following infection, and progression of HIV correlates with worsening psoriasis.² Psoriatic arthropathy also affects 23% to 50% of HIV-positive patients with psoriasis worldwide, which may be higher than the general population,¹ with more severe joint disease.

The management of psoriatic disease in the HIV-positive population is challenging. The current first-line recommendations for treatment include topical therapies, phototherapy, and highly active antiretroviral therapy (HAART), followed by oral retinoids as second-line agents.³ However, the clinical course of psoriasis in HIV-positive patients often is progressive and refractory²; therefore, these therapies often are inadequate to control both skin and joint manifestations. Most other currently available systemic therapies for psoriatic disease are immunosuppressive, which poses a distinct clinical challenge because HIV-positive patients are already immunocompromised.

There currently are many systemic immunosuppressive agents used for the treatment of psoriatic disease, including oral agents (eg, methotrexate, hydroxyurea, cyclosporine), as well as newer biologic medications, including tumor necrosis factor (TNF) α inhibitors etanercept, adalimumab, infliximab, golimumab, and certolizumab pegol. Golimumab and certolizumab pegol currently are indicated for psoriatic arthritis only. Other newer biologic therapies include ustekinumab, which inhibits IL-12 and IL-23, and secukinumab, which inhibits IL-17A. The purpose of this systematic review is to evaluate the most current literature to explore the efficacy and safety data as they pertain to systemic immunosuppressive therapies for the treatment of psoriatic disease in HIV-positive individuals.

Methods

To investigate the efficacy and safety of systemic immunosuppressive therapies for psoriatic disease in HIV-positive individuals, a PubMed search of articles indexed for MEDLINE (1985-2015) was conducted using the terms psoriasis and HIV and psoriatic arthritis and HIV combined with each of the following systemic immunosuppressive agents: methotrexate, hydroxyurea, cyclosporine, etanercept, adalimumab, infliximab, golimumab, certolizumab pegol, ustekinumab, and secukinumab. Pediatric cases and articles that were not available in the English language were excluded.

For each case, patient demographic information (ie, age, sex), prior failed psoriasis treatments, and history of HAART were documented. The dosing regimen of the systemic agent was noted when different from the US Food and Drug administration–approved dosage for psoriasis or psoriatic arthritis. The duration of immunosuppressive therapy as well as pretreatment and posttreatment CD4 and viral counts (when available) were collected. The response to treatment and adverse effects were summarized.

Results

Our review of the literature yielded a total of 25 reported cases of systemic immunosuppressive therapies used to treat psoriatic disease in HIV-positive patients, including methotrexate, cyclosporine, etanercept, adalimumab, in-fliximab, and ustekinumab (Table). There were no reports of the use of hydroxyurea, golimumab, certolizumab pegol, or secukinumab to treat psoriatic disease in this patient population.

Methotrexate
Eight individual cases of methotrexate used to treat psoriasis and/or psoriatic arthritis in HIV-positive patients were reported.^4-6 Duvic et al⁶ described 4 patients with psoriatic disease that was treated with methotrexate with varying efficacy. One patient developed toxic encephalopathy, which improved after discontinuation of methotrexate; however, he died 5 months later from pneumocystis pneumonia. In this early study, none of the 4 patients were on antiretroviral therapy for HIV.⁶

In the cases reported by Masson et al⁴ and Maurer et al,⁵ 4 patients were treated with a single antiretroviral agent and received appropriate prophylaxis against opportunistic infections. In 1 case, methotrexate was given at a chemotherapeutic dose of 525 mg once weekly for Kaposi sarcoma.⁴ In 2 of 4 cases, the patients developed pneumocystis pneumonia.^4,5

Cyclosporine
There were 2 case reports of successful treatment of psoriatic disease with cyclosporine in HIV-positive patients.^7,8 Skin and joint manifestations improved rapidly without reports of infection for 2⁷ and 8 years.⁸ Both patients were treated with one antiretroviral agent.^7,8

Etanercept
There were 5 case reports of successful treatment of psoriatic disease with etanercept. In all 5 cases the patients were on HAART, and the CD4 count increased or remained stable and viral count became undetectable or remained stable following treatment.^9-13 In 2 cases, the patient also had hepatitis C virus, which remained stable throughout the treatment period.^9,12 The maximum duration of treatment was 6 years, with only 1 reported adverse event.¹³ In this case reported by Aboulafia et al,¹³ the patient experienced recurrent polymicrobial infections, including enterococcal cellulitis, cystitis, and bacteremia, as well as pseudomonas pneumonia and septic arthritis. Therapy was discontinued at 6 months. Four months after discontinuation of etanercept, the patient died from infectious causes.¹³

Adalimumab
There was 1 case of successful treatment of psoriatic disease with adalimumab in an HIV-positive patient. In this case, the patient was on HAART, and CD4 and viral counts improved substantially after 30 months of treatment.¹⁴

Infliximab
Six individual cases of successful treatment of psoriatic disease with infliximab were reported.^15-17 In a report by Cepeda et al,¹⁵ HIV-positive patients with various rheumatologic diseases were chosen to receive etanercept followed by adalimumab and/or infliximab if clinical improvement was not observed on etanercept. In 3 patients with psoriasis and psoriatic arthritis, inadequate response was observed on etanercept. Two of these 3 patients received adalimumab with only partial response. All 3 were treated with infliximab in the end and showed excellent response. One of the patients experienced facial abscess responsive to antibiotics and was continued on infliximab therapy without further complications. In all 6 cases of infliximab therapy, the patients were on HAART, and CD4 and viral counts improved or remained stable.¹⁵

Ustekinumab
There were 3 case reports of successful treatment of psoriatic disease with ustekinumab in HIV-positive patients on HAART. CD4 and viral counts improved or remained stable.^18-20

Comment

Currently, all of the systemic immunosuppressive therapies approved for psoriatic disease have a warning by the US Food and Drug Administration for increased risk of serious infection. Given such labels, these therapies are not routinely prescribed for HIV-positive patients who are already immunocompromised; however, many HIV-positive patients have severe psoriatic disease that cannot be adequately treated with first- and second-line therapies including topical agents, phototherapy, or oral retinoids.

Our comprehensive review yielded a total of 25 reported cases of systemic immunosuppressive therapies used to treat psoriatic disease in HIV-positive patients including methotrexate, cyclosporine, etanercept, adalimumab, in-fliximab, and ustekinumab. Although data are limited to case reports and case series, some trends were observed.

Efficacy
In most of the cases reviewed, the patients had inadequate improvement of psoriatic disease with first- and second-line therapies, which included antiretrovirals alone, topical agents, phototherapy, and oral retinoids. Some cases reported poor response to methotrexate and cyclosporine.^4-8 Biologic agents were effective in many such cases.

Safety
Overall, there were 11 cases in which the patient was not on adequate HAART while being treated with systemic immunosuppressive therapy for psoriatic disease.^4-8,15 Of them, 3 were associated with serious infection while on methotrexate.^5,6 There was only 1 report of serious infection¹³ of 14 cases in which the patient was on concomitant HAART. In this case, which reported polymicrobial infections and subsequent death of the patient, the infections continued after discontinuing etanercept; thus, the association is unclear. Interestingly, despite multiple infections, the CD4 and viral counts were stable throughout treatment with etanercept.¹³

From reviewing the 4 total cases^5,6,13 of serious infection, HAART appears to be a valuable concomitant treatment during systemic immunosuppressive therapy for HIV-positive patients; however, it does not necessarily prevent serious infections from occurring, and thus the clinician’s diligence in monitoring for signs and symptoms of infection remains important.

CD4 and Viral Counts
Although reports of CD4 and viral counts were not available in earlier studies,^4-8 there were 15 cases that reported consistent pretreatment and posttreatment CD4 and viral counts during treatment with etanercept, adalimumab, infliximab, and ustekinumab.^9-20 In all cases, the CD4 count was stable or increased. Similarly, the viral count was stable or decreased. All patients, except 1 by Cepeda et al,¹⁵ were on concomitant HAART.^9-14,16-20

Although data are limited, treatment of psoriatic disease with biologic agents when used in combination with HAART may have beneficial effects on CD4 and viral counts. Tumor necrosis factor has a role in HIV expression through the action of nuclear factor κβ.²¹ An increase in TNF levels is shown to be associated with increased viral count, decreased CD4 count, and increased symptoms of HIV progression, such as fever, fatigue, cachexia, and dementia.²² Although more studies are necessary, TNF-α inhibitors may have a positive effect on HIV while simultaneously treating psoriatic disease. Other cytokines (eg, IL-12, IL-23, IL-17) involved in the mechanism of action of other biologic agents (ustekinumab and secukinumab) have not been shown to be directly associated with HIV activity; however, studies have shown that IL-10 has a role in inhibiting HIV-1 replication and inhibits secretion of proinflammatory cytokines such as IL-12 and TNF-α.²¹ It may be speculated that the inhibition of IL-12 and TNF-α may create a positive feedback effect to increase IL-10, which in turn inhibits HIV replication.

Conclusion

Although there are limited data on the efficacy and safety of systemic immunosuppressive therapies for the treatment of psoriatic disease in HIV-positive patients, a review of 25 individual cases suggest that these treatments are not only required but also are sufficient to treat some of the most resistant cases. It is possible that with adequate concomitant HAART and monitoring for signs and symptoms of infection, the likelihood of serious infection may be low. Furthermore, biologic agents may have a positive effect over other systemic immunosuppressive agents, such as methotrexate and cyclosporine, in improving CD4 and viral counts when used in combination with HAART. Although randomized controlled trials are necessary, current biologic therapies such as etanercept, adalimumab, infliximab, and ustekinumab may be safe viable options as third-line treatment of severe psoriasis in the HIV-positive population.

The prevalence of psoriasis among human immunodeficiency virus (HIV)–positive patients in the United States is reported to be approximately 1% to 3%, which is similar to the rates reported for the general population.¹ Recalcitrant cases of psoriasis in patients with no history of the condition can be the initial manifestation of HIV infection. In patients with preexisting psoriasis, a flare of their disease can be seen following infection, and progression of HIV correlates with worsening psoriasis.² Psoriatic arthropathy also affects 23% to 50% of HIV-positive patients with psoriasis worldwide, which may be higher than the general population,¹ with more severe joint disease.

The management of psoriatic disease in the HIV-positive population is challenging. The current first-line recommendations for treatment include topical therapies, phototherapy, and highly active antiretroviral therapy (HAART), followed by oral retinoids as second-line agents.³ However, the clinical course of psoriasis in HIV-positive patients often is progressive and refractory²; therefore, these therapies often are inadequate to control both skin and joint manifestations. Most other currently available systemic therapies for psoriatic disease are immunosuppressive, which poses a distinct clinical challenge because HIV-positive patients are already immunocompromised.

There currently are many systemic immunosuppressive agents used for the treatment of psoriatic disease, including oral agents (eg, methotrexate, hydroxyurea, cyclosporine), as well as newer biologic medications, including tumor necrosis factor (TNF) α inhibitors etanercept, adalimumab, infliximab, golimumab, and certolizumab pegol. Golimumab and certolizumab pegol currently are indicated for psoriatic arthritis only. Other newer biologic therapies include ustekinumab, which inhibits IL-12 and IL-23, and secukinumab, which inhibits IL-17A. The purpose of this systematic review is to evaluate the most current literature to explore the efficacy and safety data as they pertain to systemic immunosuppressive therapies for the treatment of psoriatic disease in HIV-positive individuals.

Methods

To investigate the efficacy and safety of systemic immunosuppressive therapies for psoriatic disease in HIV-positive individuals, a PubMed search of articles indexed for MEDLINE (1985-2015) was conducted using the terms psoriasis and HIV and psoriatic arthritis and HIV combined with each of the following systemic immunosuppressive agents: methotrexate, hydroxyurea, cyclosporine, etanercept, adalimumab, infliximab, golimumab, certolizumab pegol, ustekinumab, and secukinumab. Pediatric cases and articles that were not available in the English language were excluded.

For each case, patient demographic information (ie, age, sex), prior failed psoriasis treatments, and history of HAART were documented. The dosing regimen of the systemic agent was noted when different from the US Food and Drug administration–approved dosage for psoriasis or psoriatic arthritis. The duration of immunosuppressive therapy as well as pretreatment and posttreatment CD4 and viral counts (when available) were collected. The response to treatment and adverse effects were summarized.

Results

Our review of the literature yielded a total of 25 reported cases of systemic immunosuppressive therapies used to treat psoriatic disease in HIV-positive patients, including methotrexate, cyclosporine, etanercept, adalimumab, in-fliximab, and ustekinumab (Table). There were no reports of the use of hydroxyurea, golimumab, certolizumab pegol, or secukinumab to treat psoriatic disease in this patient population.

Methotrexate
Eight individual cases of methotrexate used to treat psoriasis and/or psoriatic arthritis in HIV-positive patients were reported.^4-6 Duvic et al⁶ described 4 patients with psoriatic disease that was treated with methotrexate with varying efficacy. One patient developed toxic encephalopathy, which improved after discontinuation of methotrexate; however, he died 5 months later from pneumocystis pneumonia. In this early study, none of the 4 patients were on antiretroviral therapy for HIV.⁶

In the cases reported by Masson et al⁴ and Maurer et al,⁵ 4 patients were treated with a single antiretroviral agent and received appropriate prophylaxis against opportunistic infections. In 1 case, methotrexate was given at a chemotherapeutic dose of 525 mg once weekly for Kaposi sarcoma.⁴ In 2 of 4 cases, the patients developed pneumocystis pneumonia.^4,5

Cyclosporine
There were 2 case reports of successful treatment of psoriatic disease with cyclosporine in HIV-positive patients.^7,8 Skin and joint manifestations improved rapidly without reports of infection for 2⁷ and 8 years.⁸ Both patients were treated with one antiretroviral agent.^7,8

Etanercept
There were 5 case reports of successful treatment of psoriatic disease with etanercept. In all 5 cases the patients were on HAART, and the CD4 count increased or remained stable and viral count became undetectable or remained stable following treatment.^9-13 In 2 cases, the patient also had hepatitis C virus, which remained stable throughout the treatment period.^9,12 The maximum duration of treatment was 6 years, with only 1 reported adverse event.¹³ In this case reported by Aboulafia et al,¹³ the patient experienced recurrent polymicrobial infections, including enterococcal cellulitis, cystitis, and bacteremia, as well as pseudomonas pneumonia and septic arthritis. Therapy was discontinued at 6 months. Four months after discontinuation of etanercept, the patient died from infectious causes.¹³

Adalimumab
There was 1 case of successful treatment of psoriatic disease with adalimumab in an HIV-positive patient. In this case, the patient was on HAART, and CD4 and viral counts improved substantially after 30 months of treatment.¹⁴

Infliximab
Six individual cases of successful treatment of psoriatic disease with infliximab were reported.^15-17 In a report by Cepeda et al,¹⁵ HIV-positive patients with various rheumatologic diseases were chosen to receive etanercept followed by adalimumab and/or infliximab if clinical improvement was not observed on etanercept. In 3 patients with psoriasis and psoriatic arthritis, inadequate response was observed on etanercept. Two of these 3 patients received adalimumab with only partial response. All 3 were treated with infliximab in the end and showed excellent response. One of the patients experienced facial abscess responsive to antibiotics and was continued on infliximab therapy without further complications. In all 6 cases of infliximab therapy, the patients were on HAART, and CD4 and viral counts improved or remained stable.¹⁵

Ustekinumab
There were 3 case reports of successful treatment of psoriatic disease with ustekinumab in HIV-positive patients on HAART. CD4 and viral counts improved or remained stable.^18-20

Comment

Currently, all of the systemic immunosuppressive therapies approved for psoriatic disease have a warning by the US Food and Drug Administration for increased risk of serious infection. Given such labels, these therapies are not routinely prescribed for HIV-positive patients who are already immunocompromised; however, many HIV-positive patients have severe psoriatic disease that cannot be adequately treated with first- and second-line therapies including topical agents, phototherapy, or oral retinoids.

Our comprehensive review yielded a total of 25 reported cases of systemic immunosuppressive therapies used to treat psoriatic disease in HIV-positive patients including methotrexate, cyclosporine, etanercept, adalimumab, in-fliximab, and ustekinumab. Although data are limited to case reports and case series, some trends were observed.

Efficacy
In most of the cases reviewed, the patients had inadequate improvement of psoriatic disease with first- and second-line therapies, which included antiretrovirals alone, topical agents, phototherapy, and oral retinoids. Some cases reported poor response to methotrexate and cyclosporine.^4-8 Biologic agents were effective in many such cases.

Safety
Overall, there were 11 cases in which the patient was not on adequate HAART while being treated with systemic immunosuppressive therapy for psoriatic disease.^4-8,15 Of them, 3 were associated with serious infection while on methotrexate.^5,6 There was only 1 report of serious infection¹³ of 14 cases in which the patient was on concomitant HAART. In this case, which reported polymicrobial infections and subsequent death of the patient, the infections continued after discontinuing etanercept; thus, the association is unclear. Interestingly, despite multiple infections, the CD4 and viral counts were stable throughout treatment with etanercept.¹³

From reviewing the 4 total cases^5,6,13 of serious infection, HAART appears to be a valuable concomitant treatment during systemic immunosuppressive therapy for HIV-positive patients; however, it does not necessarily prevent serious infections from occurring, and thus the clinician’s diligence in monitoring for signs and symptoms of infection remains important.

CD4 and Viral Counts
Although reports of CD4 and viral counts were not available in earlier studies,^4-8 there were 15 cases that reported consistent pretreatment and posttreatment CD4 and viral counts during treatment with etanercept, adalimumab, infliximab, and ustekinumab.^9-20 In all cases, the CD4 count was stable or increased. Similarly, the viral count was stable or decreased. All patients, except 1 by Cepeda et al,¹⁵ were on concomitant HAART.^9-14,16-20

Although data are limited, treatment of psoriatic disease with biologic agents when used in combination with HAART may have beneficial effects on CD4 and viral counts. Tumor necrosis factor has a role in HIV expression through the action of nuclear factor κβ.²¹ An increase in TNF levels is shown to be associated with increased viral count, decreased CD4 count, and increased symptoms of HIV progression, such as fever, fatigue, cachexia, and dementia.²² Although more studies are necessary, TNF-α inhibitors may have a positive effect on HIV while simultaneously treating psoriatic disease. Other cytokines (eg, IL-12, IL-23, IL-17) involved in the mechanism of action of other biologic agents (ustekinumab and secukinumab) have not been shown to be directly associated with HIV activity; however, studies have shown that IL-10 has a role in inhibiting HIV-1 replication and inhibits secretion of proinflammatory cytokines such as IL-12 and TNF-α.²¹ It may be speculated that the inhibition of IL-12 and TNF-α may create a positive feedback effect to increase IL-10, which in turn inhibits HIV replication.

Conclusion

Although there are limited data on the efficacy and safety of systemic immunosuppressive therapies for the treatment of psoriatic disease in HIV-positive patients, a review of 25 individual cases suggest that these treatments are not only required but also are sufficient to treat some of the most resistant cases. It is possible that with adequate concomitant HAART and monitoring for signs and symptoms of infection, the likelihood of serious infection may be low. Furthermore, biologic agents may have a positive effect over other systemic immunosuppressive agents, such as methotrexate and cyclosporine, in improving CD4 and viral counts when used in combination with HAART. Although randomized controlled trials are necessary, current biologic therapies such as etanercept, adalimumab, infliximab, and ustekinumab may be safe viable options as third-line treatment of severe psoriasis in the HIV-positive population.

The prevalence of psoriasis among human immunodeficiency virus (HIV)–positive patients in the United States is reported to be approximately 1% to 3%, which is similar to the rates reported for the general population.¹ Recalcitrant cases of psoriasis in patients with no history of the condition can be the initial manifestation of HIV infection. In patients with preexisting psoriasis, a flare of their disease can be seen following infection, and progression of HIV correlates with worsening psoriasis.² Psoriatic arthropathy also affects 23% to 50% of HIV-positive patients with psoriasis worldwide, which may be higher than the general population,¹ with more severe joint disease.

The management of psoriatic disease in the HIV-positive population is challenging. The current first-line recommendations for treatment include topical therapies, phototherapy, and highly active antiretroviral therapy (HAART), followed by oral retinoids as second-line agents.³ However, the clinical course of psoriasis in HIV-positive patients often is progressive and refractory²; therefore, these therapies often are inadequate to control both skin and joint manifestations. Most other currently available systemic therapies for psoriatic disease are immunosuppressive, which poses a distinct clinical challenge because HIV-positive patients are already immunocompromised.

There currently are many systemic immunosuppressive agents used for the treatment of psoriatic disease, including oral agents (eg, methotrexate, hydroxyurea, cyclosporine), as well as newer biologic medications, including tumor necrosis factor (TNF) α inhibitors etanercept, adalimumab, infliximab, golimumab, and certolizumab pegol. Golimumab and certolizumab pegol currently are indicated for psoriatic arthritis only. Other newer biologic therapies include ustekinumab, which inhibits IL-12 and IL-23, and secukinumab, which inhibits IL-17A. The purpose of this systematic review is to evaluate the most current literature to explore the efficacy and safety data as they pertain to systemic immunosuppressive therapies for the treatment of psoriatic disease in HIV-positive individuals.

Methods

To investigate the efficacy and safety of systemic immunosuppressive therapies for psoriatic disease in HIV-positive individuals, a PubMed search of articles indexed for MEDLINE (1985-2015) was conducted using the terms psoriasis and HIV and psoriatic arthritis and HIV combined with each of the following systemic immunosuppressive agents: methotrexate, hydroxyurea, cyclosporine, etanercept, adalimumab, infliximab, golimumab, certolizumab pegol, ustekinumab, and secukinumab. Pediatric cases and articles that were not available in the English language were excluded.

For each case, patient demographic information (ie, age, sex), prior failed psoriasis treatments, and history of HAART were documented. The dosing regimen of the systemic agent was noted when different from the US Food and Drug administration–approved dosage for psoriasis or psoriatic arthritis. The duration of immunosuppressive therapy as well as pretreatment and posttreatment CD4 and viral counts (when available) were collected. The response to treatment and adverse effects were summarized.

Results

Our review of the literature yielded a total of 25 reported cases of systemic immunosuppressive therapies used to treat psoriatic disease in HIV-positive patients, including methotrexate, cyclosporine, etanercept, adalimumab, in-fliximab, and ustekinumab (Table). There were no reports of the use of hydroxyurea, golimumab, certolizumab pegol, or secukinumab to treat psoriatic disease in this patient population.

Methotrexate
Eight individual cases of methotrexate used to treat psoriasis and/or psoriatic arthritis in HIV-positive patients were reported.^4-6 Duvic et al⁶ described 4 patients with psoriatic disease that was treated with methotrexate with varying efficacy. One patient developed toxic encephalopathy, which improved after discontinuation of methotrexate; however, he died 5 months later from pneumocystis pneumonia. In this early study, none of the 4 patients were on antiretroviral therapy for HIV.⁶

In the cases reported by Masson et al⁴ and Maurer et al,⁵ 4 patients were treated with a single antiretroviral agent and received appropriate prophylaxis against opportunistic infections. In 1 case, methotrexate was given at a chemotherapeutic dose of 525 mg once weekly for Kaposi sarcoma.⁴ In 2 of 4 cases, the patients developed pneumocystis pneumonia.^4,5

Cyclosporine
There were 2 case reports of successful treatment of psoriatic disease with cyclosporine in HIV-positive patients.^7,8 Skin and joint manifestations improved rapidly without reports of infection for 2⁷ and 8 years.⁸ Both patients were treated with one antiretroviral agent.^7,8

Etanercept
There were 5 case reports of successful treatment of psoriatic disease with etanercept. In all 5 cases the patients were on HAART, and the CD4 count increased or remained stable and viral count became undetectable or remained stable following treatment.^9-13 In 2 cases, the patient also had hepatitis C virus, which remained stable throughout the treatment period.^9,12 The maximum duration of treatment was 6 years, with only 1 reported adverse event.¹³ In this case reported by Aboulafia et al,¹³ the patient experienced recurrent polymicrobial infections, including enterococcal cellulitis, cystitis, and bacteremia, as well as pseudomonas pneumonia and septic arthritis. Therapy was discontinued at 6 months. Four months after discontinuation of etanercept, the patient died from infectious causes.¹³

Adalimumab
There was 1 case of successful treatment of psoriatic disease with adalimumab in an HIV-positive patient. In this case, the patient was on HAART, and CD4 and viral counts improved substantially after 30 months of treatment.¹⁴

Infliximab
Six individual cases of successful treatment of psoriatic disease with infliximab were reported.^15-17 In a report by Cepeda et al,¹⁵ HIV-positive patients with various rheumatologic diseases were chosen to receive etanercept followed by adalimumab and/or infliximab if clinical improvement was not observed on etanercept. In 3 patients with psoriasis and psoriatic arthritis, inadequate response was observed on etanercept. Two of these 3 patients received adalimumab with only partial response. All 3 were treated with infliximab in the end and showed excellent response. One of the patients experienced facial abscess responsive to antibiotics and was continued on infliximab therapy without further complications. In all 6 cases of infliximab therapy, the patients were on HAART, and CD4 and viral counts improved or remained stable.¹⁵

Ustekinumab
There were 3 case reports of successful treatment of psoriatic disease with ustekinumab in HIV-positive patients on HAART. CD4 and viral counts improved or remained stable.^18-20

Comment

Currently, all of the systemic immunosuppressive therapies approved for psoriatic disease have a warning by the US Food and Drug Administration for increased risk of serious infection. Given such labels, these therapies are not routinely prescribed for HIV-positive patients who are already immunocompromised; however, many HIV-positive patients have severe psoriatic disease that cannot be adequately treated with first- and second-line therapies including topical agents, phototherapy, or oral retinoids.

Our comprehensive review yielded a total of 25 reported cases of systemic immunosuppressive therapies used to treat psoriatic disease in HIV-positive patients including methotrexate, cyclosporine, etanercept, adalimumab, in-fliximab, and ustekinumab. Although data are limited to case reports and case series, some trends were observed.

Efficacy
In most of the cases reviewed, the patients had inadequate improvement of psoriatic disease with first- and second-line therapies, which included antiretrovirals alone, topical agents, phototherapy, and oral retinoids. Some cases reported poor response to methotrexate and cyclosporine.^4-8 Biologic agents were effective in many such cases.

Safety
Overall, there were 11 cases in which the patient was not on adequate HAART while being treated with systemic immunosuppressive therapy for psoriatic disease.^4-8,15 Of them, 3 were associated with serious infection while on methotrexate.^5,6 There was only 1 report of serious infection¹³ of 14 cases in which the patient was on concomitant HAART. In this case, which reported polymicrobial infections and subsequent death of the patient, the infections continued after discontinuing etanercept; thus, the association is unclear. Interestingly, despite multiple infections, the CD4 and viral counts were stable throughout treatment with etanercept.¹³

From reviewing the 4 total cases^5,6,13 of serious infection, HAART appears to be a valuable concomitant treatment during systemic immunosuppressive therapy for HIV-positive patients; however, it does not necessarily prevent serious infections from occurring, and thus the clinician’s diligence in monitoring for signs and symptoms of infection remains important.

CD4 and Viral Counts
Although reports of CD4 and viral counts were not available in earlier studies,^4-8 there were 15 cases that reported consistent pretreatment and posttreatment CD4 and viral counts during treatment with etanercept, adalimumab, infliximab, and ustekinumab.^9-20 In all cases, the CD4 count was stable or increased. Similarly, the viral count was stable or decreased. All patients, except 1 by Cepeda et al,¹⁵ were on concomitant HAART.^9-14,16-20

Although data are limited, treatment of psoriatic disease with biologic agents when used in combination with HAART may have beneficial effects on CD4 and viral counts. Tumor necrosis factor has a role in HIV expression through the action of nuclear factor κβ.²¹ An increase in TNF levels is shown to be associated with increased viral count, decreased CD4 count, and increased symptoms of HIV progression, such as fever, fatigue, cachexia, and dementia.²² Although more studies are necessary, TNF-α inhibitors may have a positive effect on HIV while simultaneously treating psoriatic disease. Other cytokines (eg, IL-12, IL-23, IL-17) involved in the mechanism of action of other biologic agents (ustekinumab and secukinumab) have not been shown to be directly associated with HIV activity; however, studies have shown that IL-10 has a role in inhibiting HIV-1 replication and inhibits secretion of proinflammatory cytokines such as IL-12 and TNF-α.²¹ It may be speculated that the inhibition of IL-12 and TNF-α may create a positive feedback effect to increase IL-10, which in turn inhibits HIV replication.

Conclusion

Although there are limited data on the efficacy and safety of systemic immunosuppressive therapies for the treatment of psoriatic disease in HIV-positive patients, a review of 25 individual cases suggest that these treatments are not only required but also are sufficient to treat some of the most resistant cases. It is possible that with adequate concomitant HAART and monitoring for signs and symptoms of infection, the likelihood of serious infection may be low. Furthermore, biologic agents may have a positive effect over other systemic immunosuppressive agents, such as methotrexate and cyclosporine, in improving CD4 and viral counts when used in combination with HAART. Although randomized controlled trials are necessary, current biologic therapies such as etanercept, adalimumab, infliximab, and ustekinumab may be safe viable options as third-line treatment of severe psoriasis in the HIV-positive population.

Over the last decade we have come to understand the nature of psoriasis as a systemic inflammatory condition rather than as simply a skin disease. With this concept, we have continued to identify systemic comorbidities associated with psoriasis, including cardiovascular risk, diabetes mellitus, and metabolic syndrome. As dermatologists, we must serve as the gatekeeper for our patients with psoriasis and help to screen for comorbidities as well as provide appropriate counseling and referral.

Of the potential benefits of novel systemic therapies for psoriasis, the potential for addressing comorbid conditions with these treatments is critically important. Therefore, when I discuss psoriasis treatments, I always review and emphasize the anti-inflammatory effects of these agents. Although we know that psoriasis increases the risk for vascular inflammation and major adverse cardiovascular events (MACEs), it has been unclear if psoriasis duration affects these risks.

Egeberg et al¹ utilized 2 resources to understand the effect of psoriasis duration on vascular disease and cardiovascular events: a human imaging study and a population-based study of cardiovascular disease events. In the first part of the study, patients with psoriasis (N=190) underwent fludeoxyglucose F 18 positron emission tomography/computed tomography. Next, MACE risk was examined using nationwide registries (adjusted hazard ratio in patients with psoriasis [n=87,161] vs the general population [n=4,234,793]). In the imaging study, participants had low cardiovascular risk by traditional risk scores. The authors found that vascular inflammation as demonstrated by the imaging system was significantly associated with disease duration (β=.171; P=.002). In the population-based study, psoriasis duration had a strong relationship with MACE risk (1.0% per additional year of psoriasis duration [hazard ratio, 1.010; 95% confidence interval, 1.007-1.013]). The researchers reported that every standard deviation increase in disease duration increased the target-to-background ratio by 2.5%, which translated into an absolute increase of approximately 10% in future adverse events.¹

Therefore, the authors concluded that there were negative effects of psoriasis duration on vascular inflammation and MACEs,¹ which suggests that the cumulative duration of low-grade chronic inflammation may accelerate vascular disease development and MACEs. The authors therefore noted that providers should consider inquiring about duration of disease to counsel for heightened cardiovascular disease risk in psoriasis patients.¹

We have some evidence that therapeutic intervention may be useful. Wu et al² compared MACE risk in psoriasis patients receiving methotrexate or tumor necrosis factor α (TNF-α) inhibitors. They also assessed the impact of TNF-α inhibitor treatment duration on MACE risk. The authors concluded that psoriasis patients receiving TNF-α inhibitors had a lower MACE risk compared to those receiving methotrexate. Cumulative exposure to TNF-α inhibitors was associated with a reduced risk for MACEs.²

The findings of these studies are poignant and help to further emphasize the importance of proper identification and treatment of psoriasis and its comorbidities. This information also adds an element of urgency to the way we look at this disease and demonstrates that we must intervene as soon as possible in this process.

Over the last decade we have come to understand the nature of psoriasis as a systemic inflammatory condition rather than as simply a skin disease. With this concept, we have continued to identify systemic comorbidities associated with psoriasis, including cardiovascular risk, diabetes mellitus, and metabolic syndrome. As dermatologists, we must serve as the gatekeeper for our patients with psoriasis and help to screen for comorbidities as well as provide appropriate counseling and referral.

Of the potential benefits of novel systemic therapies for psoriasis, the potential for addressing comorbid conditions with these treatments is critically important. Therefore, when I discuss psoriasis treatments, I always review and emphasize the anti-inflammatory effects of these agents. Although we know that psoriasis increases the risk for vascular inflammation and major adverse cardiovascular events (MACEs), it has been unclear if psoriasis duration affects these risks.

Egeberg et al¹ utilized 2 resources to understand the effect of psoriasis duration on vascular disease and cardiovascular events: a human imaging study and a population-based study of cardiovascular disease events. In the first part of the study, patients with psoriasis (N=190) underwent fludeoxyglucose F 18 positron emission tomography/computed tomography. Next, MACE risk was examined using nationwide registries (adjusted hazard ratio in patients with psoriasis [n=87,161] vs the general population [n=4,234,793]). In the imaging study, participants had low cardiovascular risk by traditional risk scores. The authors found that vascular inflammation as demonstrated by the imaging system was significantly associated with disease duration (β=.171; P=.002). In the population-based study, psoriasis duration had a strong relationship with MACE risk (1.0% per additional year of psoriasis duration [hazard ratio, 1.010; 95% confidence interval, 1.007-1.013]). The researchers reported that every standard deviation increase in disease duration increased the target-to-background ratio by 2.5%, which translated into an absolute increase of approximately 10% in future adverse events.¹

Therefore, the authors concluded that there were negative effects of psoriasis duration on vascular inflammation and MACEs,¹ which suggests that the cumulative duration of low-grade chronic inflammation may accelerate vascular disease development and MACEs. The authors therefore noted that providers should consider inquiring about duration of disease to counsel for heightened cardiovascular disease risk in psoriasis patients.¹

We have some evidence that therapeutic intervention may be useful. Wu et al² compared MACE risk in psoriasis patients receiving methotrexate or tumor necrosis factor α (TNF-α) inhibitors. They also assessed the impact of TNF-α inhibitor treatment duration on MACE risk. The authors concluded that psoriasis patients receiving TNF-α inhibitors had a lower MACE risk compared to those receiving methotrexate. Cumulative exposure to TNF-α inhibitors was associated with a reduced risk for MACEs.²

The findings of these studies are poignant and help to further emphasize the importance of proper identification and treatment of psoriasis and its comorbidities. This information also adds an element of urgency to the way we look at this disease and demonstrates that we must intervene as soon as possible in this process.

Over the last decade we have come to understand the nature of psoriasis as a systemic inflammatory condition rather than as simply a skin disease. With this concept, we have continued to identify systemic comorbidities associated with psoriasis, including cardiovascular risk, diabetes mellitus, and metabolic syndrome. As dermatologists, we must serve as the gatekeeper for our patients with psoriasis and help to screen for comorbidities as well as provide appropriate counseling and referral.

Of the potential benefits of novel systemic therapies for psoriasis, the potential for addressing comorbid conditions with these treatments is critically important. Therefore, when I discuss psoriasis treatments, I always review and emphasize the anti-inflammatory effects of these agents. Although we know that psoriasis increases the risk for vascular inflammation and major adverse cardiovascular events (MACEs), it has been unclear if psoriasis duration affects these risks.

Egeberg et al¹ utilized 2 resources to understand the effect of psoriasis duration on vascular disease and cardiovascular events: a human imaging study and a population-based study of cardiovascular disease events. In the first part of the study, patients with psoriasis (N=190) underwent fludeoxyglucose F 18 positron emission tomography/computed tomography. Next, MACE risk was examined using nationwide registries (adjusted hazard ratio in patients with psoriasis [n=87,161] vs the general population [n=4,234,793]). In the imaging study, participants had low cardiovascular risk by traditional risk scores. The authors found that vascular inflammation as demonstrated by the imaging system was significantly associated with disease duration (β=.171; P=.002). In the population-based study, psoriasis duration had a strong relationship with MACE risk (1.0% per additional year of psoriasis duration [hazard ratio, 1.010; 95% confidence interval, 1.007-1.013]). The researchers reported that every standard deviation increase in disease duration increased the target-to-background ratio by 2.5%, which translated into an absolute increase of approximately 10% in future adverse events.¹

Therefore, the authors concluded that there were negative effects of psoriasis duration on vascular inflammation and MACEs,¹ which suggests that the cumulative duration of low-grade chronic inflammation may accelerate vascular disease development and MACEs. The authors therefore noted that providers should consider inquiring about duration of disease to counsel for heightened cardiovascular disease risk in psoriasis patients.¹

We have some evidence that therapeutic intervention may be useful. Wu et al² compared MACE risk in psoriasis patients receiving methotrexate or tumor necrosis factor α (TNF-α) inhibitors. They also assessed the impact of TNF-α inhibitor treatment duration on MACE risk. The authors concluded that psoriasis patients receiving TNF-α inhibitors had a lower MACE risk compared to those receiving methotrexate. Cumulative exposure to TNF-α inhibitors was associated with a reduced risk for MACEs.²

The findings of these studies are poignant and help to further emphasize the importance of proper identification and treatment of psoriasis and its comorbidities. This information also adds an element of urgency to the way we look at this disease and demonstrates that we must intervene as soon as possible in this process.

Biologic agents have provided patients with moderate to severe psoriasis with treatment alternatives that have improved systemic safety profiles and disease control¹; however, case reports of associated neurologic complications have been emerging. Tumor necrosis factor α (TNF-α) inhibitors have been associated with central and peripheral demyelinating disorders. Notably, efalizumab was withdrawn from the market for its association with fatal cases of progressive multifocal leukoencephalopathy (PML).^2,3 It is imperative for dermatologists to be familiar with the clinical presentation, evaluation, and diagnostic criteria of neurologic complications of biologic agents used in the treatment of psoriasis.

Leukoencephalopathy

Progressive multifocal leukoencephalopathy is a fatal demyelinating neurodegenerative disease caused by reactivation of the ubiquitous John Cunningham virus. Primary asymptomatic infection is thought to occur during childhood, then the virus remains latent. Reactivation usually occurs during severe immunosuppression and is classically described in human immunodeficiency virus infection, lymphoproliferative disorders, and other forms of cancer.⁴ A summary of PML and its association with biologics is found in Table 1.^5-13 Few case reports of TNF-α inhibitor–associated PML exist, mostly in the presence of confounding factors such as immunosuppression or underlying autoimmune disease.^10-13 Presenting symptoms of PML often are subacute, rapidly progressive, and can be focal or multifocal and include motor, cognitive, and visual deficits. Of note, there are 2 reported cases of ustekinumab associated with reversible posterior leukoencephalopathy syndrome, which is a hypertensive encephalopathy characterized by headache, altered mental status, vision abnormalities, and seizures.^14,15 Fortunately, this disease is reversible with blood pressure control and removal of the immunosuppressive agent.¹⁶

Demyelinating Disorders

Clinical presentation of demyelinating events associated with biologic agents are varied but include optic neuritis, multiple sclerosis, transverse myelitis, and Guillain-Barré syndrome, among others.^17-28 These demyelinating disorders with their salient features and associated biologics are summarized in Table 2.^17-20,22-28 Patients on biologic agents, especially TNF-α inhibitors, with new-onset visual, motor, or sensory changes warrant closer inspection. Currently, there are no data on any neurologic side effects occurring with the new biologic secukinumab.²⁹

Conclusion

Biologic agents are effective in treating moderate to severe plaque psoriasis, but awareness of associated neurological adverse effects, though rare, is important to consider. Physicians need to be able to counsel patients concerning these risks and promote informed decision-making prior to initiating biologics. Patients with a personal or strong family history of demyelinating disease should be considered for alternative treatment options before initiating anti–TNF-α therapy. Since the withdrawal of efalizumab, no new cases of PML have been reported in patients who were previously on a long-term course. Dermatologists should be vigilant in detecting signs of neurological complications so that an expedited evaluation and neurology referral may prevent progression of disease.

Biologic agents have provided patients with moderate to severe psoriasis with treatment alternatives that have improved systemic safety profiles and disease control¹; however, case reports of associated neurologic complications have been emerging. Tumor necrosis factor α (TNF-α) inhibitors have been associated with central and peripheral demyelinating disorders. Notably, efalizumab was withdrawn from the market for its association with fatal cases of progressive multifocal leukoencephalopathy (PML).^2,3 It is imperative for dermatologists to be familiar with the clinical presentation, evaluation, and diagnostic criteria of neurologic complications of biologic agents used in the treatment of psoriasis.

Leukoencephalopathy

Progressive multifocal leukoencephalopathy is a fatal demyelinating neurodegenerative disease caused by reactivation of the ubiquitous John Cunningham virus. Primary asymptomatic infection is thought to occur during childhood, then the virus remains latent. Reactivation usually occurs during severe immunosuppression and is classically described in human immunodeficiency virus infection, lymphoproliferative disorders, and other forms of cancer.⁴ A summary of PML and its association with biologics is found in Table 1.^5-13 Few case reports of TNF-α inhibitor–associated PML exist, mostly in the presence of confounding factors such as immunosuppression or underlying autoimmune disease.^10-13 Presenting symptoms of PML often are subacute, rapidly progressive, and can be focal or multifocal and include motor, cognitive, and visual deficits. Of note, there are 2 reported cases of ustekinumab associated with reversible posterior leukoencephalopathy syndrome, which is a hypertensive encephalopathy characterized by headache, altered mental status, vision abnormalities, and seizures.^14,15 Fortunately, this disease is reversible with blood pressure control and removal of the immunosuppressive agent.¹⁶

Demyelinating Disorders

Clinical presentation of demyelinating events associated with biologic agents are varied but include optic neuritis, multiple sclerosis, transverse myelitis, and Guillain-Barré syndrome, among others.^17-28 These demyelinating disorders with their salient features and associated biologics are summarized in Table 2.^17-20,22-28 Patients on biologic agents, especially TNF-α inhibitors, with new-onset visual, motor, or sensory changes warrant closer inspection. Currently, there are no data on any neurologic side effects occurring with the new biologic secukinumab.²⁹

Conclusion

Biologic agents are effective in treating moderate to severe plaque psoriasis, but awareness of associated neurological adverse effects, though rare, is important to consider. Physicians need to be able to counsel patients concerning these risks and promote informed decision-making prior to initiating biologics. Patients with a personal or strong family history of demyelinating disease should be considered for alternative treatment options before initiating anti–TNF-α therapy. Since the withdrawal of efalizumab, no new cases of PML have been reported in patients who were previously on a long-term course. Dermatologists should be vigilant in detecting signs of neurological complications so that an expedited evaluation and neurology referral may prevent progression of disease.

Biologic agents have provided patients with moderate to severe psoriasis with treatment alternatives that have improved systemic safety profiles and disease control¹; however, case reports of associated neurologic complications have been emerging. Tumor necrosis factor α (TNF-α) inhibitors have been associated with central and peripheral demyelinating disorders. Notably, efalizumab was withdrawn from the market for its association with fatal cases of progressive multifocal leukoencephalopathy (PML).^2,3 It is imperative for dermatologists to be familiar with the clinical presentation, evaluation, and diagnostic criteria of neurologic complications of biologic agents used in the treatment of psoriasis.

Leukoencephalopathy

Progressive multifocal leukoencephalopathy is a fatal demyelinating neurodegenerative disease caused by reactivation of the ubiquitous John Cunningham virus. Primary asymptomatic infection is thought to occur during childhood, then the virus remains latent. Reactivation usually occurs during severe immunosuppression and is classically described in human immunodeficiency virus infection, lymphoproliferative disorders, and other forms of cancer.⁴ A summary of PML and its association with biologics is found in Table 1.^5-13 Few case reports of TNF-α inhibitor–associated PML exist, mostly in the presence of confounding factors such as immunosuppression or underlying autoimmune disease.^10-13 Presenting symptoms of PML often are subacute, rapidly progressive, and can be focal or multifocal and include motor, cognitive, and visual deficits. Of note, there are 2 reported cases of ustekinumab associated with reversible posterior leukoencephalopathy syndrome, which is a hypertensive encephalopathy characterized by headache, altered mental status, vision abnormalities, and seizures.^14,15 Fortunately, this disease is reversible with blood pressure control and removal of the immunosuppressive agent.¹⁶

Demyelinating Disorders

Clinical presentation of demyelinating events associated with biologic agents are varied but include optic neuritis, multiple sclerosis, transverse myelitis, and Guillain-Barré syndrome, among others.^17-28 These demyelinating disorders with their salient features and associated biologics are summarized in Table 2.^17-20,22-28 Patients on biologic agents, especially TNF-α inhibitors, with new-onset visual, motor, or sensory changes warrant closer inspection. Currently, there are no data on any neurologic side effects occurring with the new biologic secukinumab.²⁹

Conclusion

Biologic agents are effective in treating moderate to severe plaque psoriasis, but awareness of associated neurological adverse effects, though rare, is important to consider. Physicians need to be able to counsel patients concerning these risks and promote informed decision-making prior to initiating biologics. Patients with a personal or strong family history of demyelinating disease should be considered for alternative treatment options before initiating anti–TNF-α therapy. Since the withdrawal of efalizumab, no new cases of PML have been reported in patients who were previously on a long-term course. Dermatologists should be vigilant in detecting signs of neurological complications so that an expedited evaluation and neurology referral may prevent progression of disease.

The incidence of melanoma is increasing at a rate greater than any other cancer,¹ possibly due to the increasing use of indoor tanning devices. These devices emit unnaturally high levels of UVA and low levels of UVA and UVB rays.² The risks of using these devices include increased incidence of melanoma (3438 cases attributed to indoor tanning in 2008) and keratinocytes cancer (increased risk of squamous cell carcinoma by 67% and basal cell carcinoma by 29%), severe sunburns (61.1% of female users and 44.6% of male users have reported sunburns), and aggravation of underlying disorders such as systemic lupus erythematosus.^3-5

The literature varies in its explanation of how indoor tanning increases the risk of developing melanoma. Some authors suggest it is due to increased frequency of use, duration of sessions, and years of using tanning devices.^1,6 Others suggest the increased cancer risk is the result of starting to tan at an earlier age.^2,3,6-10 There is conflicting literature on the level of increased risk of melanoma in those who tan indoors at a young age (<35 years). Although the estimated rate of increased skin cancer risk varies, with rates up to 75% compared to nonusers, nearly all sources support an increased rate.⁶ Despite the growing body of knowledge that indoor tanning is dangerous, as well as the academic publication of these risks (eg, carcinogenesis, short-term and long-term eye injury, burns, UV sensitivity when combined with certain medications), teenagers in the United States and affluent countries appear to disregard the risks of tanning.¹¹

Tanning companies have promoted the misconception that only UVB rays cause cell damage and UVA rays, which the devices emit, result in “damage-free” or “safe” tans.^2,3 Until 2013, indoor tanning devices were classified by the US Food and Drug Administration (FDA) as class I, indicating that they are safe in terms of electrical shock. Many indoor tanning facilities have promoted the FDA “safe” label without clarifying that the safety indications only referred to electrical-shock potential. Nonetheless, it is known now that these devices, which emit high UVA and low UVB rays, promote melanoma, nonmelanoma skin cancers, and severe sunburns, as well as aggravate existing conditions (eg, systemic lupus erythematosus).⁴ As a result of an unacceptably high incidence of these disease complications, a 2014 FDA regulation categorized tanning beds as class II, requiring that tanning bed users be informed of the risk of skin cancer in an effort to reverse the growing trend of indoor tanning.¹² Despite these regulatory interventions, it is not clear if this knowledge of cancer risk deters patients from indoor tanning.

The purpose of this study was to investigate the patients’ perspective on indoor tanning behaviors as associated with the severity of their melanoma and the time frame in which they were diagnosed as well as their perceived views on the safety of indoor tanning and the frequency in which they continue to tan indoors. This information is highly relevant in helping to determine if requiring a warning of the risk of skin cancer will deter patients from this unhealthy habit, especially given recent reclassification of sunbeds as class II by the FDA. Additional insights from these data may clarify if indoor tanning decreases the time frame in which melanoma is diagnosed or increases the severity of the resulting melanoma. Moreover, it will help elucidate whether or not the age at which indoor tanning is initiated affects the time frame to melanoma onset and corresponding severity.

Methods

An original unvalidated online survey was conducted worldwide via a link distributed to the following supporting institutions: Advanced Dermatology & Cosmetic Surgery, Ameriderm Research, Melanoma Research Foundation (a melanoma patient advocacy group), Florida State University Department of Dermatology, Moffitt Cancer Center Cutaneous Oncology Program, Cleveland Clinic, Ohio State University Division of Medical Oncology, Harvard Medical School Department of Dermatology, The University of Texas MD Anderson Cancer Center Department of Dermatology, University of Colorado Department of Dermatology, and Northwestern University Department of Dermatology. However, there was not confirmation that all of these institutions promoted the survey. Additionally, respondents were recruited through patient advocacy groups and social media sites including Facebook, Twitter, LinkedIn, Tumblr, and Instagram. The patient advocacy groups and social media sites invited participation through recruitment announcements, including DermNetNZ (a global dermatology patient information site), with additional help from the International Federation of Dermatology Clinical Trial Network.

The survey was restricted to those who were self-identified as 18 years or older and who self-reported a diagnosis of melanoma following the use of indoor tanning devices. The survey was hosted by SurveyMonkey, which allowed consent to be obtained and responses to remain anonymous. Access to the survey was sponsored by the Basal Cell Carcinoma Nevus Syndrome Life Support Network. The University of Central Florida (Orlando, Florida) institutional review board reviewed and approved this study as exempt human research.

Survey responses collected from January 2014 to June 2015 were analyzed herein. The survey contained 58 questions and was divided into different topics including indoor tanning background (eg, states/countries in which participants tanned indoors, age when they first tanned, frequency of tanning), consenting process (eg, length, did someone review the consent with participants, what was contained in the consent), indoor tanning and melanoma (eg, how long after tanning did melanoma develop, age at development, location of melanoma), indoor tanning postmelanoma (eg, did participants tan after diagnosis and why), and other risk factors (eg, did participants smoke or drink pre- or postmelanoma).

Statistical Analysis
The data consist of both categorical and continuous variables. The categorical variables included age (<35 years or ≥35 years), frequency of indoor tanning (≤1 time weekly or >1 time weekly), and onset of melanoma diagnosis (within or after 5 years of indoor tanning). The continuous variables consisted of current age, age at start of indoor tanning, age at melanoma diagnosis, Breslow depth, and Clark level. Frequency of indoor tanning and warning of the risk of skin cancer were converted to be used as both categorical and continuous variables. For frequency of indoor tanning, the variables less than or equal to once weekly and more than once weekly were used as categorical variables, whereas less than monthly, 1 time monthly, 4 times monthly, 2 times weekly, and more than 2 times weekly were used as continuous variables. For warning of the risk of skin cancer, no and yes were converted to 0 and 1 for use in the Spearman correlations, which allowed for greater analyses among other variables. Spearman correlation was used to determine if a significant relationship existed among the age at melanoma diagnosis, age at start of indoor tanning, Breslow depth, Clark level, frequency of indoor and outdoor tanning, and knowledge and warning of the risk of skin cancer. All data were analyzed by use of IBM SPSS Statistics (version 21.0).

Difference in proportions among groups, age, frequency of tanning, onset of melanoma diagnosis within or after 5 years of starting indoor tanning, and knowledge of cancer risks was tested for significance using the χ² test. Reported P values were 2-tailed, corresponding with a significance level of P<.05. All data were analyzed using SPSS (version 21.0). All statistical analyses were conducted independent of the participants’ sex.

Results

Of the 454 participants who accessed the survey, 448 were analyzed in this study; 6 participants did not complete the questionnaire. Both males and females were analyzed: 289 females, 12 males, and 153 who did not report gender. The age range of participants was 18 to 69 years. The age at start of indoor tanning ranged from 8 to 54 years, with a mean of 22 years. Additional participant characteristics are described in Table 1. The mean frequency of indoor tanning was reported as 2 times weekly. When participants were asked if they were warned of the risk of skin cancer, 21.5% reported yes while 78.4% reported not being told of the risk. This knowledge was compared to their frequency of indoor tanning. Having the knowledge of the risk of skin cancer had no influence on their frequency of indoor tanning (Table 2).

Among responders, those who perceived indoor tanning as safer than outdoor tanning tanned indoors more frequently than those who do not (Spearman r=−0.224; P<.05)(Table 3). The frequency of indoor tanning was divided into those who tanned indoors more than once weekly and those who tanned indoors once a week or less. This study showed that the frequency of indoor tanning had no effect on the latency time between the commencement of indoor tanning and diagnosis of melanoma (Table 4). The time frame from the onset of melanoma diagnosis also was compared to the age at which the participants started to tan indoors. Age was divided into those younger than 35 years and those 35 years and older. There was no correlation between the age when indoor tanning began and the time frame in which the melanoma was diagnosed (eTable).

Comment

Thirty million Americans utilize indoor tanning devices at least once a year.¹³ UVA light comprises the majority of the spectrum used by indoor tanning devices, with a fraction (<5%) being UVB light. Until recently, UVB light was the only solar spectrum considered carcinogenic. In 2009, the International Agency for Research on Cancer classified the whole spectrum as carcinogenic to humans.^5,11 Despite this evidence, indoor tanning facilities have promoted indoor tanning as damage free.³ The goal of this study was to collect the patient perspective on the safety of indoor tanning, indoor tanning behaviors, time frame of onset of melanoma, and the severity (ie, Breslow depth) of those melanomas.

Melanoma is the most prevalent cancer in females aged 25 to 29 years.³ The median age of diagnosis of melanoma (with and without the use of indoor tanning devices) is approximately 60 years¹⁴ versus our study, which found the average age at diagnosis was 37.6 years. Our findings are consistent with other literature in that those who start indoor tanning earlier (<35 years of age) develop melanoma at an earlier age.^14,15 Cust et al¹⁴ also promoted the idea that patients develop melanoma earlier because younger individuals are more biologically susceptible to the carcinogenic effects of artificial UV light. However, our study found that those who started indoor tanning at an older age reported being diagnosed with a melanoma of greater Breslow depth, seemingly incongruent with the aforementioned hypothesis. One limitation is the age range for this research sample (18–69 years). The young age range may be attributable to the recruitment through social media, which is geared toward a younger population. Additionally, indoor tanning is a relatively new phenomenon practiced since the 1980s,² which may contribute to the younger sample size. However, 2.7 billion individuals use social media worldwide with 40% of those older than 65 years on social media.¹⁶

Prior research has shown that those who start indoor tanning before the age of 35 years have a 75% increased risk of developing melanoma.¹⁴ Another study also has suggested that UVA-rich sunlamps may shorten the latency period for induction of melanoma and nonmelanoma skin cancers.³ Our study used similar age cutoffs in concluding that there was no earlier onset of melanoma diagnosis between those who started indoor tanning before the age of 35 years and those who started at the age of 35 years or older. Limitations include that our study is cross-sectional, and therefore time course cannot be established. Also, survey responses were self-reported, allowing the possibility of recall bias.

A plethora of research has been conducted to determine if there is a connection between the use of indoor tanning devices and developing melanoma. Cust et al¹⁴ suggested the risk of melanoma was 41% higher for those who had ever used a sunbed in comparison to those who had not. Other studies describe the difficulty in making the connection between indoor tanning and melanoma, as those who more frequently tan indoors also more frequently tan outdoors,¹¹ as suggested by this study. However, there is a paucity of literature on the patients’ perspectives on the safety of indoor tanning. This study determined that those who more frequently tan indoors believed that indoor tanning is safer than outdoor tanning. With this altered perception promoted by the indoor tanning industry, the FDA has added a warning label to all indoor tanning devices about the risk of skin cancer. Our study revealed that having the knowledge of the risk of skin cancer had no influence on the frequency of indoor tanning. This concerning finding highlights a pressing need for an alternative approach to increase awareness of the harmful consequences that accompany indoor tanning. Further studies may elaborate on potential effective methods and messages to relate to an indoor tanning population comprised mostly of young females.

Acknowledgments
Supported and funded by the Basal Cell Carcinoma Nevus Syndrome Life Support Network. This research project was completed as part of the FIRE Module at the University of Central Florida, College of Medicine. We thank the FIRE Module faculty and staff for their assistance with this project.

The incidence of melanoma is increasing at a rate greater than any other cancer,¹ possibly due to the increasing use of indoor tanning devices. These devices emit unnaturally high levels of UVA and low levels of UVA and UVB rays.² The risks of using these devices include increased incidence of melanoma (3438 cases attributed to indoor tanning in 2008) and keratinocytes cancer (increased risk of squamous cell carcinoma by 67% and basal cell carcinoma by 29%), severe sunburns (61.1% of female users and 44.6% of male users have reported sunburns), and aggravation of underlying disorders such as systemic lupus erythematosus.^3-5

The literature varies in its explanation of how indoor tanning increases the risk of developing melanoma. Some authors suggest it is due to increased frequency of use, duration of sessions, and years of using tanning devices.^1,6 Others suggest the increased cancer risk is the result of starting to tan at an earlier age.^2,3,6-10 There is conflicting literature on the level of increased risk of melanoma in those who tan indoors at a young age (<35 years). Although the estimated rate of increased skin cancer risk varies, with rates up to 75% compared to nonusers, nearly all sources support an increased rate.⁶ Despite the growing body of knowledge that indoor tanning is dangerous, as well as the academic publication of these risks (eg, carcinogenesis, short-term and long-term eye injury, burns, UV sensitivity when combined with certain medications), teenagers in the United States and affluent countries appear to disregard the risks of tanning.¹¹

Tanning companies have promoted the misconception that only UVB rays cause cell damage and UVA rays, which the devices emit, result in “damage-free” or “safe” tans.^2,3 Until 2013, indoor tanning devices were classified by the US Food and Drug Administration (FDA) as class I, indicating that they are safe in terms of electrical shock. Many indoor tanning facilities have promoted the FDA “safe” label without clarifying that the safety indications only referred to electrical-shock potential. Nonetheless, it is known now that these devices, which emit high UVA and low UVB rays, promote melanoma, nonmelanoma skin cancers, and severe sunburns, as well as aggravate existing conditions (eg, systemic lupus erythematosus).⁴ As a result of an unacceptably high incidence of these disease complications, a 2014 FDA regulation categorized tanning beds as class II, requiring that tanning bed users be informed of the risk of skin cancer in an effort to reverse the growing trend of indoor tanning.¹² Despite these regulatory interventions, it is not clear if this knowledge of cancer risk deters patients from indoor tanning.

The purpose of this study was to investigate the patients’ perspective on indoor tanning behaviors as associated with the severity of their melanoma and the time frame in which they were diagnosed as well as their perceived views on the safety of indoor tanning and the frequency in which they continue to tan indoors. This information is highly relevant in helping to determine if requiring a warning of the risk of skin cancer will deter patients from this unhealthy habit, especially given recent reclassification of sunbeds as class II by the FDA. Additional insights from these data may clarify if indoor tanning decreases the time frame in which melanoma is diagnosed or increases the severity of the resulting melanoma. Moreover, it will help elucidate whether or not the age at which indoor tanning is initiated affects the time frame to melanoma onset and corresponding severity.

Methods

An original unvalidated online survey was conducted worldwide via a link distributed to the following supporting institutions: Advanced Dermatology & Cosmetic Surgery, Ameriderm Research, Melanoma Research Foundation (a melanoma patient advocacy group), Florida State University Department of Dermatology, Moffitt Cancer Center Cutaneous Oncology Program, Cleveland Clinic, Ohio State University Division of Medical Oncology, Harvard Medical School Department of Dermatology, The University of Texas MD Anderson Cancer Center Department of Dermatology, University of Colorado Department of Dermatology, and Northwestern University Department of Dermatology. However, there was not confirmation that all of these institutions promoted the survey. Additionally, respondents were recruited through patient advocacy groups and social media sites including Facebook, Twitter, LinkedIn, Tumblr, and Instagram. The patient advocacy groups and social media sites invited participation through recruitment announcements, including DermNetNZ (a global dermatology patient information site), with additional help from the International Federation of Dermatology Clinical Trial Network.

The survey was restricted to those who were self-identified as 18 years or older and who self-reported a diagnosis of melanoma following the use of indoor tanning devices. The survey was hosted by SurveyMonkey, which allowed consent to be obtained and responses to remain anonymous. Access to the survey was sponsored by the Basal Cell Carcinoma Nevus Syndrome Life Support Network. The University of Central Florida (Orlando, Florida) institutional review board reviewed and approved this study as exempt human research.

Survey responses collected from January 2014 to June 2015 were analyzed herein. The survey contained 58 questions and was divided into different topics including indoor tanning background (eg, states/countries in which participants tanned indoors, age when they first tanned, frequency of tanning), consenting process (eg, length, did someone review the consent with participants, what was contained in the consent), indoor tanning and melanoma (eg, how long after tanning did melanoma develop, age at development, location of melanoma), indoor tanning postmelanoma (eg, did participants tan after diagnosis and why), and other risk factors (eg, did participants smoke or drink pre- or postmelanoma).

Statistical Analysis
The data consist of both categorical and continuous variables. The categorical variables included age (<35 years or ≥35 years), frequency of indoor tanning (≤1 time weekly or >1 time weekly), and onset of melanoma diagnosis (within or after 5 years of indoor tanning). The continuous variables consisted of current age, age at start of indoor tanning, age at melanoma diagnosis, Breslow depth, and Clark level. Frequency of indoor tanning and warning of the risk of skin cancer were converted to be used as both categorical and continuous variables. For frequency of indoor tanning, the variables less than or equal to once weekly and more than once weekly were used as categorical variables, whereas less than monthly, 1 time monthly, 4 times monthly, 2 times weekly, and more than 2 times weekly were used as continuous variables. For warning of the risk of skin cancer, no and yes were converted to 0 and 1 for use in the Spearman correlations, which allowed for greater analyses among other variables. Spearman correlation was used to determine if a significant relationship existed among the age at melanoma diagnosis, age at start of indoor tanning, Breslow depth, Clark level, frequency of indoor and outdoor tanning, and knowledge and warning of the risk of skin cancer. All data were analyzed by use of IBM SPSS Statistics (version 21.0).

Difference in proportions among groups, age, frequency of tanning, onset of melanoma diagnosis within or after 5 years of starting indoor tanning, and knowledge of cancer risks was tested for significance using the χ² test. Reported P values were 2-tailed, corresponding with a significance level of P<.05. All data were analyzed using SPSS (version 21.0). All statistical analyses were conducted independent of the participants’ sex.

Results

Of the 454 participants who accessed the survey, 448 were analyzed in this study; 6 participants did not complete the questionnaire. Both males and females were analyzed: 289 females, 12 males, and 153 who did not report gender. The age range of participants was 18 to 69 years. The age at start of indoor tanning ranged from 8 to 54 years, with a mean of 22 years. Additional participant characteristics are described in Table 1. The mean frequency of indoor tanning was reported as 2 times weekly. When participants were asked if they were warned of the risk of skin cancer, 21.5% reported yes while 78.4% reported not being told of the risk. This knowledge was compared to their frequency of indoor tanning. Having the knowledge of the risk of skin cancer had no influence on their frequency of indoor tanning (Table 2).

Among responders, those who perceived indoor tanning as safer than outdoor tanning tanned indoors more frequently than those who do not (Spearman r=−0.224; P<.05)(Table 3). The frequency of indoor tanning was divided into those who tanned indoors more than once weekly and those who tanned indoors once a week or less. This study showed that the frequency of indoor tanning had no effect on the latency time between the commencement of indoor tanning and diagnosis of melanoma (Table 4). The time frame from the onset of melanoma diagnosis also was compared to the age at which the participants started to tan indoors. Age was divided into those younger than 35 years and those 35 years and older. There was no correlation between the age when indoor tanning began and the time frame in which the melanoma was diagnosed (eTable).

Comment

Thirty million Americans utilize indoor tanning devices at least once a year.¹³ UVA light comprises the majority of the spectrum used by indoor tanning devices, with a fraction (<5%) being UVB light. Until recently, UVB light was the only solar spectrum considered carcinogenic. In 2009, the International Agency for Research on Cancer classified the whole spectrum as carcinogenic to humans.^5,11 Despite this evidence, indoor tanning facilities have promoted indoor tanning as damage free.³ The goal of this study was to collect the patient perspective on the safety of indoor tanning, indoor tanning behaviors, time frame of onset of melanoma, and the severity (ie, Breslow depth) of those melanomas.

Melanoma is the most prevalent cancer in females aged 25 to 29 years.³ The median age of diagnosis of melanoma (with and without the use of indoor tanning devices) is approximately 60 years¹⁴ versus our study, which found the average age at diagnosis was 37.6 years. Our findings are consistent with other literature in that those who start indoor tanning earlier (<35 years of age) develop melanoma at an earlier age.^14,15 Cust et al¹⁴ also promoted the idea that patients develop melanoma earlier because younger individuals are more biologically susceptible to the carcinogenic effects of artificial UV light. However, our study found that those who started indoor tanning at an older age reported being diagnosed with a melanoma of greater Breslow depth, seemingly incongruent with the aforementioned hypothesis. One limitation is the age range for this research sample (18–69 years). The young age range may be attributable to the recruitment through social media, which is geared toward a younger population. Additionally, indoor tanning is a relatively new phenomenon practiced since the 1980s,² which may contribute to the younger sample size. However, 2.7 billion individuals use social media worldwide with 40% of those older than 65 years on social media.¹⁶

Prior research has shown that those who start indoor tanning before the age of 35 years have a 75% increased risk of developing melanoma.¹⁴ Another study also has suggested that UVA-rich sunlamps may shorten the latency period for induction of melanoma and nonmelanoma skin cancers.³ Our study used similar age cutoffs in concluding that there was no earlier onset of melanoma diagnosis between those who started indoor tanning before the age of 35 years and those who started at the age of 35 years or older. Limitations include that our study is cross-sectional, and therefore time course cannot be established. Also, survey responses were self-reported, allowing the possibility of recall bias.

A plethora of research has been conducted to determine if there is a connection between the use of indoor tanning devices and developing melanoma. Cust et al¹⁴ suggested the risk of melanoma was 41% higher for those who had ever used a sunbed in comparison to those who had not. Other studies describe the difficulty in making the connection between indoor tanning and melanoma, as those who more frequently tan indoors also more frequently tan outdoors,¹¹ as suggested by this study. However, there is a paucity of literature on the patients’ perspectives on the safety of indoor tanning. This study determined that those who more frequently tan indoors believed that indoor tanning is safer than outdoor tanning. With this altered perception promoted by the indoor tanning industry, the FDA has added a warning label to all indoor tanning devices about the risk of skin cancer. Our study revealed that having the knowledge of the risk of skin cancer had no influence on the frequency of indoor tanning. This concerning finding highlights a pressing need for an alternative approach to increase awareness of the harmful consequences that accompany indoor tanning. Further studies may elaborate on potential effective methods and messages to relate to an indoor tanning population comprised mostly of young females.

Acknowledgments
Supported and funded by the Basal Cell Carcinoma Nevus Syndrome Life Support Network. This research project was completed as part of the FIRE Module at the University of Central Florida, College of Medicine. We thank the FIRE Module faculty and staff for their assistance with this project.

The incidence of melanoma is increasing at a rate greater than any other cancer,¹ possibly due to the increasing use of indoor tanning devices. These devices emit unnaturally high levels of UVA and low levels of UVA and UVB rays.² The risks of using these devices include increased incidence of melanoma (3438 cases attributed to indoor tanning in 2008) and keratinocytes cancer (increased risk of squamous cell carcinoma by 67% and basal cell carcinoma by 29%), severe sunburns (61.1% of female users and 44.6% of male users have reported sunburns), and aggravation of underlying disorders such as systemic lupus erythematosus.^3-5

The literature varies in its explanation of how indoor tanning increases the risk of developing melanoma. Some authors suggest it is due to increased frequency of use, duration of sessions, and years of using tanning devices.^1,6 Others suggest the increased cancer risk is the result of starting to tan at an earlier age.^2,3,6-10 There is conflicting literature on the level of increased risk of melanoma in those who tan indoors at a young age (<35 years). Although the estimated rate of increased skin cancer risk varies, with rates up to 75% compared to nonusers, nearly all sources support an increased rate.⁶ Despite the growing body of knowledge that indoor tanning is dangerous, as well as the academic publication of these risks (eg, carcinogenesis, short-term and long-term eye injury, burns, UV sensitivity when combined with certain medications), teenagers in the United States and affluent countries appear to disregard the risks of tanning.¹¹

Tanning companies have promoted the misconception that only UVB rays cause cell damage and UVA rays, which the devices emit, result in “damage-free” or “safe” tans.^2,3 Until 2013, indoor tanning devices were classified by the US Food and Drug Administration (FDA) as class I, indicating that they are safe in terms of electrical shock. Many indoor tanning facilities have promoted the FDA “safe” label without clarifying that the safety indications only referred to electrical-shock potential. Nonetheless, it is known now that these devices, which emit high UVA and low UVB rays, promote melanoma, nonmelanoma skin cancers, and severe sunburns, as well as aggravate existing conditions (eg, systemic lupus erythematosus).⁴ As a result of an unacceptably high incidence of these disease complications, a 2014 FDA regulation categorized tanning beds as class II, requiring that tanning bed users be informed of the risk of skin cancer in an effort to reverse the growing trend of indoor tanning.¹² Despite these regulatory interventions, it is not clear if this knowledge of cancer risk deters patients from indoor tanning.

The purpose of this study was to investigate the patients’ perspective on indoor tanning behaviors as associated with the severity of their melanoma and the time frame in which they were diagnosed as well as their perceived views on the safety of indoor tanning and the frequency in which they continue to tan indoors. This information is highly relevant in helping to determine if requiring a warning of the risk of skin cancer will deter patients from this unhealthy habit, especially given recent reclassification of sunbeds as class II by the FDA. Additional insights from these data may clarify if indoor tanning decreases the time frame in which melanoma is diagnosed or increases the severity of the resulting melanoma. Moreover, it will help elucidate whether or not the age at which indoor tanning is initiated affects the time frame to melanoma onset and corresponding severity.

Methods

An original unvalidated online survey was conducted worldwide via a link distributed to the following supporting institutions: Advanced Dermatology & Cosmetic Surgery, Ameriderm Research, Melanoma Research Foundation (a melanoma patient advocacy group), Florida State University Department of Dermatology, Moffitt Cancer Center Cutaneous Oncology Program, Cleveland Clinic, Ohio State University Division of Medical Oncology, Harvard Medical School Department of Dermatology, The University of Texas MD Anderson Cancer Center Department of Dermatology, University of Colorado Department of Dermatology, and Northwestern University Department of Dermatology. However, there was not confirmation that all of these institutions promoted the survey. Additionally, respondents were recruited through patient advocacy groups and social media sites including Facebook, Twitter, LinkedIn, Tumblr, and Instagram. The patient advocacy groups and social media sites invited participation through recruitment announcements, including DermNetNZ (a global dermatology patient information site), with additional help from the International Federation of Dermatology Clinical Trial Network.

The survey was restricted to those who were self-identified as 18 years or older and who self-reported a diagnosis of melanoma following the use of indoor tanning devices. The survey was hosted by SurveyMonkey, which allowed consent to be obtained and responses to remain anonymous. Access to the survey was sponsored by the Basal Cell Carcinoma Nevus Syndrome Life Support Network. The University of Central Florida (Orlando, Florida) institutional review board reviewed and approved this study as exempt human research.

Survey responses collected from January 2014 to June 2015 were analyzed herein. The survey contained 58 questions and was divided into different topics including indoor tanning background (eg, states/countries in which participants tanned indoors, age when they first tanned, frequency of tanning), consenting process (eg, length, did someone review the consent with participants, what was contained in the consent), indoor tanning and melanoma (eg, how long after tanning did melanoma develop, age at development, location of melanoma), indoor tanning postmelanoma (eg, did participants tan after diagnosis and why), and other risk factors (eg, did participants smoke or drink pre- or postmelanoma).

Statistical Analysis
The data consist of both categorical and continuous variables. The categorical variables included age (<35 years or ≥35 years), frequency of indoor tanning (≤1 time weekly or >1 time weekly), and onset of melanoma diagnosis (within or after 5 years of indoor tanning). The continuous variables consisted of current age, age at start of indoor tanning, age at melanoma diagnosis, Breslow depth, and Clark level. Frequency of indoor tanning and warning of the risk of skin cancer were converted to be used as both categorical and continuous variables. For frequency of indoor tanning, the variables less than or equal to once weekly and more than once weekly were used as categorical variables, whereas less than monthly, 1 time monthly, 4 times monthly, 2 times weekly, and more than 2 times weekly were used as continuous variables. For warning of the risk of skin cancer, no and yes were converted to 0 and 1 for use in the Spearman correlations, which allowed for greater analyses among other variables. Spearman correlation was used to determine if a significant relationship existed among the age at melanoma diagnosis, age at start of indoor tanning, Breslow depth, Clark level, frequency of indoor and outdoor tanning, and knowledge and warning of the risk of skin cancer. All data were analyzed by use of IBM SPSS Statistics (version 21.0).

Difference in proportions among groups, age, frequency of tanning, onset of melanoma diagnosis within or after 5 years of starting indoor tanning, and knowledge of cancer risks was tested for significance using the χ² test. Reported P values were 2-tailed, corresponding with a significance level of P<.05. All data were analyzed using SPSS (version 21.0). All statistical analyses were conducted independent of the participants’ sex.

Results

Of the 454 participants who accessed the survey, 448 were analyzed in this study; 6 participants did not complete the questionnaire. Both males and females were analyzed: 289 females, 12 males, and 153 who did not report gender. The age range of participants was 18 to 69 years. The age at start of indoor tanning ranged from 8 to 54 years, with a mean of 22 years. Additional participant characteristics are described in Table 1. The mean frequency of indoor tanning was reported as 2 times weekly. When participants were asked if they were warned of the risk of skin cancer, 21.5% reported yes while 78.4% reported not being told of the risk. This knowledge was compared to their frequency of indoor tanning. Having the knowledge of the risk of skin cancer had no influence on their frequency of indoor tanning (Table 2).

Among responders, those who perceived indoor tanning as safer than outdoor tanning tanned indoors more frequently than those who do not (Spearman r=−0.224; P<.05)(Table 3). The frequency of indoor tanning was divided into those who tanned indoors more than once weekly and those who tanned indoors once a week or less. This study showed that the frequency of indoor tanning had no effect on the latency time between the commencement of indoor tanning and diagnosis of melanoma (Table 4). The time frame from the onset of melanoma diagnosis also was compared to the age at which the participants started to tan indoors. Age was divided into those younger than 35 years and those 35 years and older. There was no correlation between the age when indoor tanning began and the time frame in which the melanoma was diagnosed (eTable).

Comment

Thirty million Americans utilize indoor tanning devices at least once a year.¹³ UVA light comprises the majority of the spectrum used by indoor tanning devices, with a fraction (<5%) being UVB light. Until recently, UVB light was the only solar spectrum considered carcinogenic. In 2009, the International Agency for Research on Cancer classified the whole spectrum as carcinogenic to humans.^5,11 Despite this evidence, indoor tanning facilities have promoted indoor tanning as damage free.³ The goal of this study was to collect the patient perspective on the safety of indoor tanning, indoor tanning behaviors, time frame of onset of melanoma, and the severity (ie, Breslow depth) of those melanomas.

Melanoma is the most prevalent cancer in females aged 25 to 29 years.³ The median age of diagnosis of melanoma (with and without the use of indoor tanning devices) is approximately 60 years¹⁴ versus our study, which found the average age at diagnosis was 37.6 years. Our findings are consistent with other literature in that those who start indoor tanning earlier (<35 years of age) develop melanoma at an earlier age.^14,15 Cust et al¹⁴ also promoted the idea that patients develop melanoma earlier because younger individuals are more biologically susceptible to the carcinogenic effects of artificial UV light. However, our study found that those who started indoor tanning at an older age reported being diagnosed with a melanoma of greater Breslow depth, seemingly incongruent with the aforementioned hypothesis. One limitation is the age range for this research sample (18–69 years). The young age range may be attributable to the recruitment through social media, which is geared toward a younger population. Additionally, indoor tanning is a relatively new phenomenon practiced since the 1980s,² which may contribute to the younger sample size. However, 2.7 billion individuals use social media worldwide with 40% of those older than 65 years on social media.¹⁶

Prior research has shown that those who start indoor tanning before the age of 35 years have a 75% increased risk of developing melanoma.¹⁴ Another study also has suggested that UVA-rich sunlamps may shorten the latency period for induction of melanoma and nonmelanoma skin cancers.³ Our study used similar age cutoffs in concluding that there was no earlier onset of melanoma diagnosis between those who started indoor tanning before the age of 35 years and those who started at the age of 35 years or older. Limitations include that our study is cross-sectional, and therefore time course cannot be established. Also, survey responses were self-reported, allowing the possibility of recall bias.

A plethora of research has been conducted to determine if there is a connection between the use of indoor tanning devices and developing melanoma. Cust et al¹⁴ suggested the risk of melanoma was 41% higher for those who had ever used a sunbed in comparison to those who had not. Other studies describe the difficulty in making the connection between indoor tanning and melanoma, as those who more frequently tan indoors also more frequently tan outdoors,¹¹ as suggested by this study. However, there is a paucity of literature on the patients’ perspectives on the safety of indoor tanning. This study determined that those who more frequently tan indoors believed that indoor tanning is safer than outdoor tanning. With this altered perception promoted by the indoor tanning industry, the FDA has added a warning label to all indoor tanning devices about the risk of skin cancer. Our study revealed that having the knowledge of the risk of skin cancer had no influence on the frequency of indoor tanning. This concerning finding highlights a pressing need for an alternative approach to increase awareness of the harmful consequences that accompany indoor tanning. Further studies may elaborate on potential effective methods and messages to relate to an indoor tanning population comprised mostly of young females.

Acknowledgments
Supported and funded by the Basal Cell Carcinoma Nevus Syndrome Life Support Network. This research project was completed as part of the FIRE Module at the University of Central Florida, College of Medicine. We thank the FIRE Module faculty and staff for their assistance with this project.

Zero Suicide is a key concept of the 2012 National Strategy for Suicide Prevention. It uses a “programmatic approach” to quality improvement, based on the realization that suicidal individuals often fall through the cracks in a “sometimes fragmented and distracted” health care system.

A task force identified 7 essential elements of care for health and behavioral health care systems to adopt, including promoting a “safety-oriented” culture, training a competent and caring workforce, using evidence-based treatments, and providing continuous contact and support. The program represents a commitment to both patient safety and to the safety and support of clinical staff who care for suicidal patients.

The Zero Suicide tool kit includes readings, videos, webinars, and other resources, such as a Mental Health Guide developed by the VA to ensure a “safe and therapeutically enriching environment” and a checklist to review inpatient mental health units for environmental hazards. The tool kit also provides thoughtful supplements, such as hospital care cards to send to patients after discharge and a “caring letter template” that includes caring phrases in the Puyallup language with English translations.

The 8 facilities receiving grants are Apache Behavioral Health Service in Whiteriver, Arizona; Chinle Comprehensive Healthcare Facility in Arizona; Fort Defiance Indian Hospital Board in Arizona; Gallup Indian Medical Center in New Mexico; Lawton Indian Hospital in Oklahoma; Menominee Indian Tribe of Wisconsin in Keshena; Pueblo of Acoma in New Mexico; and Rocky Boy Health Board, Box Elder in Montana.

Zero Suicide is a key concept of the 2012 National Strategy for Suicide Prevention. It uses a “programmatic approach” to quality improvement, based on the realization that suicidal individuals often fall through the cracks in a “sometimes fragmented and distracted” health care system.

A task force identified 7 essential elements of care for health and behavioral health care systems to adopt, including promoting a “safety-oriented” culture, training a competent and caring workforce, using evidence-based treatments, and providing continuous contact and support. The program represents a commitment to both patient safety and to the safety and support of clinical staff who care for suicidal patients.

The Zero Suicide tool kit includes readings, videos, webinars, and other resources, such as a Mental Health Guide developed by the VA to ensure a “safe and therapeutically enriching environment” and a checklist to review inpatient mental health units for environmental hazards. The tool kit also provides thoughtful supplements, such as hospital care cards to send to patients after discharge and a “caring letter template” that includes caring phrases in the Puyallup language with English translations.

The 8 facilities receiving grants are Apache Behavioral Health Service in Whiteriver, Arizona; Chinle Comprehensive Healthcare Facility in Arizona; Fort Defiance Indian Hospital Board in Arizona; Gallup Indian Medical Center in New Mexico; Lawton Indian Hospital in Oklahoma; Menominee Indian Tribe of Wisconsin in Keshena; Pueblo of Acoma in New Mexico; and Rocky Boy Health Board, Box Elder in Montana.

Zero Suicide is a key concept of the 2012 National Strategy for Suicide Prevention. It uses a “programmatic approach” to quality improvement, based on the realization that suicidal individuals often fall through the cracks in a “sometimes fragmented and distracted” health care system.

A task force identified 7 essential elements of care for health and behavioral health care systems to adopt, including promoting a “safety-oriented” culture, training a competent and caring workforce, using evidence-based treatments, and providing continuous contact and support. The program represents a commitment to both patient safety and to the safety and support of clinical staff who care for suicidal patients.

The Zero Suicide tool kit includes readings, videos, webinars, and other resources, such as a Mental Health Guide developed by the VA to ensure a “safe and therapeutically enriching environment” and a checklist to review inpatient mental health units for environmental hazards. The tool kit also provides thoughtful supplements, such as hospital care cards to send to patients after discharge and a “caring letter template” that includes caring phrases in the Puyallup language with English translations.

The 8 facilities receiving grants are Apache Behavioral Health Service in Whiteriver, Arizona; Chinle Comprehensive Healthcare Facility in Arizona; Fort Defiance Indian Hospital Board in Arizona; Gallup Indian Medical Center in New Mexico; Lawton Indian Hospital in Oklahoma; Menominee Indian Tribe of Wisconsin in Keshena; Pueblo of Acoma in New Mexico; and Rocky Boy Health Board, Box Elder in Montana.

© Todd Buchanan 2017

ATLANTA—A 2-drug combination has produced a high response rate in a small trial of patients with relapsed/refractory (R/R), Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL).

The combination, inotuzumab ozogamicin and bosutinib, produced an overall response rate of 81% in this ongoing, phase 1/2 trial.

Nitin Jain, MD, of the University of Texas MD Anderson Cancer Center in Houston, presented phase 1 results from the study at the 2017 ASH Annual Meeting (abstract 143*).

He reported results in 16 patients, 14 with R/R, Ph+ ALL and 2 with chronic myeloid leukemia in lymphoid blast phase.

The patients received inotuzumab ozogamicin at 0.8 mg/m² on day 1, 0.5 mg/m² on day 8, and 0.5 mg/m² on day 15 of cycle 1. Patients who achieved a response received inotuzumab ozogamicin at 1 mg/m² once every 4 weeks for subsequent cycles. Six cycles were planned.

Patients also received bosutinib at 300 mg, 400 mg, or 500 mg once a day for 4-week cycles. The median number of cycles was 2.5 (range, 1-8).

The maximum-tolerated dose has not been established, but there were 2 dose-limiting toxicities (DLTs). One DLT occurred with the 400 mg dose of bosutinib, and 1 occurred with the 500 mg dose. Both DLTs were grade 3 skin rash.

The investigators are continuing accrual with the 500 mg dose of bosutinib for the phase 2 portion of the trial, with 22 additional patients.

Response and survival

The overall response rate was 81% (n=13). This included a complete response (CR) in 8 patients, a CR with incomplete blood count recovery in 3 patients, and a CR with incomplete platelet recovery in 2 patients.

All responses occurred among the patients with ALL.

Twelve responders achieved complete cytogenetic remission, 11 achieved a major molecular response, 8 achieved a complete molecular response, and 9 were negative by flow cytometry.

The median duration of response was 8.8 months.

Of the 13 responders, 6 went on to receive an allogeneic stem cell transplant. Five of these patients are still alive, but 1 died from relapse.

The median overall survival was 10.7 months.

“These data suggest the tolerability and efficacy of inotuzumab ozogamicin and bosutinib in R/R Ph+ ALL,” Dr Jain said. “And we are looking forward to the next phase of this study.”

Dr Jain disclosed receiving research funding from Celgene, Verastem, BMS, Incyte, Pharmacyclics, ADC Therapeutics, Genentech, AbbVie, Pfizer, Astra Zeneca, Janssen, Cellectis, and Seattle Genetics. He disclosed membership on boards of directors/advisory committees for Verastem, Servier, Novimmune, Pharmacyclics, Novartis, ADC Therapeutics, AbbVie, Pfizer, Adaptive Biotechnologies, and Janssen.

*Data in the presentation differ from the abstract.

© Todd Buchanan 2017

ATLANTA—A 2-drug combination has produced a high response rate in a small trial of patients with relapsed/refractory (R/R), Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL).

The combination, inotuzumab ozogamicin and bosutinib, produced an overall response rate of 81% in this ongoing, phase 1/2 trial.

Nitin Jain, MD, of the University of Texas MD Anderson Cancer Center in Houston, presented phase 1 results from the study at the 2017 ASH Annual Meeting (abstract 143*).

He reported results in 16 patients, 14 with R/R, Ph+ ALL and 2 with chronic myeloid leukemia in lymphoid blast phase.

The patients received inotuzumab ozogamicin at 0.8 mg/m² on day 1, 0.5 mg/m² on day 8, and 0.5 mg/m² on day 15 of cycle 1. Patients who achieved a response received inotuzumab ozogamicin at 1 mg/m² once every 4 weeks for subsequent cycles. Six cycles were planned.

Patients also received bosutinib at 300 mg, 400 mg, or 500 mg once a day for 4-week cycles. The median number of cycles was 2.5 (range, 1-8).

The maximum-tolerated dose has not been established, but there were 2 dose-limiting toxicities (DLTs). One DLT occurred with the 400 mg dose of bosutinib, and 1 occurred with the 500 mg dose. Both DLTs were grade 3 skin rash.

The investigators are continuing accrual with the 500 mg dose of bosutinib for the phase 2 portion of the trial, with 22 additional patients.

Response and survival

The overall response rate was 81% (n=13). This included a complete response (CR) in 8 patients, a CR with incomplete blood count recovery in 3 patients, and a CR with incomplete platelet recovery in 2 patients.

All responses occurred among the patients with ALL.

Twelve responders achieved complete cytogenetic remission, 11 achieved a major molecular response, 8 achieved a complete molecular response, and 9 were negative by flow cytometry.

The median duration of response was 8.8 months.

Of the 13 responders, 6 went on to receive an allogeneic stem cell transplant. Five of these patients are still alive, but 1 died from relapse.

The median overall survival was 10.7 months.

“These data suggest the tolerability and efficacy of inotuzumab ozogamicin and bosutinib in R/R Ph+ ALL,” Dr Jain said. “And we are looking forward to the next phase of this study.”

Dr Jain disclosed receiving research funding from Celgene, Verastem, BMS, Incyte, Pharmacyclics, ADC Therapeutics, Genentech, AbbVie, Pfizer, Astra Zeneca, Janssen, Cellectis, and Seattle Genetics. He disclosed membership on boards of directors/advisory committees for Verastem, Servier, Novimmune, Pharmacyclics, Novartis, ADC Therapeutics, AbbVie, Pfizer, Adaptive Biotechnologies, and Janssen.

*Data in the presentation differ from the abstract.

© Todd Buchanan 2017

ATLANTA—A 2-drug combination has produced a high response rate in a small trial of patients with relapsed/refractory (R/R), Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL).

The combination, inotuzumab ozogamicin and bosutinib, produced an overall response rate of 81% in this ongoing, phase 1/2 trial.

Nitin Jain, MD, of the University of Texas MD Anderson Cancer Center in Houston, presented phase 1 results from the study at the 2017 ASH Annual Meeting (abstract 143*).

He reported results in 16 patients, 14 with R/R, Ph+ ALL and 2 with chronic myeloid leukemia in lymphoid blast phase.

The patients received inotuzumab ozogamicin at 0.8 mg/m² on day 1, 0.5 mg/m² on day 8, and 0.5 mg/m² on day 15 of cycle 1. Patients who achieved a response received inotuzumab ozogamicin at 1 mg/m² once every 4 weeks for subsequent cycles. Six cycles were planned.

Patients also received bosutinib at 300 mg, 400 mg, or 500 mg once a day for 4-week cycles. The median number of cycles was 2.5 (range, 1-8).

The maximum-tolerated dose has not been established, but there were 2 dose-limiting toxicities (DLTs). One DLT occurred with the 400 mg dose of bosutinib, and 1 occurred with the 500 mg dose. Both DLTs were grade 3 skin rash.

The investigators are continuing accrual with the 500 mg dose of bosutinib for the phase 2 portion of the trial, with 22 additional patients.

Response and survival

The overall response rate was 81% (n=13). This included a complete response (CR) in 8 patients, a CR with incomplete blood count recovery in 3 patients, and a CR with incomplete platelet recovery in 2 patients.

All responses occurred among the patients with ALL.

Twelve responders achieved complete cytogenetic remission, 11 achieved a major molecular response, 8 achieved a complete molecular response, and 9 were negative by flow cytometry.

The median duration of response was 8.8 months.

Of the 13 responders, 6 went on to receive an allogeneic stem cell transplant. Five of these patients are still alive, but 1 died from relapse.

The median overall survival was 10.7 months.

“These data suggest the tolerability and efficacy of inotuzumab ozogamicin and bosutinib in R/R Ph+ ALL,” Dr Jain said. “And we are looking forward to the next phase of this study.”

Dr Jain disclosed receiving research funding from Celgene, Verastem, BMS, Incyte, Pharmacyclics, ADC Therapeutics, Genentech, AbbVie, Pfizer, Astra Zeneca, Janssen, Cellectis, and Seattle Genetics. He disclosed membership on boards of directors/advisory committees for Verastem, Servier, Novimmune, Pharmacyclics, Novartis, ADC Therapeutics, AbbVie, Pfizer, Adaptive Biotechnologies, and Janssen.

*Data in the presentation differ from the abstract.

Weight loss caused by metabolic and bariatric surgery (MBS) independently predicts the normalization of dyslipedemia, elevated blood pressure, hyperinsulinemia, diabetes, and elevated high-sensitivity C-reactive protein (hs-CRP) in severely obese adolescents, according to results of a longitudinal, multicenter prospective study.

In the study of 242 severely obese adolescents undergoing MBS between Feb. 28, 2007, and Dec. 30, 2011, Marc Michalsky, MD, of Nationwide Children’s Hospital, Columbus, Ohio, and his colleagues found that, with every 10% increase in weight loss, patients were 24%, 11%, 14%, 13%, and 19% more likely to resolve dyslipidemia, elevated blood pressure, hyperinsulinemia, diabetes, and elevated hs-CRP, respectively.

moodboard/thinkstockphotos

AGA Resource
GIs are uniquely positioned to lead a care team to help patients with obesity achieve a healthy weight. The AGA Obesity Practice Guide provides a comprehensive, multidisciplinary process to personalize innovative obesity care for safe and effective weight management.

[email protected]

SOURCE: Michalsky M et al. Pediatrics. 2018 Jan 8. doi: 10.1542/peds.2017-2485.

Weight loss caused by metabolic and bariatric surgery (MBS) independently predicts the normalization of dyslipedemia, elevated blood pressure, hyperinsulinemia, diabetes, and elevated high-sensitivity C-reactive protein (hs-CRP) in severely obese adolescents, according to results of a longitudinal, multicenter prospective study.

In the study of 242 severely obese adolescents undergoing MBS between Feb. 28, 2007, and Dec. 30, 2011, Marc Michalsky, MD, of Nationwide Children’s Hospital, Columbus, Ohio, and his colleagues found that, with every 10% increase in weight loss, patients were 24%, 11%, 14%, 13%, and 19% more likely to resolve dyslipidemia, elevated blood pressure, hyperinsulinemia, diabetes, and elevated hs-CRP, respectively.

moodboard/thinkstockphotos

AGA Resource
GIs are uniquely positioned to lead a care team to help patients with obesity achieve a healthy weight. The AGA Obesity Practice Guide provides a comprehensive, multidisciplinary process to personalize innovative obesity care for safe and effective weight management.

[email protected]

SOURCE: Michalsky M et al. Pediatrics. 2018 Jan 8. doi: 10.1542/peds.2017-2485.

Weight loss caused by metabolic and bariatric surgery (MBS) independently predicts the normalization of dyslipedemia, elevated blood pressure, hyperinsulinemia, diabetes, and elevated high-sensitivity C-reactive protein (hs-CRP) in severely obese adolescents, according to results of a longitudinal, multicenter prospective study.

In the study of 242 severely obese adolescents undergoing MBS between Feb. 28, 2007, and Dec. 30, 2011, Marc Michalsky, MD, of Nationwide Children’s Hospital, Columbus, Ohio, and his colleagues found that, with every 10% increase in weight loss, patients were 24%, 11%, 14%, 13%, and 19% more likely to resolve dyslipidemia, elevated blood pressure, hyperinsulinemia, diabetes, and elevated hs-CRP, respectively.

moodboard/thinkstockphotos

AGA Resource
GIs are uniquely positioned to lead a care team to help patients with obesity achieve a healthy weight. The AGA Obesity Practice Guide provides a comprehensive, multidisciplinary process to personalize innovative obesity care for safe and effective weight management.

[email protected]

SOURCE: Michalsky M et al. Pediatrics. 2018 Jan 8. doi: 10.1542/peds.2017-2485.

Weight loss caused by metabolic and bariatric surgery (MBS) independently predicts the normalization of dyslipidemia, elevated blood pressure (EPB), hyperinsulinemia, diabetes, and elevated high-sensitivity C-reactive protein (hs-CRP) in severely obese adolescents, according to results of a longitudinal, multicenter prospective study.

In the study of 242 severely obese adolescents undergoing MBS between Feb. 28, 2007, and Dec. 30, 2011, Marc Michalsky, MD, of Nationwide Children’s Hospital, Columbus, Ohio, and his colleagues found that with every 10% increase in weight loss, patients were 24%, 11%, 14%, 13%, and 19% more likely to resolve dyslipidemia, EBP, hyperinsulinemia, diabetes, and elevated hs-CRP, respectively.

moodboard/thinkstockphotos

Dr. Inge has worked as a consultant for Standard Bariatrics, UpToDate, and Independent Medical Expert Consulting Services; all of these companies are unrelated to this research. John B. Dixon, PhD, has received support for his research through a National Health and Medical Research Council research fellowship. Anita Courcoulas, MD, has received grants from various health care groups and companies. All other authors had no relevant financial disclosures. The study was funded by a variety of institutional grants and the National Institutes of Health.

[email protected]

SOURCE: M Michalsky et al. Pediatrics. 2018 Jan 8. doi: 10.1542/peds.2017-2485.

Weight loss caused by metabolic and bariatric surgery (MBS) independently predicts the normalization of dyslipidemia, elevated blood pressure (EPB), hyperinsulinemia, diabetes, and elevated high-sensitivity C-reactive protein (hs-CRP) in severely obese adolescents, according to results of a longitudinal, multicenter prospective study.

In the study of 242 severely obese adolescents undergoing MBS between Feb. 28, 2007, and Dec. 30, 2011, Marc Michalsky, MD, of Nationwide Children’s Hospital, Columbus, Ohio, and his colleagues found that with every 10% increase in weight loss, patients were 24%, 11%, 14%, 13%, and 19% more likely to resolve dyslipidemia, EBP, hyperinsulinemia, diabetes, and elevated hs-CRP, respectively.

moodboard/thinkstockphotos

Dr. Inge has worked as a consultant for Standard Bariatrics, UpToDate, and Independent Medical Expert Consulting Services; all of these companies are unrelated to this research. John B. Dixon, PhD, has received support for his research through a National Health and Medical Research Council research fellowship. Anita Courcoulas, MD, has received grants from various health care groups and companies. All other authors had no relevant financial disclosures. The study was funded by a variety of institutional grants and the National Institutes of Health.

[email protected]

SOURCE: M Michalsky et al. Pediatrics. 2018 Jan 8. doi: 10.1542/peds.2017-2485.

Weight loss caused by metabolic and bariatric surgery (MBS) independently predicts the normalization of dyslipidemia, elevated blood pressure (EPB), hyperinsulinemia, diabetes, and elevated high-sensitivity C-reactive protein (hs-CRP) in severely obese adolescents, according to results of a longitudinal, multicenter prospective study.

In the study of 242 severely obese adolescents undergoing MBS between Feb. 28, 2007, and Dec. 30, 2011, Marc Michalsky, MD, of Nationwide Children’s Hospital, Columbus, Ohio, and his colleagues found that with every 10% increase in weight loss, patients were 24%, 11%, 14%, 13%, and 19% more likely to resolve dyslipidemia, EBP, hyperinsulinemia, diabetes, and elevated hs-CRP, respectively.

moodboard/thinkstockphotos

Dr. Inge has worked as a consultant for Standard Bariatrics, UpToDate, and Independent Medical Expert Consulting Services; all of these companies are unrelated to this research. John B. Dixon, PhD, has received support for his research through a National Health and Medical Research Council research fellowship. Anita Courcoulas, MD, has received grants from various health care groups and companies. All other authors had no relevant financial disclosures. The study was funded by a variety of institutional grants and the National Institutes of Health.

[email protected]

SOURCE: M Michalsky et al. Pediatrics. 2018 Jan 8. doi: 10.1542/peds.2017-2485.

IN THIS ARTICLE

• Presenting symptoms
• Diagnostic tests
• Differential diagnostic criteria

Multiple myeloma (MM) is a fatal, malignant neoplasm that originates in the plasma cells of bone marrow. A genetic mutation in the plasma cells creates myeloma cells, which replicate and produce monoclonal protein (M-protein). This accumulation of cells and abnormal protein can result in destruction and eventual marrow failure.^1,2

MM’s insidious nature means it often goes undetected or misdiagnosed in its early stages; this delayed diagnosis can cause sequelae that limit quality of life. Furthermore, the five-year survival rate for myeloma varies by stage at which the disease is diagnosed: from 48% for distant (metastasized) myeloma to 71% for localized disease.³ It has also been noted that, in the past two decades, improvements in available treatment options and supportive care have contributed to a doubling of median survival time (from three years to six years).⁴ It is therefore paramount that providers be aware of MM and its signs to facilitate early diagnosis and treatment.

INCIDENCE AND EPIDEMIOLOGY

MM accounts for 1% of all cancers and about 10% of all hematologic malignancies.⁵ In 2017, the American Cancer Society estimated that more than 30,000 new cases of MM would be diagnosed in the United States.⁶ Additionally, MM was expected to cause more than 12,000 deaths last year.⁶

Median age at diagnosis is 69.³ In fact, 75% of men are older than 75 and 79% of women are older than 70 at diagnosis.¹

Apart from age, other risk factors for MM have been identified but not fully explicated. For example, the disease is more common in men than in women (with men comprising two-thirds of new cases per year).³ MM is also two to three times more common in black than in white persons, making it the most common hematologic malignancy in this demographic group.^3,7

The possibility of a genetic predisposition has also been studied. Several analyses have indicated an increased risk for MM in patients with a family history of the disease—as much as four times higher in those with an affected first-degree relative. This risk was further elevated in black compared with white patients (odds ratios, 17.4 and 1.5, respectively).⁷ However, many patients with MM have no relatives with this disorder.^6,8

DISEASE PROGRESSION

Almost all patients who develop MM also experience an asymptomatic premalignant stage called monoclonal gammopathy of undetermined significance (MGUS). MGUS is present in 3% to 4% of the general population older than 50 and is often an incidental finding. This stage almost always precedes MM—but because it is asymptomatic, only 10% of individuals diagnosed with MM have a known history of MGUS.⁸

In some patients, an asymptomatic intermediate stage called smoldering multiple myeloma (SMM) can be identified. SMM progresses to MM at a rate of 10% per year for the first five years; the rate decreases to 3% per year over the following five years, and 1% per year after that.⁸

MM is not curable, but as noted, the survival rate is steadily increasing due to rapidly evolving treatment regimens. Discussion of treatment is outside the scope of this article, but early diagnosis can improve quality of life and clinical outcomes and prolong life expectancy.

SYMPTOMS

The initial symptoms of MM can be nonspecific and may lead the provider to suspect a host of other conditions.^2,6 (Those for advanced disease are also vague but tend to be more pronounced.) These may include fatigue, weakness, easy bruising or bleeding, and bone pain. Other common clinical manifestations of MM are anemia, chronic infection, bone disease, and/or renal failure.^1,4 Patients may also experience loss of appetite, nausea, vomiting, increased thirst, and increased urination.⁹

Recent studies have shown that patients with SMM and/or MGUS also exhibit early signs of bone disease and increased risk for fracture.¹⁰ Eighty percent of patients who progress to MM have evidence of pathologic bone fractures.¹⁰ It is also possible for bones in the spine to weaken and collapse, pressing on the spinal nerves. This is known as spinal cord compression, which can manifest with sudden, severe back pain or numbness and/or muscle weakness (most often in the legs).⁶

MM must be included in the differential diagnosis, particularly when symptoms do not point to one specific disease process. Without early diagnosis, disease progression can result in complications such as bone fracture and osteoporosis, reduced kidney function, peripheral neuropathy, chronic anemia, and ultimately, death.^2,6 The presence of bone fractures increases mortality risk by 20%.¹⁰

Evidence of MM may be discovered during routine bloodwork and screening tests, while presenting symptoms or subtle changes in lab results can raise suspicion for the disease. Initial bloodwork abnormalities include anemia, elevated calcium levels, renal insufficiency, and/or elevated protein levels.⁸

A combination of abnormalities in the complete blood count (CBC) and complete metabolic panel (CMP), along with symptoms, should alert the provider to the possibility of MM, prompting additional workup. Table 1 outlines suggested diagnostic tests; the possible findings are discussed below.

CBC. The CBC may reveal abnormalities including anemia (which occurs in 75% of patients with MM), thrombocytopenia, and leukopenia.^1,8 These findings can contribute to fatigue, increased incidence of infection, and abnormal bruising of the skin.^2,8

CMP. A CMP may show increases in ­serum calcium or protein. Hypercalcemia occurs in 15% of patients with MM, leading to symptoms such as loss of appetite, nausea, vomiting, increased urination, weakness, and confusion.⁸ An increase in protein may alter the albumin/globulin ratio, which should raise suspicion for MM. A decrease in albumin can signify disease severity. Also, the CMP may show worsening renal function and elevated serum creatinine, which occurs in 20% of patients with MM.⁸

Serum protein electrophoresis (SPEP). Suspicion of MM should prompt the clinician to evaluate proteins via SPEP. This test may be indicated for patients with anemia, hypercalcemia, bone pain, and unexplained neuropathy.⁹ The electrophoresis separates proteins based on their physical properties. This identifies the presence and amount of M-protein, which can determine the extent of the disease.¹ M-protein is identified in approximately 82% of patients with MM using this test.⁸

Serum free light chain (FLC) assay. This diagnostic test can identify MM in individuals with high clinical suspicion for the disease but no discernible M-protein on SPEP; it increases sensitivity to 97%.⁸ The serum FLC assay evaluates for presence and ratio of free light chains—proteins produced by plasma cells. This test is also useful for monitoring treatment response and disease progression.¹

Urine protein electrophoresis (UPEP). The UPEP separates proteins according to charge, which is helpful for classifying renal injury. Protein patterns are interpreted and may be reported as glomerular, tubular, or mixed. UPEP also tests for M-protein in the urine.^1,11

24-hour urine. The 24-h urine test quantifies the amount and type of protein excreted in the urine and helps determine the extent of kidney disease.¹

Skeletal survey. MM causes significant bone changes that can be identified with radiographic studies. The most common locations for fractures are the vertebral, pelvic, and clavicular areas.¹⁰ Currently, the skeletal survey is the gold standard for detecting fractures and osteolytic lesions associated with MM.¹⁰ Radiographic films ordered for other purposes may uncover abnormalities in bones.

Bone mineral density (BMD) test. Most often, BMD testing is used to evaluate treatment and progression of bone involvement. Because it can uncover osteopenia or osteoporosis, however, it can also be used to corroborate the diagnosis of MM.¹⁰

Once the presence of M-protein is identified, patients are referred for specialty care. At that time, further workup will include a bone marrow biopsy and imaging studies, such as additional radiographic films, CT scans (without contrast, as contrast dye can damage frail kidneys), and MRI.^1,8 These diagnostic tests provide useful information for the classification of the disease and guide initiation of treatment.

CLASSIFICATION OF DISEASE

MM can be classified into three stages—MGUS, SMM, and MM—based on recommendations from the International Myeloma Working Group.¹² Table 2 outlines the diagnostic criteria for each stage.

Individuals with MGUS and SMM are considered asymptomatic; guidelines do not recommend treatment for these patients. Those who are diagnosed with MM are referred to oncologists and treated based on current clinical practice guidelines.¹

CONCLUSION

Multiple myeloma is a malignant neoplasm without a cure. Presenting symptoms may include anemia, bone pain, elevated creatinine or serum protein, fatigue, and hypercalcemia. Early diagnosis is key to early intervention and treatment, which can improve quality of life and clinical outcomes for those affected. Primary care providers play a major role in recognizing the subtle symptoms and ordering the appropriate diagnostic tests.

IN THIS ARTICLE

• Presenting symptoms
• Diagnostic tests
• Differential diagnostic criteria

Multiple myeloma (MM) is a fatal, malignant neoplasm that originates in the plasma cells of bone marrow. A genetic mutation in the plasma cells creates myeloma cells, which replicate and produce monoclonal protein (M-protein). This accumulation of cells and abnormal protein can result in destruction and eventual marrow failure.^1,2

MM’s insidious nature means it often goes undetected or misdiagnosed in its early stages; this delayed diagnosis can cause sequelae that limit quality of life. Furthermore, the five-year survival rate for myeloma varies by stage at which the disease is diagnosed: from 48% for distant (metastasized) myeloma to 71% for localized disease.³ It has also been noted that, in the past two decades, improvements in available treatment options and supportive care have contributed to a doubling of median survival time (from three years to six years).⁴ It is therefore paramount that providers be aware of MM and its signs to facilitate early diagnosis and treatment.

INCIDENCE AND EPIDEMIOLOGY

MM accounts for 1% of all cancers and about 10% of all hematologic malignancies.⁵ In 2017, the American Cancer Society estimated that more than 30,000 new cases of MM would be diagnosed in the United States.⁶ Additionally, MM was expected to cause more than 12,000 deaths last year.⁶

Median age at diagnosis is 69.³ In fact, 75% of men are older than 75 and 79% of women are older than 70 at diagnosis.¹

Apart from age, other risk factors for MM have been identified but not fully explicated. For example, the disease is more common in men than in women (with men comprising two-thirds of new cases per year).³ MM is also two to three times more common in black than in white persons, making it the most common hematologic malignancy in this demographic group.^3,7

The possibility of a genetic predisposition has also been studied. Several analyses have indicated an increased risk for MM in patients with a family history of the disease—as much as four times higher in those with an affected first-degree relative. This risk was further elevated in black compared with white patients (odds ratios, 17.4 and 1.5, respectively).⁷ However, many patients with MM have no relatives with this disorder.^6,8

DISEASE PROGRESSION

Almost all patients who develop MM also experience an asymptomatic premalignant stage called monoclonal gammopathy of undetermined significance (MGUS). MGUS is present in 3% to 4% of the general population older than 50 and is often an incidental finding. This stage almost always precedes MM—but because it is asymptomatic, only 10% of individuals diagnosed with MM have a known history of MGUS.⁸

In some patients, an asymptomatic intermediate stage called smoldering multiple myeloma (SMM) can be identified. SMM progresses to MM at a rate of 10% per year for the first five years; the rate decreases to 3% per year over the following five years, and 1% per year after that.⁸

MM is not curable, but as noted, the survival rate is steadily increasing due to rapidly evolving treatment regimens. Discussion of treatment is outside the scope of this article, but early diagnosis can improve quality of life and clinical outcomes and prolong life expectancy.

SYMPTOMS

The initial symptoms of MM can be nonspecific and may lead the provider to suspect a host of other conditions.^2,6 (Those for advanced disease are also vague but tend to be more pronounced.) These may include fatigue, weakness, easy bruising or bleeding, and bone pain. Other common clinical manifestations of MM are anemia, chronic infection, bone disease, and/or renal failure.^1,4 Patients may also experience loss of appetite, nausea, vomiting, increased thirst, and increased urination.⁹

Recent studies have shown that patients with SMM and/or MGUS also exhibit early signs of bone disease and increased risk for fracture.¹⁰ Eighty percent of patients who progress to MM have evidence of pathologic bone fractures.¹⁰ It is also possible for bones in the spine to weaken and collapse, pressing on the spinal nerves. This is known as spinal cord compression, which can manifest with sudden, severe back pain or numbness and/or muscle weakness (most often in the legs).⁶

MM must be included in the differential diagnosis, particularly when symptoms do not point to one specific disease process. Without early diagnosis, disease progression can result in complications such as bone fracture and osteoporosis, reduced kidney function, peripheral neuropathy, chronic anemia, and ultimately, death.^2,6 The presence of bone fractures increases mortality risk by 20%.¹⁰

Evidence of MM may be discovered during routine bloodwork and screening tests, while presenting symptoms or subtle changes in lab results can raise suspicion for the disease. Initial bloodwork abnormalities include anemia, elevated calcium levels, renal insufficiency, and/or elevated protein levels.⁸

A combination of abnormalities in the complete blood count (CBC) and complete metabolic panel (CMP), along with symptoms, should alert the provider to the possibility of MM, prompting additional workup. Table 1 outlines suggested diagnostic tests; the possible findings are discussed below.

CBC. The CBC may reveal abnormalities including anemia (which occurs in 75% of patients with MM), thrombocytopenia, and leukopenia.^1,8 These findings can contribute to fatigue, increased incidence of infection, and abnormal bruising of the skin.^2,8

CMP. A CMP may show increases in ­serum calcium or protein. Hypercalcemia occurs in 15% of patients with MM, leading to symptoms such as loss of appetite, nausea, vomiting, increased urination, weakness, and confusion.⁸ An increase in protein may alter the albumin/globulin ratio, which should raise suspicion for MM. A decrease in albumin can signify disease severity. Also, the CMP may show worsening renal function and elevated serum creatinine, which occurs in 20% of patients with MM.⁸

Serum protein electrophoresis (SPEP). Suspicion of MM should prompt the clinician to evaluate proteins via SPEP. This test may be indicated for patients with anemia, hypercalcemia, bone pain, and unexplained neuropathy.⁹ The electrophoresis separates proteins based on their physical properties. This identifies the presence and amount of M-protein, which can determine the extent of the disease.¹ M-protein is identified in approximately 82% of patients with MM using this test.⁸

Serum free light chain (FLC) assay. This diagnostic test can identify MM in individuals with high clinical suspicion for the disease but no discernible M-protein on SPEP; it increases sensitivity to 97%.⁸ The serum FLC assay evaluates for presence and ratio of free light chains—proteins produced by plasma cells. This test is also useful for monitoring treatment response and disease progression.¹

Urine protein electrophoresis (UPEP). The UPEP separates proteins according to charge, which is helpful for classifying renal injury. Protein patterns are interpreted and may be reported as glomerular, tubular, or mixed. UPEP also tests for M-protein in the urine.^1,11

24-hour urine. The 24-h urine test quantifies the amount and type of protein excreted in the urine and helps determine the extent of kidney disease.¹

Skeletal survey. MM causes significant bone changes that can be identified with radiographic studies. The most common locations for fractures are the vertebral, pelvic, and clavicular areas.¹⁰ Currently, the skeletal survey is the gold standard for detecting fractures and osteolytic lesions associated with MM.¹⁰ Radiographic films ordered for other purposes may uncover abnormalities in bones.

Bone mineral density (BMD) test. Most often, BMD testing is used to evaluate treatment and progression of bone involvement. Because it can uncover osteopenia or osteoporosis, however, it can also be used to corroborate the diagnosis of MM.¹⁰

Once the presence of M-protein is identified, patients are referred for specialty care. At that time, further workup will include a bone marrow biopsy and imaging studies, such as additional radiographic films, CT scans (without contrast, as contrast dye can damage frail kidneys), and MRI.^1,8 These diagnostic tests provide useful information for the classification of the disease and guide initiation of treatment.

CLASSIFICATION OF DISEASE

MM can be classified into three stages—MGUS, SMM, and MM—based on recommendations from the International Myeloma Working Group.¹² Table 2 outlines the diagnostic criteria for each stage.

Individuals with MGUS and SMM are considered asymptomatic; guidelines do not recommend treatment for these patients. Those who are diagnosed with MM are referred to oncologists and treated based on current clinical practice guidelines.¹

CONCLUSION

Multiple myeloma is a malignant neoplasm without a cure. Presenting symptoms may include anemia, bone pain, elevated creatinine or serum protein, fatigue, and hypercalcemia. Early diagnosis is key to early intervention and treatment, which can improve quality of life and clinical outcomes for those affected. Primary care providers play a major role in recognizing the subtle symptoms and ordering the appropriate diagnostic tests.

IN THIS ARTICLE

• Presenting symptoms
• Diagnostic tests
• Differential diagnostic criteria

Multiple myeloma (MM) is a fatal, malignant neoplasm that originates in the plasma cells of bone marrow. A genetic mutation in the plasma cells creates myeloma cells, which replicate and produce monoclonal protein (M-protein). This accumulation of cells and abnormal protein can result in destruction and eventual marrow failure.^1,2

MM’s insidious nature means it often goes undetected or misdiagnosed in its early stages; this delayed diagnosis can cause sequelae that limit quality of life. Furthermore, the five-year survival rate for myeloma varies by stage at which the disease is diagnosed: from 48% for distant (metastasized) myeloma to 71% for localized disease.³ It has also been noted that, in the past two decades, improvements in available treatment options and supportive care have contributed to a doubling of median survival time (from three years to six years).⁴ It is therefore paramount that providers be aware of MM and its signs to facilitate early diagnosis and treatment.

INCIDENCE AND EPIDEMIOLOGY

MM accounts for 1% of all cancers and about 10% of all hematologic malignancies.⁵ In 2017, the American Cancer Society estimated that more than 30,000 new cases of MM would be diagnosed in the United States.⁶ Additionally, MM was expected to cause more than 12,000 deaths last year.⁶

Median age at diagnosis is 69.³ In fact, 75% of men are older than 75 and 79% of women are older than 70 at diagnosis.¹

Apart from age, other risk factors for MM have been identified but not fully explicated. For example, the disease is more common in men than in women (with men comprising two-thirds of new cases per year).³ MM is also two to three times more common in black than in white persons, making it the most common hematologic malignancy in this demographic group.^3,7

The possibility of a genetic predisposition has also been studied. Several analyses have indicated an increased risk for MM in patients with a family history of the disease—as much as four times higher in those with an affected first-degree relative. This risk was further elevated in black compared with white patients (odds ratios, 17.4 and 1.5, respectively).⁷ However, many patients with MM have no relatives with this disorder.^6,8

DISEASE PROGRESSION

Almost all patients who develop MM also experience an asymptomatic premalignant stage called monoclonal gammopathy of undetermined significance (MGUS). MGUS is present in 3% to 4% of the general population older than 50 and is often an incidental finding. This stage almost always precedes MM—but because it is asymptomatic, only 10% of individuals diagnosed with MM have a known history of MGUS.⁸

In some patients, an asymptomatic intermediate stage called smoldering multiple myeloma (SMM) can be identified. SMM progresses to MM at a rate of 10% per year for the first five years; the rate decreases to 3% per year over the following five years, and 1% per year after that.⁸

MM is not curable, but as noted, the survival rate is steadily increasing due to rapidly evolving treatment regimens. Discussion of treatment is outside the scope of this article, but early diagnosis can improve quality of life and clinical outcomes and prolong life expectancy.

SYMPTOMS

The initial symptoms of MM can be nonspecific and may lead the provider to suspect a host of other conditions.^2,6 (Those for advanced disease are also vague but tend to be more pronounced.) These may include fatigue, weakness, easy bruising or bleeding, and bone pain. Other common clinical manifestations of MM are anemia, chronic infection, bone disease, and/or renal failure.^1,4 Patients may also experience loss of appetite, nausea, vomiting, increased thirst, and increased urination.⁹

Recent studies have shown that patients with SMM and/or MGUS also exhibit early signs of bone disease and increased risk for fracture.¹⁰ Eighty percent of patients who progress to MM have evidence of pathologic bone fractures.¹⁰ It is also possible for bones in the spine to weaken and collapse, pressing on the spinal nerves. This is known as spinal cord compression, which can manifest with sudden, severe back pain or numbness and/or muscle weakness (most often in the legs).⁶

MM must be included in the differential diagnosis, particularly when symptoms do not point to one specific disease process. Without early diagnosis, disease progression can result in complications such as bone fracture and osteoporosis, reduced kidney function, peripheral neuropathy, chronic anemia, and ultimately, death.^2,6 The presence of bone fractures increases mortality risk by 20%.¹⁰

Evidence of MM may be discovered during routine bloodwork and screening tests, while presenting symptoms or subtle changes in lab results can raise suspicion for the disease. Initial bloodwork abnormalities include anemia, elevated calcium levels, renal insufficiency, and/or elevated protein levels.⁸

A combination of abnormalities in the complete blood count (CBC) and complete metabolic panel (CMP), along with symptoms, should alert the provider to the possibility of MM, prompting additional workup. Table 1 outlines suggested diagnostic tests; the possible findings are discussed below.

CBC. The CBC may reveal abnormalities including anemia (which occurs in 75% of patients with MM), thrombocytopenia, and leukopenia.^1,8 These findings can contribute to fatigue, increased incidence of infection, and abnormal bruising of the skin.^2,8

CMP. A CMP may show increases in ­serum calcium or protein. Hypercalcemia occurs in 15% of patients with MM, leading to symptoms such as loss of appetite, nausea, vomiting, increased urination, weakness, and confusion.⁸ An increase in protein may alter the albumin/globulin ratio, which should raise suspicion for MM. A decrease in albumin can signify disease severity. Also, the CMP may show worsening renal function and elevated serum creatinine, which occurs in 20% of patients with MM.⁸

Serum protein electrophoresis (SPEP). Suspicion of MM should prompt the clinician to evaluate proteins via SPEP. This test may be indicated for patients with anemia, hypercalcemia, bone pain, and unexplained neuropathy.⁹ The electrophoresis separates proteins based on their physical properties. This identifies the presence and amount of M-protein, which can determine the extent of the disease.¹ M-protein is identified in approximately 82% of patients with MM using this test.⁸

Serum free light chain (FLC) assay. This diagnostic test can identify MM in individuals with high clinical suspicion for the disease but no discernible M-protein on SPEP; it increases sensitivity to 97%.⁸ The serum FLC assay evaluates for presence and ratio of free light chains—proteins produced by plasma cells. This test is also useful for monitoring treatment response and disease progression.¹

Urine protein electrophoresis (UPEP). The UPEP separates proteins according to charge, which is helpful for classifying renal injury. Protein patterns are interpreted and may be reported as glomerular, tubular, or mixed. UPEP also tests for M-protein in the urine.^1,11

24-hour urine. The 24-h urine test quantifies the amount and type of protein excreted in the urine and helps determine the extent of kidney disease.¹

Skeletal survey. MM causes significant bone changes that can be identified with radiographic studies. The most common locations for fractures are the vertebral, pelvic, and clavicular areas.¹⁰ Currently, the skeletal survey is the gold standard for detecting fractures and osteolytic lesions associated with MM.¹⁰ Radiographic films ordered for other purposes may uncover abnormalities in bones.

Bone mineral density (BMD) test. Most often, BMD testing is used to evaluate treatment and progression of bone involvement. Because it can uncover osteopenia or osteoporosis, however, it can also be used to corroborate the diagnosis of MM.¹⁰

Once the presence of M-protein is identified, patients are referred for specialty care. At that time, further workup will include a bone marrow biopsy and imaging studies, such as additional radiographic films, CT scans (without contrast, as contrast dye can damage frail kidneys), and MRI.^1,8 These diagnostic tests provide useful information for the classification of the disease and guide initiation of treatment.

CLASSIFICATION OF DISEASE

MM can be classified into three stages—MGUS, SMM, and MM—based on recommendations from the International Myeloma Working Group.¹² Table 2 outlines the diagnostic criteria for each stage.

Individuals with MGUS and SMM are considered asymptomatic; guidelines do not recommend treatment for these patients. Those who are diagnosed with MM are referred to oncologists and treated based on current clinical practice guidelines.¹

CONCLUSION

Multiple myeloma is a malignant neoplasm without a cure. Presenting symptoms may include anemia, bone pain, elevated creatinine or serum protein, fatigue, and hypercalcemia. Early diagnosis is key to early intervention and treatment, which can improve quality of life and clinical outcomes for those affected. Primary care providers play a major role in recognizing the subtle symptoms and ordering the appropriate diagnostic tests.

This video was filmed at Metabolic & Endocrine Disease Summit (MEDS). Click here to learn more.

This video was filmed at Metabolic & Endocrine Disease Summit (MEDS). Click here to learn more.

This video was filmed at Metabolic & Endocrine Disease Summit (MEDS). Click here to learn more.