B-Cell Lymphoma ICYMI

The psychosocial impact of psoriasis is a critical component of disease burden. Psoriatic patients have high rates of depression and anxiety, problems at work, and difficulties with interpersonal relationships and intimacy.¹ A National Psoriasis Foundation (NPF) survey from 2003 to 2011 reported that psoriasis affects overall emotional well-being in 88% of patients and enjoyment of life in 82% of patients.²

The reasons for psychosocial burden stem from public misconceptions and disease stigma. A survey of 1005 individuals (age range, 16–64 years) about their perceptions of psoriasis revealed that 16.5% believed that psoriasis is contagious and 6.8% believed that psoriasis is related to personal hygiene.³ Fifty percent practiced discriminatory behavior toward psoriatic patients, including reluctance to shake hands (28.8%) and engage in sexual relations/intercourse (44.1%). Sixty-five percent of psoriatic patients felt their appearance is unsightly, and 73% felt self-conscious about having psoriasis.²

The psychosocial burden exists despite medical treatment of the disease. In a cross-sectional study of 1184 psoriatic patients, 70.2% had impaired quality of life (QOL) as measured by the dermatology life quality index (DLQI), even after receiving a 4-week treatment for psoriasis.⁴ Medical treatment of psoriasis is not enough; providers need to assess overall QOL and provide treatment and resources for these patients in addition to symptomatic management.

There have been many studies on the psychosocial burden of psoriasis, but few have focused on a dermatology resident’s role in addressing this issue. This article will review psychosocial domains—psychiatric comorbidities and social functioning including occupational functioning, interpersonal relationships, and sexual functioning— and discuss a dermatology resident’s role in assessing and addressing each of these areas.

Methods

A PubMed search of articles indexed for MEDLINE was conducted using the following terms: psoriasis, depression, anxiety, work productivity, sexual functioning, and interpersonal relationships. Selected articles covered prevalence, assessment, and management of each psychosocial domain.

Results

Psychiatric Comorbidities

Prevalence
A high prevalence of psychiatric comorbidities exists in psoriatic patients. In a study of 469,097 patients with psoriasis, depression was the third most prevalent comorbidity (17.91%), following hyperlipidemia (45.64%) and hypertension (42.19%).⁵ In a 10-year longitudinal, population-based, prospective cohort study, antidepressant prescriptions were twice as frequent in psoriatic patients (17.8%) compared to control (7.9%)(P<.001).⁶ In a meta-analysis of 98 studies investigating psoriatic patients and psychiatric comorbidities, patients with psoriasis were 1.5 times more likely to experience depression (odds ratio [OR]: 1.57; 95% CI, 1.40-1.76) and use antidepressants (OR: 4.24; 95% CI, 1.53-11.76) compared to control.⁷ Patients with psoriasis were more likely to attempt suicide (OR: 1.32; 95% CI, 1.14-1.54) and complete suicide (OR: 1.20; 95% CI, 1.04-1.39) compared to people without psoriasis.⁸ A 1-year cross-sectional study of 90 psoriatic patients reported 78.7% were diagnosed with depression and 76.7% were diagnosed with anxiety. Seventy-two percent reported both anxiety and depression, correlating with worse QOL (χ²=26.7; P<.05).⁹

Assessment
Psychiatric comorbidities are assessed using clinical judgment and formal screening questionnaires in research studies. Signs of depression in patients with psoriasis can manifest as poor treatment adherence and recurrent flares of psoriasis.^10,11 Psoriatic patients with psychiatric comorbidities were less likely to be adherent to treatment (risk ratio: 0.35; P<.003).¹⁰ The patient health questionnaire (PHQ) 9 and generalized anxiety disorder scale (GAD) 7 are validated and reliable questionnaires. The first 2 questions in PHQ-9 and GAD-7 screen for depression and anxiety, respectively.^12-14 These 2-question screens are practical in a fast-paced dermatology outpatient setting. Systematic questionnaires specifically targeting mood disorders may be more beneficial than the widely used DLQI, which may not adequately capture mood disorders. Over the course of 10 months, 607 patients with psoriasis were asked to fill out the PHQ-9, GAD-7, and DLQI. Thirty-eight percent of patients with major depressive disorder had a DLQI score lower than 10, while 46% of patients with generalized anxiety disorder had a DLQI score lower than 10.¹⁵ Other questionnaires, including the hospital anxiety and depression scale and Beck depression inventory, are valid instruments with high sensitivity but are commonly used for research purposes and may not be clinically feasible.¹⁶

Management
Dermatologists should refer patients with depression and/or anxiety to psychiatry. Interventions include pharmacologic and nonpharmacologic management. First-line therapy for depression and anxiety is a combination of selective serotonin reuptake inhibitors and cognitive behavioral therapy.¹⁷ In addition, providers can direct patients to online resources such as the NPF website, where patients with psoriasis can access information about the signs and symptoms of mood disorders and contact the patient navigation center for further help.¹⁸

Social Functioning

Occupational Prevalence
The NPF found that 92% of patients with psoriasis or psoriatic arthritis (PsA) surveyed between 2003 and 2011 cited their psoriasis as reason for unemployment.² In a survey of 43 patients asked about social and occupational functioning using the social and occupational assessment scale, 62.5% of psoriatic patients reported distress at work and 51.1% reported decreased efficiency at work.¹⁹ A national online survey that was conducted in France and issued to patients with and without psoriasis assessed overall QOL and work productivity using the work productivity and activity impairment questionnaire for psoriasis (WPAI-PSO). Of 714 patients with psoriasis and PsA, the latter had a 57.6% decrease in work productivity over 7 days compared to 27.9% in controls (P<.05).²⁰ Occupational impairment leads to lost wages and hinders advancement, further exacerbating the psychosocial burden of psoriasis.²¹

Occupational Assessment
Formal assessment of occupational function can be done with the WPAI-PSO, a 6-question valid instrument.²² Providers may look for risk factors associated with greater loss in work productivity to help identify and offer support for patients. Patients with increased severity of itching, pain, and scaling experienced a greater decrease in work productivity.^21,23 Patients with PsA warrant early detection and treatment because they experience greater physical restraints that can interfere with work activities. Of the 459 psoriatic patients without a prior diagnosis of PsA who filled out the PsA screening and evaluation questionnaire, 144 (31.4%) received a score of 44 or higher and were referred to rheumatology for further evaluation with the classification criteria for PsA. Nine percent of patients failed to be screened and remained undiagnosed with PsA.²⁴ In a study using the health assessment questionnaire to assess 400 patients with PsA, those with worse physical function due to joint pain and stiffness were less likely to remain employed (OR: 0.56; P=.02).²⁵

Occupational Management
Identifying and coordinating symptoms of PsA between dermatology and rheumatology is beneficial for patients who experience debilitating symptoms. There are a variety of treatments available for PsA. According to the European League Against Rheumatism 2015 guidelines developed from expert opinion and systematic reviews for PsA management, there are 4 phases of treatment, with reassessment every 3 to 6 months for effectiveness of therapy.^26,27 Phase I involves initiating nonsteroidal anti-inflammatory drugs with or without glucocorticoid injections. Phase II involves synthetic disease-modifying drugs, including methotrexate, leflunomide, sulfasalazine, or cyclosporine. Phase III involves adding a second synthetic disease-modifying drug or starting a biologic, such as an anti–tumor necrosis factor, IL-12/IL-23, or IL-17 inhibitor. Phase IV involves switching to a different drug in either aforementioned class.^26,27 Treatment with biologics improves work productivity as assessed by WPAI-PSO for psoriasis and PsA.^28-30 Encouraging patients to speak up in the workplace and request small accommodations such as timely breaks or ergonomic chairs can help patients feel more comfortable and supported in the work environment.¹⁸ Patients who felt supported at work were more likely to remain employed.²⁵

Interpersonal Relationships Prevalence
Misinformation about psoriasis, fear of rejection, and feelings of isolation may contribute to interpersonal conflict. Patients have feelings of shame and self-consciousness that hinder them from engaging in social activities and seeking out relationships.³¹ Twenty-nine percent of patients feel that psoriasis has interfered with establishing relationships because of negative self-esteem associated with the disease,³² and 26.3% have experienced people avoiding physical contact.³³ Family and spouses of patients with psoriasis may be secondarily affected due to economic and emotional distress. Ninety-eight percent of family members of psoriatic patients experienced emotional distress and 54% experienced the burden of care.³⁴ In a survey of 63 relatives and partners of patients with psoriasis, 57% experienced psychological distress, including anxiety and worry over a psoriatic patient’s future.³⁵

Interpersonal Relationships Assessment
Current available tools, including the DLQI and short form health survey, measure overall QOL, including social functioning, but may not be practical in a clinic setting. Although no quick-screening test to assess for this domain exists, providers are encouraged to ask patients about disease impact on interpersonal relationships. The family DLQI questionnaire, adapted from the DLQI, may help physicians and social workers evaluate the burden on a patient’s family members.³⁴

Interpersonal Relationships Management
It may be difficult for providers to address problems with interpersonal relationships without accessible tools. Patients may not be accompanied by family or friends during appointments, and it is difficult to screen for these issues during visits. Providers may offer resources such as the NPF website, which provides information about support groups. It also provides tips on dating and connecting to others in the community who share similar experiences.¹⁸ Encouraging patients to seek family or couples therapy also may be beneficial. Increased social support can lead to better QOL and fewer depressive symptoms.³⁶

Sexual Functioning Prevalence
Psoriasis affects both physical and psychological components of sexual function. Among 3485 patients with skin conditions who were surveyed about sexual function, 34% of psoriatic patients reported that psoriasis interfered with sexual functioning at least to a certain degree.³⁷ Sexual impairment was strongly associated with depression, anxiety, and suicidal ideation; 24% of depressed patients and 20% of anxious patients experienced sexual problems a lot or very much, based on the DLQI.³⁷ Depending on the questionnaire used, the prevalence of sexual dysfunction due to psoriasis ranged from 35.5% to 71.3%.³⁸ In an observational cohort study of 158 participants (n=79 psoriasis patients and n=79 controls), 34.2% of patients with psoriasis experienced erectile dysfunction compared to 17.7% of controls.³⁹ Forty-two percent of psoriatic patients with genital involvement reported dyspareunia, 32% reported worsening of genital psoriasis after intercourse, and 43% reported decreased frequency of intercourse.⁴⁰

Sexual Functioning Assessment
The Skindex-29, DLQI, and psoriasis disability index are available QOL tools that include one question evaluating difficulties with sexual function. The Massachusetts General Hospital sexual functioning questionnaire is a 5-item validated tool that specifically assesses sexual dysfunction.⁴¹ Distribution of lesions can help identify patients who are more likely to experience sexual dysfunction. In 160 patients who completed the questionnaire and self-reported psoriasis area and severity index, lesions on the abdomen, genitals, lumbar region, and buttocks were associated with worse sexual functioning (OR: 7.9; 95% CI, 2.3-33.4; P<.05).⁴² Dermatologists could assess for sexual problems using either formal questionnaires or direct conversations during the routine psoriasis visit, as patients may be suffering in silence due to this sensitive topic.

Sexual Functioning Management
Better disease control leads to improved sexual function, as patients experience fewer feelings of shame, anxiety, and depression, as well as improvement of physical symptoms that can interfere with sexual functioning.^38,43,44 Reducing friction, warmth, and moisture, as well as avoiding tight clothing, can help those with genital psoriasis. Patients are advised to reapply topical medications after sexual intercourse. Patients also can apply makeup to disguise psoriasis and help reduce feelings of self-consciousness that can impede sexual intimacy.¹⁸

Comment

The psychosocial burden of psoriasis penetrates many facets of patient lives. Psoriasis can invoke feelings of shame and embarrassment that are worsened by the public’s misconceptions about psoriasis, resulting in serious mental health issues that can cause even greater disability. Depression and anxiety are prevalent in patients with psoriasis. The characteristic symptoms of pain and pruritus along with psychiatric comorbidities can have an underestimated impact on daily activities, including employment, interpersonal relationships, and sexual function. Such dysfunctions have serious implications toward wages, professional advancement, social support, and overall QOL.

Dermatology providers play an important role in screening for these problems through validated questionnaires and identifying risks. Simple screening questions such as the PHQ-9 can be beneficial and feasible during dermatology visits. Screening for PsA can help patients avoid problems at work. Sexual dysfunction is a sensitive topic; however, providers can use a 1-question screen from valid questionnaires and inquire about the location of lesions as opportunities to address this issue.

Interventions lead to better disease control, which concurrently improves overall QOL. These interventions depend on both patient adherence and a physician’s commitment to finding an optimal treatment regimen for each individual. Medical management; coordinating care; developing treatment plans with psychiatry, rheumatology, and primary care providers; and psychological counseling and services may be necessary and beneficial (Table). Offering accessible resources such as the NPF website helps patients access information outside the clinic when it is not feasible to address all these concerns in a single visit. Psoriasis requires more than just medical management; it requires dermatology providers to use a multidisciplinary approach to address the psychosocial aspects of the disease.

Conclusion

The psychosocial burden of psoriasis is immense. Stigma, public misconception, mental health concerns, and occupational and interpersonal difficulty are the basis of disease burden. Providers play a vital role in assessing the effect psoriasis has on different areas of patients’ lives and providing appropriate interventions and resources to reduce disease burden.

The psychosocial impact of psoriasis is a critical component of disease burden. Psoriatic patients have high rates of depression and anxiety, problems at work, and difficulties with interpersonal relationships and intimacy.¹ A National Psoriasis Foundation (NPF) survey from 2003 to 2011 reported that psoriasis affects overall emotional well-being in 88% of patients and enjoyment of life in 82% of patients.²

The reasons for psychosocial burden stem from public misconceptions and disease stigma. A survey of 1005 individuals (age range, 16–64 years) about their perceptions of psoriasis revealed that 16.5% believed that psoriasis is contagious and 6.8% believed that psoriasis is related to personal hygiene.³ Fifty percent practiced discriminatory behavior toward psoriatic patients, including reluctance to shake hands (28.8%) and engage in sexual relations/intercourse (44.1%). Sixty-five percent of psoriatic patients felt their appearance is unsightly, and 73% felt self-conscious about having psoriasis.²

The psychosocial burden exists despite medical treatment of the disease. In a cross-sectional study of 1184 psoriatic patients, 70.2% had impaired quality of life (QOL) as measured by the dermatology life quality index (DLQI), even after receiving a 4-week treatment for psoriasis.⁴ Medical treatment of psoriasis is not enough; providers need to assess overall QOL and provide treatment and resources for these patients in addition to symptomatic management.

There have been many studies on the psychosocial burden of psoriasis, but few have focused on a dermatology resident’s role in addressing this issue. This article will review psychosocial domains—psychiatric comorbidities and social functioning including occupational functioning, interpersonal relationships, and sexual functioning— and discuss a dermatology resident’s role in assessing and addressing each of these areas.

Methods

A PubMed search of articles indexed for MEDLINE was conducted using the following terms: psoriasis, depression, anxiety, work productivity, sexual functioning, and interpersonal relationships. Selected articles covered prevalence, assessment, and management of each psychosocial domain.

Results

Psychiatric Comorbidities

Prevalence
A high prevalence of psychiatric comorbidities exists in psoriatic patients. In a study of 469,097 patients with psoriasis, depression was the third most prevalent comorbidity (17.91%), following hyperlipidemia (45.64%) and hypertension (42.19%).⁵ In a 10-year longitudinal, population-based, prospective cohort study, antidepressant prescriptions were twice as frequent in psoriatic patients (17.8%) compared to control (7.9%)(P<.001).⁶ In a meta-analysis of 98 studies investigating psoriatic patients and psychiatric comorbidities, patients with psoriasis were 1.5 times more likely to experience depression (odds ratio [OR]: 1.57; 95% CI, 1.40-1.76) and use antidepressants (OR: 4.24; 95% CI, 1.53-11.76) compared to control.⁷ Patients with psoriasis were more likely to attempt suicide (OR: 1.32; 95% CI, 1.14-1.54) and complete suicide (OR: 1.20; 95% CI, 1.04-1.39) compared to people without psoriasis.⁸ A 1-year cross-sectional study of 90 psoriatic patients reported 78.7% were diagnosed with depression and 76.7% were diagnosed with anxiety. Seventy-two percent reported both anxiety and depression, correlating with worse QOL (χ²=26.7; P<.05).⁹

Assessment
Psychiatric comorbidities are assessed using clinical judgment and formal screening questionnaires in research studies. Signs of depression in patients with psoriasis can manifest as poor treatment adherence and recurrent flares of psoriasis.^10,11 Psoriatic patients with psychiatric comorbidities were less likely to be adherent to treatment (risk ratio: 0.35; P<.003).¹⁰ The patient health questionnaire (PHQ) 9 and generalized anxiety disorder scale (GAD) 7 are validated and reliable questionnaires. The first 2 questions in PHQ-9 and GAD-7 screen for depression and anxiety, respectively.^12-14 These 2-question screens are practical in a fast-paced dermatology outpatient setting. Systematic questionnaires specifically targeting mood disorders may be more beneficial than the widely used DLQI, which may not adequately capture mood disorders. Over the course of 10 months, 607 patients with psoriasis were asked to fill out the PHQ-9, GAD-7, and DLQI. Thirty-eight percent of patients with major depressive disorder had a DLQI score lower than 10, while 46% of patients with generalized anxiety disorder had a DLQI score lower than 10.¹⁵ Other questionnaires, including the hospital anxiety and depression scale and Beck depression inventory, are valid instruments with high sensitivity but are commonly used for research purposes and may not be clinically feasible.¹⁶

Management
Dermatologists should refer patients with depression and/or anxiety to psychiatry. Interventions include pharmacologic and nonpharmacologic management. First-line therapy for depression and anxiety is a combination of selective serotonin reuptake inhibitors and cognitive behavioral therapy.¹⁷ In addition, providers can direct patients to online resources such as the NPF website, where patients with psoriasis can access information about the signs and symptoms of mood disorders and contact the patient navigation center for further help.¹⁸

Social Functioning

Occupational Prevalence
The NPF found that 92% of patients with psoriasis or psoriatic arthritis (PsA) surveyed between 2003 and 2011 cited their psoriasis as reason for unemployment.² In a survey of 43 patients asked about social and occupational functioning using the social and occupational assessment scale, 62.5% of psoriatic patients reported distress at work and 51.1% reported decreased efficiency at work.¹⁹ A national online survey that was conducted in France and issued to patients with and without psoriasis assessed overall QOL and work productivity using the work productivity and activity impairment questionnaire for psoriasis (WPAI-PSO). Of 714 patients with psoriasis and PsA, the latter had a 57.6% decrease in work productivity over 7 days compared to 27.9% in controls (P<.05).²⁰ Occupational impairment leads to lost wages and hinders advancement, further exacerbating the psychosocial burden of psoriasis.²¹

Occupational Assessment
Formal assessment of occupational function can be done with the WPAI-PSO, a 6-question valid instrument.²² Providers may look for risk factors associated with greater loss in work productivity to help identify and offer support for patients. Patients with increased severity of itching, pain, and scaling experienced a greater decrease in work productivity.^21,23 Patients with PsA warrant early detection and treatment because they experience greater physical restraints that can interfere with work activities. Of the 459 psoriatic patients without a prior diagnosis of PsA who filled out the PsA screening and evaluation questionnaire, 144 (31.4%) received a score of 44 or higher and were referred to rheumatology for further evaluation with the classification criteria for PsA. Nine percent of patients failed to be screened and remained undiagnosed with PsA.²⁴ In a study using the health assessment questionnaire to assess 400 patients with PsA, those with worse physical function due to joint pain and stiffness were less likely to remain employed (OR: 0.56; P=.02).²⁵

Occupational Management
Identifying and coordinating symptoms of PsA between dermatology and rheumatology is beneficial for patients who experience debilitating symptoms. There are a variety of treatments available for PsA. According to the European League Against Rheumatism 2015 guidelines developed from expert opinion and systematic reviews for PsA management, there are 4 phases of treatment, with reassessment every 3 to 6 months for effectiveness of therapy.^26,27 Phase I involves initiating nonsteroidal anti-inflammatory drugs with or without glucocorticoid injections. Phase II involves synthetic disease-modifying drugs, including methotrexate, leflunomide, sulfasalazine, or cyclosporine. Phase III involves adding a second synthetic disease-modifying drug or starting a biologic, such as an anti–tumor necrosis factor, IL-12/IL-23, or IL-17 inhibitor. Phase IV involves switching to a different drug in either aforementioned class.^26,27 Treatment with biologics improves work productivity as assessed by WPAI-PSO for psoriasis and PsA.^28-30 Encouraging patients to speak up in the workplace and request small accommodations such as timely breaks or ergonomic chairs can help patients feel more comfortable and supported in the work environment.¹⁸ Patients who felt supported at work were more likely to remain employed.²⁵

Interpersonal Relationships Prevalence
Misinformation about psoriasis, fear of rejection, and feelings of isolation may contribute to interpersonal conflict. Patients have feelings of shame and self-consciousness that hinder them from engaging in social activities and seeking out relationships.³¹ Twenty-nine percent of patients feel that psoriasis has interfered with establishing relationships because of negative self-esteem associated with the disease,³² and 26.3% have experienced people avoiding physical contact.³³ Family and spouses of patients with psoriasis may be secondarily affected due to economic and emotional distress. Ninety-eight percent of family members of psoriatic patients experienced emotional distress and 54% experienced the burden of care.³⁴ In a survey of 63 relatives and partners of patients with psoriasis, 57% experienced psychological distress, including anxiety and worry over a psoriatic patient’s future.³⁵

Interpersonal Relationships Assessment
Current available tools, including the DLQI and short form health survey, measure overall QOL, including social functioning, but may not be practical in a clinic setting. Although no quick-screening test to assess for this domain exists, providers are encouraged to ask patients about disease impact on interpersonal relationships. The family DLQI questionnaire, adapted from the DLQI, may help physicians and social workers evaluate the burden on a patient’s family members.³⁴

Interpersonal Relationships Management
It may be difficult for providers to address problems with interpersonal relationships without accessible tools. Patients may not be accompanied by family or friends during appointments, and it is difficult to screen for these issues during visits. Providers may offer resources such as the NPF website, which provides information about support groups. It also provides tips on dating and connecting to others in the community who share similar experiences.¹⁸ Encouraging patients to seek family or couples therapy also may be beneficial. Increased social support can lead to better QOL and fewer depressive symptoms.³⁶

Sexual Functioning Prevalence
Psoriasis affects both physical and psychological components of sexual function. Among 3485 patients with skin conditions who were surveyed about sexual function, 34% of psoriatic patients reported that psoriasis interfered with sexual functioning at least to a certain degree.³⁷ Sexual impairment was strongly associated with depression, anxiety, and suicidal ideation; 24% of depressed patients and 20% of anxious patients experienced sexual problems a lot or very much, based on the DLQI.³⁷ Depending on the questionnaire used, the prevalence of sexual dysfunction due to psoriasis ranged from 35.5% to 71.3%.³⁸ In an observational cohort study of 158 participants (n=79 psoriasis patients and n=79 controls), 34.2% of patients with psoriasis experienced erectile dysfunction compared to 17.7% of controls.³⁹ Forty-two percent of psoriatic patients with genital involvement reported dyspareunia, 32% reported worsening of genital psoriasis after intercourse, and 43% reported decreased frequency of intercourse.⁴⁰

Sexual Functioning Assessment
The Skindex-29, DLQI, and psoriasis disability index are available QOL tools that include one question evaluating difficulties with sexual function. The Massachusetts General Hospital sexual functioning questionnaire is a 5-item validated tool that specifically assesses sexual dysfunction.⁴¹ Distribution of lesions can help identify patients who are more likely to experience sexual dysfunction. In 160 patients who completed the questionnaire and self-reported psoriasis area and severity index, lesions on the abdomen, genitals, lumbar region, and buttocks were associated with worse sexual functioning (OR: 7.9; 95% CI, 2.3-33.4; P<.05).⁴² Dermatologists could assess for sexual problems using either formal questionnaires or direct conversations during the routine psoriasis visit, as patients may be suffering in silence due to this sensitive topic.

Sexual Functioning Management
Better disease control leads to improved sexual function, as patients experience fewer feelings of shame, anxiety, and depression, as well as improvement of physical symptoms that can interfere with sexual functioning.^38,43,44 Reducing friction, warmth, and moisture, as well as avoiding tight clothing, can help those with genital psoriasis. Patients are advised to reapply topical medications after sexual intercourse. Patients also can apply makeup to disguise psoriasis and help reduce feelings of self-consciousness that can impede sexual intimacy.¹⁸

Comment

The psychosocial burden of psoriasis penetrates many facets of patient lives. Psoriasis can invoke feelings of shame and embarrassment that are worsened by the public’s misconceptions about psoriasis, resulting in serious mental health issues that can cause even greater disability. Depression and anxiety are prevalent in patients with psoriasis. The characteristic symptoms of pain and pruritus along with psychiatric comorbidities can have an underestimated impact on daily activities, including employment, interpersonal relationships, and sexual function. Such dysfunctions have serious implications toward wages, professional advancement, social support, and overall QOL.

Dermatology providers play an important role in screening for these problems through validated questionnaires and identifying risks. Simple screening questions such as the PHQ-9 can be beneficial and feasible during dermatology visits. Screening for PsA can help patients avoid problems at work. Sexual dysfunction is a sensitive topic; however, providers can use a 1-question screen from valid questionnaires and inquire about the location of lesions as opportunities to address this issue.

Interventions lead to better disease control, which concurrently improves overall QOL. These interventions depend on both patient adherence and a physician’s commitment to finding an optimal treatment regimen for each individual. Medical management; coordinating care; developing treatment plans with psychiatry, rheumatology, and primary care providers; and psychological counseling and services may be necessary and beneficial (Table). Offering accessible resources such as the NPF website helps patients access information outside the clinic when it is not feasible to address all these concerns in a single visit. Psoriasis requires more than just medical management; it requires dermatology providers to use a multidisciplinary approach to address the psychosocial aspects of the disease.

Conclusion

The psychosocial burden of psoriasis is immense. Stigma, public misconception, mental health concerns, and occupational and interpersonal difficulty are the basis of disease burden. Providers play a vital role in assessing the effect psoriasis has on different areas of patients’ lives and providing appropriate interventions and resources to reduce disease burden.

The psychosocial impact of psoriasis is a critical component of disease burden. Psoriatic patients have high rates of depression and anxiety, problems at work, and difficulties with interpersonal relationships and intimacy.¹ A National Psoriasis Foundation (NPF) survey from 2003 to 2011 reported that psoriasis affects overall emotional well-being in 88% of patients and enjoyment of life in 82% of patients.²

The reasons for psychosocial burden stem from public misconceptions and disease stigma. A survey of 1005 individuals (age range, 16–64 years) about their perceptions of psoriasis revealed that 16.5% believed that psoriasis is contagious and 6.8% believed that psoriasis is related to personal hygiene.³ Fifty percent practiced discriminatory behavior toward psoriatic patients, including reluctance to shake hands (28.8%) and engage in sexual relations/intercourse (44.1%). Sixty-five percent of psoriatic patients felt their appearance is unsightly, and 73% felt self-conscious about having psoriasis.²

The psychosocial burden exists despite medical treatment of the disease. In a cross-sectional study of 1184 psoriatic patients, 70.2% had impaired quality of life (QOL) as measured by the dermatology life quality index (DLQI), even after receiving a 4-week treatment for psoriasis.⁴ Medical treatment of psoriasis is not enough; providers need to assess overall QOL and provide treatment and resources for these patients in addition to symptomatic management.

There have been many studies on the psychosocial burden of psoriasis, but few have focused on a dermatology resident’s role in addressing this issue. This article will review psychosocial domains—psychiatric comorbidities and social functioning including occupational functioning, interpersonal relationships, and sexual functioning— and discuss a dermatology resident’s role in assessing and addressing each of these areas.

Methods

A PubMed search of articles indexed for MEDLINE was conducted using the following terms: psoriasis, depression, anxiety, work productivity, sexual functioning, and interpersonal relationships. Selected articles covered prevalence, assessment, and management of each psychosocial domain.

Results

Psychiatric Comorbidities

Prevalence
A high prevalence of psychiatric comorbidities exists in psoriatic patients. In a study of 469,097 patients with psoriasis, depression was the third most prevalent comorbidity (17.91%), following hyperlipidemia (45.64%) and hypertension (42.19%).⁵ In a 10-year longitudinal, population-based, prospective cohort study, antidepressant prescriptions were twice as frequent in psoriatic patients (17.8%) compared to control (7.9%)(P<.001).⁶ In a meta-analysis of 98 studies investigating psoriatic patients and psychiatric comorbidities, patients with psoriasis were 1.5 times more likely to experience depression (odds ratio [OR]: 1.57; 95% CI, 1.40-1.76) and use antidepressants (OR: 4.24; 95% CI, 1.53-11.76) compared to control.⁷ Patients with psoriasis were more likely to attempt suicide (OR: 1.32; 95% CI, 1.14-1.54) and complete suicide (OR: 1.20; 95% CI, 1.04-1.39) compared to people without psoriasis.⁸ A 1-year cross-sectional study of 90 psoriatic patients reported 78.7% were diagnosed with depression and 76.7% were diagnosed with anxiety. Seventy-two percent reported both anxiety and depression, correlating with worse QOL (χ²=26.7; P<.05).⁹

Assessment
Psychiatric comorbidities are assessed using clinical judgment and formal screening questionnaires in research studies. Signs of depression in patients with psoriasis can manifest as poor treatment adherence and recurrent flares of psoriasis.^10,11 Psoriatic patients with psychiatric comorbidities were less likely to be adherent to treatment (risk ratio: 0.35; P<.003).¹⁰ The patient health questionnaire (PHQ) 9 and generalized anxiety disorder scale (GAD) 7 are validated and reliable questionnaires. The first 2 questions in PHQ-9 and GAD-7 screen for depression and anxiety, respectively.^12-14 These 2-question screens are practical in a fast-paced dermatology outpatient setting. Systematic questionnaires specifically targeting mood disorders may be more beneficial than the widely used DLQI, which may not adequately capture mood disorders. Over the course of 10 months, 607 patients with psoriasis were asked to fill out the PHQ-9, GAD-7, and DLQI. Thirty-eight percent of patients with major depressive disorder had a DLQI score lower than 10, while 46% of patients with generalized anxiety disorder had a DLQI score lower than 10.¹⁵ Other questionnaires, including the hospital anxiety and depression scale and Beck depression inventory, are valid instruments with high sensitivity but are commonly used for research purposes and may not be clinically feasible.¹⁶

Management
Dermatologists should refer patients with depression and/or anxiety to psychiatry. Interventions include pharmacologic and nonpharmacologic management. First-line therapy for depression and anxiety is a combination of selective serotonin reuptake inhibitors and cognitive behavioral therapy.¹⁷ In addition, providers can direct patients to online resources such as the NPF website, where patients with psoriasis can access information about the signs and symptoms of mood disorders and contact the patient navigation center for further help.¹⁸

Social Functioning

Occupational Prevalence
The NPF found that 92% of patients with psoriasis or psoriatic arthritis (PsA) surveyed between 2003 and 2011 cited their psoriasis as reason for unemployment.² In a survey of 43 patients asked about social and occupational functioning using the social and occupational assessment scale, 62.5% of psoriatic patients reported distress at work and 51.1% reported decreased efficiency at work.¹⁹ A national online survey that was conducted in France and issued to patients with and without psoriasis assessed overall QOL and work productivity using the work productivity and activity impairment questionnaire for psoriasis (WPAI-PSO). Of 714 patients with psoriasis and PsA, the latter had a 57.6% decrease in work productivity over 7 days compared to 27.9% in controls (P<.05).²⁰ Occupational impairment leads to lost wages and hinders advancement, further exacerbating the psychosocial burden of psoriasis.²¹

Occupational Assessment
Formal assessment of occupational function can be done with the WPAI-PSO, a 6-question valid instrument.²² Providers may look for risk factors associated with greater loss in work productivity to help identify and offer support for patients. Patients with increased severity of itching, pain, and scaling experienced a greater decrease in work productivity.^21,23 Patients with PsA warrant early detection and treatment because they experience greater physical restraints that can interfere with work activities. Of the 459 psoriatic patients without a prior diagnosis of PsA who filled out the PsA screening and evaluation questionnaire, 144 (31.4%) received a score of 44 or higher and were referred to rheumatology for further evaluation with the classification criteria for PsA. Nine percent of patients failed to be screened and remained undiagnosed with PsA.²⁴ In a study using the health assessment questionnaire to assess 400 patients with PsA, those with worse physical function due to joint pain and stiffness were less likely to remain employed (OR: 0.56; P=.02).²⁵

Occupational Management
Identifying and coordinating symptoms of PsA between dermatology and rheumatology is beneficial for patients who experience debilitating symptoms. There are a variety of treatments available for PsA. According to the European League Against Rheumatism 2015 guidelines developed from expert opinion and systematic reviews for PsA management, there are 4 phases of treatment, with reassessment every 3 to 6 months for effectiveness of therapy.^26,27 Phase I involves initiating nonsteroidal anti-inflammatory drugs with or without glucocorticoid injections. Phase II involves synthetic disease-modifying drugs, including methotrexate, leflunomide, sulfasalazine, or cyclosporine. Phase III involves adding a second synthetic disease-modifying drug or starting a biologic, such as an anti–tumor necrosis factor, IL-12/IL-23, or IL-17 inhibitor. Phase IV involves switching to a different drug in either aforementioned class.^26,27 Treatment with biologics improves work productivity as assessed by WPAI-PSO for psoriasis and PsA.^28-30 Encouraging patients to speak up in the workplace and request small accommodations such as timely breaks or ergonomic chairs can help patients feel more comfortable and supported in the work environment.¹⁸ Patients who felt supported at work were more likely to remain employed.²⁵

Interpersonal Relationships Prevalence
Misinformation about psoriasis, fear of rejection, and feelings of isolation may contribute to interpersonal conflict. Patients have feelings of shame and self-consciousness that hinder them from engaging in social activities and seeking out relationships.³¹ Twenty-nine percent of patients feel that psoriasis has interfered with establishing relationships because of negative self-esteem associated with the disease,³² and 26.3% have experienced people avoiding physical contact.³³ Family and spouses of patients with psoriasis may be secondarily affected due to economic and emotional distress. Ninety-eight percent of family members of psoriatic patients experienced emotional distress and 54% experienced the burden of care.³⁴ In a survey of 63 relatives and partners of patients with psoriasis, 57% experienced psychological distress, including anxiety and worry over a psoriatic patient’s future.³⁵

Interpersonal Relationships Assessment
Current available tools, including the DLQI and short form health survey, measure overall QOL, including social functioning, but may not be practical in a clinic setting. Although no quick-screening test to assess for this domain exists, providers are encouraged to ask patients about disease impact on interpersonal relationships. The family DLQI questionnaire, adapted from the DLQI, may help physicians and social workers evaluate the burden on a patient’s family members.³⁴

Interpersonal Relationships Management
It may be difficult for providers to address problems with interpersonal relationships without accessible tools. Patients may not be accompanied by family or friends during appointments, and it is difficult to screen for these issues during visits. Providers may offer resources such as the NPF website, which provides information about support groups. It also provides tips on dating and connecting to others in the community who share similar experiences.¹⁸ Encouraging patients to seek family or couples therapy also may be beneficial. Increased social support can lead to better QOL and fewer depressive symptoms.³⁶

Sexual Functioning Prevalence
Psoriasis affects both physical and psychological components of sexual function. Among 3485 patients with skin conditions who were surveyed about sexual function, 34% of psoriatic patients reported that psoriasis interfered with sexual functioning at least to a certain degree.³⁷ Sexual impairment was strongly associated with depression, anxiety, and suicidal ideation; 24% of depressed patients and 20% of anxious patients experienced sexual problems a lot or very much, based on the DLQI.³⁷ Depending on the questionnaire used, the prevalence of sexual dysfunction due to psoriasis ranged from 35.5% to 71.3%.³⁸ In an observational cohort study of 158 participants (n=79 psoriasis patients and n=79 controls), 34.2% of patients with psoriasis experienced erectile dysfunction compared to 17.7% of controls.³⁹ Forty-two percent of psoriatic patients with genital involvement reported dyspareunia, 32% reported worsening of genital psoriasis after intercourse, and 43% reported decreased frequency of intercourse.⁴⁰

Sexual Functioning Assessment
The Skindex-29, DLQI, and psoriasis disability index are available QOL tools that include one question evaluating difficulties with sexual function. The Massachusetts General Hospital sexual functioning questionnaire is a 5-item validated tool that specifically assesses sexual dysfunction.⁴¹ Distribution of lesions can help identify patients who are more likely to experience sexual dysfunction. In 160 patients who completed the questionnaire and self-reported psoriasis area and severity index, lesions on the abdomen, genitals, lumbar region, and buttocks were associated with worse sexual functioning (OR: 7.9; 95% CI, 2.3-33.4; P<.05).⁴² Dermatologists could assess for sexual problems using either formal questionnaires or direct conversations during the routine psoriasis visit, as patients may be suffering in silence due to this sensitive topic.

Sexual Functioning Management
Better disease control leads to improved sexual function, as patients experience fewer feelings of shame, anxiety, and depression, as well as improvement of physical symptoms that can interfere with sexual functioning.^38,43,44 Reducing friction, warmth, and moisture, as well as avoiding tight clothing, can help those with genital psoriasis. Patients are advised to reapply topical medications after sexual intercourse. Patients also can apply makeup to disguise psoriasis and help reduce feelings of self-consciousness that can impede sexual intimacy.¹⁸

Comment

The psychosocial burden of psoriasis penetrates many facets of patient lives. Psoriasis can invoke feelings of shame and embarrassment that are worsened by the public’s misconceptions about psoriasis, resulting in serious mental health issues that can cause even greater disability. Depression and anxiety are prevalent in patients with psoriasis. The characteristic symptoms of pain and pruritus along with psychiatric comorbidities can have an underestimated impact on daily activities, including employment, interpersonal relationships, and sexual function. Such dysfunctions have serious implications toward wages, professional advancement, social support, and overall QOL.

Dermatology providers play an important role in screening for these problems through validated questionnaires and identifying risks. Simple screening questions such as the PHQ-9 can be beneficial and feasible during dermatology visits. Screening for PsA can help patients avoid problems at work. Sexual dysfunction is a sensitive topic; however, providers can use a 1-question screen from valid questionnaires and inquire about the location of lesions as opportunities to address this issue.

Interventions lead to better disease control, which concurrently improves overall QOL. These interventions depend on both patient adherence and a physician’s commitment to finding an optimal treatment regimen for each individual. Medical management; coordinating care; developing treatment plans with psychiatry, rheumatology, and primary care providers; and psychological counseling and services may be necessary and beneficial (Table). Offering accessible resources such as the NPF website helps patients access information outside the clinic when it is not feasible to address all these concerns in a single visit. Psoriasis requires more than just medical management; it requires dermatology providers to use a multidisciplinary approach to address the psychosocial aspects of the disease.

Conclusion

The psychosocial burden of psoriasis is immense. Stigma, public misconception, mental health concerns, and occupational and interpersonal difficulty are the basis of disease burden. Providers play a vital role in assessing the effect psoriasis has on different areas of patients’ lives and providing appropriate interventions and resources to reduce disease burden.

Psoriasis is a chronic autoimmune skin disease affecting approximately 6.7 million adults in the United States.¹ Although its pathogenesis is not yet clear, risk factors and triggers provide insight into potential pathways by which psoriasis can occur. There is notable overlap between risk factors and triggers of psoriasis; perceived risk factors might, in fact, be triggers causing manifestation of disease in predisposed persons. In this review, we summarize the key factors contributing to onset and exacerbation of psoriasis. When learning to manage this chronic disease, it also may be helpful to educate patients about how these elements may affect the course of psoriasis.

Genetics

The pathogenesis of psoriasis has a strong genetic component, with approximately 70% and 20% concordance rates in monozygotic and dizygotic twins, respectively.² Moreover, studies have shown a positive family history in approximately 35% of patients.^3,4 Family-based studies have found a 50% risk of developing psoriasis in patients with 2 affected parents.⁵ However, the genetics of psoriasis are complex and are attributed to many different genes. Thus far, genes involving antigen presentation, T-cell receptor development and polarization, and the nuclear factor κβ (NF-κβ) pathway have been identified.⁶

HLA-Cw6
The most well-studied gene implicated in psoriasis is HLA-Cw6, which encodes a major histocompatibility complex class I allele supporting psoriasis as a T cell–mediated reaction to an autoantigen.⁶ Two potential antigens for HLA-Cw6 recently have been identified: LL-37, a cathelicidin-related antimicrobial peptide, and the A disintegrin and metalloproteinase with thrombospondin motifs-like protein 5 (ADAMTSL5), found on melanocytes and keratinocytes.⁷ The percentage of psoriasis patients with HLA-Cw6 ranges from 10.5% to 77.2%, with higher frequency in white individuals than in Asians.⁷

HLA-Cw6 manifests as specific features in psoriasis, including onset of disease before 21 years of age.⁸ It also is more strongly associated with guttate-type psoriasis, greater body surface area involvement, and higher incidence of Köbner phenomenon. Patients with positive HLA-Cw6 also reported worsening of psoriasis during and after throat infection.⁹

Caspase Recruitment Domain Family Member 14
Another gene mutation implicated in psoriasis pathogenesis is caspase recruitment domain family member 14, CARD14 (formerly PSORS2), a gene encoding a scaffolding protein important in the activation of NF-κβ.^10,11 Missense CARD14 mutations cause upregulation of NF-κβ through formation of a complex with adapter protein B-cell lymphoma 10 (BCL10) and mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1),¹² which, in turn, causes increased transcription of cytokines IL-8, C-C motif chemokine ligand 20 (CCL-20), and IL-36 gamma in the keratinocyte.¹³ Mutations in CARD14 alone lead to psoriasiform skin in mice through amplified activation of the IL-23/IL-17 axis.^14,15 Patients with a mutation in a CARD14 variant (p.Arg820Trp) have demonstrated better response to tumor necrosis factor (TNF) inhibitors.¹⁶

Further characterization of the genetic pathogenesis of psoriasis might lead to better targeted therapies, including the possibility of MALT1 inhibitors as a treatment option.¹²

Infection

Streptococcus
The association between streptococcal infection and psoriasis was first documented more than 100 years ago, specifically the onset of acute guttate psoriasis.^17,18 Although classically described following throat infection, psoriasis also occurs following streptococcal vulvovaginitis and perianal streptococcal infection.^19,20

This type of psoriasis is typically self-limited but can recur with subsequent streptococcal infections or initiate a more chronic plaque psoriasis. Patients have a 1 in 3 risk of developing chronic psoriasis within 10 years of a single episode of acute guttate psoriasis.²¹ Moreover, in many patients with existing plaque psoriasis, throat infection exacerbates psoriatic symptoms.²² The mechanism of exacerbation is likely due to cross-reactivity between streptococcal M surface antigen and human keratinocytes and might also be influenced by inherited abnormalities in immune response.^23-26 Therefore, tonsillectomy has been studied as a possible treatment of psoriasis but is likely helpful only in patients with exacerbations of disease that are closely associated with recurrent tonsillitis.²⁷

Human Immunodeficiency Virus
The prevalence of psoriasis in human immunodeficiency virus (HIV) patients is similar to or greater than the general population.²⁸ Human immunodeficiency virus infection causes new onset of psoriasis and exacerbation of existing psoriasis; severity often is correlated with worsening immune function.^28,29

The clinical subtypes of psoriasis that occur most frequently with HIV include guttate, inverse, and erythrodermic, though patients may present with any subtype.²⁸ The mechanism is puzzling because HIV is primarily mediated by helper T cell 2 (T_H2) cytokines, whereas psoriasis is mainly driven by helper T cell 1 (T_H1) cytokines.³⁰ Furthermore, despite increased severity with lower CD4⁺ counts, treatments further lowering T-cell counts paradoxically improve symptoms.³¹ Current literature suggests that expansion of CD8⁺ memory T cells might be the primary mechanism in the exacerbation of psoriasis in HIV-mediated immunosuppression.³⁰

Treatment of HIV-associated psoriasis presents challenges because many therapeutics cause further immunosuppression. The National Psoriasis Foundation recommends topical preparations as first-line agents for mild to moderate psoriasis.³² For moderate to severe psoriasis, retroviral agents may be effective as first-line monotherapy or when supplemented by phototherapy with UVB or psoralen plus UVA. Retinoids can be used as second-line agents.³² For cases of severe refractory psoriasis, cyclosporine, methotrexate, TNF inhibitors, or hydroxyurea can be considered. There also is evidence that apremilast is effective without risk for worsening immune function.³³

Other Infections
Other bacteria associated with triggering or exacerbating psoriasis include Staphylococcus aureus and Helicobacter pylori.^34,35 Fungi, such as species of the genera Malassezia and Candida, and other viruses, including papillomaviruses and retroviruses, also have been implicated.³⁴

Medications

Numerous medications can trigger psoriasis, including lithium, nonsteroidal anti-inflammatory drugs, antimalarials, beta-blockers, and angiotensin-converting enzyme inhibitors.³⁴ More recent literature suggests that TNF inhibitors also can paradoxically induce psoriasis in rare cases.³⁵

Lithium
Psoriasis is the most common cutaneous adverse effect of lithium.³⁴ It is more likely to exacerbate existing disease but also can induce onset of psoriasis; it also can cause disease that is more refractory to treatment.^34,36 Current literature hypothesizes that lithium triggers psoriasis by interference of intracellular calcium channels through reduction of inositol, thereby affecting keratinocyte proliferation and differentiation.³⁴ Lithium also inhibits glycogen synthase kinase-3 (GSK-3), a serine threonine kinase, which, in turn, induces human keratinocyte proliferation.³⁷ However, it is unlikely lithium alone can induce psoriasis; genetic predisposition is necessary.

TNF Inhibitors
Tumor necrosis factor inhibitors such as adalimumab, etanercept, certolizumab pegol, golimumab, and infliximab are used in various inflammatory diseases, including psoriasis. Interestingly, there have been more than 200 reported cases of suspected TNF inhibitor–induced or –exacerbated psoriasis.³⁸ This phenomenon appears to occur more frequently with infliximab and is most likely to occur in the first year of treatment of Crohn disease and rheumatoid arthritis.³⁸ Plaque psoriasis is the most common form, but 15% to 26% of cases presented with 2 or more morphologies.^38,39

Treatment options include discontinuing therapy, though many patients experience resolution while continuing treatment or switching to another TNF inhibitor.^38-40 Traditional topical therapies also have been used with success.⁴⁰ The pathogenesis of this phenomenon is still unclear but is thought to involve both the IL-23/helper T cell 17 (T_H17) axis and dysregulation of IFN-α in the setting of TNF suppression.³⁸

Lifestyle

Obesity is a chronic low-grade inflammatory state that can contribute to the onset of psoriasis or exacerbation of existing disease.^41,42 Smoking also is thought to increase the risk for psoriasis, perhaps by a similar mechanism. Lee et al⁴³ found a strong positive correlation between the amount or duration of smoking and the incidence of psoriasis.

The relationship between psoriasis and alcohol consumption is less clear than it is between psoriasis and obesity or smoking; greater consumption is found in psoriasis patients, but evidence is insufficient to deem alcohol a risk factor.⁴⁴

Conclusion

Various factors, including genetics, infection, pharmacotherapeutic, and lifestyle, can all contribute to the induction or exacerbation of psoriasis. These factors can provide clues to the pathogenesis of psoriasis as well as help clinicians better counsel patients about their disease.

Psoriasis is a chronic autoimmune skin disease affecting approximately 6.7 million adults in the United States.¹ Although its pathogenesis is not yet clear, risk factors and triggers provide insight into potential pathways by which psoriasis can occur. There is notable overlap between risk factors and triggers of psoriasis; perceived risk factors might, in fact, be triggers causing manifestation of disease in predisposed persons. In this review, we summarize the key factors contributing to onset and exacerbation of psoriasis. When learning to manage this chronic disease, it also may be helpful to educate patients about how these elements may affect the course of psoriasis.

Genetics

The pathogenesis of psoriasis has a strong genetic component, with approximately 70% and 20% concordance rates in monozygotic and dizygotic twins, respectively.² Moreover, studies have shown a positive family history in approximately 35% of patients.^3,4 Family-based studies have found a 50% risk of developing psoriasis in patients with 2 affected parents.⁵ However, the genetics of psoriasis are complex and are attributed to many different genes. Thus far, genes involving antigen presentation, T-cell receptor development and polarization, and the nuclear factor κβ (NF-κβ) pathway have been identified.⁶

HLA-Cw6
The most well-studied gene implicated in psoriasis is HLA-Cw6, which encodes a major histocompatibility complex class I allele supporting psoriasis as a T cell–mediated reaction to an autoantigen.⁶ Two potential antigens for HLA-Cw6 recently have been identified: LL-37, a cathelicidin-related antimicrobial peptide, and the A disintegrin and metalloproteinase with thrombospondin motifs-like protein 5 (ADAMTSL5), found on melanocytes and keratinocytes.⁷ The percentage of psoriasis patients with HLA-Cw6 ranges from 10.5% to 77.2%, with higher frequency in white individuals than in Asians.⁷

HLA-Cw6 manifests as specific features in psoriasis, including onset of disease before 21 years of age.⁸ It also is more strongly associated with guttate-type psoriasis, greater body surface area involvement, and higher incidence of Köbner phenomenon. Patients with positive HLA-Cw6 also reported worsening of psoriasis during and after throat infection.⁹

Caspase Recruitment Domain Family Member 14
Another gene mutation implicated in psoriasis pathogenesis is caspase recruitment domain family member 14, CARD14 (formerly PSORS2), a gene encoding a scaffolding protein important in the activation of NF-κβ.^10,11 Missense CARD14 mutations cause upregulation of NF-κβ through formation of a complex with adapter protein B-cell lymphoma 10 (BCL10) and mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1),¹² which, in turn, causes increased transcription of cytokines IL-8, C-C motif chemokine ligand 20 (CCL-20), and IL-36 gamma in the keratinocyte.¹³ Mutations in CARD14 alone lead to psoriasiform skin in mice through amplified activation of the IL-23/IL-17 axis.^14,15 Patients with a mutation in a CARD14 variant (p.Arg820Trp) have demonstrated better response to tumor necrosis factor (TNF) inhibitors.¹⁶

Further characterization of the genetic pathogenesis of psoriasis might lead to better targeted therapies, including the possibility of MALT1 inhibitors as a treatment option.¹²

Infection

Streptococcus
The association between streptococcal infection and psoriasis was first documented more than 100 years ago, specifically the onset of acute guttate psoriasis.^17,18 Although classically described following throat infection, psoriasis also occurs following streptococcal vulvovaginitis and perianal streptococcal infection.^19,20

This type of psoriasis is typically self-limited but can recur with subsequent streptococcal infections or initiate a more chronic plaque psoriasis. Patients have a 1 in 3 risk of developing chronic psoriasis within 10 years of a single episode of acute guttate psoriasis.²¹ Moreover, in many patients with existing plaque psoriasis, throat infection exacerbates psoriatic symptoms.²² The mechanism of exacerbation is likely due to cross-reactivity between streptococcal M surface antigen and human keratinocytes and might also be influenced by inherited abnormalities in immune response.^23-26 Therefore, tonsillectomy has been studied as a possible treatment of psoriasis but is likely helpful only in patients with exacerbations of disease that are closely associated with recurrent tonsillitis.²⁷

Human Immunodeficiency Virus
The prevalence of psoriasis in human immunodeficiency virus (HIV) patients is similar to or greater than the general population.²⁸ Human immunodeficiency virus infection causes new onset of psoriasis and exacerbation of existing psoriasis; severity often is correlated with worsening immune function.^28,29

The clinical subtypes of psoriasis that occur most frequently with HIV include guttate, inverse, and erythrodermic, though patients may present with any subtype.²⁸ The mechanism is puzzling because HIV is primarily mediated by helper T cell 2 (T_H2) cytokines, whereas psoriasis is mainly driven by helper T cell 1 (T_H1) cytokines.³⁰ Furthermore, despite increased severity with lower CD4⁺ counts, treatments further lowering T-cell counts paradoxically improve symptoms.³¹ Current literature suggests that expansion of CD8⁺ memory T cells might be the primary mechanism in the exacerbation of psoriasis in HIV-mediated immunosuppression.³⁰

Treatment of HIV-associated psoriasis presents challenges because many therapeutics cause further immunosuppression. The National Psoriasis Foundation recommends topical preparations as first-line agents for mild to moderate psoriasis.³² For moderate to severe psoriasis, retroviral agents may be effective as first-line monotherapy or when supplemented by phototherapy with UVB or psoralen plus UVA. Retinoids can be used as second-line agents.³² For cases of severe refractory psoriasis, cyclosporine, methotrexate, TNF inhibitors, or hydroxyurea can be considered. There also is evidence that apremilast is effective without risk for worsening immune function.³³

Other Infections
Other bacteria associated with triggering or exacerbating psoriasis include Staphylococcus aureus and Helicobacter pylori.^34,35 Fungi, such as species of the genera Malassezia and Candida, and other viruses, including papillomaviruses and retroviruses, also have been implicated.³⁴

Medications

Numerous medications can trigger psoriasis, including lithium, nonsteroidal anti-inflammatory drugs, antimalarials, beta-blockers, and angiotensin-converting enzyme inhibitors.³⁴ More recent literature suggests that TNF inhibitors also can paradoxically induce psoriasis in rare cases.³⁵

Lithium
Psoriasis is the most common cutaneous adverse effect of lithium.³⁴ It is more likely to exacerbate existing disease but also can induce onset of psoriasis; it also can cause disease that is more refractory to treatment.^34,36 Current literature hypothesizes that lithium triggers psoriasis by interference of intracellular calcium channels through reduction of inositol, thereby affecting keratinocyte proliferation and differentiation.³⁴ Lithium also inhibits glycogen synthase kinase-3 (GSK-3), a serine threonine kinase, which, in turn, induces human keratinocyte proliferation.³⁷ However, it is unlikely lithium alone can induce psoriasis; genetic predisposition is necessary.

TNF Inhibitors
Tumor necrosis factor inhibitors such as adalimumab, etanercept, certolizumab pegol, golimumab, and infliximab are used in various inflammatory diseases, including psoriasis. Interestingly, there have been more than 200 reported cases of suspected TNF inhibitor–induced or –exacerbated psoriasis.³⁸ This phenomenon appears to occur more frequently with infliximab and is most likely to occur in the first year of treatment of Crohn disease and rheumatoid arthritis.³⁸ Plaque psoriasis is the most common form, but 15% to 26% of cases presented with 2 or more morphologies.^38,39

Treatment options include discontinuing therapy, though many patients experience resolution while continuing treatment or switching to another TNF inhibitor.^38-40 Traditional topical therapies also have been used with success.⁴⁰ The pathogenesis of this phenomenon is still unclear but is thought to involve both the IL-23/helper T cell 17 (T_H17) axis and dysregulation of IFN-α in the setting of TNF suppression.³⁸

Lifestyle

Obesity is a chronic low-grade inflammatory state that can contribute to the onset of psoriasis or exacerbation of existing disease.^41,42 Smoking also is thought to increase the risk for psoriasis, perhaps by a similar mechanism. Lee et al⁴³ found a strong positive correlation between the amount or duration of smoking and the incidence of psoriasis.

The relationship between psoriasis and alcohol consumption is less clear than it is between psoriasis and obesity or smoking; greater consumption is found in psoriasis patients, but evidence is insufficient to deem alcohol a risk factor.⁴⁴

Conclusion

Various factors, including genetics, infection, pharmacotherapeutic, and lifestyle, can all contribute to the induction or exacerbation of psoriasis. These factors can provide clues to the pathogenesis of psoriasis as well as help clinicians better counsel patients about their disease.

Psoriasis is a chronic autoimmune skin disease affecting approximately 6.7 million adults in the United States.¹ Although its pathogenesis is not yet clear, risk factors and triggers provide insight into potential pathways by which psoriasis can occur. There is notable overlap between risk factors and triggers of psoriasis; perceived risk factors might, in fact, be triggers causing manifestation of disease in predisposed persons. In this review, we summarize the key factors contributing to onset and exacerbation of psoriasis. When learning to manage this chronic disease, it also may be helpful to educate patients about how these elements may affect the course of psoriasis.

Genetics

The pathogenesis of psoriasis has a strong genetic component, with approximately 70% and 20% concordance rates in monozygotic and dizygotic twins, respectively.² Moreover, studies have shown a positive family history in approximately 35% of patients.^3,4 Family-based studies have found a 50% risk of developing psoriasis in patients with 2 affected parents.⁵ However, the genetics of psoriasis are complex and are attributed to many different genes. Thus far, genes involving antigen presentation, T-cell receptor development and polarization, and the nuclear factor κβ (NF-κβ) pathway have been identified.⁶

HLA-Cw6
The most well-studied gene implicated in psoriasis is HLA-Cw6, which encodes a major histocompatibility complex class I allele supporting psoriasis as a T cell–mediated reaction to an autoantigen.⁶ Two potential antigens for HLA-Cw6 recently have been identified: LL-37, a cathelicidin-related antimicrobial peptide, and the A disintegrin and metalloproteinase with thrombospondin motifs-like protein 5 (ADAMTSL5), found on melanocytes and keratinocytes.⁷ The percentage of psoriasis patients with HLA-Cw6 ranges from 10.5% to 77.2%, with higher frequency in white individuals than in Asians.⁷

HLA-Cw6 manifests as specific features in psoriasis, including onset of disease before 21 years of age.⁸ It also is more strongly associated with guttate-type psoriasis, greater body surface area involvement, and higher incidence of Köbner phenomenon. Patients with positive HLA-Cw6 also reported worsening of psoriasis during and after throat infection.⁹

Caspase Recruitment Domain Family Member 14
Another gene mutation implicated in psoriasis pathogenesis is caspase recruitment domain family member 14, CARD14 (formerly PSORS2), a gene encoding a scaffolding protein important in the activation of NF-κβ.^10,11 Missense CARD14 mutations cause upregulation of NF-κβ through formation of a complex with adapter protein B-cell lymphoma 10 (BCL10) and mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1),¹² which, in turn, causes increased transcription of cytokines IL-8, C-C motif chemokine ligand 20 (CCL-20), and IL-36 gamma in the keratinocyte.¹³ Mutations in CARD14 alone lead to psoriasiform skin in mice through amplified activation of the IL-23/IL-17 axis.^14,15 Patients with a mutation in a CARD14 variant (p.Arg820Trp) have demonstrated better response to tumor necrosis factor (TNF) inhibitors.¹⁶

Further characterization of the genetic pathogenesis of psoriasis might lead to better targeted therapies, including the possibility of MALT1 inhibitors as a treatment option.¹²

Infection

Streptococcus
The association between streptococcal infection and psoriasis was first documented more than 100 years ago, specifically the onset of acute guttate psoriasis.^17,18 Although classically described following throat infection, psoriasis also occurs following streptococcal vulvovaginitis and perianal streptococcal infection.^19,20

This type of psoriasis is typically self-limited but can recur with subsequent streptococcal infections or initiate a more chronic plaque psoriasis. Patients have a 1 in 3 risk of developing chronic psoriasis within 10 years of a single episode of acute guttate psoriasis.²¹ Moreover, in many patients with existing plaque psoriasis, throat infection exacerbates psoriatic symptoms.²² The mechanism of exacerbation is likely due to cross-reactivity between streptococcal M surface antigen and human keratinocytes and might also be influenced by inherited abnormalities in immune response.^23-26 Therefore, tonsillectomy has been studied as a possible treatment of psoriasis but is likely helpful only in patients with exacerbations of disease that are closely associated with recurrent tonsillitis.²⁷

Human Immunodeficiency Virus
The prevalence of psoriasis in human immunodeficiency virus (HIV) patients is similar to or greater than the general population.²⁸ Human immunodeficiency virus infection causes new onset of psoriasis and exacerbation of existing psoriasis; severity often is correlated with worsening immune function.^28,29

The clinical subtypes of psoriasis that occur most frequently with HIV include guttate, inverse, and erythrodermic, though patients may present with any subtype.²⁸ The mechanism is puzzling because HIV is primarily mediated by helper T cell 2 (T_H2) cytokines, whereas psoriasis is mainly driven by helper T cell 1 (T_H1) cytokines.³⁰ Furthermore, despite increased severity with lower CD4⁺ counts, treatments further lowering T-cell counts paradoxically improve symptoms.³¹ Current literature suggests that expansion of CD8⁺ memory T cells might be the primary mechanism in the exacerbation of psoriasis in HIV-mediated immunosuppression.³⁰

Treatment of HIV-associated psoriasis presents challenges because many therapeutics cause further immunosuppression. The National Psoriasis Foundation recommends topical preparations as first-line agents for mild to moderate psoriasis.³² For moderate to severe psoriasis, retroviral agents may be effective as first-line monotherapy or when supplemented by phototherapy with UVB or psoralen plus UVA. Retinoids can be used as second-line agents.³² For cases of severe refractory psoriasis, cyclosporine, methotrexate, TNF inhibitors, or hydroxyurea can be considered. There also is evidence that apremilast is effective without risk for worsening immune function.³³

Other Infections
Other bacteria associated with triggering or exacerbating psoriasis include Staphylococcus aureus and Helicobacter pylori.^34,35 Fungi, such as species of the genera Malassezia and Candida, and other viruses, including papillomaviruses and retroviruses, also have been implicated.³⁴

Medications

Numerous medications can trigger psoriasis, including lithium, nonsteroidal anti-inflammatory drugs, antimalarials, beta-blockers, and angiotensin-converting enzyme inhibitors.³⁴ More recent literature suggests that TNF inhibitors also can paradoxically induce psoriasis in rare cases.³⁵

Lithium
Psoriasis is the most common cutaneous adverse effect of lithium.³⁴ It is more likely to exacerbate existing disease but also can induce onset of psoriasis; it also can cause disease that is more refractory to treatment.^34,36 Current literature hypothesizes that lithium triggers psoriasis by interference of intracellular calcium channels through reduction of inositol, thereby affecting keratinocyte proliferation and differentiation.³⁴ Lithium also inhibits glycogen synthase kinase-3 (GSK-3), a serine threonine kinase, which, in turn, induces human keratinocyte proliferation.³⁷ However, it is unlikely lithium alone can induce psoriasis; genetic predisposition is necessary.

TNF Inhibitors
Tumor necrosis factor inhibitors such as adalimumab, etanercept, certolizumab pegol, golimumab, and infliximab are used in various inflammatory diseases, including psoriasis. Interestingly, there have been more than 200 reported cases of suspected TNF inhibitor–induced or –exacerbated psoriasis.³⁸ This phenomenon appears to occur more frequently with infliximab and is most likely to occur in the first year of treatment of Crohn disease and rheumatoid arthritis.³⁸ Plaque psoriasis is the most common form, but 15% to 26% of cases presented with 2 or more morphologies.^38,39

Treatment options include discontinuing therapy, though many patients experience resolution while continuing treatment or switching to another TNF inhibitor.^38-40 Traditional topical therapies also have been used with success.⁴⁰ The pathogenesis of this phenomenon is still unclear but is thought to involve both the IL-23/helper T cell 17 (T_H17) axis and dysregulation of IFN-α in the setting of TNF suppression.³⁸

Lifestyle

Obesity is a chronic low-grade inflammatory state that can contribute to the onset of psoriasis or exacerbation of existing disease.^41,42 Smoking also is thought to increase the risk for psoriasis, perhaps by a similar mechanism. Lee et al⁴³ found a strong positive correlation between the amount or duration of smoking and the incidence of psoriasis.

The relationship between psoriasis and alcohol consumption is less clear than it is between psoriasis and obesity or smoking; greater consumption is found in psoriasis patients, but evidence is insufficient to deem alcohol a risk factor.⁴⁴

Conclusion

Various factors, including genetics, infection, pharmacotherapeutic, and lifestyle, can all contribute to the induction or exacerbation of psoriasis. These factors can provide clues to the pathogenesis of psoriasis as well as help clinicians better counsel patients about their disease.

Psoriasis is a T cell–mediated inflammatory disease that manifests as erythematous scaling plaques of the skin. In recent decades, our understanding of psoriasis has transformed from a disease isolated to the skin to a systemic disease impacting the overall health of those affected.

With recent elucidation of the pathways driving psoriasis, development of targeted therapies has resulted in an influx of options to the market. Navigating the options can seem overwhelming even to the seasoned clinician. Becoming familiar with a sound treatment approach during residency will create a foundation for biologic use in psoriasis patients throughout your career. Here we offer an approach to choosing biologic treatments based on individual patient characteristics, including disease severity, comorbidities, and ultimate treatment goals.

Immune Pathogenesis

Although the pathogenesis of psoriasis is complex and outside the scope of this article, we do recommend clinicians keep in mind the current understanding of pathways involved and ways our therapies alter them. Briefly, psoriasis is a T cell–mediated disease in which IL-12 and IL-23 released by activated dendritic cells activate T helper cells including T_H1, T_H17, and T_H22. These cells produce additional cytokines, including IFN-γ, tumor necrosis factor (TNF) α, IL-17, and IL-22, which propagate the immune response and lead to keratinocyte hyperproliferation. In general, psoriasis medications work by altering T-cell activation, effector cytokines, or cytokine receptors.

Comorbidities

A targeted approach should take into consideration the immune dysregulation shared by psoriasis and associated comorbidities (Table 1). One goal of biologic treatments is to improve comorbidities when possible. At minimum, selected treatments should not exacerbate these conditions.

Treatment Goals

Establishing treatment goals can help shape patient expectations and provide a plan for clinicians. In 2017, the National Psoriasis Foundation published a treat-to-target approach using body surface area (BSA) measurements at baseline, 3 months, and then every 6 months after starting a new treatment.¹² The target response is a decrease in psoriasis to 1% or less BSA at 3 months and to maintain this response when evaluated at 6-month intervals. Alternatively, a target of 3% BSA after 3 months is satisfactory if the patient improves by 75% BSA overall. If these targets are not met after 6 months, therapeutic alternatives can be considered.¹²

Biologic Treatment of Psoriasis

Treatment options for patients with psoriasis depend first on disease severity. Topicals and phototherapy are first line for mild to moderate disease. For moderate to severe disease, addition of systemic agents such as methotrexate, cyclosporine, or acitretin; small-molecular-weight immunomodulators such as apremilast; or biologic medications should be considered. Current biologics available for moderate to severe plaque psoriasis target TNF-α, IL-12/IL-23, IL-23, IL-17A, or IL-17A receptor.

TNF-α Inhibitors

Tumor necrosis factor α inhibitors have been available for treatment of autoimmune disease for nearly 20 years. These medications block either soluble cytokine or membrane-bound cytokine. All are given as subcutaneous injections, except for infliximab, which is a weight-based infusion.

Efficacy
Tumor necrosis factor α inhibitors are the first class to demonstrate long-term efficacy and safety in both psoriasis and psoriatic arthritis (PsA). Etanercept was approved for adults with PsA in 2002 and psoriasis in 2004, and later for pediatric psoriasis (≥4 years of age) in 2016 (Table 2). Although etanercept has a sustained safety profile, the response rates are not as high as other anti–TNF-α inhibitors. Adalimumab is one of the most prescribed biologics, with a total of 10 indications at present, including PsA. Infliximab is an intravenous infusion that demonstrates a rapid and sustained response in most patients. The dose and dosing interval can be adjusted according to response. Certolizumab pegol was approved for PsA in 2013 and for psoriasis in 2018.

Safety
To evaluate long-term safety, a multicenter prospective registry study (Psoriasis Longitudinal Assessment and Registry [PSOLAR]) was initiated in 2007 to follow clinical outcomes. Data through 2013 showed no significant increase in rates of infection, malignancy, or major adverse cardiovascular events in more than 12,000 patients.¹³

Conflicting information exists in the literature regarding risk for malignancy with TNF-α inhibitors. One recent retrospective cohort study suggested a slightly increased risk for malignancies other than nonmelanoma skin cancers in patients on TNF-α inhibitors for more than 12 months (relative risk, 1.54).¹⁴ Reports of increased risk for cutaneous squamous cell carcinomas necessitate regular skin checks.¹⁵ A potential risk for lymphoma has been noted, though having psoriasis itself imparts an increased risk for Hodgkin and cutaneous T-cell lymphoma.¹⁶

Reactivation of tuberculosis and hepatitis have been reported with TNF-α inhibition. Data suggest that infliximab may be associated with more serious infections.¹³

Demyelinating conditions such as multiple sclerosis have occurred de novo or worsened in patients on TNF-α inhibitors.¹⁷ Tumor necrosis factor α blockers should be avoided in patients with decompensated heart failure. Rare cases of liver enzyme elevation and cytopenia have been noted. Additionally, lupuslike syndromes, which are generally reversible upon discontinuation, have occurred in some patients.

Patient Selection
Tumor necrosis factor α inhibitors are the treatment of choice for patients with comorbid PsA. This class halts progression of joint destruction over time.¹⁸Select TNF-α inhibitors are indicated for inflammatory bowel disease (IBD) and are a preferred treatment in this patient population. Specifically, adalimumab and infliximab are approved for both Crohn disease (CD) and ulcerative colitis. Certolizumab pegol is approved for CD.

Tumor necrosis factor α is upregulated in obesity, cardiovascular disease, and atherosclerotic plaques. Evidence suggests that TNF-α blockers may lower cardiovascular risk over time.¹⁹ For patients with obesity, infliximab is a good option, as it is the only TNF-α inhibitor with weight-based dosing.

In patients with frequent infections or history of hepatitis C, etanercept has been the biologic most commonly used when no alternatives exist, in part due to its shorter half-life.

IL-12/IL-23 Inhibitor

Ustekinumab is a monoclonal antibody that binds the p40 subunit shared by IL-12 and IL-23, blocking their ability to bind receptors. IL-12 and IL-23 play a role in activating naïve T cells to become T_H1 or T_H17 cells, respectively.

Efficacy and Safety
Clinical trials demonstrate long-term efficacy of ustekinumab, which was approved for psoriasis in 2009, PsA in 2013, and later pediatric psoriasis (≥12 years of age) in 2017. Dosing is listed in Table 2.

Laboratory abnormalities did not arise in trials. Periodic tuberculosis screening is required. Prospective data over 5 years showed very low rates of adverse events (AEs), serious infections, malignancies, and major adverse cardiovascular events.²⁰ Ustekinumab did not worsen or improve demyelinating disease and appears safe in this population.

Patient Selection
Ustekinumab is approved for PsA and is a good option for those who are not candidates for TNF-α and IL-17 inhibitors. Ustekinumab also is approved for CD. The dosing interval of 12 weeks makes ustekinumab convenient for patients. Two dosages exist based on the patient’s weight, offering an advantage to obese patients.

IL-17/IL-17R Inhibitors

Activated T_H17 cells produce the IL-17 cytokine family, which stimulates keratinocyte proliferation and dermal inflammation. Secukinumab is a fully human monoclonal antibody, and ixekizumab is a humanized monoclonal antibody; both target IL-17A. Brodalumab targets the IL-17A receptor.

Efficacy and Safety
IL-17 inhibitors showed impressive and rapid responses in trials.^21-23 The subsets of patients who responded well and continued treatment in extension trials demonstrated that these treatments maintain efficacy over time.^24-26

In addition to tuberculosis reactivation, there is a small increased risk for cutaneous candidiasis with IL-17 inhibitors, which can be managed without stopping treatment. Laboratory abnormalities were limited to mild neutropenia, which was not associated with increased risk for infection.^21-23 With ixekizumab, neutropenia was seen more commonly in the first 12 weeks.²²

IL-17 is highly expressed in the gut mucosa, and its inhibition is thought to weaken the barrier function of the gut mucosa, promoting inflammation. As a consequence, this class is contraindicated in patients with IBD due to exacerbations of existing IBD and cases of new-onset IBD.^21-23 Symptoms of diarrhea, abdominal pain, blood in stool, or nighttime stooling on review of gastrointestinal tract symptoms should prompt further evaluation.

Brodalumab has a unique warning for risk for suicidal ideation and behavior.²³ Depression is more common in the psoriasis population in general; therefore, physicians should be aware of this potential comorbidity regardless of the treatment plan. Because the response rates are so impressive with brodalumab, the Risk Evaluation and Mitigation Strategy (REMS) program was established to ensure understanding of this risk so that patients can be appropriately counseled and managed.

Patient Selection
The improvement in psoriasis is rapid and may occur as early as week 2 to 3 of treatment after initiation of IL-17 inhibitors. Ixekizumab and secukinumab also are approved for PsA. Although improvement in joint disease is not as fast as with the anti-TNF inhibitors, notable improvement occurs by week 20 to 24.²⁷

IL-23 Inhibitors

Guselkumab and tildrakizumab are the newest biologics for psoriasis, approved in 2017 and 2018, respectively. Both are monoclonal antibodies against the p19 subunit of IL-23, which blocks activation of T_H17 cells.

Efficacy and Safety
Guselkumab and tildrakizumab demonstrated efficacy with minimal AEs or precautions noted thus far.^28,29 Infections are again a risk, making tuberculosis testing the only recommended monitoring.

Patient Selection
Both medications offer another effective and safe option for patients with psoriasis. Similar to ustekinumab, the dosing interval of 12 weeks for tildrakizumab is ideal for patients who have needle phobia or are unable to administer their own injections.

Special Populations

Pregnancy

Antibodies cross the placenta as pregnancy progresses, with the highest rate in the third trimester. Certolizumab pegol has shown the lowest concentrations in infant serum, possibly due to its unique structure lacking the fragment crystallizable region required for passage through the placenta.³⁰ For this reason, certolizumab pegol is a treatment of choice if biologic therapy is warranted during pregnancy.

Much of the pregnancy data for the remaining TNF-α inhibitors come from patients with rheumatoid arthritis or CD. In these populations, rates of major birth defects and miscarriages do not differ greatly from untreated women with these conditions.³¹ One retrospective study of unintentional pregnancies in women receiving ustekinumab showed rates of AEs similar to the general population.³²

Pregnancy data for IL-17 or IL-23 inhibitors are largely limited to animal studies. One retrospective study of women exposed to secukinumab early in gestation showed no increased risk for pregnancy-related AEs.³³ Discontinuation is still recommended for patients who become pregnant.

Pediatric Patients

Etanercept is approved for pediatric psoriatic patients 4 years and older. Children with juvenile idiopathic arthritis who are 2 years and older can receive etanercept. Ustekinumab is safe and effective for pediatric psoriatic patients 12 years and older, offering a second biologic option in children.

Although not approved for pediatric psoriasis, adalimumab is approved in pediatric CD (≥6 years of age) and for juvenile idiopathic arthritis (≥2 years of age). Infliximab is approved for children 6 years and older with CD or ulcerative colitis.

Monitoring

Periodic tuberculosis screening is recommended for all biologics. For patients with latent tuberculosis, biologics may be restarted after 1 month of treatment of tuberculosis.

Prior to initiation of biologics, patients should be screened for hepatitis with hepatitis B surface antigen and antibody, hepatitis B core antibody, and hepatitis C antibody. Patients at risk for human immunodeficiency virus also should be screened.

Generally, complete blood cell count and comprehensive metabolic profile are advisable prior to starting a biologic. Opinions differ on frequency of repeating laboratory work. Complete blood cell count and comprehensive metabolic profile should be monitored at least every 3 to 6 months in patients on TNF-α inhibitors, and neutrophil count should be monitored during the induction phase of IL-17 inhibitors.

All patients with psoriasis should maintain age-appropriate cancer screenings, especially those on biologics. If malignancy is discovered, biologic medication should be discontinued. Debate exists as to when therapy can be safely restarted following treatment of malignancy. Patients who are considered at low risk for recurrence may opt to restart a biologic after 5 years, or sooner if symptoms warrant.³⁴ This decision should involve the patient’s cancer specialist.

Conclusion

Treatment choices are based on psoriasis type and severity, comorbidities, patient preferences, and drug accessibility. One approach is detailed in Table 3. As research advances the understanding of psoriasis, this field will continue to rapidly change. Knowledge of the immunopathogenesis of psoriasis and its relation to comorbidities can direct your decision-making for individual patients.

Psoriasis is a T cell–mediated inflammatory disease that manifests as erythematous scaling plaques of the skin. In recent decades, our understanding of psoriasis has transformed from a disease isolated to the skin to a systemic disease impacting the overall health of those affected.

With recent elucidation of the pathways driving psoriasis, development of targeted therapies has resulted in an influx of options to the market. Navigating the options can seem overwhelming even to the seasoned clinician. Becoming familiar with a sound treatment approach during residency will create a foundation for biologic use in psoriasis patients throughout your career. Here we offer an approach to choosing biologic treatments based on individual patient characteristics, including disease severity, comorbidities, and ultimate treatment goals.

Immune Pathogenesis

Although the pathogenesis of psoriasis is complex and outside the scope of this article, we do recommend clinicians keep in mind the current understanding of pathways involved and ways our therapies alter them. Briefly, psoriasis is a T cell–mediated disease in which IL-12 and IL-23 released by activated dendritic cells activate T helper cells including T_H1, T_H17, and T_H22. These cells produce additional cytokines, including IFN-γ, tumor necrosis factor (TNF) α, IL-17, and IL-22, which propagate the immune response and lead to keratinocyte hyperproliferation. In general, psoriasis medications work by altering T-cell activation, effector cytokines, or cytokine receptors.

Comorbidities

A targeted approach should take into consideration the immune dysregulation shared by psoriasis and associated comorbidities (Table 1). One goal of biologic treatments is to improve comorbidities when possible. At minimum, selected treatments should not exacerbate these conditions.

Treatment Goals

Establishing treatment goals can help shape patient expectations and provide a plan for clinicians. In 2017, the National Psoriasis Foundation published a treat-to-target approach using body surface area (BSA) measurements at baseline, 3 months, and then every 6 months after starting a new treatment.¹² The target response is a decrease in psoriasis to 1% or less BSA at 3 months and to maintain this response when evaluated at 6-month intervals. Alternatively, a target of 3% BSA after 3 months is satisfactory if the patient improves by 75% BSA overall. If these targets are not met after 6 months, therapeutic alternatives can be considered.¹²

Biologic Treatment of Psoriasis

Treatment options for patients with psoriasis depend first on disease severity. Topicals and phototherapy are first line for mild to moderate disease. For moderate to severe disease, addition of systemic agents such as methotrexate, cyclosporine, or acitretin; small-molecular-weight immunomodulators such as apremilast; or biologic medications should be considered. Current biologics available for moderate to severe plaque psoriasis target TNF-α, IL-12/IL-23, IL-23, IL-17A, or IL-17A receptor.

TNF-α Inhibitors

Tumor necrosis factor α inhibitors have been available for treatment of autoimmune disease for nearly 20 years. These medications block either soluble cytokine or membrane-bound cytokine. All are given as subcutaneous injections, except for infliximab, which is a weight-based infusion.

Efficacy
Tumor necrosis factor α inhibitors are the first class to demonstrate long-term efficacy and safety in both psoriasis and psoriatic arthritis (PsA). Etanercept was approved for adults with PsA in 2002 and psoriasis in 2004, and later for pediatric psoriasis (≥4 years of age) in 2016 (Table 2). Although etanercept has a sustained safety profile, the response rates are not as high as other anti–TNF-α inhibitors. Adalimumab is one of the most prescribed biologics, with a total of 10 indications at present, including PsA. Infliximab is an intravenous infusion that demonstrates a rapid and sustained response in most patients. The dose and dosing interval can be adjusted according to response. Certolizumab pegol was approved for PsA in 2013 and for psoriasis in 2018.

Safety
To evaluate long-term safety, a multicenter prospective registry study (Psoriasis Longitudinal Assessment and Registry [PSOLAR]) was initiated in 2007 to follow clinical outcomes. Data through 2013 showed no significant increase in rates of infection, malignancy, or major adverse cardiovascular events in more than 12,000 patients.¹³

Conflicting information exists in the literature regarding risk for malignancy with TNF-α inhibitors. One recent retrospective cohort study suggested a slightly increased risk for malignancies other than nonmelanoma skin cancers in patients on TNF-α inhibitors for more than 12 months (relative risk, 1.54).¹⁴ Reports of increased risk for cutaneous squamous cell carcinomas necessitate regular skin checks.¹⁵ A potential risk for lymphoma has been noted, though having psoriasis itself imparts an increased risk for Hodgkin and cutaneous T-cell lymphoma.¹⁶

Reactivation of tuberculosis and hepatitis have been reported with TNF-α inhibition. Data suggest that infliximab may be associated with more serious infections.¹³

Demyelinating conditions such as multiple sclerosis have occurred de novo or worsened in patients on TNF-α inhibitors.¹⁷ Tumor necrosis factor α blockers should be avoided in patients with decompensated heart failure. Rare cases of liver enzyme elevation and cytopenia have been noted. Additionally, lupuslike syndromes, which are generally reversible upon discontinuation, have occurred in some patients.

Patient Selection
Tumor necrosis factor α inhibitors are the treatment of choice for patients with comorbid PsA. This class halts progression of joint destruction over time.¹⁸Select TNF-α inhibitors are indicated for inflammatory bowel disease (IBD) and are a preferred treatment in this patient population. Specifically, adalimumab and infliximab are approved for both Crohn disease (CD) and ulcerative colitis. Certolizumab pegol is approved for CD.

Tumor necrosis factor α is upregulated in obesity, cardiovascular disease, and atherosclerotic plaques. Evidence suggests that TNF-α blockers may lower cardiovascular risk over time.¹⁹ For patients with obesity, infliximab is a good option, as it is the only TNF-α inhibitor with weight-based dosing.

In patients with frequent infections or history of hepatitis C, etanercept has been the biologic most commonly used when no alternatives exist, in part due to its shorter half-life.

IL-12/IL-23 Inhibitor

Ustekinumab is a monoclonal antibody that binds the p40 subunit shared by IL-12 and IL-23, blocking their ability to bind receptors. IL-12 and IL-23 play a role in activating naïve T cells to become T_H1 or T_H17 cells, respectively.

Efficacy and Safety
Clinical trials demonstrate long-term efficacy of ustekinumab, which was approved for psoriasis in 2009, PsA in 2013, and later pediatric psoriasis (≥12 years of age) in 2017. Dosing is listed in Table 2.

Laboratory abnormalities did not arise in trials. Periodic tuberculosis screening is required. Prospective data over 5 years showed very low rates of adverse events (AEs), serious infections, malignancies, and major adverse cardiovascular events.²⁰ Ustekinumab did not worsen or improve demyelinating disease and appears safe in this population.

Patient Selection
Ustekinumab is approved for PsA and is a good option for those who are not candidates for TNF-α and IL-17 inhibitors. Ustekinumab also is approved for CD. The dosing interval of 12 weeks makes ustekinumab convenient for patients. Two dosages exist based on the patient’s weight, offering an advantage to obese patients.

IL-17/IL-17R Inhibitors

Activated T_H17 cells produce the IL-17 cytokine family, which stimulates keratinocyte proliferation and dermal inflammation. Secukinumab is a fully human monoclonal antibody, and ixekizumab is a humanized monoclonal antibody; both target IL-17A. Brodalumab targets the IL-17A receptor.

Efficacy and Safety
IL-17 inhibitors showed impressive and rapid responses in trials.^21-23 The subsets of patients who responded well and continued treatment in extension trials demonstrated that these treatments maintain efficacy over time.^24-26

In addition to tuberculosis reactivation, there is a small increased risk for cutaneous candidiasis with IL-17 inhibitors, which can be managed without stopping treatment. Laboratory abnormalities were limited to mild neutropenia, which was not associated with increased risk for infection.^21-23 With ixekizumab, neutropenia was seen more commonly in the first 12 weeks.²²

IL-17 is highly expressed in the gut mucosa, and its inhibition is thought to weaken the barrier function of the gut mucosa, promoting inflammation. As a consequence, this class is contraindicated in patients with IBD due to exacerbations of existing IBD and cases of new-onset IBD.^21-23 Symptoms of diarrhea, abdominal pain, blood in stool, or nighttime stooling on review of gastrointestinal tract symptoms should prompt further evaluation.

Brodalumab has a unique warning for risk for suicidal ideation and behavior.²³ Depression is more common in the psoriasis population in general; therefore, physicians should be aware of this potential comorbidity regardless of the treatment plan. Because the response rates are so impressive with brodalumab, the Risk Evaluation and Mitigation Strategy (REMS) program was established to ensure understanding of this risk so that patients can be appropriately counseled and managed.

Patient Selection
The improvement in psoriasis is rapid and may occur as early as week 2 to 3 of treatment after initiation of IL-17 inhibitors. Ixekizumab and secukinumab also are approved for PsA. Although improvement in joint disease is not as fast as with the anti-TNF inhibitors, notable improvement occurs by week 20 to 24.²⁷

IL-23 Inhibitors

Guselkumab and tildrakizumab are the newest biologics for psoriasis, approved in 2017 and 2018, respectively. Both are monoclonal antibodies against the p19 subunit of IL-23, which blocks activation of T_H17 cells.

Efficacy and Safety
Guselkumab and tildrakizumab demonstrated efficacy with minimal AEs or precautions noted thus far.^28,29 Infections are again a risk, making tuberculosis testing the only recommended monitoring.

Patient Selection
Both medications offer another effective and safe option for patients with psoriasis. Similar to ustekinumab, the dosing interval of 12 weeks for tildrakizumab is ideal for patients who have needle phobia or are unable to administer their own injections.

Special Populations

Pregnancy

Antibodies cross the placenta as pregnancy progresses, with the highest rate in the third trimester. Certolizumab pegol has shown the lowest concentrations in infant serum, possibly due to its unique structure lacking the fragment crystallizable region required for passage through the placenta.³⁰ For this reason, certolizumab pegol is a treatment of choice if biologic therapy is warranted during pregnancy.

Much of the pregnancy data for the remaining TNF-α inhibitors come from patients with rheumatoid arthritis or CD. In these populations, rates of major birth defects and miscarriages do not differ greatly from untreated women with these conditions.³¹ One retrospective study of unintentional pregnancies in women receiving ustekinumab showed rates of AEs similar to the general population.³²

Pregnancy data for IL-17 or IL-23 inhibitors are largely limited to animal studies. One retrospective study of women exposed to secukinumab early in gestation showed no increased risk for pregnancy-related AEs.³³ Discontinuation is still recommended for patients who become pregnant.

Pediatric Patients

Etanercept is approved for pediatric psoriatic patients 4 years and older. Children with juvenile idiopathic arthritis who are 2 years and older can receive etanercept. Ustekinumab is safe and effective for pediatric psoriatic patients 12 years and older, offering a second biologic option in children.

Although not approved for pediatric psoriasis, adalimumab is approved in pediatric CD (≥6 years of age) and for juvenile idiopathic arthritis (≥2 years of age). Infliximab is approved for children 6 years and older with CD or ulcerative colitis.

Monitoring

Periodic tuberculosis screening is recommended for all biologics. For patients with latent tuberculosis, biologics may be restarted after 1 month of treatment of tuberculosis.

Prior to initiation of biologics, patients should be screened for hepatitis with hepatitis B surface antigen and antibody, hepatitis B core antibody, and hepatitis C antibody. Patients at risk for human immunodeficiency virus also should be screened.

Generally, complete blood cell count and comprehensive metabolic profile are advisable prior to starting a biologic. Opinions differ on frequency of repeating laboratory work. Complete blood cell count and comprehensive metabolic profile should be monitored at least every 3 to 6 months in patients on TNF-α inhibitors, and neutrophil count should be monitored during the induction phase of IL-17 inhibitors.

All patients with psoriasis should maintain age-appropriate cancer screenings, especially those on biologics. If malignancy is discovered, biologic medication should be discontinued. Debate exists as to when therapy can be safely restarted following treatment of malignancy. Patients who are considered at low risk for recurrence may opt to restart a biologic after 5 years, or sooner if symptoms warrant.³⁴ This decision should involve the patient’s cancer specialist.

Conclusion

Treatment choices are based on psoriasis type and severity, comorbidities, patient preferences, and drug accessibility. One approach is detailed in Table 3. As research advances the understanding of psoriasis, this field will continue to rapidly change. Knowledge of the immunopathogenesis of psoriasis and its relation to comorbidities can direct your decision-making for individual patients.

Psoriasis is a T cell–mediated inflammatory disease that manifests as erythematous scaling plaques of the skin. In recent decades, our understanding of psoriasis has transformed from a disease isolated to the skin to a systemic disease impacting the overall health of those affected.

With recent elucidation of the pathways driving psoriasis, development of targeted therapies has resulted in an influx of options to the market. Navigating the options can seem overwhelming even to the seasoned clinician. Becoming familiar with a sound treatment approach during residency will create a foundation for biologic use in psoriasis patients throughout your career. Here we offer an approach to choosing biologic treatments based on individual patient characteristics, including disease severity, comorbidities, and ultimate treatment goals.

Immune Pathogenesis

Although the pathogenesis of psoriasis is complex and outside the scope of this article, we do recommend clinicians keep in mind the current understanding of pathways involved and ways our therapies alter them. Briefly, psoriasis is a T cell–mediated disease in which IL-12 and IL-23 released by activated dendritic cells activate T helper cells including T_H1, T_H17, and T_H22. These cells produce additional cytokines, including IFN-γ, tumor necrosis factor (TNF) α, IL-17, and IL-22, which propagate the immune response and lead to keratinocyte hyperproliferation. In general, psoriasis medications work by altering T-cell activation, effector cytokines, or cytokine receptors.

Comorbidities

A targeted approach should take into consideration the immune dysregulation shared by psoriasis and associated comorbidities (Table 1). One goal of biologic treatments is to improve comorbidities when possible. At minimum, selected treatments should not exacerbate these conditions.

Treatment Goals

Establishing treatment goals can help shape patient expectations and provide a plan for clinicians. In 2017, the National Psoriasis Foundation published a treat-to-target approach using body surface area (BSA) measurements at baseline, 3 months, and then every 6 months after starting a new treatment.¹² The target response is a decrease in psoriasis to 1% or less BSA at 3 months and to maintain this response when evaluated at 6-month intervals. Alternatively, a target of 3% BSA after 3 months is satisfactory if the patient improves by 75% BSA overall. If these targets are not met after 6 months, therapeutic alternatives can be considered.¹²

Biologic Treatment of Psoriasis

Treatment options for patients with psoriasis depend first on disease severity. Topicals and phototherapy are first line for mild to moderate disease. For moderate to severe disease, addition of systemic agents such as methotrexate, cyclosporine, or acitretin; small-molecular-weight immunomodulators such as apremilast; or biologic medications should be considered. Current biologics available for moderate to severe plaque psoriasis target TNF-α, IL-12/IL-23, IL-23, IL-17A, or IL-17A receptor.

TNF-α Inhibitors

Tumor necrosis factor α inhibitors have been available for treatment of autoimmune disease for nearly 20 years. These medications block either soluble cytokine or membrane-bound cytokine. All are given as subcutaneous injections, except for infliximab, which is a weight-based infusion.

Efficacy
Tumor necrosis factor α inhibitors are the first class to demonstrate long-term efficacy and safety in both psoriasis and psoriatic arthritis (PsA). Etanercept was approved for adults with PsA in 2002 and psoriasis in 2004, and later for pediatric psoriasis (≥4 years of age) in 2016 (Table 2). Although etanercept has a sustained safety profile, the response rates are not as high as other anti–TNF-α inhibitors. Adalimumab is one of the most prescribed biologics, with a total of 10 indications at present, including PsA. Infliximab is an intravenous infusion that demonstrates a rapid and sustained response in most patients. The dose and dosing interval can be adjusted according to response. Certolizumab pegol was approved for PsA in 2013 and for psoriasis in 2018.

Safety
To evaluate long-term safety, a multicenter prospective registry study (Psoriasis Longitudinal Assessment and Registry [PSOLAR]) was initiated in 2007 to follow clinical outcomes. Data through 2013 showed no significant increase in rates of infection, malignancy, or major adverse cardiovascular events in more than 12,000 patients.¹³

Conflicting information exists in the literature regarding risk for malignancy with TNF-α inhibitors. One recent retrospective cohort study suggested a slightly increased risk for malignancies other than nonmelanoma skin cancers in patients on TNF-α inhibitors for more than 12 months (relative risk, 1.54).¹⁴ Reports of increased risk for cutaneous squamous cell carcinomas necessitate regular skin checks.¹⁵ A potential risk for lymphoma has been noted, though having psoriasis itself imparts an increased risk for Hodgkin and cutaneous T-cell lymphoma.¹⁶

Reactivation of tuberculosis and hepatitis have been reported with TNF-α inhibition. Data suggest that infliximab may be associated with more serious infections.¹³

Demyelinating conditions such as multiple sclerosis have occurred de novo or worsened in patients on TNF-α inhibitors.¹⁷ Tumor necrosis factor α blockers should be avoided in patients with decompensated heart failure. Rare cases of liver enzyme elevation and cytopenia have been noted. Additionally, lupuslike syndromes, which are generally reversible upon discontinuation, have occurred in some patients.

Patient Selection
Tumor necrosis factor α inhibitors are the treatment of choice for patients with comorbid PsA. This class halts progression of joint destruction over time.¹⁸Select TNF-α inhibitors are indicated for inflammatory bowel disease (IBD) and are a preferred treatment in this patient population. Specifically, adalimumab and infliximab are approved for both Crohn disease (CD) and ulcerative colitis. Certolizumab pegol is approved for CD.

Tumor necrosis factor α is upregulated in obesity, cardiovascular disease, and atherosclerotic plaques. Evidence suggests that TNF-α blockers may lower cardiovascular risk over time.¹⁹ For patients with obesity, infliximab is a good option, as it is the only TNF-α inhibitor with weight-based dosing.

In patients with frequent infections or history of hepatitis C, etanercept has been the biologic most commonly used when no alternatives exist, in part due to its shorter half-life.

IL-12/IL-23 Inhibitor

Ustekinumab is a monoclonal antibody that binds the p40 subunit shared by IL-12 and IL-23, blocking their ability to bind receptors. IL-12 and IL-23 play a role in activating naïve T cells to become T_H1 or T_H17 cells, respectively.

Efficacy and Safety
Clinical trials demonstrate long-term efficacy of ustekinumab, which was approved for psoriasis in 2009, PsA in 2013, and later pediatric psoriasis (≥12 years of age) in 2017. Dosing is listed in Table 2.

Laboratory abnormalities did not arise in trials. Periodic tuberculosis screening is required. Prospective data over 5 years showed very low rates of adverse events (AEs), serious infections, malignancies, and major adverse cardiovascular events.²⁰ Ustekinumab did not worsen or improve demyelinating disease and appears safe in this population.

Patient Selection
Ustekinumab is approved for PsA and is a good option for those who are not candidates for TNF-α and IL-17 inhibitors. Ustekinumab also is approved for CD. The dosing interval of 12 weeks makes ustekinumab convenient for patients. Two dosages exist based on the patient’s weight, offering an advantage to obese patients.

IL-17/IL-17R Inhibitors

Activated T_H17 cells produce the IL-17 cytokine family, which stimulates keratinocyte proliferation and dermal inflammation. Secukinumab is a fully human monoclonal antibody, and ixekizumab is a humanized monoclonal antibody; both target IL-17A. Brodalumab targets the IL-17A receptor.

Efficacy and Safety
IL-17 inhibitors showed impressive and rapid responses in trials.^21-23 The subsets of patients who responded well and continued treatment in extension trials demonstrated that these treatments maintain efficacy over time.^24-26

In addition to tuberculosis reactivation, there is a small increased risk for cutaneous candidiasis with IL-17 inhibitors, which can be managed without stopping treatment. Laboratory abnormalities were limited to mild neutropenia, which was not associated with increased risk for infection.^21-23 With ixekizumab, neutropenia was seen more commonly in the first 12 weeks.²²

IL-17 is highly expressed in the gut mucosa, and its inhibition is thought to weaken the barrier function of the gut mucosa, promoting inflammation. As a consequence, this class is contraindicated in patients with IBD due to exacerbations of existing IBD and cases of new-onset IBD.^21-23 Symptoms of diarrhea, abdominal pain, blood in stool, or nighttime stooling on review of gastrointestinal tract symptoms should prompt further evaluation.

Brodalumab has a unique warning for risk for suicidal ideation and behavior.²³ Depression is more common in the psoriasis population in general; therefore, physicians should be aware of this potential comorbidity regardless of the treatment plan. Because the response rates are so impressive with brodalumab, the Risk Evaluation and Mitigation Strategy (REMS) program was established to ensure understanding of this risk so that patients can be appropriately counseled and managed.

Patient Selection
The improvement in psoriasis is rapid and may occur as early as week 2 to 3 of treatment after initiation of IL-17 inhibitors. Ixekizumab and secukinumab also are approved for PsA. Although improvement in joint disease is not as fast as with the anti-TNF inhibitors, notable improvement occurs by week 20 to 24.²⁷

IL-23 Inhibitors

Guselkumab and tildrakizumab are the newest biologics for psoriasis, approved in 2017 and 2018, respectively. Both are monoclonal antibodies against the p19 subunit of IL-23, which blocks activation of T_H17 cells.

Efficacy and Safety
Guselkumab and tildrakizumab demonstrated efficacy with minimal AEs or precautions noted thus far.^28,29 Infections are again a risk, making tuberculosis testing the only recommended monitoring.

Patient Selection
Both medications offer another effective and safe option for patients with psoriasis. Similar to ustekinumab, the dosing interval of 12 weeks for tildrakizumab is ideal for patients who have needle phobia or are unable to administer their own injections.

Special Populations

Pregnancy

Antibodies cross the placenta as pregnancy progresses, with the highest rate in the third trimester. Certolizumab pegol has shown the lowest concentrations in infant serum, possibly due to its unique structure lacking the fragment crystallizable region required for passage through the placenta.³⁰ For this reason, certolizumab pegol is a treatment of choice if biologic therapy is warranted during pregnancy.

Much of the pregnancy data for the remaining TNF-α inhibitors come from patients with rheumatoid arthritis or CD. In these populations, rates of major birth defects and miscarriages do not differ greatly from untreated women with these conditions.³¹ One retrospective study of unintentional pregnancies in women receiving ustekinumab showed rates of AEs similar to the general population.³²

Pregnancy data for IL-17 or IL-23 inhibitors are largely limited to animal studies. One retrospective study of women exposed to secukinumab early in gestation showed no increased risk for pregnancy-related AEs.³³ Discontinuation is still recommended for patients who become pregnant.

Pediatric Patients

Etanercept is approved for pediatric psoriatic patients 4 years and older. Children with juvenile idiopathic arthritis who are 2 years and older can receive etanercept. Ustekinumab is safe and effective for pediatric psoriatic patients 12 years and older, offering a second biologic option in children.

Although not approved for pediatric psoriasis, adalimumab is approved in pediatric CD (≥6 years of age) and for juvenile idiopathic arthritis (≥2 years of age). Infliximab is approved for children 6 years and older with CD or ulcerative colitis.

Monitoring

Periodic tuberculosis screening is recommended for all biologics. For patients with latent tuberculosis, biologics may be restarted after 1 month of treatment of tuberculosis.

Prior to initiation of biologics, patients should be screened for hepatitis with hepatitis B surface antigen and antibody, hepatitis B core antibody, and hepatitis C antibody. Patients at risk for human immunodeficiency virus also should be screened.

Generally, complete blood cell count and comprehensive metabolic profile are advisable prior to starting a biologic. Opinions differ on frequency of repeating laboratory work. Complete blood cell count and comprehensive metabolic profile should be monitored at least every 3 to 6 months in patients on TNF-α inhibitors, and neutrophil count should be monitored during the induction phase of IL-17 inhibitors.

All patients with psoriasis should maintain age-appropriate cancer screenings, especially those on biologics. If malignancy is discovered, biologic medication should be discontinued. Debate exists as to when therapy can be safely restarted following treatment of malignancy. Patients who are considered at low risk for recurrence may opt to restart a biologic after 5 years, or sooner if symptoms warrant.³⁴ This decision should involve the patient’s cancer specialist.

Conclusion

Treatment choices are based on psoriasis type and severity, comorbidities, patient preferences, and drug accessibility. One approach is detailed in Table 3. As research advances the understanding of psoriasis, this field will continue to rapidly change. Knowledge of the immunopathogenesis of psoriasis and its relation to comorbidities can direct your decision-making for individual patients.

Increased understanding of the pathophysiology of psoriasis has been one of the driving forces in the development of new therapies. An understanding of the processes involved is important in the optimal management of the disease. The last 30 years of research and clinical practice have revolutionized our understanding of the pathogenesis of psoriasis as the dysregulation of immunity triggered by environmental and genetic stimuli. Psoriasis was originally regarded as a primary disorder of epidermal hyperproliferation. However, experimental models and clinical results from immunomodulating therapies have refined this perspective in conceptualizing psoriasis as a genetically programmed pathologic interaction among resident skin cells; infiltrating immunocytes; and a host of proinflammatory cytokines, chemokines, and growth factors produced by these immunocytes. Two populations of immunocytes and their respective signaling molecules collaborate in the pathogenesis: (1) innate immunocytes, mediated by antigen-presenting cells (APCs)(including natural killer [NK] T lymphocytes, Langerhans cells, and neutrophils), and (2) acquired or adaptive immunocytes, mediated by mature CD4⁺ and CD8⁺ T lymphocytes in the skin. Such dysregulation of immunity and subsequent inflammation is responsible for the development and perpetuation of the clinical plaques and histological inflammatory infiltrate characteristic of psoriasis.

Although psoriasis is considered to be an immune-mediated disease in which intralesional T lymphocytes and their proinflammatory signals trigger primed basal layer keratinocytes to rapidly proliferate, debate and research focus on the stimulus that incites this inflammatory process. Our current understanding considers psoriasis to be triggered by exogenous or endogenous environmental stimuli in genetically susceptible individuals. Such stimuli include group A streptococcal pharyngitis, viremia, allergic drug reactions, antimalarial drugs, lithium, beta-blockers, IFN-α, withdrawal of systemic corticosteroids, local trauma (Köbner phenomenon), and emotional stress. These stimuli correlate with the onset or flares of psoriatic lesions. Psoriasis genetics centers on susceptibility loci and corresponding candidate genes, particularly the psoriasis susceptibility (PSORS) 1 locus on the major histocompatibility complex (MHC) class I region. Current research on the pathogenesis of psoriasis examines the complex interactions among immunologic mechanisms, environmental stimuli, and genetic susceptibility. After discussing the clinical presentation and histopathologic features of psoriasis, we will review the pathophysiology of psoriasis through noteworthy developments, including serendipitous observations, reactions to therapies, clinical trials, and animal model systems that have shaped our view of the disease process. In addition to the classic skin lesions, approximately 23% of psoriasis patients develop psoriatic arthritis, with a 10-year latency after diagnosis of psoriasis.¹

Principles of Immunity

The immune system, intended to protect its host from foreign invaders and unregulated cell growth, employs 2 main effector pathways—the innate and the acquired (or adaptive) immune responses—both of which contribute to the pathophysiology of psoriasis.² Innate immunity responses occur within minutes to hours of antigen exposure but fail to develop memory for when the antigen is encountered again. However, adaptive immunity responses take days to weeks to respond after challenged with an antigen. The adaptive immune cells have the capacity to respond to a greater range of antigens and develop immunologic memory via rearrangement of antigen receptors on B and T cells. These specialized B and T cells can then be promptly mobilized and differentiated into mature effector cells that protect the host from a foreign pathogen.

Innate and adaptive immune responses are highly intertwined; they can initiate, perpetuate, and terminate the immune mechanisms responsible for inflammation. They can modify the nature of the immune response by altering the relative proportions of type 1 (T_H1), type 2 (T_H2), and the more recently discovered type 17 (T_H17) subset of helper T cells and their respective signaling molecules. A T_H1 response is essential for a cellular immunologic reaction to intracellular bacteria and viruses or cellular immunity. A T_H2 response promotes IgE synthesis, eosinophilia, and mast cell maturation for extracellular parasites and helminthes as well as humoral immunity, while a T_H17 response is important for cell-mediated immunity to extracellular bacteria and plays a role in autoimmunity.³ The innate and adaptive immune responses employ common effector molecules such as chemokines and cytokines, which are essential in mediating an immune response.

Implicating Dysregulation of Immunity

Our present appreciation of the pathogenesis of psoriasis is based on the history of trial-and-error therapies; serendipitous discoveries; and the current immune targeting drugs used in a variety of chronic inflammatory conditions, including rheumatoid arthritis, ankylosing spondylitis, and inflammatory bowel disease. Before the mid-1980s, research focused on the hyperproliferative epidermal cells as the primary pathology because a markedly thickened epidermis was indeed demonstrated on histologic specimens. Altered cell-cycle kinetics were thought to be the culprit behind the hyperkeratotic plaques. Thus, initial treatments centered on oncologic and antimitotic therapies used to arrest keratinocyte proliferation with agents such as arsenic, ammoniated mercury, and methotrexate.⁴

However, a paradigm shift from targeting epidermal keratinocytes to immunocyte populations was recognized when a patient receiving cyclosporine to prevent transplant rejection noted clearing of psoriatic lesions in the 1980s.⁵ Cyclosporine was observed to inhibit messenger RNA transcription of T-cell cytokines, thereby implicating immunologic dysregulation, specifically T-cell hyperactivity, in the pathogenesis of psoriasis.⁶ However, the concentrations of oral cyclosporine reached in the epidermis exerted direct effects on keratinocyte proliferation and lymphocyte function in these patients.⁷ Thus, the question was raised as to whether the keratinocytes or the lymphocytes drove the psoriatic plaques. The use of an IL-2 diphtheria toxin-fusion protein, denileukin diftitox, specific for activated T cells with high-affinity IL-2 receptors and nonreactive with keratinocytes, distinguished which cell type was responsible. This targeted T-cell toxin provided clinical and histological clearing of psoriatic plaques. Thus, T lymphocytes rather than keratinocytes were recognized as the definitive driver behind the psoriatic plaques.⁸

Additional studies have demonstrated that treatments that induce prolonged clearing of psoriatic lesions without continuous therapy, such as psoralen plus UVA irradiation, decreased the numbers of T cells in plaques by at least 90%.⁹ However, treatments that require continual therapy for satisfactory clinical results, such as cyclosporine and etretinate, simply suppress T-cell activity and proliferation.^10,11 Further evidence has linked cellular immunity with the pathogenesis of psoriasis, defining it as a T_H1-type disease. Natural killer T cells were shown to be involved through the use of a severe combined immunodeficient mouse model. They were injected into prepsoriatic skin grafted on immunodeficient mice, creating a psoriatic plaque with an immune response showing cytokines from T_H1 cells rather than T_H2 cells.¹² When psoriatic plaques were treated topically with the toll-like receptor 7 agonist imiquimod, aggravation and spreading of the plaques were noted. The exacerbation of psoriasis was accompanied by an induction of lesional T_H1-type interferon produced by plasmacytoid dendritic cell (DC) precursors. Plasmacytoid DCs were observed to compose up to 16% of the total dermal infiltrate in psoriatic skin lesions based on their coexpression of BDCA2 and CD123.¹³ Additionally, cancer patients being treated with interferon alfa experienced induction of psoriasis.¹⁴ Moreover, patients being treated for warts with intralesional interferon alfa developed psoriatic plaques in neighboring prior asymptomatic skin.¹⁵ Patients with psoriasis who were treated with interferon gamma, a T_H1 cytokine type, also developed new plaques correlating with the sites of injection.¹⁶

Intralesional T Lymphocytes

Psoriatic lesions contain a host of innate immunocytes, such as APCs, NK cells, and neutrophils, as well as adaptive T cells and an inflammatory infiltrate. These cells include CD4 and CD8 subtypes in which the CD8⁺ cells predominate in the epidermis, while CD4⁺ cells show preference for the dermis.¹⁷ There are 2 groups of CD8⁺ cells: one group migrates to the epidermis, expressing the integrin CD103, while the other group is found in the dermis but may be headed to or from the epidermis. The CD8⁺ cells residing in the epidermis that express the integrin CD103 are capable of interacting with E-cadherin, which enables these cells to travel to the epidermis and bind resident cells. Immunophenotyping reveals that these mature T cells represent chiefly activated memory cells, including CD2⁺, CD3⁺, CD5⁺, CLA, CD28, and CD45RO⁺.¹⁸ Many of these cells express activation markers such as HLA-DR, CD25, and CD27, in addition to the T-cell receptor (TCR).

T-Lymphocyte Stimulation

Both mature CD4⁺ and CD8⁺ T cells can respond to the peptides presented by APCs. Although the specific antigen that these T cells are reacting to has not yet been elucidated, several antigenic stimuli have been proposed, including self-proteins, microbial pathogens, and microbial superantigens. The premise that self-reactive T lymphocytes may contribute to the disease process is derived from the molecular mimicry theory in which an exuberant immune response to a pathogen produces cross-reactivity with self-antigens.¹⁹ Considering that infections have been associated with the onset of psoriasis, this theory merits consideration. However, it also has been observed that T cells can be activated without antigens or superantigens but rather with direct contact with accessory cells.²⁰ No single theory has clearly emerged. Researchers continue to search for the inciting stimulus that triggers the T lymphocyte and attempt to determine whether T cells are reacting to a self-derived or non–self-derived antigen.

T-Lymphocyte Signaling

T-cell signaling is a highly coordinated process in which T lymphocytes recognize antigens via presentation by mature APCs in the skin rather than the lymphoid tissues. Such APCs expose antigenic peptides via class I or II MHC molecules for which receptors are present on the T-cell surface. The antigen recognition complex at the T-cell and APC interface, in concert with a host of antigen-independent co-stimulatory signals, regulates T-cell signaling and is referred to as the immunologic synapse. The antigen presentation and network of co-stimulatory and adhesion molecules optimize T-cell activation, and dermal DCs release IL-12 and IL-23 to promote a T_H1 and T_H17 response, respectively. The growth factors released by these helper T cells sustain neoangiogenesis, stimulate epidermal hyperproliferation, alter epidermal differentiation, and decrease susceptibility to apoptosis that characterizes the erythematous hypertrophic scaling lesions of psoriasis.²¹ Furthermore, the cytokines produced from the immunologic response, such as tumor necrosis factor (TNF) α, IFN-γ, and IL-2, correspond to cytokines that are upregulated in psoriatic plaques.²²

Integral components of the immunologic synapse complex include co-stimulatory signals such as CD28, CD40, CD80, and CD86, as well as adhesion molecules such as cytotoxic T-lymphocyte antigen 4 and lymphocyte function-associated antigen (LFA) 1, which possess corresponding receptors on the T cell. These molecules play a key role in T-cell signaling, as their disruption has been shown to decrease T-cell responsiveness and associated inflammation. The B7 family of molecules routinely interacts with CD28 T cells to co-stimulate T-cell activation. Cytotoxic T-lymphocyte antigen 4 immunoglobulin, an antibody on the T-cell surface, targets B7 and interferes with signaling between B7 and CD28. In psoriatic patients, this blockade was demonstrated to attenuate the T-cell response and correlated with a clinical and histological decrease in psoriasiform hyperplasia.²³ Biologic therapies that disrupt the LFA-1 component of the immunologic synapse also have demonstrated efficacy in the treatment of psoriasis. Alefacept is a human LFA-3 fusion protein that binds CD2 on T cells and blocks the interaction between LFA-3 on APCs and CD2 on memory CD45RO⁺ T cells and induces apoptosis of such T cells. Efalizumab is a human monoclonal antibody to the CD11 chain of LFA-1 that blocks the interaction between LFA-1 on the T cell and intercellular adhesion molecule 1 on an APC or endothelial cell. Both alefacept and efalizumab, 2 formerly marketed biologic therapies, demonstrated remarkable clinical reduction of psoriatic lesions, and alefacept has been shown to produce disease remission for up to 18 months after discontinuation of therapy.^24-26

NK T Cells

Natural killer T cells represent a subset of CD3⁺ T cells present in psoriatic plaques. Although NK T cells possess a TCR, they differ from T cells by displaying NK receptors comprised of lectin and immunoglobulin families. These cells exhibit remarkable specificity and are activated upon recognition of glycolipids presented by CD1d molecules. This process occurs in contrast to CD4⁺ and CD8⁺ T cells, which, due to their TCR diversity, respond to peptides processed by APCs and displayed on MHC molecules. Natural killer T cells can be classified into 2 subsets: (1) one group that expresses CD4 and preferentially produces T_H1- versus T_H2-type cytokines, and (2) another group that lacks CD4 and CD8 that only produces T_H1-type cytokines. The innate immune system employs NK T cells early in the immune response because of their direct cytotoxicity and rapid production of cytokines such as IFN-γ, which promotes a T_H1 inflammatory response, and IL-4, which promotes the development of T_H2 cells. Excessive or dysfunctional NK T cells have been associated with autoimmune diseases such as multiple sclerosis and inflammatory bowel disease as well as allergic contact dermatitis.^27-29

In psoriasis, NK T cells are located in the epidermis, closely situated to epidermal keratinocytes, which suggests a role for direct antigen presentation. Furthermore, CD1d is overexpressed throughout the epidermis of psoriatic plaques, whereas normally CD1d expression is confined to terminally differentiated keratinocytes. An in vitro study examining cytokine-based inflammation demonstrative of psoriasis treated cultured CD1d-positive keratinocytes with interferon gamma in the presence of alpha-galactosylceramide of the lectin family.³⁰ Interferon gamma was observed to enhance keratinocyte CD1d expression, and subsequently, CD1d-positive keratinocytes were found to activate NK T cells to produce high levels of IFN-γ, while levels of IL-4 remained undetectable. The preferential production of IFN-γ supports a T_H1-mediated mechanism regulated by NK T cells in the immunopathogenesis of psoriasis.

Dendritic Cells

Dendritic cells are APCs that process antigens in the tissues in which they reside, after which they migrate to local lymph nodes where they present their native antigens to T cells. This process allows the T-cell response to be tailored to the appropriate antigens in the corresponding tissues. Immature DCs that capture antigens mature by migrating to the T-cell center of the lymph node where they present their antigens to either MHC molecules or the CD1 family. This presentation results in T-cell proliferation and differentiation that correlates with the required type of T-cell response. Multiple subsets of APCs, including myeloid and plasmacytoid DCs, are highly represented in the epidermis and dermis of psoriatic plaques as compared with normal skin.³¹ Dermal DCs are thought to be responsible for activating both the T_H1 and T_H17 infiltrate by secreting IL-12 and IL-23, respectively. This mixed cellular response secretes cytokines and leads to a cascade of events involving keratinocytes, fibroblasts, endothelial cells, and neutrophils that create the cutaneous lesions seen in psoriasis.³

Although DCs play a pivotal role in eliciting an immune response against a foreign invader, they also contribute to the establishment of tolerance. Throughout their maturation, DCs are continuously sensing their environment, which shapes their production of T_H1- versus T_H2-type cytokines and subsequently the nature of the T-cell response. When challenged with a virus, bacteria, or unchecked cell growth, DCs mature into APCs. However, in the absence of a strong stimulus, DCs fail to mature into APCs and present self-peptides with MHC molecules, thereby creating regulatory T cells involved in peripheral tolerance.³² If this balance between immunogenic APCs and housekeeping T cells is upset, inflammatory conditions such as psoriasis can result.

Cytokines

Cytokines are low-molecular-weight glycoproteins that function as signals to produce inflammation, defense, tissue repair and remodeling, fibrosis, angiogenesis, and restriction of neoplastic growth.³³ Cytokines are produced by immunocytes such as lymphocytes and macrophages as well as nonimmunocytes such as endothelial cells and keratinocytes. Proinflammatory cytokines include IL-1, IL-2, the IL-17 family, IFN-γ, and TNF-α, while anti-inflammatory cytokines include IL-4 and IL-10. A relative preponderance of T_H1 proinflammatory cytokines or an insufficiency of T_H2 anti-inflammatory cytokines induces local inflammation and recruitment of additional immunocyte populations, which produce added cytokines.³⁴ A vicious cycle of inflammation occurs that results in cutaneous manifestations such as a plaque. Psoriatic lesions are characterized by a relative increase of T_H1-type (eg, IL-2, IFN-γ, TNF-α, TNF-β) to T_H2-type (eg, IL-4, IL-5, IL-6, IL-9, IL-10, IL-13) cytokines and an increase in T_H17-type cytokines. Natural killer T cells stimulated by CD1d-overexpressing keratinocytes increase production of proinflammatory IFN-γ without effect on the anti-inflammatory IL-4. In addition to the cytokines produced by T cells, APCs produce IL-18, IL-23, and TNF-α found in the inflammatory infiltrate of psoriatic plaques. Both IL-18 and IL-23 stimulate T_H1 cells to produce IFN-γ, and IL-23 stimulates T_H17 cells. Clearly, a T_H1- and T_H17-type pattern governs the immune effector cells and their respective cytokines present in psoriatic skin.

Tumor Necrosis Factor α

Although a network of cytokines is responsible for the inflammation of psoriasis, TNF-α has been implicated as a master proinflammatory cytokine of the innate immune response due to its widespread targets and sources. Tumor necrosis factor α is produced by activated T cells, keratinocytes, NK cells, macrophages, monocytes, Langerhans APCs, and endothelial cells. Psoriatic lesions demonstrate high concentrations of TNF-α, while the synovial fluid of psoriatic arthritis patients demonstrates elevated concentrations of TNF-α, IL-1, IL-6, and IL-8.³⁴ In psoriasis, TNF-α supports the expression of adhesion molecules (intercellular adhesion molecule 1 and P- and E-selectin), angiogenesis via vascular endothelial growth factor, the synthesis of proinflammatory molecules (IL-1, IL-6, IL-8, and nuclear factor κβ), and keratinocyte hyperproliferation via vasoactive intestinal peptide.³⁵

A role for TNF-α in psoriasis treatment was serendipitously discovered in a trial for Crohn disease in which infliximab, a mouse-human IgG1 anti–TNF-α monoclonal antibody, was observed to clear psoriatic plaques in a patient with both Crohn disease and psoriasis.³⁶ Immunotherapies that target TNF-α, including infliximab, etanercept, and adalimumab, demonstrate notable efficacy in the treatment of psoriasis.^37-39 Tumor necrosis factor α is regarded as the driver of the inflammatory cycle of psoriasis due to its numerous modes of production, capability to amplify other proinflammatory signals, and the efficacy and rapidity with which it produces clinical improvements in psoriasis.

IL-23/T_H17 Axis

A new distinct population of helper T cells has been shown to play an important role in psoriasis. These cells develop with the help of IL-23 (secreted by dermal DCs) and subsequently secrete cytokines such as IL-17; they are, therefore, named T_H17 cells. CD161 is considered a surface marker for these cells.⁴⁰ Strong evidence for this IL-23/T_H17 axis has been shown in mouse and human models as well as in genetic studies.

IL-23 is a cytokine that shares the p40 subunit with IL-12 and has been linked to autoimmune diseases in both mice and humans.³ It is required for optimal development of T_H17 cells⁴¹ from a committed CD4⁺ T-cell population after exposure to transforming growth factor β1 in combination with other proinflammatory cytokines.^42,43 IL-23 messenger RNA is produced at higher levels in inflammatory psoriatic skin lesions versus uninvolved skin,⁴⁴ and intradermal IL-23 injections in mice produced lesions resembling psoriasis macroscopically and microscopically.⁴⁵ Furthermore, several systemic therapies have been shown to modulate IL-23 levels and correlate with clinical benefit.³ Alterations in the gene for the IL-23 receptor have been shown to be protective for psoriasis,^46-48 and the gene coding for the p40 subunit is associated with psoriasis.^46,47

Type 17 helper T cells produce a number of cytokines, such as IL-22, IL-17A, IL-17F, and IL-26; the latter 3 are considered to be specific to this lineage.⁴² IL-22 acts on outer body barrier tissues, such as the skin, and has antimicrobial activity. Blocking the activity of IL-22 in mice prevented the development of skin lesions,⁴⁹ and psoriasis patients have elevated levels of IL-22 in the skin and blood.^50,51 The IL-17 cytokines induce the expression of proinflammatory cytokines, colony-stimulating factors, and chemokines, and they recruit, mobilize, and activate neutrophils.⁵² IL-17 messenger RNA was found in lesional psoriatic skin but not unaffected skin,⁵³ and cells isolated from the dermis of psoriatic skin have been shown to produce IL-17.⁵⁴ IL-17A is not elevated in the serum of psoriatic patients (unlike other autoimmune diseases),⁵⁵ and it is, therefore, thought that T_H17 cells and IL-17A production are localized to the affected psoriatic skin. Consistent with this concept is the finding that treatments such as cyclosporin A and anti-TNF agents decrease proinflammatory cytokines in lesional skin but not in the periphery.^56-58 These cytokines released by T_H17 cells in addition to those released by T_H1 cells act on keratinocytes and produce epidermal hyperproliferation, acanthosis, and hyperparakeratosis characteristic of psoriasis.³

New therapies have been developed to target the IL-23/T_H17 axis. Ustekinumab is approved for moderate to severe plaque psoriasis. This treatment’s effect may be sustained for up to 3 years, it is generally well tolerated, and it may be useful for patients refractory to anti-TNF therapy such as etanercept.⁵⁹ Briakinumab, another blocker of IL-12 and IL-23, was studied in phase 3 clinical trials, but its development was discontinued due to safety concerns.⁶⁰ Newer drugs targeting the IL-23/T_H17 axis include secukinumab, ixekizumab, brodalumab, guselkumab, and tildrakizumab.

Genetic Basis of Psoriasis

Psoriasis is a disease of overactive immunity in genetically susceptible individuals. Because patients exhibit varying skin phenotypes, extracutaneous manifestations, and disease courses, multiple genes resulting from linkage disequilibrium are believed to be involved in the pathogenesis of psoriasis. A decade of genome-wide linkage scans have established that PSORS1 is the strongest susceptibility locus demonstrable through family linkage studies; PSORS1 is responsible for up to 50% of the genetic component of psoriasis.⁶¹ More recently, HLA-Cw6 has received the most attention as a candidate gene of the PSORS1 susceptibility locus on the MHC class I region on chromosome 6p21.3.⁶² This gene may function in antigen presentation via MHC class I, which aids in the activation of the overactive T cells characteristic of psoriatic inflammation.

Studies involving the IL-23/T_H17 axis have shown genetics to play a role. Individuals may be protected from psoriasis with a nonsynonymous nucleotide substitution in the IL23R gene,^47-49 and certain haplotypes of the IL23R gene are associated with the disease^47,49 in addition to other autoimmune conditions.

Genomic scans have shown additional susceptibility loci for psoriasis on chromosomes 1q21, 3q21, 4q32-35, 16q12, and 17q25. Two regions on chromosome 17q were recently localized via mapping, which demonstrated a 6 megabase pairs separation, thereby indicating independent linkage factors. Genes SLC9A3R1 and NAT9 are present in the first region, while RAPTOR is demonstrated in the second region.⁶³SLC9A3R1 and NAT9 are players that regulate signal transduction, the immunologic synapse, and T-cell growth. RAPTOR is involved in T-cell function and growth pathways. Using these genes as an example, we can predict that the alterations of regulatory genes, even those yet undetermined, can enhance T-cell proliferation and inflammation manifested in psoriasis.

Conclusion

Psoriasis is a complex disease whereby multiple exogenous and endogenous stimuli incite already heightened innate immune responses in genetically predetermined individuals. The disease process is a result of a network of cell types, including T cells, DCs, and keratinocytes that, with the production of cytokines, generate a chronic inflammatory state. Our understanding of these cellular interactions and cytokines originates from developments, some meticulously planned, others serendipitous, in the fields of immunology, cell and molecular biology, and genetics. Such progress has fostered the creation of targeted immune therapy that has demonstrated remarkable efficacy in psoriasis treatment. Further study of the underlying pathophysiology of psoriasis may provide additional targets for therapy.

Increased understanding of the pathophysiology of psoriasis has been one of the driving forces in the development of new therapies. An understanding of the processes involved is important in the optimal management of the disease. The last 30 years of research and clinical practice have revolutionized our understanding of the pathogenesis of psoriasis as the dysregulation of immunity triggered by environmental and genetic stimuli. Psoriasis was originally regarded as a primary disorder of epidermal hyperproliferation. However, experimental models and clinical results from immunomodulating therapies have refined this perspective in conceptualizing psoriasis as a genetically programmed pathologic interaction among resident skin cells; infiltrating immunocytes; and a host of proinflammatory cytokines, chemokines, and growth factors produced by these immunocytes. Two populations of immunocytes and their respective signaling molecules collaborate in the pathogenesis: (1) innate immunocytes, mediated by antigen-presenting cells (APCs)(including natural killer [NK] T lymphocytes, Langerhans cells, and neutrophils), and (2) acquired or adaptive immunocytes, mediated by mature CD4⁺ and CD8⁺ T lymphocytes in the skin. Such dysregulation of immunity and subsequent inflammation is responsible for the development and perpetuation of the clinical plaques and histological inflammatory infiltrate characteristic of psoriasis.

Although psoriasis is considered to be an immune-mediated disease in which intralesional T lymphocytes and their proinflammatory signals trigger primed basal layer keratinocytes to rapidly proliferate, debate and research focus on the stimulus that incites this inflammatory process. Our current understanding considers psoriasis to be triggered by exogenous or endogenous environmental stimuli in genetically susceptible individuals. Such stimuli include group A streptococcal pharyngitis, viremia, allergic drug reactions, antimalarial drugs, lithium, beta-blockers, IFN-α, withdrawal of systemic corticosteroids, local trauma (Köbner phenomenon), and emotional stress. These stimuli correlate with the onset or flares of psoriatic lesions. Psoriasis genetics centers on susceptibility loci and corresponding candidate genes, particularly the psoriasis susceptibility (PSORS) 1 locus on the major histocompatibility complex (MHC) class I region. Current research on the pathogenesis of psoriasis examines the complex interactions among immunologic mechanisms, environmental stimuli, and genetic susceptibility. After discussing the clinical presentation and histopathologic features of psoriasis, we will review the pathophysiology of psoriasis through noteworthy developments, including serendipitous observations, reactions to therapies, clinical trials, and animal model systems that have shaped our view of the disease process. In addition to the classic skin lesions, approximately 23% of psoriasis patients develop psoriatic arthritis, with a 10-year latency after diagnosis of psoriasis.¹

Principles of Immunity

The immune system, intended to protect its host from foreign invaders and unregulated cell growth, employs 2 main effector pathways—the innate and the acquired (or adaptive) immune responses—both of which contribute to the pathophysiology of psoriasis.² Innate immunity responses occur within minutes to hours of antigen exposure but fail to develop memory for when the antigen is encountered again. However, adaptive immunity responses take days to weeks to respond after challenged with an antigen. The adaptive immune cells have the capacity to respond to a greater range of antigens and develop immunologic memory via rearrangement of antigen receptors on B and T cells. These specialized B and T cells can then be promptly mobilized and differentiated into mature effector cells that protect the host from a foreign pathogen.

Innate and adaptive immune responses are highly intertwined; they can initiate, perpetuate, and terminate the immune mechanisms responsible for inflammation. They can modify the nature of the immune response by altering the relative proportions of type 1 (T_H1), type 2 (T_H2), and the more recently discovered type 17 (T_H17) subset of helper T cells and their respective signaling molecules. A T_H1 response is essential for a cellular immunologic reaction to intracellular bacteria and viruses or cellular immunity. A T_H2 response promotes IgE synthesis, eosinophilia, and mast cell maturation for extracellular parasites and helminthes as well as humoral immunity, while a T_H17 response is important for cell-mediated immunity to extracellular bacteria and plays a role in autoimmunity.³ The innate and adaptive immune responses employ common effector molecules such as chemokines and cytokines, which are essential in mediating an immune response.

Implicating Dysregulation of Immunity

Our present appreciation of the pathogenesis of psoriasis is based on the history of trial-and-error therapies; serendipitous discoveries; and the current immune targeting drugs used in a variety of chronic inflammatory conditions, including rheumatoid arthritis, ankylosing spondylitis, and inflammatory bowel disease. Before the mid-1980s, research focused on the hyperproliferative epidermal cells as the primary pathology because a markedly thickened epidermis was indeed demonstrated on histologic specimens. Altered cell-cycle kinetics were thought to be the culprit behind the hyperkeratotic plaques. Thus, initial treatments centered on oncologic and antimitotic therapies used to arrest keratinocyte proliferation with agents such as arsenic, ammoniated mercury, and methotrexate.⁴

However, a paradigm shift from targeting epidermal keratinocytes to immunocyte populations was recognized when a patient receiving cyclosporine to prevent transplant rejection noted clearing of psoriatic lesions in the 1980s.⁵ Cyclosporine was observed to inhibit messenger RNA transcription of T-cell cytokines, thereby implicating immunologic dysregulation, specifically T-cell hyperactivity, in the pathogenesis of psoriasis.⁶ However, the concentrations of oral cyclosporine reached in the epidermis exerted direct effects on keratinocyte proliferation and lymphocyte function in these patients.⁷ Thus, the question was raised as to whether the keratinocytes or the lymphocytes drove the psoriatic plaques. The use of an IL-2 diphtheria toxin-fusion protein, denileukin diftitox, specific for activated T cells with high-affinity IL-2 receptors and nonreactive with keratinocytes, distinguished which cell type was responsible. This targeted T-cell toxin provided clinical and histological clearing of psoriatic plaques. Thus, T lymphocytes rather than keratinocytes were recognized as the definitive driver behind the psoriatic plaques.⁸

Additional studies have demonstrated that treatments that induce prolonged clearing of psoriatic lesions without continuous therapy, such as psoralen plus UVA irradiation, decreased the numbers of T cells in plaques by at least 90%.⁹ However, treatments that require continual therapy for satisfactory clinical results, such as cyclosporine and etretinate, simply suppress T-cell activity and proliferation.^10,11 Further evidence has linked cellular immunity with the pathogenesis of psoriasis, defining it as a T_H1-type disease. Natural killer T cells were shown to be involved through the use of a severe combined immunodeficient mouse model. They were injected into prepsoriatic skin grafted on immunodeficient mice, creating a psoriatic plaque with an immune response showing cytokines from T_H1 cells rather than T_H2 cells.¹² When psoriatic plaques were treated topically with the toll-like receptor 7 agonist imiquimod, aggravation and spreading of the plaques were noted. The exacerbation of psoriasis was accompanied by an induction of lesional T_H1-type interferon produced by plasmacytoid dendritic cell (DC) precursors. Plasmacytoid DCs were observed to compose up to 16% of the total dermal infiltrate in psoriatic skin lesions based on their coexpression of BDCA2 and CD123.¹³ Additionally, cancer patients being treated with interferon alfa experienced induction of psoriasis.¹⁴ Moreover, patients being treated for warts with intralesional interferon alfa developed psoriatic plaques in neighboring prior asymptomatic skin.¹⁵ Patients with psoriasis who were treated with interferon gamma, a T_H1 cytokine type, also developed new plaques correlating with the sites of injection.¹⁶

Intralesional T Lymphocytes

Psoriatic lesions contain a host of innate immunocytes, such as APCs, NK cells, and neutrophils, as well as adaptive T cells and an inflammatory infiltrate. These cells include CD4 and CD8 subtypes in which the CD8⁺ cells predominate in the epidermis, while CD4⁺ cells show preference for the dermis.¹⁷ There are 2 groups of CD8⁺ cells: one group migrates to the epidermis, expressing the integrin CD103, while the other group is found in the dermis but may be headed to or from the epidermis. The CD8⁺ cells residing in the epidermis that express the integrin CD103 are capable of interacting with E-cadherin, which enables these cells to travel to the epidermis and bind resident cells. Immunophenotyping reveals that these mature T cells represent chiefly activated memory cells, including CD2⁺, CD3⁺, CD5⁺, CLA, CD28, and CD45RO⁺.¹⁸ Many of these cells express activation markers such as HLA-DR, CD25, and CD27, in addition to the T-cell receptor (TCR).

T-Lymphocyte Stimulation

Both mature CD4⁺ and CD8⁺ T cells can respond to the peptides presented by APCs. Although the specific antigen that these T cells are reacting to has not yet been elucidated, several antigenic stimuli have been proposed, including self-proteins, microbial pathogens, and microbial superantigens. The premise that self-reactive T lymphocytes may contribute to the disease process is derived from the molecular mimicry theory in which an exuberant immune response to a pathogen produces cross-reactivity with self-antigens.¹⁹ Considering that infections have been associated with the onset of psoriasis, this theory merits consideration. However, it also has been observed that T cells can be activated without antigens or superantigens but rather with direct contact with accessory cells.²⁰ No single theory has clearly emerged. Researchers continue to search for the inciting stimulus that triggers the T lymphocyte and attempt to determine whether T cells are reacting to a self-derived or non–self-derived antigen.

T-Lymphocyte Signaling

T-cell signaling is a highly coordinated process in which T lymphocytes recognize antigens via presentation by mature APCs in the skin rather than the lymphoid tissues. Such APCs expose antigenic peptides via class I or II MHC molecules for which receptors are present on the T-cell surface. The antigen recognition complex at the T-cell and APC interface, in concert with a host of antigen-independent co-stimulatory signals, regulates T-cell signaling and is referred to as the immunologic synapse. The antigen presentation and network of co-stimulatory and adhesion molecules optimize T-cell activation, and dermal DCs release IL-12 and IL-23 to promote a T_H1 and T_H17 response, respectively. The growth factors released by these helper T cells sustain neoangiogenesis, stimulate epidermal hyperproliferation, alter epidermal differentiation, and decrease susceptibility to apoptosis that characterizes the erythematous hypertrophic scaling lesions of psoriasis.²¹ Furthermore, the cytokines produced from the immunologic response, such as tumor necrosis factor (TNF) α, IFN-γ, and IL-2, correspond to cytokines that are upregulated in psoriatic plaques.²²

Integral components of the immunologic synapse complex include co-stimulatory signals such as CD28, CD40, CD80, and CD86, as well as adhesion molecules such as cytotoxic T-lymphocyte antigen 4 and lymphocyte function-associated antigen (LFA) 1, which possess corresponding receptors on the T cell. These molecules play a key role in T-cell signaling, as their disruption has been shown to decrease T-cell responsiveness and associated inflammation. The B7 family of molecules routinely interacts with CD28 T cells to co-stimulate T-cell activation. Cytotoxic T-lymphocyte antigen 4 immunoglobulin, an antibody on the T-cell surface, targets B7 and interferes with signaling between B7 and CD28. In psoriatic patients, this blockade was demonstrated to attenuate the T-cell response and correlated with a clinical and histological decrease in psoriasiform hyperplasia.²³ Biologic therapies that disrupt the LFA-1 component of the immunologic synapse also have demonstrated efficacy in the treatment of psoriasis. Alefacept is a human LFA-3 fusion protein that binds CD2 on T cells and blocks the interaction between LFA-3 on APCs and CD2 on memory CD45RO⁺ T cells and induces apoptosis of such T cells. Efalizumab is a human monoclonal antibody to the CD11 chain of LFA-1 that blocks the interaction between LFA-1 on the T cell and intercellular adhesion molecule 1 on an APC or endothelial cell. Both alefacept and efalizumab, 2 formerly marketed biologic therapies, demonstrated remarkable clinical reduction of psoriatic lesions, and alefacept has been shown to produce disease remission for up to 18 months after discontinuation of therapy.^24-26

NK T Cells

Natural killer T cells represent a subset of CD3⁺ T cells present in psoriatic plaques. Although NK T cells possess a TCR, they differ from T cells by displaying NK receptors comprised of lectin and immunoglobulin families. These cells exhibit remarkable specificity and are activated upon recognition of glycolipids presented by CD1d molecules. This process occurs in contrast to CD4⁺ and CD8⁺ T cells, which, due to their TCR diversity, respond to peptides processed by APCs and displayed on MHC molecules. Natural killer T cells can be classified into 2 subsets: (1) one group that expresses CD4 and preferentially produces T_H1- versus T_H2-type cytokines, and (2) another group that lacks CD4 and CD8 that only produces T_H1-type cytokines. The innate immune system employs NK T cells early in the immune response because of their direct cytotoxicity and rapid production of cytokines such as IFN-γ, which promotes a T_H1 inflammatory response, and IL-4, which promotes the development of T_H2 cells. Excessive or dysfunctional NK T cells have been associated with autoimmune diseases such as multiple sclerosis and inflammatory bowel disease as well as allergic contact dermatitis.^27-29

In psoriasis, NK T cells are located in the epidermis, closely situated to epidermal keratinocytes, which suggests a role for direct antigen presentation. Furthermore, CD1d is overexpressed throughout the epidermis of psoriatic plaques, whereas normally CD1d expression is confined to terminally differentiated keratinocytes. An in vitro study examining cytokine-based inflammation demonstrative of psoriasis treated cultured CD1d-positive keratinocytes with interferon gamma in the presence of alpha-galactosylceramide of the lectin family.³⁰ Interferon gamma was observed to enhance keratinocyte CD1d expression, and subsequently, CD1d-positive keratinocytes were found to activate NK T cells to produce high levels of IFN-γ, while levels of IL-4 remained undetectable. The preferential production of IFN-γ supports a T_H1-mediated mechanism regulated by NK T cells in the immunopathogenesis of psoriasis.

Dendritic Cells

Dendritic cells are APCs that process antigens in the tissues in which they reside, after which they migrate to local lymph nodes where they present their native antigens to T cells. This process allows the T-cell response to be tailored to the appropriate antigens in the corresponding tissues. Immature DCs that capture antigens mature by migrating to the T-cell center of the lymph node where they present their antigens to either MHC molecules or the CD1 family. This presentation results in T-cell proliferation and differentiation that correlates with the required type of T-cell response. Multiple subsets of APCs, including myeloid and plasmacytoid DCs, are highly represented in the epidermis and dermis of psoriatic plaques as compared with normal skin.³¹ Dermal DCs are thought to be responsible for activating both the T_H1 and T_H17 infiltrate by secreting IL-12 and IL-23, respectively. This mixed cellular response secretes cytokines and leads to a cascade of events involving keratinocytes, fibroblasts, endothelial cells, and neutrophils that create the cutaneous lesions seen in psoriasis.³

Although DCs play a pivotal role in eliciting an immune response against a foreign invader, they also contribute to the establishment of tolerance. Throughout their maturation, DCs are continuously sensing their environment, which shapes their production of T_H1- versus T_H2-type cytokines and subsequently the nature of the T-cell response. When challenged with a virus, bacteria, or unchecked cell growth, DCs mature into APCs. However, in the absence of a strong stimulus, DCs fail to mature into APCs and present self-peptides with MHC molecules, thereby creating regulatory T cells involved in peripheral tolerance.³² If this balance between immunogenic APCs and housekeeping T cells is upset, inflammatory conditions such as psoriasis can result.

Cytokines

Cytokines are low-molecular-weight glycoproteins that function as signals to produce inflammation, defense, tissue repair and remodeling, fibrosis, angiogenesis, and restriction of neoplastic growth.³³ Cytokines are produced by immunocytes such as lymphocytes and macrophages as well as nonimmunocytes such as endothelial cells and keratinocytes. Proinflammatory cytokines include IL-1, IL-2, the IL-17 family, IFN-γ, and TNF-α, while anti-inflammatory cytokines include IL-4 and IL-10. A relative preponderance of T_H1 proinflammatory cytokines or an insufficiency of T_H2 anti-inflammatory cytokines induces local inflammation and recruitment of additional immunocyte populations, which produce added cytokines.³⁴ A vicious cycle of inflammation occurs that results in cutaneous manifestations such as a plaque. Psoriatic lesions are characterized by a relative increase of T_H1-type (eg, IL-2, IFN-γ, TNF-α, TNF-β) to T_H2-type (eg, IL-4, IL-5, IL-6, IL-9, IL-10, IL-13) cytokines and an increase in T_H17-type cytokines. Natural killer T cells stimulated by CD1d-overexpressing keratinocytes increase production of proinflammatory IFN-γ without effect on the anti-inflammatory IL-4. In addition to the cytokines produced by T cells, APCs produce IL-18, IL-23, and TNF-α found in the inflammatory infiltrate of psoriatic plaques. Both IL-18 and IL-23 stimulate T_H1 cells to produce IFN-γ, and IL-23 stimulates T_H17 cells. Clearly, a T_H1- and T_H17-type pattern governs the immune effector cells and their respective cytokines present in psoriatic skin.

Tumor Necrosis Factor α

Although a network of cytokines is responsible for the inflammation of psoriasis, TNF-α has been implicated as a master proinflammatory cytokine of the innate immune response due to its widespread targets and sources. Tumor necrosis factor α is produced by activated T cells, keratinocytes, NK cells, macrophages, monocytes, Langerhans APCs, and endothelial cells. Psoriatic lesions demonstrate high concentrations of TNF-α, while the synovial fluid of psoriatic arthritis patients demonstrates elevated concentrations of TNF-α, IL-1, IL-6, and IL-8.³⁴ In psoriasis, TNF-α supports the expression of adhesion molecules (intercellular adhesion molecule 1 and P- and E-selectin), angiogenesis via vascular endothelial growth factor, the synthesis of proinflammatory molecules (IL-1, IL-6, IL-8, and nuclear factor κβ), and keratinocyte hyperproliferation via vasoactive intestinal peptide.³⁵

A role for TNF-α in psoriasis treatment was serendipitously discovered in a trial for Crohn disease in which infliximab, a mouse-human IgG1 anti–TNF-α monoclonal antibody, was observed to clear psoriatic plaques in a patient with both Crohn disease and psoriasis.³⁶ Immunotherapies that target TNF-α, including infliximab, etanercept, and adalimumab, demonstrate notable efficacy in the treatment of psoriasis.^37-39 Tumor necrosis factor α is regarded as the driver of the inflammatory cycle of psoriasis due to its numerous modes of production, capability to amplify other proinflammatory signals, and the efficacy and rapidity with which it produces clinical improvements in psoriasis.

IL-23/T_H17 Axis

A new distinct population of helper T cells has been shown to play an important role in psoriasis. These cells develop with the help of IL-23 (secreted by dermal DCs) and subsequently secrete cytokines such as IL-17; they are, therefore, named T_H17 cells. CD161 is considered a surface marker for these cells.⁴⁰ Strong evidence for this IL-23/T_H17 axis has been shown in mouse and human models as well as in genetic studies.

IL-23 is a cytokine that shares the p40 subunit with IL-12 and has been linked to autoimmune diseases in both mice and humans.³ It is required for optimal development of T_H17 cells⁴¹ from a committed CD4⁺ T-cell population after exposure to transforming growth factor β1 in combination with other proinflammatory cytokines.^42,43 IL-23 messenger RNA is produced at higher levels in inflammatory psoriatic skin lesions versus uninvolved skin,⁴⁴ and intradermal IL-23 injections in mice produced lesions resembling psoriasis macroscopically and microscopically.⁴⁵ Furthermore, several systemic therapies have been shown to modulate IL-23 levels and correlate with clinical benefit.³ Alterations in the gene for the IL-23 receptor have been shown to be protective for psoriasis,^46-48 and the gene coding for the p40 subunit is associated with psoriasis.^46,47

Type 17 helper T cells produce a number of cytokines, such as IL-22, IL-17A, IL-17F, and IL-26; the latter 3 are considered to be specific to this lineage.⁴² IL-22 acts on outer body barrier tissues, such as the skin, and has antimicrobial activity. Blocking the activity of IL-22 in mice prevented the development of skin lesions,⁴⁹ and psoriasis patients have elevated levels of IL-22 in the skin and blood.^50,51 The IL-17 cytokines induce the expression of proinflammatory cytokines, colony-stimulating factors, and chemokines, and they recruit, mobilize, and activate neutrophils.⁵² IL-17 messenger RNA was found in lesional psoriatic skin but not unaffected skin,⁵³ and cells isolated from the dermis of psoriatic skin have been shown to produce IL-17.⁵⁴ IL-17A is not elevated in the serum of psoriatic patients (unlike other autoimmune diseases),⁵⁵ and it is, therefore, thought that T_H17 cells and IL-17A production are localized to the affected psoriatic skin. Consistent with this concept is the finding that treatments such as cyclosporin A and anti-TNF agents decrease proinflammatory cytokines in lesional skin but not in the periphery.^56-58 These cytokines released by T_H17 cells in addition to those released by T_H1 cells act on keratinocytes and produce epidermal hyperproliferation, acanthosis, and hyperparakeratosis characteristic of psoriasis.³

New therapies have been developed to target the IL-23/T_H17 axis. Ustekinumab is approved for moderate to severe plaque psoriasis. This treatment’s effect may be sustained for up to 3 years, it is generally well tolerated, and it may be useful for patients refractory to anti-TNF therapy such as etanercept.⁵⁹ Briakinumab, another blocker of IL-12 and IL-23, was studied in phase 3 clinical trials, but its development was discontinued due to safety concerns.⁶⁰ Newer drugs targeting the IL-23/T_H17 axis include secukinumab, ixekizumab, brodalumab, guselkumab, and tildrakizumab.

Genetic Basis of Psoriasis

Psoriasis is a disease of overactive immunity in genetically susceptible individuals. Because patients exhibit varying skin phenotypes, extracutaneous manifestations, and disease courses, multiple genes resulting from linkage disequilibrium are believed to be involved in the pathogenesis of psoriasis. A decade of genome-wide linkage scans have established that PSORS1 is the strongest susceptibility locus demonstrable through family linkage studies; PSORS1 is responsible for up to 50% of the genetic component of psoriasis.⁶¹ More recently, HLA-Cw6 has received the most attention as a candidate gene of the PSORS1 susceptibility locus on the MHC class I region on chromosome 6p21.3.⁶² This gene may function in antigen presentation via MHC class I, which aids in the activation of the overactive T cells characteristic of psoriatic inflammation.

Studies involving the IL-23/T_H17 axis have shown genetics to play a role. Individuals may be protected from psoriasis with a nonsynonymous nucleotide substitution in the IL23R gene,^47-49 and certain haplotypes of the IL23R gene are associated with the disease^47,49 in addition to other autoimmune conditions.

Genomic scans have shown additional susceptibility loci for psoriasis on chromosomes 1q21, 3q21, 4q32-35, 16q12, and 17q25. Two regions on chromosome 17q were recently localized via mapping, which demonstrated a 6 megabase pairs separation, thereby indicating independent linkage factors. Genes SLC9A3R1 and NAT9 are present in the first region, while RAPTOR is demonstrated in the second region.⁶³SLC9A3R1 and NAT9 are players that regulate signal transduction, the immunologic synapse, and T-cell growth. RAPTOR is involved in T-cell function and growth pathways. Using these genes as an example, we can predict that the alterations of regulatory genes, even those yet undetermined, can enhance T-cell proliferation and inflammation manifested in psoriasis.

Conclusion

Psoriasis is a complex disease whereby multiple exogenous and endogenous stimuli incite already heightened innate immune responses in genetically predetermined individuals. The disease process is a result of a network of cell types, including T cells, DCs, and keratinocytes that, with the production of cytokines, generate a chronic inflammatory state. Our understanding of these cellular interactions and cytokines originates from developments, some meticulously planned, others serendipitous, in the fields of immunology, cell and molecular biology, and genetics. Such progress has fostered the creation of targeted immune therapy that has demonstrated remarkable efficacy in psoriasis treatment. Further study of the underlying pathophysiology of psoriasis may provide additional targets for therapy.

Increased understanding of the pathophysiology of psoriasis has been one of the driving forces in the development of new therapies. An understanding of the processes involved is important in the optimal management of the disease. The last 30 years of research and clinical practice have revolutionized our understanding of the pathogenesis of psoriasis as the dysregulation of immunity triggered by environmental and genetic stimuli. Psoriasis was originally regarded as a primary disorder of epidermal hyperproliferation. However, experimental models and clinical results from immunomodulating therapies have refined this perspective in conceptualizing psoriasis as a genetically programmed pathologic interaction among resident skin cells; infiltrating immunocytes; and a host of proinflammatory cytokines, chemokines, and growth factors produced by these immunocytes. Two populations of immunocytes and their respective signaling molecules collaborate in the pathogenesis: (1) innate immunocytes, mediated by antigen-presenting cells (APCs)(including natural killer [NK] T lymphocytes, Langerhans cells, and neutrophils), and (2) acquired or adaptive immunocytes, mediated by mature CD4⁺ and CD8⁺ T lymphocytes in the skin. Such dysregulation of immunity and subsequent inflammation is responsible for the development and perpetuation of the clinical plaques and histological inflammatory infiltrate characteristic of psoriasis.

Although psoriasis is considered to be an immune-mediated disease in which intralesional T lymphocytes and their proinflammatory signals trigger primed basal layer keratinocytes to rapidly proliferate, debate and research focus on the stimulus that incites this inflammatory process. Our current understanding considers psoriasis to be triggered by exogenous or endogenous environmental stimuli in genetically susceptible individuals. Such stimuli include group A streptococcal pharyngitis, viremia, allergic drug reactions, antimalarial drugs, lithium, beta-blockers, IFN-α, withdrawal of systemic corticosteroids, local trauma (Köbner phenomenon), and emotional stress. These stimuli correlate with the onset or flares of psoriatic lesions. Psoriasis genetics centers on susceptibility loci and corresponding candidate genes, particularly the psoriasis susceptibility (PSORS) 1 locus on the major histocompatibility complex (MHC) class I region. Current research on the pathogenesis of psoriasis examines the complex interactions among immunologic mechanisms, environmental stimuli, and genetic susceptibility. After discussing the clinical presentation and histopathologic features of psoriasis, we will review the pathophysiology of psoriasis through noteworthy developments, including serendipitous observations, reactions to therapies, clinical trials, and animal model systems that have shaped our view of the disease process. In addition to the classic skin lesions, approximately 23% of psoriasis patients develop psoriatic arthritis, with a 10-year latency after diagnosis of psoriasis.¹

Principles of Immunity

The immune system, intended to protect its host from foreign invaders and unregulated cell growth, employs 2 main effector pathways—the innate and the acquired (or adaptive) immune responses—both of which contribute to the pathophysiology of psoriasis.² Innate immunity responses occur within minutes to hours of antigen exposure but fail to develop memory for when the antigen is encountered again. However, adaptive immunity responses take days to weeks to respond after challenged with an antigen. The adaptive immune cells have the capacity to respond to a greater range of antigens and develop immunologic memory via rearrangement of antigen receptors on B and T cells. These specialized B and T cells can then be promptly mobilized and differentiated into mature effector cells that protect the host from a foreign pathogen.

Innate and adaptive immune responses are highly intertwined; they can initiate, perpetuate, and terminate the immune mechanisms responsible for inflammation. They can modify the nature of the immune response by altering the relative proportions of type 1 (T_H1), type 2 (T_H2), and the more recently discovered type 17 (T_H17) subset of helper T cells and their respective signaling molecules. A T_H1 response is essential for a cellular immunologic reaction to intracellular bacteria and viruses or cellular immunity. A T_H2 response promotes IgE synthesis, eosinophilia, and mast cell maturation for extracellular parasites and helminthes as well as humoral immunity, while a T_H17 response is important for cell-mediated immunity to extracellular bacteria and plays a role in autoimmunity.³ The innate and adaptive immune responses employ common effector molecules such as chemokines and cytokines, which are essential in mediating an immune response.

Implicating Dysregulation of Immunity

Our present appreciation of the pathogenesis of psoriasis is based on the history of trial-and-error therapies; serendipitous discoveries; and the current immune targeting drugs used in a variety of chronic inflammatory conditions, including rheumatoid arthritis, ankylosing spondylitis, and inflammatory bowel disease. Before the mid-1980s, research focused on the hyperproliferative epidermal cells as the primary pathology because a markedly thickened epidermis was indeed demonstrated on histologic specimens. Altered cell-cycle kinetics were thought to be the culprit behind the hyperkeratotic plaques. Thus, initial treatments centered on oncologic and antimitotic therapies used to arrest keratinocyte proliferation with agents such as arsenic, ammoniated mercury, and methotrexate.⁴

However, a paradigm shift from targeting epidermal keratinocytes to immunocyte populations was recognized when a patient receiving cyclosporine to prevent transplant rejection noted clearing of psoriatic lesions in the 1980s.⁵ Cyclosporine was observed to inhibit messenger RNA transcription of T-cell cytokines, thereby implicating immunologic dysregulation, specifically T-cell hyperactivity, in the pathogenesis of psoriasis.⁶ However, the concentrations of oral cyclosporine reached in the epidermis exerted direct effects on keratinocyte proliferation and lymphocyte function in these patients.⁷ Thus, the question was raised as to whether the keratinocytes or the lymphocytes drove the psoriatic plaques. The use of an IL-2 diphtheria toxin-fusion protein, denileukin diftitox, specific for activated T cells with high-affinity IL-2 receptors and nonreactive with keratinocytes, distinguished which cell type was responsible. This targeted T-cell toxin provided clinical and histological clearing of psoriatic plaques. Thus, T lymphocytes rather than keratinocytes were recognized as the definitive driver behind the psoriatic plaques.⁸

Additional studies have demonstrated that treatments that induce prolonged clearing of psoriatic lesions without continuous therapy, such as psoralen plus UVA irradiation, decreased the numbers of T cells in plaques by at least 90%.⁹ However, treatments that require continual therapy for satisfactory clinical results, such as cyclosporine and etretinate, simply suppress T-cell activity and proliferation.^10,11 Further evidence has linked cellular immunity with the pathogenesis of psoriasis, defining it as a T_H1-type disease. Natural killer T cells were shown to be involved through the use of a severe combined immunodeficient mouse model. They were injected into prepsoriatic skin grafted on immunodeficient mice, creating a psoriatic plaque with an immune response showing cytokines from T_H1 cells rather than T_H2 cells.¹² When psoriatic plaques were treated topically with the toll-like receptor 7 agonist imiquimod, aggravation and spreading of the plaques were noted. The exacerbation of psoriasis was accompanied by an induction of lesional T_H1-type interferon produced by plasmacytoid dendritic cell (DC) precursors. Plasmacytoid DCs were observed to compose up to 16% of the total dermal infiltrate in psoriatic skin lesions based on their coexpression of BDCA2 and CD123.¹³ Additionally, cancer patients being treated with interferon alfa experienced induction of psoriasis.¹⁴ Moreover, patients being treated for warts with intralesional interferon alfa developed psoriatic plaques in neighboring prior asymptomatic skin.¹⁵ Patients with psoriasis who were treated with interferon gamma, a T_H1 cytokine type, also developed new plaques correlating with the sites of injection.¹⁶

Intralesional T Lymphocytes

Psoriatic lesions contain a host of innate immunocytes, such as APCs, NK cells, and neutrophils, as well as adaptive T cells and an inflammatory infiltrate. These cells include CD4 and CD8 subtypes in which the CD8⁺ cells predominate in the epidermis, while CD4⁺ cells show preference for the dermis.¹⁷ There are 2 groups of CD8⁺ cells: one group migrates to the epidermis, expressing the integrin CD103, while the other group is found in the dermis but may be headed to or from the epidermis. The CD8⁺ cells residing in the epidermis that express the integrin CD103 are capable of interacting with E-cadherin, which enables these cells to travel to the epidermis and bind resident cells. Immunophenotyping reveals that these mature T cells represent chiefly activated memory cells, including CD2⁺, CD3⁺, CD5⁺, CLA, CD28, and CD45RO⁺.¹⁸ Many of these cells express activation markers such as HLA-DR, CD25, and CD27, in addition to the T-cell receptor (TCR).

T-Lymphocyte Stimulation

Both mature CD4⁺ and CD8⁺ T cells can respond to the peptides presented by APCs. Although the specific antigen that these T cells are reacting to has not yet been elucidated, several antigenic stimuli have been proposed, including self-proteins, microbial pathogens, and microbial superantigens. The premise that self-reactive T lymphocytes may contribute to the disease process is derived from the molecular mimicry theory in which an exuberant immune response to a pathogen produces cross-reactivity with self-antigens.¹⁹ Considering that infections have been associated with the onset of psoriasis, this theory merits consideration. However, it also has been observed that T cells can be activated without antigens or superantigens but rather with direct contact with accessory cells.²⁰ No single theory has clearly emerged. Researchers continue to search for the inciting stimulus that triggers the T lymphocyte and attempt to determine whether T cells are reacting to a self-derived or non–self-derived antigen.

T-Lymphocyte Signaling

T-cell signaling is a highly coordinated process in which T lymphocytes recognize antigens via presentation by mature APCs in the skin rather than the lymphoid tissues. Such APCs expose antigenic peptides via class I or II MHC molecules for which receptors are present on the T-cell surface. The antigen recognition complex at the T-cell and APC interface, in concert with a host of antigen-independent co-stimulatory signals, regulates T-cell signaling and is referred to as the immunologic synapse. The antigen presentation and network of co-stimulatory and adhesion molecules optimize T-cell activation, and dermal DCs release IL-12 and IL-23 to promote a T_H1 and T_H17 response, respectively. The growth factors released by these helper T cells sustain neoangiogenesis, stimulate epidermal hyperproliferation, alter epidermal differentiation, and decrease susceptibility to apoptosis that characterizes the erythematous hypertrophic scaling lesions of psoriasis.²¹ Furthermore, the cytokines produced from the immunologic response, such as tumor necrosis factor (TNF) α, IFN-γ, and IL-2, correspond to cytokines that are upregulated in psoriatic plaques.²²

Integral components of the immunologic synapse complex include co-stimulatory signals such as CD28, CD40, CD80, and CD86, as well as adhesion molecules such as cytotoxic T-lymphocyte antigen 4 and lymphocyte function-associated antigen (LFA) 1, which possess corresponding receptors on the T cell. These molecules play a key role in T-cell signaling, as their disruption has been shown to decrease T-cell responsiveness and associated inflammation. The B7 family of molecules routinely interacts with CD28 T cells to co-stimulate T-cell activation. Cytotoxic T-lymphocyte antigen 4 immunoglobulin, an antibody on the T-cell surface, targets B7 and interferes with signaling between B7 and CD28. In psoriatic patients, this blockade was demonstrated to attenuate the T-cell response and correlated with a clinical and histological decrease in psoriasiform hyperplasia.²³ Biologic therapies that disrupt the LFA-1 component of the immunologic synapse also have demonstrated efficacy in the treatment of psoriasis. Alefacept is a human LFA-3 fusion protein that binds CD2 on T cells and blocks the interaction between LFA-3 on APCs and CD2 on memory CD45RO⁺ T cells and induces apoptosis of such T cells. Efalizumab is a human monoclonal antibody to the CD11 chain of LFA-1 that blocks the interaction between LFA-1 on the T cell and intercellular adhesion molecule 1 on an APC or endothelial cell. Both alefacept and efalizumab, 2 formerly marketed biologic therapies, demonstrated remarkable clinical reduction of psoriatic lesions, and alefacept has been shown to produce disease remission for up to 18 months after discontinuation of therapy.^24-26

NK T Cells

Natural killer T cells represent a subset of CD3⁺ T cells present in psoriatic plaques. Although NK T cells possess a TCR, they differ from T cells by displaying NK receptors comprised of lectin and immunoglobulin families. These cells exhibit remarkable specificity and are activated upon recognition of glycolipids presented by CD1d molecules. This process occurs in contrast to CD4⁺ and CD8⁺ T cells, which, due to their TCR diversity, respond to peptides processed by APCs and displayed on MHC molecules. Natural killer T cells can be classified into 2 subsets: (1) one group that expresses CD4 and preferentially produces T_H1- versus T_H2-type cytokines, and (2) another group that lacks CD4 and CD8 that only produces T_H1-type cytokines. The innate immune system employs NK T cells early in the immune response because of their direct cytotoxicity and rapid production of cytokines such as IFN-γ, which promotes a T_H1 inflammatory response, and IL-4, which promotes the development of T_H2 cells. Excessive or dysfunctional NK T cells have been associated with autoimmune diseases such as multiple sclerosis and inflammatory bowel disease as well as allergic contact dermatitis.^27-29

In psoriasis, NK T cells are located in the epidermis, closely situated to epidermal keratinocytes, which suggests a role for direct antigen presentation. Furthermore, CD1d is overexpressed throughout the epidermis of psoriatic plaques, whereas normally CD1d expression is confined to terminally differentiated keratinocytes. An in vitro study examining cytokine-based inflammation demonstrative of psoriasis treated cultured CD1d-positive keratinocytes with interferon gamma in the presence of alpha-galactosylceramide of the lectin family.³⁰ Interferon gamma was observed to enhance keratinocyte CD1d expression, and subsequently, CD1d-positive keratinocytes were found to activate NK T cells to produce high levels of IFN-γ, while levels of IL-4 remained undetectable. The preferential production of IFN-γ supports a T_H1-mediated mechanism regulated by NK T cells in the immunopathogenesis of psoriasis.

Dendritic Cells

Dendritic cells are APCs that process antigens in the tissues in which they reside, after which they migrate to local lymph nodes where they present their native antigens to T cells. This process allows the T-cell response to be tailored to the appropriate antigens in the corresponding tissues. Immature DCs that capture antigens mature by migrating to the T-cell center of the lymph node where they present their antigens to either MHC molecules or the CD1 family. This presentation results in T-cell proliferation and differentiation that correlates with the required type of T-cell response. Multiple subsets of APCs, including myeloid and plasmacytoid DCs, are highly represented in the epidermis and dermis of psoriatic plaques as compared with normal skin.³¹ Dermal DCs are thought to be responsible for activating both the T_H1 and T_H17 infiltrate by secreting IL-12 and IL-23, respectively. This mixed cellular response secretes cytokines and leads to a cascade of events involving keratinocytes, fibroblasts, endothelial cells, and neutrophils that create the cutaneous lesions seen in psoriasis.³

Although DCs play a pivotal role in eliciting an immune response against a foreign invader, they also contribute to the establishment of tolerance. Throughout their maturation, DCs are continuously sensing their environment, which shapes their production of T_H1- versus T_H2-type cytokines and subsequently the nature of the T-cell response. When challenged with a virus, bacteria, or unchecked cell growth, DCs mature into APCs. However, in the absence of a strong stimulus, DCs fail to mature into APCs and present self-peptides with MHC molecules, thereby creating regulatory T cells involved in peripheral tolerance.³² If this balance between immunogenic APCs and housekeeping T cells is upset, inflammatory conditions such as psoriasis can result.

Cytokines

Cytokines are low-molecular-weight glycoproteins that function as signals to produce inflammation, defense, tissue repair and remodeling, fibrosis, angiogenesis, and restriction of neoplastic growth.³³ Cytokines are produced by immunocytes such as lymphocytes and macrophages as well as nonimmunocytes such as endothelial cells and keratinocytes. Proinflammatory cytokines include IL-1, IL-2, the IL-17 family, IFN-γ, and TNF-α, while anti-inflammatory cytokines include IL-4 and IL-10. A relative preponderance of T_H1 proinflammatory cytokines or an insufficiency of T_H2 anti-inflammatory cytokines induces local inflammation and recruitment of additional immunocyte populations, which produce added cytokines.³⁴ A vicious cycle of inflammation occurs that results in cutaneous manifestations such as a plaque. Psoriatic lesions are characterized by a relative increase of T_H1-type (eg, IL-2, IFN-γ, TNF-α, TNF-β) to T_H2-type (eg, IL-4, IL-5, IL-6, IL-9, IL-10, IL-13) cytokines and an increase in T_H17-type cytokines. Natural killer T cells stimulated by CD1d-overexpressing keratinocytes increase production of proinflammatory IFN-γ without effect on the anti-inflammatory IL-4. In addition to the cytokines produced by T cells, APCs produce IL-18, IL-23, and TNF-α found in the inflammatory infiltrate of psoriatic plaques. Both IL-18 and IL-23 stimulate T_H1 cells to produce IFN-γ, and IL-23 stimulates T_H17 cells. Clearly, a T_H1- and T_H17-type pattern governs the immune effector cells and their respective cytokines present in psoriatic skin.

Tumor Necrosis Factor α

Although a network of cytokines is responsible for the inflammation of psoriasis, TNF-α has been implicated as a master proinflammatory cytokine of the innate immune response due to its widespread targets and sources. Tumor necrosis factor α is produced by activated T cells, keratinocytes, NK cells, macrophages, monocytes, Langerhans APCs, and endothelial cells. Psoriatic lesions demonstrate high concentrations of TNF-α, while the synovial fluid of psoriatic arthritis patients demonstrates elevated concentrations of TNF-α, IL-1, IL-6, and IL-8.³⁴ In psoriasis, TNF-α supports the expression of adhesion molecules (intercellular adhesion molecule 1 and P- and E-selectin), angiogenesis via vascular endothelial growth factor, the synthesis of proinflammatory molecules (IL-1, IL-6, IL-8, and nuclear factor κβ), and keratinocyte hyperproliferation via vasoactive intestinal peptide.³⁵

A role for TNF-α in psoriasis treatment was serendipitously discovered in a trial for Crohn disease in which infliximab, a mouse-human IgG1 anti–TNF-α monoclonal antibody, was observed to clear psoriatic plaques in a patient with both Crohn disease and psoriasis.³⁶ Immunotherapies that target TNF-α, including infliximab, etanercept, and adalimumab, demonstrate notable efficacy in the treatment of psoriasis.^37-39 Tumor necrosis factor α is regarded as the driver of the inflammatory cycle of psoriasis due to its numerous modes of production, capability to amplify other proinflammatory signals, and the efficacy and rapidity with which it produces clinical improvements in psoriasis.

IL-23/T_H17 Axis

A new distinct population of helper T cells has been shown to play an important role in psoriasis. These cells develop with the help of IL-23 (secreted by dermal DCs) and subsequently secrete cytokines such as IL-17; they are, therefore, named T_H17 cells. CD161 is considered a surface marker for these cells.⁴⁰ Strong evidence for this IL-23/T_H17 axis has been shown in mouse and human models as well as in genetic studies.

IL-23 is a cytokine that shares the p40 subunit with IL-12 and has been linked to autoimmune diseases in both mice and humans.³ It is required for optimal development of T_H17 cells⁴¹ from a committed CD4⁺ T-cell population after exposure to transforming growth factor β1 in combination with other proinflammatory cytokines.^42,43 IL-23 messenger RNA is produced at higher levels in inflammatory psoriatic skin lesions versus uninvolved skin,⁴⁴ and intradermal IL-23 injections in mice produced lesions resembling psoriasis macroscopically and microscopically.⁴⁵ Furthermore, several systemic therapies have been shown to modulate IL-23 levels and correlate with clinical benefit.³ Alterations in the gene for the IL-23 receptor have been shown to be protective for psoriasis,^46-48 and the gene coding for the p40 subunit is associated with psoriasis.^46,47

Type 17 helper T cells produce a number of cytokines, such as IL-22, IL-17A, IL-17F, and IL-26; the latter 3 are considered to be specific to this lineage.⁴² IL-22 acts on outer body barrier tissues, such as the skin, and has antimicrobial activity. Blocking the activity of IL-22 in mice prevented the development of skin lesions,⁴⁹ and psoriasis patients have elevated levels of IL-22 in the skin and blood.^50,51 The IL-17 cytokines induce the expression of proinflammatory cytokines, colony-stimulating factors, and chemokines, and they recruit, mobilize, and activate neutrophils.⁵² IL-17 messenger RNA was found in lesional psoriatic skin but not unaffected skin,⁵³ and cells isolated from the dermis of psoriatic skin have been shown to produce IL-17.⁵⁴ IL-17A is not elevated in the serum of psoriatic patients (unlike other autoimmune diseases),⁵⁵ and it is, therefore, thought that T_H17 cells and IL-17A production are localized to the affected psoriatic skin. Consistent with this concept is the finding that treatments such as cyclosporin A and anti-TNF agents decrease proinflammatory cytokines in lesional skin but not in the periphery.^56-58 These cytokines released by T_H17 cells in addition to those released by T_H1 cells act on keratinocytes and produce epidermal hyperproliferation, acanthosis, and hyperparakeratosis characteristic of psoriasis.³

New therapies have been developed to target the IL-23/T_H17 axis. Ustekinumab is approved for moderate to severe plaque psoriasis. This treatment’s effect may be sustained for up to 3 years, it is generally well tolerated, and it may be useful for patients refractory to anti-TNF therapy such as etanercept.⁵⁹ Briakinumab, another blocker of IL-12 and IL-23, was studied in phase 3 clinical trials, but its development was discontinued due to safety concerns.⁶⁰ Newer drugs targeting the IL-23/T_H17 axis include secukinumab, ixekizumab, brodalumab, guselkumab, and tildrakizumab.

Genetic Basis of Psoriasis

Psoriasis is a disease of overactive immunity in genetically susceptible individuals. Because patients exhibit varying skin phenotypes, extracutaneous manifestations, and disease courses, multiple genes resulting from linkage disequilibrium are believed to be involved in the pathogenesis of psoriasis. A decade of genome-wide linkage scans have established that PSORS1 is the strongest susceptibility locus demonstrable through family linkage studies; PSORS1 is responsible for up to 50% of the genetic component of psoriasis.⁶¹ More recently, HLA-Cw6 has received the most attention as a candidate gene of the PSORS1 susceptibility locus on the MHC class I region on chromosome 6p21.3.⁶² This gene may function in antigen presentation via MHC class I, which aids in the activation of the overactive T cells characteristic of psoriatic inflammation.

Studies involving the IL-23/T_H17 axis have shown genetics to play a role. Individuals may be protected from psoriasis with a nonsynonymous nucleotide substitution in the IL23R gene,^47-49 and certain haplotypes of the IL23R gene are associated with the disease^47,49 in addition to other autoimmune conditions.

Genomic scans have shown additional susceptibility loci for psoriasis on chromosomes 1q21, 3q21, 4q32-35, 16q12, and 17q25. Two regions on chromosome 17q were recently localized via mapping, which demonstrated a 6 megabase pairs separation, thereby indicating independent linkage factors. Genes SLC9A3R1 and NAT9 are present in the first region, while RAPTOR is demonstrated in the second region.⁶³SLC9A3R1 and NAT9 are players that regulate signal transduction, the immunologic synapse, and T-cell growth. RAPTOR is involved in T-cell function and growth pathways. Using these genes as an example, we can predict that the alterations of regulatory genes, even those yet undetermined, can enhance T-cell proliferation and inflammation manifested in psoriasis.

Conclusion

Psoriasis is a complex disease whereby multiple exogenous and endogenous stimuli incite already heightened innate immune responses in genetically predetermined individuals. The disease process is a result of a network of cell types, including T cells, DCs, and keratinocytes that, with the production of cytokines, generate a chronic inflammatory state. Our understanding of these cellular interactions and cytokines originates from developments, some meticulously planned, others serendipitous, in the fields of immunology, cell and molecular biology, and genetics. Such progress has fostered the creation of targeted immune therapy that has demonstrated remarkable efficacy in psoriasis treatment. Further study of the underlying pathophysiology of psoriasis may provide additional targets for therapy.

This special issue is dedicated to resident education on psoriasis. With that in mind, we hope to address many topics of interest to those in training. Over the years, diet has been a hot topic among psoriasis patients. They want to know how diet affects psoriasis and what changes can be made to their diet to improve their condition. Although they have expected specific answers, my response has usually been that they should, of course, eat an overall healthy and balanced diet, and lose weight if necessary. I have continued, however, that no specific diet has been recommended. However, now we have some information that may start to give us some answers.

The Mediterranean diet has been regarded as a healthy regimen.¹ This diet emphasizes eating primarily plant-based foods, such as fruits and vegetables; whole grains; legumes; and nuts. Other recommendations include replacing butter with healthy fats such as olive oil and canola oil, using herbs and spices instead of salt to flavor foods, and limiting red meat to no more than a few times a month.¹

As we know, psoriasis is a chronic inflammatory disease. The Mediterranean diet has been shown to reduce chronic inflammation and has a positive effect on the risk for metabolic syndrome and cardiovascular events.¹ Phan et al¹ hypothesized a positive effect of the Mediterranean diet on psoriasis. They performed a study to assess the association between a score that reflects the adhesion to a Mediterranean diet (MEDI-LITE) and the onset and/or severity of psoriasis.¹

The NutriNet-Santé program is an ongoing, observational, web-based questionnaire cohort study launched in France in May 2009.¹ Data were collected and analyzed between April 2017 and June 2017. Individuals with psoriasis were identified utilizing a validated online questionnaire and then categorized by disease severity into 1 of 3 groups: severe psoriasis, nonsevere psoriasis, and psoriasis free.¹

During the initial 2 years of participation in the cohort, data on dietary intake (including alcohol) were gathered to calculate the MEDI-LITE score, ranging from 0 (no adherence) to 18 (maximum adherence).¹ Of the 158,361 total web-based participants, 35,735 (23%) replied to the psoriasis questionnaire.¹ Of the respondents, 3557 (10%) individuals reported having psoriasis. The condition was severe in 878 cases (24.7%), and 299 (8.4%) incident cases were recorded (cases occurring >2 years after participant inclusion in the cohort). After adjustment for confounding factors, the investigators found a significant inverse relationship between the MEDI-LITE score and having severe psoriasis (odds ratio [OR], 0.71; 95% CI, 0.55-0.92 for the MEDI-LITE score’s second tertile [score of 8 to 9]; and OR, 0.78; 95% CI, 0.59-1.01 for the third tertile [score of 10 to 18]).¹

The authors noted that patients with severe psoriasis displayed low levels of adherence to the Mediterranean diet.¹ They commented that this finding supports the hypothesis that the Mediterranean diet may slow the progression of psoriasis. If these findings are confirmed, adherence to a Mediterranean diet should be integrated into the routine management of moderate to severe psoriasis.¹ These findings are by no means definitive, but it is a first step in helping us define more specific dietary recommendations for psoriasis.

This issue includes several articles looking at various facets of psoriasis important to residents, including the pathophysiology of psoriasis,² treatment approach using biologic therapies,³ risk factors and triggers for psoriasis,⁴ and the psychosocial impact of psoriasis.⁵ We hope that you find this issue enjoyable and informative.

This special issue is dedicated to resident education on psoriasis. With that in mind, we hope to address many topics of interest to those in training. Over the years, diet has been a hot topic among psoriasis patients. They want to know how diet affects psoriasis and what changes can be made to their diet to improve their condition. Although they have expected specific answers, my response has usually been that they should, of course, eat an overall healthy and balanced diet, and lose weight if necessary. I have continued, however, that no specific diet has been recommended. However, now we have some information that may start to give us some answers.

The Mediterranean diet has been regarded as a healthy regimen.¹ This diet emphasizes eating primarily plant-based foods, such as fruits and vegetables; whole grains; legumes; and nuts. Other recommendations include replacing butter with healthy fats such as olive oil and canola oil, using herbs and spices instead of salt to flavor foods, and limiting red meat to no more than a few times a month.¹

As we know, psoriasis is a chronic inflammatory disease. The Mediterranean diet has been shown to reduce chronic inflammation and has a positive effect on the risk for metabolic syndrome and cardiovascular events.¹ Phan et al¹ hypothesized a positive effect of the Mediterranean diet on psoriasis. They performed a study to assess the association between a score that reflects the adhesion to a Mediterranean diet (MEDI-LITE) and the onset and/or severity of psoriasis.¹

The NutriNet-Santé program is an ongoing, observational, web-based questionnaire cohort study launched in France in May 2009.¹ Data were collected and analyzed between April 2017 and June 2017. Individuals with psoriasis were identified utilizing a validated online questionnaire and then categorized by disease severity into 1 of 3 groups: severe psoriasis, nonsevere psoriasis, and psoriasis free.¹

During the initial 2 years of participation in the cohort, data on dietary intake (including alcohol) were gathered to calculate the MEDI-LITE score, ranging from 0 (no adherence) to 18 (maximum adherence).¹ Of the 158,361 total web-based participants, 35,735 (23%) replied to the psoriasis questionnaire.¹ Of the respondents, 3557 (10%) individuals reported having psoriasis. The condition was severe in 878 cases (24.7%), and 299 (8.4%) incident cases were recorded (cases occurring >2 years after participant inclusion in the cohort). After adjustment for confounding factors, the investigators found a significant inverse relationship between the MEDI-LITE score and having severe psoriasis (odds ratio [OR], 0.71; 95% CI, 0.55-0.92 for the MEDI-LITE score’s second tertile [score of 8 to 9]; and OR, 0.78; 95% CI, 0.59-1.01 for the third tertile [score of 10 to 18]).¹

The authors noted that patients with severe psoriasis displayed low levels of adherence to the Mediterranean diet.¹ They commented that this finding supports the hypothesis that the Mediterranean diet may slow the progression of psoriasis. If these findings are confirmed, adherence to a Mediterranean diet should be integrated into the routine management of moderate to severe psoriasis.¹ These findings are by no means definitive, but it is a first step in helping us define more specific dietary recommendations for psoriasis.

This issue includes several articles looking at various facets of psoriasis important to residents, including the pathophysiology of psoriasis,² treatment approach using biologic therapies,³ risk factors and triggers for psoriasis,⁴ and the psychosocial impact of psoriasis.⁵ We hope that you find this issue enjoyable and informative.

This special issue is dedicated to resident education on psoriasis. With that in mind, we hope to address many topics of interest to those in training. Over the years, diet has been a hot topic among psoriasis patients. They want to know how diet affects psoriasis and what changes can be made to their diet to improve their condition. Although they have expected specific answers, my response has usually been that they should, of course, eat an overall healthy and balanced diet, and lose weight if necessary. I have continued, however, that no specific diet has been recommended. However, now we have some information that may start to give us some answers.

The Mediterranean diet has been regarded as a healthy regimen.¹ This diet emphasizes eating primarily plant-based foods, such as fruits and vegetables; whole grains; legumes; and nuts. Other recommendations include replacing butter with healthy fats such as olive oil and canola oil, using herbs and spices instead of salt to flavor foods, and limiting red meat to no more than a few times a month.¹

As we know, psoriasis is a chronic inflammatory disease. The Mediterranean diet has been shown to reduce chronic inflammation and has a positive effect on the risk for metabolic syndrome and cardiovascular events.¹ Phan et al¹ hypothesized a positive effect of the Mediterranean diet on psoriasis. They performed a study to assess the association between a score that reflects the adhesion to a Mediterranean diet (MEDI-LITE) and the onset and/or severity of psoriasis.¹

The NutriNet-Santé program is an ongoing, observational, web-based questionnaire cohort study launched in France in May 2009.¹ Data were collected and analyzed between April 2017 and June 2017. Individuals with psoriasis were identified utilizing a validated online questionnaire and then categorized by disease severity into 1 of 3 groups: severe psoriasis, nonsevere psoriasis, and psoriasis free.¹

During the initial 2 years of participation in the cohort, data on dietary intake (including alcohol) were gathered to calculate the MEDI-LITE score, ranging from 0 (no adherence) to 18 (maximum adherence).¹ Of the 158,361 total web-based participants, 35,735 (23%) replied to the psoriasis questionnaire.¹ Of the respondents, 3557 (10%) individuals reported having psoriasis. The condition was severe in 878 cases (24.7%), and 299 (8.4%) incident cases were recorded (cases occurring >2 years after participant inclusion in the cohort). After adjustment for confounding factors, the investigators found a significant inverse relationship between the MEDI-LITE score and having severe psoriasis (odds ratio [OR], 0.71; 95% CI, 0.55-0.92 for the MEDI-LITE score’s second tertile [score of 8 to 9]; and OR, 0.78; 95% CI, 0.59-1.01 for the third tertile [score of 10 to 18]).¹

The authors noted that patients with severe psoriasis displayed low levels of adherence to the Mediterranean diet.¹ They commented that this finding supports the hypothesis that the Mediterranean diet may slow the progression of psoriasis. If these findings are confirmed, adherence to a Mediterranean diet should be integrated into the routine management of moderate to severe psoriasis.¹ These findings are by no means definitive, but it is a first step in helping us define more specific dietary recommendations for psoriasis.

This issue includes several articles looking at various facets of psoriasis important to residents, including the pathophysiology of psoriasis,² treatment approach using biologic therapies,³ risk factors and triggers for psoriasis,⁴ and the psychosocial impact of psoriasis.⁵ We hope that you find this issue enjoyable and informative.

ATLANTA – Among patients with relapsing-remitting multiple sclerosis, higher body mass index, but not vitamin D status, appears to be related to greater loss of gray matter brain volume over time, results from a 5-year analysis showed.

“We had previously known that obesity is a risk factor for developing MS, and among those who already have the disease, obesity-related comorbidities are associated with increased morbidity and mortality,” lead study author Ellen M. Mowry, MD, said in an interview at the annual meeting of the American Neurological Association. “Loss of brain tissue, especially as measured by reduced volume of gray matter noted on brain MRI, is predictive of long-term disability in MS. While we await the results of confirmatory studies and randomized trials, this study adds to the growing body of evidence suggesting there may be a role for modification of lifestyle factors in mitigating longer-term MS-related disability risk.”

In an effort to determine if body mass index (BMI) or vitamin D status is associated with longer-term MRI measures of neurodegeneration, Dr. Mowry and her colleagues drew from 469 patients participating in a longitudinal MS cohort study at the University of California, San Francisco, known as EPIC. Participants had clinical evaluations, brain MRI, and blood draws annually and were followed for 5 years. The main outcomes of interest were BMI and serum 25-hydroxyvitamin D levels measured over the time period, and their relationship to brain volume.


At baseline, the mean age of patients was 42 years, 70% were female, their mean BMI was 25 kg/m², and their mean serum vitamin D level was 27.8 ng/mL. Dr. Mowry, a neurologist at Johns Hopkins University, Baltimore, and her colleagues found that over time, each 1-kg/m² higher BMI was independently associated with reduced gray matter in multivariate models (–1.1 mL; P = .001). In addition, each 1-kg/m² higher BMI over time was independently associated with greater declines in normalized brain parenchymal brain volume (–1.1 mL; P = .039). Elevated vitamin D levels, however, did not appear to be meaningfully associated with brain volumes.

Dr. Mowry acknowledged certain limitations of the study, including its nonrandomized design. “Such a trial may be warranted but I believe will be challenging to conduct,” she said. “Also, this cohort was designed to assess the association of genes with brain MRI outcomes, and so the people included were racially homogeneous – only Caucasians were included. Since MS risk is especially high among African Americans in recent years, and African Americans appear overall to have a higher risk of long-term disability, it is important to evaluate these and other prognostic factors amongst a more representative group of people with MS.”

The study received funding support from the National Institutes of Health, GlaxoSmithKline, and Biogen. Dr. Mowry disclosed that she has received medication from Teva for use in a clinical trial. In addition, she has been the primary investigator for studies sponsored by Biogen and Sun Pharma, and has conducted investigator-initiated studies sponsored by Genzyme and Biogen.

[email protected]

SOURCE: Ann Neurol. 2018;84[S22]:S206-7. Abstract M250.

ATLANTA – Among patients with relapsing-remitting multiple sclerosis, higher body mass index, but not vitamin D status, appears to be related to greater loss of gray matter brain volume over time, results from a 5-year analysis showed.

“We had previously known that obesity is a risk factor for developing MS, and among those who already have the disease, obesity-related comorbidities are associated with increased morbidity and mortality,” lead study author Ellen M. Mowry, MD, said in an interview at the annual meeting of the American Neurological Association. “Loss of brain tissue, especially as measured by reduced volume of gray matter noted on brain MRI, is predictive of long-term disability in MS. While we await the results of confirmatory studies and randomized trials, this study adds to the growing body of evidence suggesting there may be a role for modification of lifestyle factors in mitigating longer-term MS-related disability risk.”

In an effort to determine if body mass index (BMI) or vitamin D status is associated with longer-term MRI measures of neurodegeneration, Dr. Mowry and her colleagues drew from 469 patients participating in a longitudinal MS cohort study at the University of California, San Francisco, known as EPIC. Participants had clinical evaluations, brain MRI, and blood draws annually and were followed for 5 years. The main outcomes of interest were BMI and serum 25-hydroxyvitamin D levels measured over the time period, and their relationship to brain volume.


At baseline, the mean age of patients was 42 years, 70% were female, their mean BMI was 25 kg/m², and their mean serum vitamin D level was 27.8 ng/mL. Dr. Mowry, a neurologist at Johns Hopkins University, Baltimore, and her colleagues found that over time, each 1-kg/m² higher BMI was independently associated with reduced gray matter in multivariate models (–1.1 mL; P = .001). In addition, each 1-kg/m² higher BMI over time was independently associated with greater declines in normalized brain parenchymal brain volume (–1.1 mL; P = .039). Elevated vitamin D levels, however, did not appear to be meaningfully associated with brain volumes.

Dr. Mowry acknowledged certain limitations of the study, including its nonrandomized design. “Such a trial may be warranted but I believe will be challenging to conduct,” she said. “Also, this cohort was designed to assess the association of genes with brain MRI outcomes, and so the people included were racially homogeneous – only Caucasians were included. Since MS risk is especially high among African Americans in recent years, and African Americans appear overall to have a higher risk of long-term disability, it is important to evaluate these and other prognostic factors amongst a more representative group of people with MS.”

The study received funding support from the National Institutes of Health, GlaxoSmithKline, and Biogen. Dr. Mowry disclosed that she has received medication from Teva for use in a clinical trial. In addition, she has been the primary investigator for studies sponsored by Biogen and Sun Pharma, and has conducted investigator-initiated studies sponsored by Genzyme and Biogen.

[email protected]

SOURCE: Ann Neurol. 2018;84[S22]:S206-7. Abstract M250.

ATLANTA – Among patients with relapsing-remitting multiple sclerosis, higher body mass index, but not vitamin D status, appears to be related to greater loss of gray matter brain volume over time, results from a 5-year analysis showed.

“We had previously known that obesity is a risk factor for developing MS, and among those who already have the disease, obesity-related comorbidities are associated with increased morbidity and mortality,” lead study author Ellen M. Mowry, MD, said in an interview at the annual meeting of the American Neurological Association. “Loss of brain tissue, especially as measured by reduced volume of gray matter noted on brain MRI, is predictive of long-term disability in MS. While we await the results of confirmatory studies and randomized trials, this study adds to the growing body of evidence suggesting there may be a role for modification of lifestyle factors in mitigating longer-term MS-related disability risk.”

In an effort to determine if body mass index (BMI) or vitamin D status is associated with longer-term MRI measures of neurodegeneration, Dr. Mowry and her colleagues drew from 469 patients participating in a longitudinal MS cohort study at the University of California, San Francisco, known as EPIC. Participants had clinical evaluations, brain MRI, and blood draws annually and were followed for 5 years. The main outcomes of interest were BMI and serum 25-hydroxyvitamin D levels measured over the time period, and their relationship to brain volume.


At baseline, the mean age of patients was 42 years, 70% were female, their mean BMI was 25 kg/m², and their mean serum vitamin D level was 27.8 ng/mL. Dr. Mowry, a neurologist at Johns Hopkins University, Baltimore, and her colleagues found that over time, each 1-kg/m² higher BMI was independently associated with reduced gray matter in multivariate models (–1.1 mL; P = .001). In addition, each 1-kg/m² higher BMI over time was independently associated with greater declines in normalized brain parenchymal brain volume (–1.1 mL; P = .039). Elevated vitamin D levels, however, did not appear to be meaningfully associated with brain volumes.

Dr. Mowry acknowledged certain limitations of the study, including its nonrandomized design. “Such a trial may be warranted but I believe will be challenging to conduct,” she said. “Also, this cohort was designed to assess the association of genes with brain MRI outcomes, and so the people included were racially homogeneous – only Caucasians were included. Since MS risk is especially high among African Americans in recent years, and African Americans appear overall to have a higher risk of long-term disability, it is important to evaluate these and other prognostic factors amongst a more representative group of people with MS.”

The study received funding support from the National Institutes of Health, GlaxoSmithKline, and Biogen. Dr. Mowry disclosed that she has received medication from Teva for use in a clinical trial. In addition, she has been the primary investigator for studies sponsored by Biogen and Sun Pharma, and has conducted investigator-initiated studies sponsored by Genzyme and Biogen.

[email protected]

SOURCE: Ann Neurol. 2018;84[S22]:S206-7. Abstract M250.

Dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (DA-EPOCH-R), which is used to treat several types of aggressive non-Hodgkin lymphomas, is associated with high rates of line-associated complications, a new study suggests.

MrArifnajafov/CC-BY-3.0

These findings, published in Clinical Lymphoma, Myeloma & Leukemia, confirm other recent findings that DA-EPOCH-R has a significantly greater rate of complications, compared with that of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) therapy.

The authors note that the use of DA-EPOCH-R is based on data from early phase trials, as well as retrospective data, that support its use as induction chemotherapy in high-grade B-cell lymphoma with MYC, BCL2, and/or BCL6 translocations. But currently, there are no data published from randomized trials that support the use of upfront DA-EPOCH-R therapy.

DA-EPOCH-R is an infusion-based therapy that requires a central venous catheter.

In their study, Rachel J. David, MD, of Wilmot Cancer Institute, Rochester, N.Y., and her colleagues conducted a retrospective study that included all patients treated with DA-EPOCH-R at their institution between March 2011 and July 2016, and also included a concurrent cohort of patients with diffuse large B-cell lymphoma (DLBCL) who were treated with R-CHOP. The goal was to identify the rates and predictors of line-associated complications linked with the use of DA-EPOCH-R therapy in this population.

The patient cohort comprised 43 patients who received DA-EPOCH-R and 44 patients who received RCHOP.

Patients in the DA-EPOCH-R cohort experienced a significantly higher rate of complications (P =.03), compared with the R-CHOP group.

In the DA-EPOCH-R cohort, 17 patients (39.5%) reported at least one LAC, which included venous thromboembolism, chemotherapy extravasation, and line-associated infection, during the study period. Grade 3 toxicity was observed in 41% of these patients.

In contrast, eight patients (18.2%) in the R-CHOP arm experienced at least one complication, with five of the eight patients experiencing grade 3-4 toxicity.

In a univariate analysis, body mass index of 35 kg/m² and the use of a peripherally inserted central catheter line were both significantly associated with a higher risk of venous thromboembolism (P = .04 and P = .02, respectively).

“For patients undergoing treatment with DA-EPOCH-R in whom the use of [central venous catheters] cannot be avoided, the morbidity of [line-associated complications] should be factored in by the clinician when determining upfront treatment,” the researchers wrote.

They reported having no conflicts of interest.
 

SOURCE: David RJ et al. Clin Lymphoma Myeloma Leuk. 2018 Aug 29. doi: 10.1016/j.clml.2018.08.014.

Dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (DA-EPOCH-R), which is used to treat several types of aggressive non-Hodgkin lymphomas, is associated with high rates of line-associated complications, a new study suggests.

MrArifnajafov/CC-BY-3.0

These findings, published in Clinical Lymphoma, Myeloma & Leukemia, confirm other recent findings that DA-EPOCH-R has a significantly greater rate of complications, compared with that of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) therapy.

The authors note that the use of DA-EPOCH-R is based on data from early phase trials, as well as retrospective data, that support its use as induction chemotherapy in high-grade B-cell lymphoma with MYC, BCL2, and/or BCL6 translocations. But currently, there are no data published from randomized trials that support the use of upfront DA-EPOCH-R therapy.

DA-EPOCH-R is an infusion-based therapy that requires a central venous catheter.

In their study, Rachel J. David, MD, of Wilmot Cancer Institute, Rochester, N.Y., and her colleagues conducted a retrospective study that included all patients treated with DA-EPOCH-R at their institution between March 2011 and July 2016, and also included a concurrent cohort of patients with diffuse large B-cell lymphoma (DLBCL) who were treated with R-CHOP. The goal was to identify the rates and predictors of line-associated complications linked with the use of DA-EPOCH-R therapy in this population.

The patient cohort comprised 43 patients who received DA-EPOCH-R and 44 patients who received RCHOP.

Patients in the DA-EPOCH-R cohort experienced a significantly higher rate of complications (P =.03), compared with the R-CHOP group.

In the DA-EPOCH-R cohort, 17 patients (39.5%) reported at least one LAC, which included venous thromboembolism, chemotherapy extravasation, and line-associated infection, during the study period. Grade 3 toxicity was observed in 41% of these patients.

In contrast, eight patients (18.2%) in the R-CHOP arm experienced at least one complication, with five of the eight patients experiencing grade 3-4 toxicity.

In a univariate analysis, body mass index of 35 kg/m² and the use of a peripherally inserted central catheter line were both significantly associated with a higher risk of venous thromboembolism (P = .04 and P = .02, respectively).

“For patients undergoing treatment with DA-EPOCH-R in whom the use of [central venous catheters] cannot be avoided, the morbidity of [line-associated complications] should be factored in by the clinician when determining upfront treatment,” the researchers wrote.

They reported having no conflicts of interest.
 

SOURCE: David RJ et al. Clin Lymphoma Myeloma Leuk. 2018 Aug 29. doi: 10.1016/j.clml.2018.08.014.

Dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (DA-EPOCH-R), which is used to treat several types of aggressive non-Hodgkin lymphomas, is associated with high rates of line-associated complications, a new study suggests.

MrArifnajafov/CC-BY-3.0

These findings, published in Clinical Lymphoma, Myeloma & Leukemia, confirm other recent findings that DA-EPOCH-R has a significantly greater rate of complications, compared with that of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) therapy.

The authors note that the use of DA-EPOCH-R is based on data from early phase trials, as well as retrospective data, that support its use as induction chemotherapy in high-grade B-cell lymphoma with MYC, BCL2, and/or BCL6 translocations. But currently, there are no data published from randomized trials that support the use of upfront DA-EPOCH-R therapy.

DA-EPOCH-R is an infusion-based therapy that requires a central venous catheter.

In their study, Rachel J. David, MD, of Wilmot Cancer Institute, Rochester, N.Y., and her colleagues conducted a retrospective study that included all patients treated with DA-EPOCH-R at their institution between March 2011 and July 2016, and also included a concurrent cohort of patients with diffuse large B-cell lymphoma (DLBCL) who were treated with R-CHOP. The goal was to identify the rates and predictors of line-associated complications linked with the use of DA-EPOCH-R therapy in this population.

The patient cohort comprised 43 patients who received DA-EPOCH-R and 44 patients who received RCHOP.

Patients in the DA-EPOCH-R cohort experienced a significantly higher rate of complications (P =.03), compared with the R-CHOP group.

In the DA-EPOCH-R cohort, 17 patients (39.5%) reported at least one LAC, which included venous thromboembolism, chemotherapy extravasation, and line-associated infection, during the study period. Grade 3 toxicity was observed in 41% of these patients.

In contrast, eight patients (18.2%) in the R-CHOP arm experienced at least one complication, with five of the eight patients experiencing grade 3-4 toxicity.

In a univariate analysis, body mass index of 35 kg/m² and the use of a peripherally inserted central catheter line were both significantly associated with a higher risk of venous thromboembolism (P = .04 and P = .02, respectively).

“For patients undergoing treatment with DA-EPOCH-R in whom the use of [central venous catheters] cannot be avoided, the morbidity of [line-associated complications] should be factored in by the clinician when determining upfront treatment,” the researchers wrote.

They reported having no conflicts of interest.
 

SOURCE: David RJ et al. Clin Lymphoma Myeloma Leuk. 2018 Aug 29. doi: 10.1016/j.clml.2018.08.014.

Bortezomib in combination with rituximab plus chemotherapy significantly improved overall survival in transplant-ineligible patients with newly diagnosed mantle cell lymphoma (MCL), compared with standard treatment, according to final results from the international, phase 3 LYM-3002 trial.

Courtesy Wikimedia Commons/Nephron/Creative Commons

After a median follow-up period of 82.0 months, median overall survival was 90.7 months among participants who were given first-line bortezomib in addition to rituximab plus cyclophosphamide, doxorubicin, and prednisone (VR-CAP) versus 55.7 months in the control arm, where patients were given rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), for a hazard ratio of 0.66 (95% confidence interval, 0.51-0.85; P = .001).

Tadeusz Robak, MD, of the Medical University of Lodz in Poland, and his colleagues also reported that patients in the bortezomib arm experienced two novel adverse effects, which were different from findings reported in the primary analysis. Each case was classified as grade 4; there was one case of gastric cancer and one case of lung adenocarcinoma.

The findings were reported in the Lancet Oncology.

Among 268 patients in the follow-up analysis set, the median age was 66 years and 31% were classified as high risk based on the MCL-specific International Prognostic Index (MIPI). For those considered high risk, no significant difference was noted when comparing the two groups on the basis of overall survival.

“When analyzed according to MIPI risk category, VR-CAP was associated with significantly improved overall survival, compared with R-CHOP in the low-risk and intermediate-risk categories, but not in the high-risk category,” the investigators wrote.

The authors acknowledged a key limitation of the study was that rituximab was not given as a maintenance therapy since it was not considered standard of care at the time of study initiation.

Moving forward, Dr. Robak and his colleagues recommended that bortezomib be investigated in combination with newer targeted therapies in order to establish best practice for treating MCL.

The study was sponsored by Janssen Pharmaceuticals. The authors reported financial ties to Janssen, Celgene, Ipsen Biopharmaceuticals, Johnson & Johnson, Novartis, and others.

SOURCE: Robak T et al. Lancet Oncol. 2018 Oct 19. doi: 10.1016/S1470-2045(18)30685-5.

Bortezomib in combination with rituximab plus chemotherapy significantly improved overall survival in transplant-ineligible patients with newly diagnosed mantle cell lymphoma (MCL), compared with standard treatment, according to final results from the international, phase 3 LYM-3002 trial.

Courtesy Wikimedia Commons/Nephron/Creative Commons

After a median follow-up period of 82.0 months, median overall survival was 90.7 months among participants who were given first-line bortezomib in addition to rituximab plus cyclophosphamide, doxorubicin, and prednisone (VR-CAP) versus 55.7 months in the control arm, where patients were given rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), for a hazard ratio of 0.66 (95% confidence interval, 0.51-0.85; P = .001).

Tadeusz Robak, MD, of the Medical University of Lodz in Poland, and his colleagues also reported that patients in the bortezomib arm experienced two novel adverse effects, which were different from findings reported in the primary analysis. Each case was classified as grade 4; there was one case of gastric cancer and one case of lung adenocarcinoma.

The findings were reported in the Lancet Oncology.

Among 268 patients in the follow-up analysis set, the median age was 66 years and 31% were classified as high risk based on the MCL-specific International Prognostic Index (MIPI). For those considered high risk, no significant difference was noted when comparing the two groups on the basis of overall survival.

“When analyzed according to MIPI risk category, VR-CAP was associated with significantly improved overall survival, compared with R-CHOP in the low-risk and intermediate-risk categories, but not in the high-risk category,” the investigators wrote.

The authors acknowledged a key limitation of the study was that rituximab was not given as a maintenance therapy since it was not considered standard of care at the time of study initiation.

Moving forward, Dr. Robak and his colleagues recommended that bortezomib be investigated in combination with newer targeted therapies in order to establish best practice for treating MCL.

The study was sponsored by Janssen Pharmaceuticals. The authors reported financial ties to Janssen, Celgene, Ipsen Biopharmaceuticals, Johnson & Johnson, Novartis, and others.

SOURCE: Robak T et al. Lancet Oncol. 2018 Oct 19. doi: 10.1016/S1470-2045(18)30685-5.

Bortezomib in combination with rituximab plus chemotherapy significantly improved overall survival in transplant-ineligible patients with newly diagnosed mantle cell lymphoma (MCL), compared with standard treatment, according to final results from the international, phase 3 LYM-3002 trial.

Courtesy Wikimedia Commons/Nephron/Creative Commons

After a median follow-up period of 82.0 months, median overall survival was 90.7 months among participants who were given first-line bortezomib in addition to rituximab plus cyclophosphamide, doxorubicin, and prednisone (VR-CAP) versus 55.7 months in the control arm, where patients were given rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), for a hazard ratio of 0.66 (95% confidence interval, 0.51-0.85; P = .001).

Tadeusz Robak, MD, of the Medical University of Lodz in Poland, and his colleagues also reported that patients in the bortezomib arm experienced two novel adverse effects, which were different from findings reported in the primary analysis. Each case was classified as grade 4; there was one case of gastric cancer and one case of lung adenocarcinoma.

The findings were reported in the Lancet Oncology.

Among 268 patients in the follow-up analysis set, the median age was 66 years and 31% were classified as high risk based on the MCL-specific International Prognostic Index (MIPI). For those considered high risk, no significant difference was noted when comparing the two groups on the basis of overall survival.

“When analyzed according to MIPI risk category, VR-CAP was associated with significantly improved overall survival, compared with R-CHOP in the low-risk and intermediate-risk categories, but not in the high-risk category,” the investigators wrote.

The authors acknowledged a key limitation of the study was that rituximab was not given as a maintenance therapy since it was not considered standard of care at the time of study initiation.

Moving forward, Dr. Robak and his colleagues recommended that bortezomib be investigated in combination with newer targeted therapies in order to establish best practice for treating MCL.

The study was sponsored by Janssen Pharmaceuticals. The authors reported financial ties to Janssen, Celgene, Ipsen Biopharmaceuticals, Johnson & Johnson, Novartis, and others.

SOURCE: Robak T et al. Lancet Oncol. 2018 Oct 19. doi: 10.1016/S1470-2045(18)30685-5.

Photo by Bill Branson

Final results of a phase 3 trial suggest bortezomib plus rituximab and chemotherapy can significantly improve overall survival (OS) in transplant-ineligible patients with newly diagnosed mantle cell lymphoma (MCL).

In the LYM-3002 trial, researchers compared bortezomib plus rituximab, cyclophosphamide, doxorubicin, and prednisone (VR-CAP) to rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP).

The median OS was significantly longer in patients who received VR-CAP than in those who received R-CHOP—90.7 months and 55.7 months, respectively.

This survival benefit was observed in patients with low- and intermediate-risk disease but not high-risk disease.

Tadeusz Robak, MD, of the Medical University of Lodz in Poland, and his colleagues reported these results in The Lancet Oncology alongside a related commentary.

The LYM-3002 trial began more than a decade ago, and initial results were published in 2015. At that time, the VR-CAP group showed a significant increase in progression-free survival compared with the R-CHOP group.

The final analysis of LYM-3002 included 268 of the original 487 MCL patients. Twenty-three percent of patients in the VR-CAP group (n=32) discontinued due to death, as did 40% of patients in the R-CHOP group (n=51). The main cause of death was progression—29% and 14%, respectively.

Among the 268 patients in the final analysis, 140 belonged to the VR-CAP group and 128 to the R-CHOP group. The patients’ median age was 66 (range, 26-83), 71% (n=190) were male, 74% (n=199) had stage IV disease, and 31% were classified as high risk based on the MCL-specific International Prognostic Index (MIPI).

About half of patients received therapies after the trial interventions (n=255, 52%)—43% (n=104) in the VR-CAP group and 62% (n=151) in the R-CHOP group. Most patients received subsequent antineoplastic therapy—77% (n=80) and 81% (n=123), respectively—and more than half received rituximab as second-line therapy—53% (n=55) and 59% (n=89), respectively.

Results

At a median follow-up of 82.0 months, the median OS was significantly longer in the VR-CAP group than in the R-CHOP group—90.7 months (95% CI, 71.4 to not estimable) and 55.7 months (95% CI, 47.2 to 68.9), respectively (hazard ratio [HR]=0.66 [95% CI, 0.51–0.85]; P=0.001).

The 4-year OS was 67.3% in the VR-CAP group and 54.3% in the R-CHOP group. The 6-year OS was 56.6% and 42.0%, respectively.

The researchers noted that VR-CAP was associated with significantly improved OS among patients in the low-risk and intermediate-risk MIPI categories but not in the high-risk category.

In the low-risk cohort, the median OS was 81.7 months in the R-CHOP group and not estimable in the VR-CAP group (HR=0.54 [95% CI, 0.30–0.95]; P≤0.05).

In the intermediate-risk cohort, the median OS was 62.2 months in the R-CHOP group and not estimable in the VR-CAP group (HR=0.55 [95% CI, 0.36–0.85]; P≤0.01).

In the high-risk cohort, the median OS was 37.1 months in the R-CHOP group and 30.4 months in the VR-CAP group (HR=1.02 [95% CI, 0.69–1.50]).

The researchers reported three new adverse events in the final analysis—grade 4 lung adenocarcinoma and grade 4 gastric cancer in the VR-CAP group as well as grade 2 pneumonia in the R-CHOP group.

The team acknowledged that a key limitation of this study was that rituximab was not given as maintenance since it was not considered standard care at the time of study initiation.

Moving forward, Dr. Robak and his colleagues recommend that bortezomib be investigated in combination with newer targeted therapies in order to establish best practice for treating MCL.

The LYM-3002 study was sponsored by Janssen Research & Development. The study authors reported financial ties to Janssen, Celgene, Ipsen, Johnson & Johnson, Novartis, and other companies.

Photo by Bill Branson

Final results of a phase 3 trial suggest bortezomib plus rituximab and chemotherapy can significantly improve overall survival (OS) in transplant-ineligible patients with newly diagnosed mantle cell lymphoma (MCL).

In the LYM-3002 trial, researchers compared bortezomib plus rituximab, cyclophosphamide, doxorubicin, and prednisone (VR-CAP) to rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP).

The median OS was significantly longer in patients who received VR-CAP than in those who received R-CHOP—90.7 months and 55.7 months, respectively.

This survival benefit was observed in patients with low- and intermediate-risk disease but not high-risk disease.

Tadeusz Robak, MD, of the Medical University of Lodz in Poland, and his colleagues reported these results in The Lancet Oncology alongside a related commentary.

The LYM-3002 trial began more than a decade ago, and initial results were published in 2015. At that time, the VR-CAP group showed a significant increase in progression-free survival compared with the R-CHOP group.

The final analysis of LYM-3002 included 268 of the original 487 MCL patients. Twenty-three percent of patients in the VR-CAP group (n=32) discontinued due to death, as did 40% of patients in the R-CHOP group (n=51). The main cause of death was progression—29% and 14%, respectively.

Among the 268 patients in the final analysis, 140 belonged to the VR-CAP group and 128 to the R-CHOP group. The patients’ median age was 66 (range, 26-83), 71% (n=190) were male, 74% (n=199) had stage IV disease, and 31% were classified as high risk based on the MCL-specific International Prognostic Index (MIPI).

About half of patients received therapies after the trial interventions (n=255, 52%)—43% (n=104) in the VR-CAP group and 62% (n=151) in the R-CHOP group. Most patients received subsequent antineoplastic therapy—77% (n=80) and 81% (n=123), respectively—and more than half received rituximab as second-line therapy—53% (n=55) and 59% (n=89), respectively.

Results

At a median follow-up of 82.0 months, the median OS was significantly longer in the VR-CAP group than in the R-CHOP group—90.7 months (95% CI, 71.4 to not estimable) and 55.7 months (95% CI, 47.2 to 68.9), respectively (hazard ratio [HR]=0.66 [95% CI, 0.51–0.85]; P=0.001).

The 4-year OS was 67.3% in the VR-CAP group and 54.3% in the R-CHOP group. The 6-year OS was 56.6% and 42.0%, respectively.

The researchers noted that VR-CAP was associated with significantly improved OS among patients in the low-risk and intermediate-risk MIPI categories but not in the high-risk category.

In the low-risk cohort, the median OS was 81.7 months in the R-CHOP group and not estimable in the VR-CAP group (HR=0.54 [95% CI, 0.30–0.95]; P≤0.05).

In the intermediate-risk cohort, the median OS was 62.2 months in the R-CHOP group and not estimable in the VR-CAP group (HR=0.55 [95% CI, 0.36–0.85]; P≤0.01).

In the high-risk cohort, the median OS was 37.1 months in the R-CHOP group and 30.4 months in the VR-CAP group (HR=1.02 [95% CI, 0.69–1.50]).

The researchers reported three new adverse events in the final analysis—grade 4 lung adenocarcinoma and grade 4 gastric cancer in the VR-CAP group as well as grade 2 pneumonia in the R-CHOP group.

The team acknowledged that a key limitation of this study was that rituximab was not given as maintenance since it was not considered standard care at the time of study initiation.

Moving forward, Dr. Robak and his colleagues recommend that bortezomib be investigated in combination with newer targeted therapies in order to establish best practice for treating MCL.

The LYM-3002 study was sponsored by Janssen Research & Development. The study authors reported financial ties to Janssen, Celgene, Ipsen, Johnson & Johnson, Novartis, and other companies.

Photo by Bill Branson

Final results of a phase 3 trial suggest bortezomib plus rituximab and chemotherapy can significantly improve overall survival (OS) in transplant-ineligible patients with newly diagnosed mantle cell lymphoma (MCL).

In the LYM-3002 trial, researchers compared bortezomib plus rituximab, cyclophosphamide, doxorubicin, and prednisone (VR-CAP) to rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP).

The median OS was significantly longer in patients who received VR-CAP than in those who received R-CHOP—90.7 months and 55.7 months, respectively.

This survival benefit was observed in patients with low- and intermediate-risk disease but not high-risk disease.

Tadeusz Robak, MD, of the Medical University of Lodz in Poland, and his colleagues reported these results in The Lancet Oncology alongside a related commentary.

The LYM-3002 trial began more than a decade ago, and initial results were published in 2015. At that time, the VR-CAP group showed a significant increase in progression-free survival compared with the R-CHOP group.

The final analysis of LYM-3002 included 268 of the original 487 MCL patients. Twenty-three percent of patients in the VR-CAP group (n=32) discontinued due to death, as did 40% of patients in the R-CHOP group (n=51). The main cause of death was progression—29% and 14%, respectively.

Among the 268 patients in the final analysis, 140 belonged to the VR-CAP group and 128 to the R-CHOP group. The patients’ median age was 66 (range, 26-83), 71% (n=190) were male, 74% (n=199) had stage IV disease, and 31% were classified as high risk based on the MCL-specific International Prognostic Index (MIPI).

About half of patients received therapies after the trial interventions (n=255, 52%)—43% (n=104) in the VR-CAP group and 62% (n=151) in the R-CHOP group. Most patients received subsequent antineoplastic therapy—77% (n=80) and 81% (n=123), respectively—and more than half received rituximab as second-line therapy—53% (n=55) and 59% (n=89), respectively.

Results

At a median follow-up of 82.0 months, the median OS was significantly longer in the VR-CAP group than in the R-CHOP group—90.7 months (95% CI, 71.4 to not estimable) and 55.7 months (95% CI, 47.2 to 68.9), respectively (hazard ratio [HR]=0.66 [95% CI, 0.51–0.85]; P=0.001).

The 4-year OS was 67.3% in the VR-CAP group and 54.3% in the R-CHOP group. The 6-year OS was 56.6% and 42.0%, respectively.

The researchers noted that VR-CAP was associated with significantly improved OS among patients in the low-risk and intermediate-risk MIPI categories but not in the high-risk category.

In the low-risk cohort, the median OS was 81.7 months in the R-CHOP group and not estimable in the VR-CAP group (HR=0.54 [95% CI, 0.30–0.95]; P≤0.05).

In the intermediate-risk cohort, the median OS was 62.2 months in the R-CHOP group and not estimable in the VR-CAP group (HR=0.55 [95% CI, 0.36–0.85]; P≤0.01).

In the high-risk cohort, the median OS was 37.1 months in the R-CHOP group and 30.4 months in the VR-CAP group (HR=1.02 [95% CI, 0.69–1.50]).

The researchers reported three new adverse events in the final analysis—grade 4 lung adenocarcinoma and grade 4 gastric cancer in the VR-CAP group as well as grade 2 pneumonia in the R-CHOP group.

The team acknowledged that a key limitation of this study was that rituximab was not given as maintenance since it was not considered standard care at the time of study initiation.

Moving forward, Dr. Robak and his colleagues recommend that bortezomib be investigated in combination with newer targeted therapies in order to establish best practice for treating MCL.

The LYM-3002 study was sponsored by Janssen Research & Development. The study authors reported financial ties to Janssen, Celgene, Ipsen, Johnson & Johnson, Novartis, and other companies.

Elderly patients with non-Hodgkin lymphoma (NHL) are more likely to die, but not relapse, within 1 year of allogeneic hematopoietic cell transplantation (alloHCT), compared with younger or middle-age patients, according to investigators.

copyright claudiobaba/iStockPhoto.com

Comorbidities also increased risks of nonrelapse mortality (NRM) at 1 year, but to a lesser extent than that of elderly status, reported lead author Charalampia Kyriakou, MD, PhD, of the department of haematology at University College London Hospital and London North West University Healthcare NHS Trust, and her colleagues.

“Although alloHCT is feasible and effective in very old patients, the increased NRM risk must be taken into account when assessing the indication for alloHCT for NHL in this age group,” the investigators wrote in Biology of Blood and Marrow Transplantation.

This decision is becoming more common, they noted. “With the advent of reduced-intensity conditioning (RIC) strategies and other improvements in transplantation technology, alloHCT is being increasingly considered in elderly patients with [relapsed and refractory] NHL.”

The retrospective study analyzed 3,919 patients with NHL who underwent alloHCT between 2003 and 2013. Patients were sorted into three age groups: young (18-50 years), middle age (51-65 years), or elderly (66-77 years).

Disease types also were reported: 1,461 patients had follicular lymphoma (FL; 37%), 1,192 had diffuse large B cell lymphoma (DLBCL; 30%), 823 had mantle cell lymphoma (MCL; 21%), and 443 had peripheral T cell lymphoma (PTCL; 11%).

At the time of alloHCT, about 85% of patients were chemosensitive, with the remainder being chemorefractory. The age groups had similar patient characteristics, with exceptions noted for unrelated donors, MCL, and RIC, which became increasingly overrepresented with age.

The results showed that NRM at 1 year was 13% for young patients, 20% for middle-age patients, and 33% for elderly patients (P less than .001). Overall survival at 3 years followed an inverse trend, decreasing with age from 60% in young patients to 54% in middle-age patients, before dropping more dramatically to 38% in the elderly (P less than .001).

In contrast to these significant associations between age and survival, relapse risk at 3 years remained relatively consistent, with young patients at 30%, middle-age patients at 31%, and elderly patients at 28% (P = .355).

The investigators noted that the risk of NRM increased most dramatically between middle age and old age, with less significant differences between the middle-age and young groups. They suggested that “age per se should have a limited impact on the indication for alloHCT for NHL in patients up to age 65 years.”

The increased risk with elderly status could not be fully explained by comorbidities, although these were more common in elderly patients. After analyzing information from a subset of patients, the investigators concluded that “the presence of comorbidities is a significant risk factor for NRM and survival, but this does not fully explain the outcome disadvantages in our [elderly] group.” Therefore, age remains an independent risk factor.

“The information provided in this cohort of patients with NHL, the largest reported to date, is useful and relevant, especially in the era of evolving therapies,” the investigators wrote. They added that the information is “even more relevant now with the availability of treatment with ... chimeric antigen receptor (CAR) T cells ... after relapse post-alloHCT.”

The investigators reported having no financial disclosures.

SOURCE: Kyriakou C et al. Biol Blood Marrow Transplant. 2018 Sep 13. doi: 10.1016/j.bbmt.2018.08.025.

Elderly patients with non-Hodgkin lymphoma (NHL) are more likely to die, but not relapse, within 1 year of allogeneic hematopoietic cell transplantation (alloHCT), compared with younger or middle-age patients, according to investigators.

copyright claudiobaba/iStockPhoto.com

Comorbidities also increased risks of nonrelapse mortality (NRM) at 1 year, but to a lesser extent than that of elderly status, reported lead author Charalampia Kyriakou, MD, PhD, of the department of haematology at University College London Hospital and London North West University Healthcare NHS Trust, and her colleagues.

“Although alloHCT is feasible and effective in very old patients, the increased NRM risk must be taken into account when assessing the indication for alloHCT for NHL in this age group,” the investigators wrote in Biology of Blood and Marrow Transplantation.

This decision is becoming more common, they noted. “With the advent of reduced-intensity conditioning (RIC) strategies and other improvements in transplantation technology, alloHCT is being increasingly considered in elderly patients with [relapsed and refractory] NHL.”

The retrospective study analyzed 3,919 patients with NHL who underwent alloHCT between 2003 and 2013. Patients were sorted into three age groups: young (18-50 years), middle age (51-65 years), or elderly (66-77 years).

Disease types also were reported: 1,461 patients had follicular lymphoma (FL; 37%), 1,192 had diffuse large B cell lymphoma (DLBCL; 30%), 823 had mantle cell lymphoma (MCL; 21%), and 443 had peripheral T cell lymphoma (PTCL; 11%).

At the time of alloHCT, about 85% of patients were chemosensitive, with the remainder being chemorefractory. The age groups had similar patient characteristics, with exceptions noted for unrelated donors, MCL, and RIC, which became increasingly overrepresented with age.

The results showed that NRM at 1 year was 13% for young patients, 20% for middle-age patients, and 33% for elderly patients (P less than .001). Overall survival at 3 years followed an inverse trend, decreasing with age from 60% in young patients to 54% in middle-age patients, before dropping more dramatically to 38% in the elderly (P less than .001).

In contrast to these significant associations between age and survival, relapse risk at 3 years remained relatively consistent, with young patients at 30%, middle-age patients at 31%, and elderly patients at 28% (P = .355).

The investigators noted that the risk of NRM increased most dramatically between middle age and old age, with less significant differences between the middle-age and young groups. They suggested that “age per se should have a limited impact on the indication for alloHCT for NHL in patients up to age 65 years.”

The increased risk with elderly status could not be fully explained by comorbidities, although these were more common in elderly patients. After analyzing information from a subset of patients, the investigators concluded that “the presence of comorbidities is a significant risk factor for NRM and survival, but this does not fully explain the outcome disadvantages in our [elderly] group.” Therefore, age remains an independent risk factor.

“The information provided in this cohort of patients with NHL, the largest reported to date, is useful and relevant, especially in the era of evolving therapies,” the investigators wrote. They added that the information is “even more relevant now with the availability of treatment with ... chimeric antigen receptor (CAR) T cells ... after relapse post-alloHCT.”

The investigators reported having no financial disclosures.

SOURCE: Kyriakou C et al. Biol Blood Marrow Transplant. 2018 Sep 13. doi: 10.1016/j.bbmt.2018.08.025.

Elderly patients with non-Hodgkin lymphoma (NHL) are more likely to die, but not relapse, within 1 year of allogeneic hematopoietic cell transplantation (alloHCT), compared with younger or middle-age patients, according to investigators.

copyright claudiobaba/iStockPhoto.com

Comorbidities also increased risks of nonrelapse mortality (NRM) at 1 year, but to a lesser extent than that of elderly status, reported lead author Charalampia Kyriakou, MD, PhD, of the department of haematology at University College London Hospital and London North West University Healthcare NHS Trust, and her colleagues.

“Although alloHCT is feasible and effective in very old patients, the increased NRM risk must be taken into account when assessing the indication for alloHCT for NHL in this age group,” the investigators wrote in Biology of Blood and Marrow Transplantation.

This decision is becoming more common, they noted. “With the advent of reduced-intensity conditioning (RIC) strategies and other improvements in transplantation technology, alloHCT is being increasingly considered in elderly patients with [relapsed and refractory] NHL.”

The retrospective study analyzed 3,919 patients with NHL who underwent alloHCT between 2003 and 2013. Patients were sorted into three age groups: young (18-50 years), middle age (51-65 years), or elderly (66-77 years).

Disease types also were reported: 1,461 patients had follicular lymphoma (FL; 37%), 1,192 had diffuse large B cell lymphoma (DLBCL; 30%), 823 had mantle cell lymphoma (MCL; 21%), and 443 had peripheral T cell lymphoma (PTCL; 11%).

At the time of alloHCT, about 85% of patients were chemosensitive, with the remainder being chemorefractory. The age groups had similar patient characteristics, with exceptions noted for unrelated donors, MCL, and RIC, which became increasingly overrepresented with age.

The results showed that NRM at 1 year was 13% for young patients, 20% for middle-age patients, and 33% for elderly patients (P less than .001). Overall survival at 3 years followed an inverse trend, decreasing with age from 60% in young patients to 54% in middle-age patients, before dropping more dramatically to 38% in the elderly (P less than .001).

In contrast to these significant associations between age and survival, relapse risk at 3 years remained relatively consistent, with young patients at 30%, middle-age patients at 31%, and elderly patients at 28% (P = .355).

The investigators noted that the risk of NRM increased most dramatically between middle age and old age, with less significant differences between the middle-age and young groups. They suggested that “age per se should have a limited impact on the indication for alloHCT for NHL in patients up to age 65 years.”

The increased risk with elderly status could not be fully explained by comorbidities, although these were more common in elderly patients. After analyzing information from a subset of patients, the investigators concluded that “the presence of comorbidities is a significant risk factor for NRM and survival, but this does not fully explain the outcome disadvantages in our [elderly] group.” Therefore, age remains an independent risk factor.

“The information provided in this cohort of patients with NHL, the largest reported to date, is useful and relevant, especially in the era of evolving therapies,” the investigators wrote. They added that the information is “even more relevant now with the availability of treatment with ... chimeric antigen receptor (CAR) T cells ... after relapse post-alloHCT.”

The investigators reported having no financial disclosures.

SOURCE: Kyriakou C et al. Biol Blood Marrow Transplant. 2018 Sep 13. doi: 10.1016/j.bbmt.2018.08.025.