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Improving Comorbidities With Psoriasis Treatment

Psoriasis is a common immune-mediated inflammatory skin disorder that affects up to 3.2% of adults in the United States.1  It is a TH1, TH17, and TH22 inflammatory disease resulting in increased levels of cytokines in the skin, including IFN-γ, tumor necrosis factor (TNF), IL-17, and IL-22. Dendritic antigen-presenting cells also are increased in the skin of patients with psoriasis resulting in increased levels of IL-23.2  Although skin disease often is its most prominent and sometimes its only documented manifestation, an understanding of psoriasis as a chronic multisystem inflammatory disorder is essential to optimize outcomes.1,3  Multiple comorbidities that may affect treatment selection often are associated with psoriasis, including psoriatic arthritis, cardiovascular disease, depression, obesity, metabolic syndrome, cardiovascular disease (CVD), cerebrovascular disease, and peripheral vascular disease. 

As with other immune-mediated inflammatory diseases, it has been hypothesized that psoriasis may influence comorbidities through shared genetic risks, environmental factors, and pathogenic factors or inflammatory pathways.2-4 For example, emerging evidence suggests that comorbidities such as metabolic syndrome may be related to the chronic inflammation that accompanies psoriasis, a finding that has important clinical implications.3 

The interplay and dependence or interdependence of psoriasis and its comorbidities is complex, and it is an area deserving of vigorous research.1 At present, observational and epidemiological data such as the present case suggest that effective treatment of psoriasis could lead to benefits “beyond the skin” and potentially even prevent future disease-associated comorbidity.1-3

Metabolic Comorbidities and Psoriasis Treatment

Although the prevalence of CVD and CVD risk factors is increased in patients with psoriasis, studies suggest that the suppression of systemic inflammation that accompanies adequate psoriasis treatment, particularly in patients with moderate to severe disease, may decrease the risk for cardiovascular comorbidities.5 For example, a number of studies have found treatment of psoriasis with methotrexate may decrease the risk for cardiovascular events, including ischemic heart disease, stroke, and cardiovascular death.6-10 Low-dose methotrexate has been shown to be particularly advantageous for decreasing CVD in patients with psoriasis.5,8 

Tumor necrosis factor α inhibitors, which are frequently used for moderate to severe plaque psoriasis, also may notably decrease cardiovascular risk.5 One study showed a significant decrease in the risk for myocardial infarction in patients with psoriasis who were treated with TNF-α inhibitors (hazard ratio, 0.50; 95% CI, 0.32-0.79)11; other studies have confirmed this benefit.12-17 Moreover, the reduction in cardiovascular events may be greater with TNF-α inhibitors than with methotrexate when the former is used for psoriasis treatment, with longer duration of TNF-α inhibition leading to greater risk reduction.18,19 

In patients with severe psoriasis, treatment with TNF-α inhibitors has been associated with improvements in subclinical CVD (abnormalities in echocardiogram), improved coronary microvascular function (determined by transthoracic Doppler echocardiography), and reduced progression in coronary artery disease (assessed by coronary computed tomography).20-22 Improvement in endothelial function (brachial artery reactivity) and carotid arterial stiffness also has been reported following 6 months of treatment with adalimumab for moderate to severe psoriasis.21 

Data concerning potential cardiovascular risk reduction with treatment of psoriasis utilizing newer agents are continuing to emerge. To date, no increase in the incidence of major adverse cardiovascular events has been shown in patients with psoriasis treated with anti–IL-17 agents, such as secukinumab; however, additional long-term studies are needed.18,23-25 

Apremilast, an oral phosphodiesterase 4 inhibitor, is another addition to the psoriasis armamentarium.26 No increase in the risk for major cardiac events has been shown in randomized controlled trials of patients with psoriasis receiving apremilast for up to 156 weeks.27,28 As with secukinumab, additional long-term, large-scale studies are needed to determine the effects of apremilast on cardiovascular risk in patients with psoriasis.5 

Other Comorbidities

Effective treatment of psoriasis also appears to benefit various other comorbidities. Numerous studies have shown an increased incidence of depression in patients with psoriasis vs controls and a concurrent improvement in psychiatric symptoms with psoriasis disease control.1 For instance, a multicenter, randomized, open-label study of 352 patients with psoriasis showed treatment with etanercept, a TNF inhibitor, significantly improved scores for concomitant depression and anxiety (P<.05).29 Similarly, a double-blind, randomized clinical trial of patients with psoriasis found significant improvement in depression at 12 weeks in patients treated with adalimumab vs placebo (P<.001).30 Likewise, a multicenter phase 3 trial of more than 600 psoriatic patients showed improved Beck depression inventory and Hamilton depression rating scale scores at 12 weeks in patients with psoriasis treated with etanercept compared to placebo.31 

A much larger analysis of 7490 patients with psoriasis compared the rates of depression among patients receiving biologic therapy, phototherapy, and conventional systemic therapy. The greatest impact on depression symptoms was seen with biologic therapy (incidence rate, 3.01/100 patient-years), followed by conventional systemic therapy (5.70/100 patient-years), and phototherapy (5.85/100 patient-years).32

Uveitis, or inflammation of the middle layer of the eye (the uvea), frequently is seen in patients with psoriasis. In a cohort study of 60,000 patients with mild psoriasis and more than 7000 patients with severe psoriasis, the incidence of uveitis in patients was significantly increased in both patients with severe disease and those with mild disease (P<.001 for both).33 In a case series of 8 patients with concomitant psoriasis and uveitis, 4 patients were treated with infliximab and 4 with adalimumab; 7 patients treated achieved remission of their uveitis.34 

Role of the TNF-α Blockade in Sickle Cell Disease

Presently, no reported human studies have shown TNF-α blockade as a possible treatment of sickle cell disease.35 However, increased levels of TNF-α have been shown to contribute to the onset of sickle cell crises and to the severity of sickle cell disease due to their integral role in the development of vascular wall dysfunction and ischemia.35,36 Studies have shown that TNF-α is released in homozygous sickle cell anemia (HbSS) disease and impedes blood flow during sickle cell crisis, resulting in worsening ischemia and painful infarction.35,36 Moreover, cytokine analysis has shown significantly (P<.05) elevated levels of TNF-α during sickle cell crises and at baseline in patients with HbSS vs healthy controls, suggesting a possible role of TNF-α in the pathogenesis of sickle cell crisis.36 

The case patient reported a 50% reduction in pain level and the use of pain medications that overlapped with the initiation of adalimumab for treatment of her psoriasis. Moreover, although radiographs showed possible psoriatic changes of the distal metatarsal row, she described sickle cell pain and pain crises that were uncharacteristic of psoriatic arthralgia.35 Although these findings are observational in nature and limited to one patient, they do suggest an interesting hypothesis. If a common inflammatory mediator is the culprit, it is possible that TNF-α inhibitors could be the preferred treatment option for patients with psoriasis and comorbid HbSS or HbSC disease. Further studies are needed to analyze the role of TNF-α inhibition in sickle cell disease.

Bottom Line

Psoriasis may influence comorbidities through shared genetic risks, environmental factors, or inflammatory pathways. Improvement in metabolic and other comorbidities have been shown with the effective treatment of psoriasis. The case described here showed improvement in sickle cell crises and pain with treatment of psoriasis with adalimumab. Tumor necrosis factor inhibitors may be an optimal choice for patients with both psoriasis and sickle cell disease. 

References
  1. Elmets CA, Leonardi CL, Davis DMR, et al. Joint AAD-NPF guidelines of care for the management and treatment of psoriasis with awareness and attention to comorbidities. J Am Acad Dermatol. 2019;80:1073-1113.
  2. Davidovici BB, Sattar N, Prinz J, et al. Psoriasis and systemic inflammatory diseases: potential mechanistic links between skin disease and co-morbid conditions. J Invest Dermatol. 2010;130:1785-1796.
  3. Oliveira Mde F, Rocha Bde O, Duarte GV. Psoriasis: classical and emerging comorbidities. An Bras Dermatol. 2015;90:9-20.
  4. Shah K, Mellars L, Changolkar A, Feldman SR. Real-world burden of comorbidities in US patients with psoriasis. J Am Acad Dermatol. 2017;77:287-292.
  5. Hu SC, Lan CE. Psoriasis and cardiovascular comorbidities: focusing on severe vascular events, cardiovascular risk factors and implications for treatment [published online October 21, 2017]. Int J Mol Sci. doi:10.3390/ijms18102211.
  6. Hugh J, Van Voorhees AS, Nijhawan RI, et al. From the Medical Board of The National Psoriasis Foundation: the risk of cardiovascular disease in individuals with psoriasis and the potential impact of current therapies. J Am Acad Dermatol. 2014;70:168-177.
  7. Churton S, Brown L, Shin TM, et al. Does treatment of psoriasis reduce the risk of cardiovascular disease? Drugs. 2014;74:169-182.
  8. Prodanovich S, Ma F, Taylor J, et al. Methotrexate reduces incidence of vascular diseases in veterans with psoriasis or rheumatoid arthritis. J Am Acad Dermatol. 2005;52:262-226.
  9. Gulliver WP, Young HM, Bachelez H, et al. Psoriasis patients treated with biologics and methotrexate have a reduced rate of myocardial infarction: a collaborative analysis using international cohorts. J Cutan Med Surg. 2016;20:550-554.
  10. Ahlehoff O, Skov L, Gislason G, et al. Cardiovascular disease event rates in patients with severe psoriasis treated with systemic anti-inflammatory drugs: a Danish real-world cohort study. J Intern Med. 2013;273:197-204.
  11. Wu JJ, Poon KY, Channual JC, et al. Association between tumor necrosis factor inhibitor therapy and myocardial infarction risk in patients with psoriasis. Arch Dermatol. 2012;148:1244-1250.
  12. Wu JJ, Poon KY. Association of ethnicity, tumor necrosis factor inhibitor therapy, and myocardial infarction risk in patients with psoriasis. J Am Acad Dermatol. 2013;69:167-168.
  13. Wu JJ, Poon KY, Bebchuk JD. Association between the type and length of tumor necrosis factor inhibitor therapy and myocardial infarction risk in patients with psoriasis. J Drugs Dermatol. 2013;12:899-903.
  14. Wu JJ, Poon KY, Bebchuk JD. Tumor necrosis factor inhibitor therapy and myocardial infarction risk in patients with psoriasis, psoriatic arthritis, or both. J Drugs Dermatol. 2014;13:932-934.
  15. Famenini S, Sako EY, Wu JJ. Effect of treating psoriasis on cardiovascular co-morbidities: focus on TNF inhibitors. Am J Clin Dermatol. 2014;15:45-50.
  16. Nguyen T, Wu JJ. Relationship between tumor necrosis factor-alpha inhibitors and cardiovascular disease in psoriasis: a review. Perm J. 2014;18:49-54.
  17. Shaaban D, Al-Mutairi N. The effect of tumour necrosis factor inhibitor therapy on the incidence of myocardial infarction in patients with psoriasis: a retrospective study [published online November 17, 2017]. J Dermatol Treat. doi:10.1080/09546634.2016.1254145. 
  18. Wu D, Hou SY, Zhao S, et al. Efficacy and safety of interleukin-17 antagonists in patients with plaque psoriasis: A meta-analysis from phase 3 randomized controlled trials. J Eur Acad Dermatol Venereol. 2017;31:992-100.
  19. Yang ZS, Lin NN, Li L, et al. The effect of TNF inhibitors on cardiovascular events in psoriasis and psoriatic arthritis: an updated meta-analysis. Clin Rev Allergy Immunol. 2016;51:240-247.
  20. Heredi E, Vegh J, Pogacsas L, et al. Subclinical cardiovascular disease and it’s improvement after long-term TNF-alpha inhibitor therapy in severe psoriatic patients. J Eur Acad Dermatol Venereol. 2016;30:1531-1536.
  21. Pina T, Corrales A, Lopez-Mejias R, et al. Anti-tumor necrosis factor-alpha therapy improves endothelial function and arterial stiffness in patients with moderate to severe psoriasis: a 6-month prospective study. J Dermatol. 2016;43:1267-1272.
  22. Piaserico S, Osto E, Famoso G, et al. Treatment with tumor necrosis factor inhibitors restores coronary microvascular function in young patients with severe psoriasis. Atherosclerosis. 2016;251:25-30.
  23. Van de Kerkhof PC, Griffiths CE, Reich K, et al. Secukinumab long-term safety experience: a pooled analysis of 10 phase II and III clinical studies in patients with moderate to severe plaque psoriasis. J Am Acad Dermatol. 2016;75:83-98.
  24. Wu JJ, Guerin A, Sundaram M, et al. Cardiovascular event risk assessment in psoriasis patients treated with tumor necrosis factor-alpha inhibitors versus methotrexate. J Am Acad Dermatol. 2017;76:81-90.
  25. Torres T, Raposo I, Selores M. IL-17 blockade in psoriasis: friend or foe in cardiovascular risk? Am J Clin Dermatol. 2016;17:107-112.
  26. Deeks ED. Apremilast: a review in psoriasis and psoriatic arthritis. Drugs. 2015;75:1393-1403.
  27. Crowley J, Thaci D, Joly P, et al. Long-term safety and tolerability of apremilast in patients with psoriasis: pooled safety analysis for >/= 156 weeks from 2 phase 3, randomized, controlled trials (ESTEEM 1 and 2). J Am Acad Dermatol. 2017;77:310-317.
  28. Kavanaugh A, Mease PJ, Gomez-Reino JJ, et al. Treatment of psoriatic arthritis in a phase 3 randomised, placebo-controlled trial with apremilast, an oral phosphodiesterase 4 inhibitor. Ann Rheum Dis. 2014;73:1020-1026.
  29. Daudén E, Griffiths CE, Ortonne JP, et al. Improvements in patient-reported outcomes in moderate-to-severe psoriasis patients receiving continuous or paused etanercept treatment over 54 weeks: the CRYSTEL study. J Eur Acad Dermatol Venereol. 2009;23:1374-1382.
  30. Menter A, Augustin M, Signorovitch J, et al. The effect of adalimumab on reducing depression symptoms in patients with moderate to severe psoriasis: a randomized clinical trial. J Am Acad Dermatol. 2010;62:812-818.
  31. Tyring S, Gottlieb A, Papp K, et al. Etanercept and clinical outcomes, fatigue, and depression in psoriasis: double-blind placebo-controlled randomised phase III trial. Lancet. 2006;367:29-35.
  32. Strober B, Gooderham M, de Jong EMGJ, et al. Depressive symptoms, depression, and the effect of biologic therapy among patients in Psoriasis Longitudinal Assessment and Registry (PSOLAR). J Am Acad Dermatol. 2018;78:70-80.
  33. Egeberg A, Khalid U, Gislason GH, et al. Association of psoriatic disease with uveitis: a Danish nationwide cohort study. JAMA Dermatol. 2015;151:1200-1205.
  34. Huynh N, Cervantes-Castaneda RA, Bhat P, et al. Biologic response modifier therapy for psoriatic ocular inflammatory disease. Ocul Immunol Inflamm. 2008;16:89-93.
  35. Pulusani S, McMurray SL, Jensen K, et al. Psoriasis treatment in patients with sickle cell disease Cutis. 2019;103:93-94.
  36. Nnodim J, Meludu SC, Dioka CE, et al. Cytokine expression in homozygous sickle cell anaemia. JKIMSU. 2015;4:34-37.
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Psoriasis is a common immune-mediated inflammatory skin disorder that affects up to 3.2% of adults in the United States.1  It is a TH1, TH17, and TH22 inflammatory disease resulting in increased levels of cytokines in the skin, including IFN-γ, tumor necrosis factor (TNF), IL-17, and IL-22. Dendritic antigen-presenting cells also are increased in the skin of patients with psoriasis resulting in increased levels of IL-23.2  Although skin disease often is its most prominent and sometimes its only documented manifestation, an understanding of psoriasis as a chronic multisystem inflammatory disorder is essential to optimize outcomes.1,3  Multiple comorbidities that may affect treatment selection often are associated with psoriasis, including psoriatic arthritis, cardiovascular disease, depression, obesity, metabolic syndrome, cardiovascular disease (CVD), cerebrovascular disease, and peripheral vascular disease. 

As with other immune-mediated inflammatory diseases, it has been hypothesized that psoriasis may influence comorbidities through shared genetic risks, environmental factors, and pathogenic factors or inflammatory pathways.2-4 For example, emerging evidence suggests that comorbidities such as metabolic syndrome may be related to the chronic inflammation that accompanies psoriasis, a finding that has important clinical implications.3 

The interplay and dependence or interdependence of psoriasis and its comorbidities is complex, and it is an area deserving of vigorous research.1 At present, observational and epidemiological data such as the present case suggest that effective treatment of psoriasis could lead to benefits “beyond the skin” and potentially even prevent future disease-associated comorbidity.1-3

Metabolic Comorbidities and Psoriasis Treatment

Although the prevalence of CVD and CVD risk factors is increased in patients with psoriasis, studies suggest that the suppression of systemic inflammation that accompanies adequate psoriasis treatment, particularly in patients with moderate to severe disease, may decrease the risk for cardiovascular comorbidities.5 For example, a number of studies have found treatment of psoriasis with methotrexate may decrease the risk for cardiovascular events, including ischemic heart disease, stroke, and cardiovascular death.6-10 Low-dose methotrexate has been shown to be particularly advantageous for decreasing CVD in patients with psoriasis.5,8 

Tumor necrosis factor α inhibitors, which are frequently used for moderate to severe plaque psoriasis, also may notably decrease cardiovascular risk.5 One study showed a significant decrease in the risk for myocardial infarction in patients with psoriasis who were treated with TNF-α inhibitors (hazard ratio, 0.50; 95% CI, 0.32-0.79)11; other studies have confirmed this benefit.12-17 Moreover, the reduction in cardiovascular events may be greater with TNF-α inhibitors than with methotrexate when the former is used for psoriasis treatment, with longer duration of TNF-α inhibition leading to greater risk reduction.18,19 

In patients with severe psoriasis, treatment with TNF-α inhibitors has been associated with improvements in subclinical CVD (abnormalities in echocardiogram), improved coronary microvascular function (determined by transthoracic Doppler echocardiography), and reduced progression in coronary artery disease (assessed by coronary computed tomography).20-22 Improvement in endothelial function (brachial artery reactivity) and carotid arterial stiffness also has been reported following 6 months of treatment with adalimumab for moderate to severe psoriasis.21 

Data concerning potential cardiovascular risk reduction with treatment of psoriasis utilizing newer agents are continuing to emerge. To date, no increase in the incidence of major adverse cardiovascular events has been shown in patients with psoriasis treated with anti–IL-17 agents, such as secukinumab; however, additional long-term studies are needed.18,23-25 

Apremilast, an oral phosphodiesterase 4 inhibitor, is another addition to the psoriasis armamentarium.26 No increase in the risk for major cardiac events has been shown in randomized controlled trials of patients with psoriasis receiving apremilast for up to 156 weeks.27,28 As with secukinumab, additional long-term, large-scale studies are needed to determine the effects of apremilast on cardiovascular risk in patients with psoriasis.5 

Other Comorbidities

Effective treatment of psoriasis also appears to benefit various other comorbidities. Numerous studies have shown an increased incidence of depression in patients with psoriasis vs controls and a concurrent improvement in psychiatric symptoms with psoriasis disease control.1 For instance, a multicenter, randomized, open-label study of 352 patients with psoriasis showed treatment with etanercept, a TNF inhibitor, significantly improved scores for concomitant depression and anxiety (P<.05).29 Similarly, a double-blind, randomized clinical trial of patients with psoriasis found significant improvement in depression at 12 weeks in patients treated with adalimumab vs placebo (P<.001).30 Likewise, a multicenter phase 3 trial of more than 600 psoriatic patients showed improved Beck depression inventory and Hamilton depression rating scale scores at 12 weeks in patients with psoriasis treated with etanercept compared to placebo.31 

A much larger analysis of 7490 patients with psoriasis compared the rates of depression among patients receiving biologic therapy, phototherapy, and conventional systemic therapy. The greatest impact on depression symptoms was seen with biologic therapy (incidence rate, 3.01/100 patient-years), followed by conventional systemic therapy (5.70/100 patient-years), and phototherapy (5.85/100 patient-years).32

Uveitis, or inflammation of the middle layer of the eye (the uvea), frequently is seen in patients with psoriasis. In a cohort study of 60,000 patients with mild psoriasis and more than 7000 patients with severe psoriasis, the incidence of uveitis in patients was significantly increased in both patients with severe disease and those with mild disease (P<.001 for both).33 In a case series of 8 patients with concomitant psoriasis and uveitis, 4 patients were treated with infliximab and 4 with adalimumab; 7 patients treated achieved remission of their uveitis.34 

Role of the TNF-α Blockade in Sickle Cell Disease

Presently, no reported human studies have shown TNF-α blockade as a possible treatment of sickle cell disease.35 However, increased levels of TNF-α have been shown to contribute to the onset of sickle cell crises and to the severity of sickle cell disease due to their integral role in the development of vascular wall dysfunction and ischemia.35,36 Studies have shown that TNF-α is released in homozygous sickle cell anemia (HbSS) disease and impedes blood flow during sickle cell crisis, resulting in worsening ischemia and painful infarction.35,36 Moreover, cytokine analysis has shown significantly (P<.05) elevated levels of TNF-α during sickle cell crises and at baseline in patients with HbSS vs healthy controls, suggesting a possible role of TNF-α in the pathogenesis of sickle cell crisis.36 

The case patient reported a 50% reduction in pain level and the use of pain medications that overlapped with the initiation of adalimumab for treatment of her psoriasis. Moreover, although radiographs showed possible psoriatic changes of the distal metatarsal row, she described sickle cell pain and pain crises that were uncharacteristic of psoriatic arthralgia.35 Although these findings are observational in nature and limited to one patient, they do suggest an interesting hypothesis. If a common inflammatory mediator is the culprit, it is possible that TNF-α inhibitors could be the preferred treatment option for patients with psoriasis and comorbid HbSS or HbSC disease. Further studies are needed to analyze the role of TNF-α inhibition in sickle cell disease.

Bottom Line

Psoriasis may influence comorbidities through shared genetic risks, environmental factors, or inflammatory pathways. Improvement in metabolic and other comorbidities have been shown with the effective treatment of psoriasis. The case described here showed improvement in sickle cell crises and pain with treatment of psoriasis with adalimumab. Tumor necrosis factor inhibitors may be an optimal choice for patients with both psoriasis and sickle cell disease. 

Psoriasis is a common immune-mediated inflammatory skin disorder that affects up to 3.2% of adults in the United States.1  It is a TH1, TH17, and TH22 inflammatory disease resulting in increased levels of cytokines in the skin, including IFN-γ, tumor necrosis factor (TNF), IL-17, and IL-22. Dendritic antigen-presenting cells also are increased in the skin of patients with psoriasis resulting in increased levels of IL-23.2  Although skin disease often is its most prominent and sometimes its only documented manifestation, an understanding of psoriasis as a chronic multisystem inflammatory disorder is essential to optimize outcomes.1,3  Multiple comorbidities that may affect treatment selection often are associated with psoriasis, including psoriatic arthritis, cardiovascular disease, depression, obesity, metabolic syndrome, cardiovascular disease (CVD), cerebrovascular disease, and peripheral vascular disease. 

As with other immune-mediated inflammatory diseases, it has been hypothesized that psoriasis may influence comorbidities through shared genetic risks, environmental factors, and pathogenic factors or inflammatory pathways.2-4 For example, emerging evidence suggests that comorbidities such as metabolic syndrome may be related to the chronic inflammation that accompanies psoriasis, a finding that has important clinical implications.3 

The interplay and dependence or interdependence of psoriasis and its comorbidities is complex, and it is an area deserving of vigorous research.1 At present, observational and epidemiological data such as the present case suggest that effective treatment of psoriasis could lead to benefits “beyond the skin” and potentially even prevent future disease-associated comorbidity.1-3

Metabolic Comorbidities and Psoriasis Treatment

Although the prevalence of CVD and CVD risk factors is increased in patients with psoriasis, studies suggest that the suppression of systemic inflammation that accompanies adequate psoriasis treatment, particularly in patients with moderate to severe disease, may decrease the risk for cardiovascular comorbidities.5 For example, a number of studies have found treatment of psoriasis with methotrexate may decrease the risk for cardiovascular events, including ischemic heart disease, stroke, and cardiovascular death.6-10 Low-dose methotrexate has been shown to be particularly advantageous for decreasing CVD in patients with psoriasis.5,8 

Tumor necrosis factor α inhibitors, which are frequently used for moderate to severe plaque psoriasis, also may notably decrease cardiovascular risk.5 One study showed a significant decrease in the risk for myocardial infarction in patients with psoriasis who were treated with TNF-α inhibitors (hazard ratio, 0.50; 95% CI, 0.32-0.79)11; other studies have confirmed this benefit.12-17 Moreover, the reduction in cardiovascular events may be greater with TNF-α inhibitors than with methotrexate when the former is used for psoriasis treatment, with longer duration of TNF-α inhibition leading to greater risk reduction.18,19 

In patients with severe psoriasis, treatment with TNF-α inhibitors has been associated with improvements in subclinical CVD (abnormalities in echocardiogram), improved coronary microvascular function (determined by transthoracic Doppler echocardiography), and reduced progression in coronary artery disease (assessed by coronary computed tomography).20-22 Improvement in endothelial function (brachial artery reactivity) and carotid arterial stiffness also has been reported following 6 months of treatment with adalimumab for moderate to severe psoriasis.21 

Data concerning potential cardiovascular risk reduction with treatment of psoriasis utilizing newer agents are continuing to emerge. To date, no increase in the incidence of major adverse cardiovascular events has been shown in patients with psoriasis treated with anti–IL-17 agents, such as secukinumab; however, additional long-term studies are needed.18,23-25 

Apremilast, an oral phosphodiesterase 4 inhibitor, is another addition to the psoriasis armamentarium.26 No increase in the risk for major cardiac events has been shown in randomized controlled trials of patients with psoriasis receiving apremilast for up to 156 weeks.27,28 As with secukinumab, additional long-term, large-scale studies are needed to determine the effects of apremilast on cardiovascular risk in patients with psoriasis.5 

Other Comorbidities

Effective treatment of psoriasis also appears to benefit various other comorbidities. Numerous studies have shown an increased incidence of depression in patients with psoriasis vs controls and a concurrent improvement in psychiatric symptoms with psoriasis disease control.1 For instance, a multicenter, randomized, open-label study of 352 patients with psoriasis showed treatment with etanercept, a TNF inhibitor, significantly improved scores for concomitant depression and anxiety (P<.05).29 Similarly, a double-blind, randomized clinical trial of patients with psoriasis found significant improvement in depression at 12 weeks in patients treated with adalimumab vs placebo (P<.001).30 Likewise, a multicenter phase 3 trial of more than 600 psoriatic patients showed improved Beck depression inventory and Hamilton depression rating scale scores at 12 weeks in patients with psoriasis treated with etanercept compared to placebo.31 

A much larger analysis of 7490 patients with psoriasis compared the rates of depression among patients receiving biologic therapy, phototherapy, and conventional systemic therapy. The greatest impact on depression symptoms was seen with biologic therapy (incidence rate, 3.01/100 patient-years), followed by conventional systemic therapy (5.70/100 patient-years), and phototherapy (5.85/100 patient-years).32

Uveitis, or inflammation of the middle layer of the eye (the uvea), frequently is seen in patients with psoriasis. In a cohort study of 60,000 patients with mild psoriasis and more than 7000 patients with severe psoriasis, the incidence of uveitis in patients was significantly increased in both patients with severe disease and those with mild disease (P<.001 for both).33 In a case series of 8 patients with concomitant psoriasis and uveitis, 4 patients were treated with infliximab and 4 with adalimumab; 7 patients treated achieved remission of their uveitis.34 

Role of the TNF-α Blockade in Sickle Cell Disease

Presently, no reported human studies have shown TNF-α blockade as a possible treatment of sickle cell disease.35 However, increased levels of TNF-α have been shown to contribute to the onset of sickle cell crises and to the severity of sickle cell disease due to their integral role in the development of vascular wall dysfunction and ischemia.35,36 Studies have shown that TNF-α is released in homozygous sickle cell anemia (HbSS) disease and impedes blood flow during sickle cell crisis, resulting in worsening ischemia and painful infarction.35,36 Moreover, cytokine analysis has shown significantly (P<.05) elevated levels of TNF-α during sickle cell crises and at baseline in patients with HbSS vs healthy controls, suggesting a possible role of TNF-α in the pathogenesis of sickle cell crisis.36 

The case patient reported a 50% reduction in pain level and the use of pain medications that overlapped with the initiation of adalimumab for treatment of her psoriasis. Moreover, although radiographs showed possible psoriatic changes of the distal metatarsal row, she described sickle cell pain and pain crises that were uncharacteristic of psoriatic arthralgia.35 Although these findings are observational in nature and limited to one patient, they do suggest an interesting hypothesis. If a common inflammatory mediator is the culprit, it is possible that TNF-α inhibitors could be the preferred treatment option for patients with psoriasis and comorbid HbSS or HbSC disease. Further studies are needed to analyze the role of TNF-α inhibition in sickle cell disease.

Bottom Line

Psoriasis may influence comorbidities through shared genetic risks, environmental factors, or inflammatory pathways. Improvement in metabolic and other comorbidities have been shown with the effective treatment of psoriasis. The case described here showed improvement in sickle cell crises and pain with treatment of psoriasis with adalimumab. Tumor necrosis factor inhibitors may be an optimal choice for patients with both psoriasis and sickle cell disease. 

References
  1. Elmets CA, Leonardi CL, Davis DMR, et al. Joint AAD-NPF guidelines of care for the management and treatment of psoriasis with awareness and attention to comorbidities. J Am Acad Dermatol. 2019;80:1073-1113.
  2. Davidovici BB, Sattar N, Prinz J, et al. Psoriasis and systemic inflammatory diseases: potential mechanistic links between skin disease and co-morbid conditions. J Invest Dermatol. 2010;130:1785-1796.
  3. Oliveira Mde F, Rocha Bde O, Duarte GV. Psoriasis: classical and emerging comorbidities. An Bras Dermatol. 2015;90:9-20.
  4. Shah K, Mellars L, Changolkar A, Feldman SR. Real-world burden of comorbidities in US patients with psoriasis. J Am Acad Dermatol. 2017;77:287-292.
  5. Hu SC, Lan CE. Psoriasis and cardiovascular comorbidities: focusing on severe vascular events, cardiovascular risk factors and implications for treatment [published online October 21, 2017]. Int J Mol Sci. doi:10.3390/ijms18102211.
  6. Hugh J, Van Voorhees AS, Nijhawan RI, et al. From the Medical Board of The National Psoriasis Foundation: the risk of cardiovascular disease in individuals with psoriasis and the potential impact of current therapies. J Am Acad Dermatol. 2014;70:168-177.
  7. Churton S, Brown L, Shin TM, et al. Does treatment of psoriasis reduce the risk of cardiovascular disease? Drugs. 2014;74:169-182.
  8. Prodanovich S, Ma F, Taylor J, et al. Methotrexate reduces incidence of vascular diseases in veterans with psoriasis or rheumatoid arthritis. J Am Acad Dermatol. 2005;52:262-226.
  9. Gulliver WP, Young HM, Bachelez H, et al. Psoriasis patients treated with biologics and methotrexate have a reduced rate of myocardial infarction: a collaborative analysis using international cohorts. J Cutan Med Surg. 2016;20:550-554.
  10. Ahlehoff O, Skov L, Gislason G, et al. Cardiovascular disease event rates in patients with severe psoriasis treated with systemic anti-inflammatory drugs: a Danish real-world cohort study. J Intern Med. 2013;273:197-204.
  11. Wu JJ, Poon KY, Channual JC, et al. Association between tumor necrosis factor inhibitor therapy and myocardial infarction risk in patients with psoriasis. Arch Dermatol. 2012;148:1244-1250.
  12. Wu JJ, Poon KY. Association of ethnicity, tumor necrosis factor inhibitor therapy, and myocardial infarction risk in patients with psoriasis. J Am Acad Dermatol. 2013;69:167-168.
  13. Wu JJ, Poon KY, Bebchuk JD. Association between the type and length of tumor necrosis factor inhibitor therapy and myocardial infarction risk in patients with psoriasis. J Drugs Dermatol. 2013;12:899-903.
  14. Wu JJ, Poon KY, Bebchuk JD. Tumor necrosis factor inhibitor therapy and myocardial infarction risk in patients with psoriasis, psoriatic arthritis, or both. J Drugs Dermatol. 2014;13:932-934.
  15. Famenini S, Sako EY, Wu JJ. Effect of treating psoriasis on cardiovascular co-morbidities: focus on TNF inhibitors. Am J Clin Dermatol. 2014;15:45-50.
  16. Nguyen T, Wu JJ. Relationship between tumor necrosis factor-alpha inhibitors and cardiovascular disease in psoriasis: a review. Perm J. 2014;18:49-54.
  17. Shaaban D, Al-Mutairi N. The effect of tumour necrosis factor inhibitor therapy on the incidence of myocardial infarction in patients with psoriasis: a retrospective study [published online November 17, 2017]. J Dermatol Treat. doi:10.1080/09546634.2016.1254145. 
  18. Wu D, Hou SY, Zhao S, et al. Efficacy and safety of interleukin-17 antagonists in patients with plaque psoriasis: A meta-analysis from phase 3 randomized controlled trials. J Eur Acad Dermatol Venereol. 2017;31:992-100.
  19. Yang ZS, Lin NN, Li L, et al. The effect of TNF inhibitors on cardiovascular events in psoriasis and psoriatic arthritis: an updated meta-analysis. Clin Rev Allergy Immunol. 2016;51:240-247.
  20. Heredi E, Vegh J, Pogacsas L, et al. Subclinical cardiovascular disease and it’s improvement after long-term TNF-alpha inhibitor therapy in severe psoriatic patients. J Eur Acad Dermatol Venereol. 2016;30:1531-1536.
  21. Pina T, Corrales A, Lopez-Mejias R, et al. Anti-tumor necrosis factor-alpha therapy improves endothelial function and arterial stiffness in patients with moderate to severe psoriasis: a 6-month prospective study. J Dermatol. 2016;43:1267-1272.
  22. Piaserico S, Osto E, Famoso G, et al. Treatment with tumor necrosis factor inhibitors restores coronary microvascular function in young patients with severe psoriasis. Atherosclerosis. 2016;251:25-30.
  23. Van de Kerkhof PC, Griffiths CE, Reich K, et al. Secukinumab long-term safety experience: a pooled analysis of 10 phase II and III clinical studies in patients with moderate to severe plaque psoriasis. J Am Acad Dermatol. 2016;75:83-98.
  24. Wu JJ, Guerin A, Sundaram M, et al. Cardiovascular event risk assessment in psoriasis patients treated with tumor necrosis factor-alpha inhibitors versus methotrexate. J Am Acad Dermatol. 2017;76:81-90.
  25. Torres T, Raposo I, Selores M. IL-17 blockade in psoriasis: friend or foe in cardiovascular risk? Am J Clin Dermatol. 2016;17:107-112.
  26. Deeks ED. Apremilast: a review in psoriasis and psoriatic arthritis. Drugs. 2015;75:1393-1403.
  27. Crowley J, Thaci D, Joly P, et al. Long-term safety and tolerability of apremilast in patients with psoriasis: pooled safety analysis for >/= 156 weeks from 2 phase 3, randomized, controlled trials (ESTEEM 1 and 2). J Am Acad Dermatol. 2017;77:310-317.
  28. Kavanaugh A, Mease PJ, Gomez-Reino JJ, et al. Treatment of psoriatic arthritis in a phase 3 randomised, placebo-controlled trial with apremilast, an oral phosphodiesterase 4 inhibitor. Ann Rheum Dis. 2014;73:1020-1026.
  29. Daudén E, Griffiths CE, Ortonne JP, et al. Improvements in patient-reported outcomes in moderate-to-severe psoriasis patients receiving continuous or paused etanercept treatment over 54 weeks: the CRYSTEL study. J Eur Acad Dermatol Venereol. 2009;23:1374-1382.
  30. Menter A, Augustin M, Signorovitch J, et al. The effect of adalimumab on reducing depression symptoms in patients with moderate to severe psoriasis: a randomized clinical trial. J Am Acad Dermatol. 2010;62:812-818.
  31. Tyring S, Gottlieb A, Papp K, et al. Etanercept and clinical outcomes, fatigue, and depression in psoriasis: double-blind placebo-controlled randomised phase III trial. Lancet. 2006;367:29-35.
  32. Strober B, Gooderham M, de Jong EMGJ, et al. Depressive symptoms, depression, and the effect of biologic therapy among patients in Psoriasis Longitudinal Assessment and Registry (PSOLAR). J Am Acad Dermatol. 2018;78:70-80.
  33. Egeberg A, Khalid U, Gislason GH, et al. Association of psoriatic disease with uveitis: a Danish nationwide cohort study. JAMA Dermatol. 2015;151:1200-1205.
  34. Huynh N, Cervantes-Castaneda RA, Bhat P, et al. Biologic response modifier therapy for psoriatic ocular inflammatory disease. Ocul Immunol Inflamm. 2008;16:89-93.
  35. Pulusani S, McMurray SL, Jensen K, et al. Psoriasis treatment in patients with sickle cell disease Cutis. 2019;103:93-94.
  36. Nnodim J, Meludu SC, Dioka CE, et al. Cytokine expression in homozygous sickle cell anaemia. JKIMSU. 2015;4:34-37.
References
  1. Elmets CA, Leonardi CL, Davis DMR, et al. Joint AAD-NPF guidelines of care for the management and treatment of psoriasis with awareness and attention to comorbidities. J Am Acad Dermatol. 2019;80:1073-1113.
  2. Davidovici BB, Sattar N, Prinz J, et al. Psoriasis and systemic inflammatory diseases: potential mechanistic links between skin disease and co-morbid conditions. J Invest Dermatol. 2010;130:1785-1796.
  3. Oliveira Mde F, Rocha Bde O, Duarte GV. Psoriasis: classical and emerging comorbidities. An Bras Dermatol. 2015;90:9-20.
  4. Shah K, Mellars L, Changolkar A, Feldman SR. Real-world burden of comorbidities in US patients with psoriasis. J Am Acad Dermatol. 2017;77:287-292.
  5. Hu SC, Lan CE. Psoriasis and cardiovascular comorbidities: focusing on severe vascular events, cardiovascular risk factors and implications for treatment [published online October 21, 2017]. Int J Mol Sci. doi:10.3390/ijms18102211.
  6. Hugh J, Van Voorhees AS, Nijhawan RI, et al. From the Medical Board of The National Psoriasis Foundation: the risk of cardiovascular disease in individuals with psoriasis and the potential impact of current therapies. J Am Acad Dermatol. 2014;70:168-177.
  7. Churton S, Brown L, Shin TM, et al. Does treatment of psoriasis reduce the risk of cardiovascular disease? Drugs. 2014;74:169-182.
  8. Prodanovich S, Ma F, Taylor J, et al. Methotrexate reduces incidence of vascular diseases in veterans with psoriasis or rheumatoid arthritis. J Am Acad Dermatol. 2005;52:262-226.
  9. Gulliver WP, Young HM, Bachelez H, et al. Psoriasis patients treated with biologics and methotrexate have a reduced rate of myocardial infarction: a collaborative analysis using international cohorts. J Cutan Med Surg. 2016;20:550-554.
  10. Ahlehoff O, Skov L, Gislason G, et al. Cardiovascular disease event rates in patients with severe psoriasis treated with systemic anti-inflammatory drugs: a Danish real-world cohort study. J Intern Med. 2013;273:197-204.
  11. Wu JJ, Poon KY, Channual JC, et al. Association between tumor necrosis factor inhibitor therapy and myocardial infarction risk in patients with psoriasis. Arch Dermatol. 2012;148:1244-1250.
  12. Wu JJ, Poon KY. Association of ethnicity, tumor necrosis factor inhibitor therapy, and myocardial infarction risk in patients with psoriasis. J Am Acad Dermatol. 2013;69:167-168.
  13. Wu JJ, Poon KY, Bebchuk JD. Association between the type and length of tumor necrosis factor inhibitor therapy and myocardial infarction risk in patients with psoriasis. J Drugs Dermatol. 2013;12:899-903.
  14. Wu JJ, Poon KY, Bebchuk JD. Tumor necrosis factor inhibitor therapy and myocardial infarction risk in patients with psoriasis, psoriatic arthritis, or both. J Drugs Dermatol. 2014;13:932-934.
  15. Famenini S, Sako EY, Wu JJ. Effect of treating psoriasis on cardiovascular co-morbidities: focus on TNF inhibitors. Am J Clin Dermatol. 2014;15:45-50.
  16. Nguyen T, Wu JJ. Relationship between tumor necrosis factor-alpha inhibitors and cardiovascular disease in psoriasis: a review. Perm J. 2014;18:49-54.
  17. Shaaban D, Al-Mutairi N. The effect of tumour necrosis factor inhibitor therapy on the incidence of myocardial infarction in patients with psoriasis: a retrospective study [published online November 17, 2017]. J Dermatol Treat. doi:10.1080/09546634.2016.1254145. 
  18. Wu D, Hou SY, Zhao S, et al. Efficacy and safety of interleukin-17 antagonists in patients with plaque psoriasis: A meta-analysis from phase 3 randomized controlled trials. J Eur Acad Dermatol Venereol. 2017;31:992-100.
  19. Yang ZS, Lin NN, Li L, et al. The effect of TNF inhibitors on cardiovascular events in psoriasis and psoriatic arthritis: an updated meta-analysis. Clin Rev Allergy Immunol. 2016;51:240-247.
  20. Heredi E, Vegh J, Pogacsas L, et al. Subclinical cardiovascular disease and it’s improvement after long-term TNF-alpha inhibitor therapy in severe psoriatic patients. J Eur Acad Dermatol Venereol. 2016;30:1531-1536.
  21. Pina T, Corrales A, Lopez-Mejias R, et al. Anti-tumor necrosis factor-alpha therapy improves endothelial function and arterial stiffness in patients with moderate to severe psoriasis: a 6-month prospective study. J Dermatol. 2016;43:1267-1272.
  22. Piaserico S, Osto E, Famoso G, et al. Treatment with tumor necrosis factor inhibitors restores coronary microvascular function in young patients with severe psoriasis. Atherosclerosis. 2016;251:25-30.
  23. Van de Kerkhof PC, Griffiths CE, Reich K, et al. Secukinumab long-term safety experience: a pooled analysis of 10 phase II and III clinical studies in patients with moderate to severe plaque psoriasis. J Am Acad Dermatol. 2016;75:83-98.
  24. Wu JJ, Guerin A, Sundaram M, et al. Cardiovascular event risk assessment in psoriasis patients treated with tumor necrosis factor-alpha inhibitors versus methotrexate. J Am Acad Dermatol. 2017;76:81-90.
  25. Torres T, Raposo I, Selores M. IL-17 blockade in psoriasis: friend or foe in cardiovascular risk? Am J Clin Dermatol. 2016;17:107-112.
  26. Deeks ED. Apremilast: a review in psoriasis and psoriatic arthritis. Drugs. 2015;75:1393-1403.
  27. Crowley J, Thaci D, Joly P, et al. Long-term safety and tolerability of apremilast in patients with psoriasis: pooled safety analysis for >/= 156 weeks from 2 phase 3, randomized, controlled trials (ESTEEM 1 and 2). J Am Acad Dermatol. 2017;77:310-317.
  28. Kavanaugh A, Mease PJ, Gomez-Reino JJ, et al. Treatment of psoriatic arthritis in a phase 3 randomised, placebo-controlled trial with apremilast, an oral phosphodiesterase 4 inhibitor. Ann Rheum Dis. 2014;73:1020-1026.
  29. Daudén E, Griffiths CE, Ortonne JP, et al. Improvements in patient-reported outcomes in moderate-to-severe psoriasis patients receiving continuous or paused etanercept treatment over 54 weeks: the CRYSTEL study. J Eur Acad Dermatol Venereol. 2009;23:1374-1382.
  30. Menter A, Augustin M, Signorovitch J, et al. The effect of adalimumab on reducing depression symptoms in patients with moderate to severe psoriasis: a randomized clinical trial. J Am Acad Dermatol. 2010;62:812-818.
  31. Tyring S, Gottlieb A, Papp K, et al. Etanercept and clinical outcomes, fatigue, and depression in psoriasis: double-blind placebo-controlled randomised phase III trial. Lancet. 2006;367:29-35.
  32. Strober B, Gooderham M, de Jong EMGJ, et al. Depressive symptoms, depression, and the effect of biologic therapy among patients in Psoriasis Longitudinal Assessment and Registry (PSOLAR). J Am Acad Dermatol. 2018;78:70-80.
  33. Egeberg A, Khalid U, Gislason GH, et al. Association of psoriatic disease with uveitis: a Danish nationwide cohort study. JAMA Dermatol. 2015;151:1200-1205.
  34. Huynh N, Cervantes-Castaneda RA, Bhat P, et al. Biologic response modifier therapy for psoriatic ocular inflammatory disease. Ocul Immunol Inflamm. 2008;16:89-93.
  35. Pulusani S, McMurray SL, Jensen K, et al. Psoriasis treatment in patients with sickle cell disease Cutis. 2019;103:93-94.
  36. Nnodim J, Meludu SC, Dioka CE, et al. Cytokine expression in homozygous sickle cell anaemia. JKIMSU. 2015;4:34-37.
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A 31-year-old woman presented with moderate to severe plaque psoriasis (70% body surface area). The patient’s medical history was positive for sickle cell disease, specifically hemoglobin SC disease (HbSC). She reported chronic dull arthralgia in the ankles that was worse at night. She was being treated by hematology with ibuprofen and ketorolac. Radiographs of the feet and ankles showed erosive changes of the distal tarsal row and metatarsal bases. At the current presentation, her HbSC pain was 8/10 on a visual analog scale. She described her sickle cell pain crises as sharp 10/10 pain in the back, elbows, and ankles, associated with mild edema lasting 1 to 2 days. Radiographs of the spine, hands, and ankles were unremarkable.

Adalimumab was chosen as a systemic therapy for psoriasis based on its potential for improvement in HbSC symptoms as well as psoriasis.

Within 17 weeks of starting adalimumab, the psoriasis body surface area decreased from 70% to 40%, and she reported a decrease in her HbSC pain from 8/10 to 4/10 at 8-week follow-up and to 0/10 at 17-week follow-up. She also reported decreased use of pain medication with rare sickle cell pain crises following initiation of adalimumab.

 

This case was adapted from Pulusani S, McMurray SL, Jensen K, et al. Psoriasis treatment in patients with sickle cell disease. Cutis. 2019;103:93-94.
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