The Psoriasis and Comorbidity Series: “Neglected” Comorbidities, Part 3–Malignancy
This is the third and final installment of our series addressing often overlooked comorbidities of psoriasis. We first discussed the bidirectional relationship between psoriasis and obstructive sleep apnea (OSA) in which psoriasis can both result from and contribute to the development or worsening of OSA. We then identified a similar bidirectional relationship between psoriasis and mental health disorders, such as anxiety and depression. Today, we will focus on psoriasis and malignancy.
Significance and Prevalence
A correlation between psoriasis and malignancy has been identified in several studies dating back to 2001. More recently, a 2020 meta-analysis of 112 cohort studies by Vaengebjerg et al found an overall increased risk of cancer in patients with psoriasis relative to the general population (relative risk [RR], 1.21; 95% CI, 1.11-1.33).1
The meta-analysis found an association with site-specific cancers, including keratinocyte cancer, lymphomas, lung cancer, and bladder cancer. Of note, psoriatic arthritis was not associated with an overall increased risk of cancer (RR, 1.02; 95% CI, 0.97-1.08), and no increased risk of cancer for patients with psoriasis treated with biologic agents was found (RR, 0.97; 95% CI, 0.85-1.10).1 In 2019, a second meta-analysis of 58 cohort and case-controlstudies found both severe psoriasis and all severities of psoriasisto be associated with an overall increased risk of cancer, (RR,1.22; 95% CI, 1.08-1.39 and 1.18; 95% CI, 1.06-1.3, respectively).2 Researchers found an increased risk of site-specific cancers, includingcolon, kidney, laryngeal, liver, esophageal, oral, and pancreaticcancers; lymphoma; and non-Hodgkin lymphoma.
A 2013 meta-analysis of 37 observational studies reported an increased rate of nonmelanoma skin cancer (NMSC); respiratory, digestive, and urinary tract cancer; and non-Hodgkin lymphoma in patients with psoriasis relative to control individuals.3 Researchers attributed the higher risk of squamous cell carcinoma (SCC) to previous treatment with psoralen-UVA (PUVA), cyclosporine, and possibly methotrexate (MTX).3 A separate study of patients with chronic psoriasis (greater than 4 years) found relative increases in lymphohematopoietic malignancies and pancreatic cancer compared with unaffected control individuals.3 Another study of patients recently diagnosed with psoriasis (within 1 year) found associations with skin cancer and malignancies of the oropharynx and larynx, digestive tract, and colorectum.3
Pathogenesis
The current data suggest a complex, multifactorial process, with contributing factors such as a chronic low-grade inflammatory state, confounding lifestyle risk factors, and the teratogenic effects of psoriasis treatment.4,5
Chronic Systemic Inflammation
The pathogenesis of systemic inflammation is the basis of extracutaneous comorbidity development and helps explain why psoriasis treatments such as systemic agents and biologics benefit these comorbidities in patients with psoriasis.6 The cytokines upregulated in psoriasis include tumor necrosis factor-alpha (TNF a), IL-1ß, IL-12, IL-17A, IL-22, IL-23, and IL-13.5 These cytokines, which upregulate the production of reactive oxygen species, have been shown to play a role in the formation of cancer via the inactivation of tumor suppressor genes and activation of oncogenes.7 For example, IL-17 signaling is specifically involved in the induction of pancreatic cancer, metastasis for breast cancer, and treatment resistance in some colorectal cancers.5
As a multisystem, immune-mediated disease, the pathophysiology of psoriasis is associated with an increased risk of lymphohematopoietic malignancies, which is an association seen in other TH1-mediated diseases, such as rheumatoid arthritis, inflammatory bowel disease, and other autoimmune diseases.5 Psoriasis has been associated with an increase in both Hodgkin and non-Hodgkin lymphoma, with the strongest association seen in cutaneous T-cell lymphoma, previously mycosis fungoides.5
Lifestyle Risk Factors
Several known lifestyle risk factors for cancer, such as smoking, alcohol use, obesity, and sun-seeking behavior, have a higher prevalence in the psoriasis population.5 Cancer types associated with both psoriasis and smoking, alcohol use, and obesity include esophageal, liver, colorectal, lung, breast, bladder, and pancreatic cancer. It is important to note that few studies have adjusted for these factors, thus more research is required to determine the level of confounding.2
Psoriasis is associated with an increased risk of NMSC, especially SCC.5 Interestingly, despite this overall increased risk, the local, chronic inflammation of psoriatic lesions rarely progresses to cancer, which could be explained by an increased expression of p53 in psoriatic skin.5 Also of note, sun-seeking behavior and use of UV tanning beds are higher among patients with psoriasis than the general population, likely due to the therapeutic effects of UV radiation on psoriatic lesions.5 This increased exposure to UV radiation can increase the patient’s risk of skin cancer and should be considered a confounder in this population.7 The increased risk of NMSC is also attributed to UV-based treatments such as PUVA.7
Psoriasis Treatment
Topicals, such as corticosteroids and calcipotriol, are generally accepted as being low risk for cutaneous malignancy.7 On the other hand, phototherapy, especially PUVA, confers a dose-dependent increased risk of skin cancer, particularly SCC.5 Studies show that PUVA radiation is associated with abnormal lentiginous melanocytic proliferations and p53 mutations that contribute to the development of melanoma and NMSC.7 Further research is required for UVB radiation.
The data for MTX are contradictory. For now, we can say that long-term (greater than 36 months) MTX use has shown an increased risk of lymphoma, whereas low-dose MTX monotherapy showed no association with any cancer.8 Of note, an increased risk of lymphoma was seen in patients treated with MTX and PUVA compared with those treated with PUVA alone.5 The risk of developing NMSC, particularly SCC, was also increased in patients treated with both MTX and PUVA.7
Cyclosporine A (CsA) has been associated with an increased risk of NMSC and lymphoma, and should not be used in combination with phototherapy before or after PUVA or in patients with a history of SCC or melanoma.4,5 A recent cohort study found that lowdose CsA (2.7–3.1 mg/kg/day) was associated with a 6-fold increase in SCC risk within 5 years.4 Like MTX, the combination of CsA and PUVA for the treatment of psoriasis was associated with an increase in both basal cell carcinoma (BCC) and SCC.7
Other oral treatments, such as retinoids and fumaric acid esters (FAE), have been used in psoriasis treatment for over 40 years and are generally considered safe regarding the risk of malignancy.5 Although data are sparse, FAE do not appear to increase the risk of malignancy in psoriasis.5 Acitretin is considered to be protective against NMSC and cutaneous T-cell lymphoma, and it has been used to suppress NMSC following organ transplantation.5 In a nested cohort study, systemic retinoid use significantly reduced the risk of SCC in patients with psoriasis treated with PUVA.8
Limited data are available regarding apremilast and other new small molecules, such as Janus kinase and tyrosine kinase inhibitors.8 It seems that TNF inhibitors do not confer an overall increased riskof cancer when excluding NMSC.5 Results suggest no increased riskof melanoma, although the data around NMSC are equivocal. Somestudies have suggested an overall increased risk of NMSC, whereasothers found an increased risk of either BCC or SCC. Further researchshould be conducted. Based on the current evidence, no increasedrisk of malignancy was seen for ustekinumab (anti-IL-12/23).Only short-term data are available for anti-IL-17s and anti-IL-23s.Although these monoclonal antibodies do not appear to alter malignancy risk, larger and longer-term studies are necessary.3
Interventions and Recommendations
First, it is important not to overstate the risk associated with cancer or cause unnecessary alarm.5 Most of these cancers are rare and do not require a change in practice.5 However, it is important to be aware of the association and that patients with psoriasis may have increased mortality from cancer.2 Additionally, the use of treatments such PUVA and CsA is expected to decrease following the rise of biologics and other new treatments.5 Thus, we should expect the incidence of NMSC due to PUVA and CsA to decrease moving forward.5
Given the large armamentarium of treatments available for psoriasis, it is important to have the patient’s history in mind when discussing treatment options.9 We recommend the joint American Academy of Dermatology (AAD)-National Psoriasis Foundation (NPF) guidelines of care, which focus on psoriasis comorbidities; topical, biologic, and systemic treatments; phototherapy; and pediatric psoriasis.3 Additionally, “the psoriasis decision tree” created by Monks et al in 2021 is a useful tool and infographic to organize treatments based on their therapeutic effect on various comorbidities.8
Our most important action in cancer risk reduction is prevention. This includes controlling the systemic inflammatory response; choosing the right treatment based on patient history and risk factors; promoting a healthy lifestyle; and staying up-to-date on routine cancer screenings, such as full skin examinations, colonoscopies, mammograms, and lung imaging. Motivating patients toward healthy lifestyle choices is no easy task, especially in a busy clinical practice. However, considering the complex, systemic nature of this disease, the importance of lifestyle changes and a comprehensive approach must be highlighted.
Finally, new prospective studies with long-term follow up, homogenous samples, and a comprehensive selection of confounding factors are required to understand the burden of cancer among patients with psoriasis.7 Clinical trials often lack the power to detect rare adverse events and the follow-up time required to establish an association with cancer. This highlights the importance of registry data and the collection of cancer risk factor data.5
In Summary
The list of comorbid diseases continues to grow as we learn more about the effects of systemic inflammation on the body. In addition to psoriasis itself, biologic, socioeconomic, and cultural factors, such as sex, age, income, and education level, can each act as a risk factor for comorbid disease.6 Therefore, increased awareness and understanding of comorbidities is critical to the management of psoriasis.
Early detection and treatment are important. An integrated approach should be taken to ensure that treatment does not interfere with the management of comorbid conditions and vice versa.4 The joint AAD-NPF guidelines of care recommend directly involving patients in their care through education, shared decision-making, and building a therapeutic alliance to achieve patient engagement and comprehensive care with enhanced quality of life.3 Treatment options, along with risks, benefits, and alternatives, should be explained and patient preference should be discussed to create a shared plan.3 This approach can empower patients and possibly improve patient satisfaction and adherence. We recommend the involvement of a designated biologic coordinator for continuity in care, office organization, and prior authorization follow up. Participation in a psoriasis registry is also recommended to track comorbidities and adverse events within patients treated with systemic therapies.
References
1. Vaengebjerg S, Skov L, Egeberg A, Loft ND. Prevalence, incidence, and risk of cancer in patients with psoriasis and psoriatic arthritis: a systematic review and meta-analysis. JAMA Dermatol. 2020;156(4):421-429. doi:10.1001/jamadermatol.2020.0024
2. Trafford AM, Parisi R, Kontopantelis E, Griffi ths CEM, Ashcroft DM. Association of psoriasis with the risk of developing or dying of cancer: a systematic review and meta-analysis. JAMA Dermatol. 2019;155(12):1390-1403. doi:10.1001/jamadermatol.2019.3056
3. 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(4):1073-113. doi:10.1016/j.jaad.2018.11.058
4. Ni C, Chiu MW. Psoriasis and comorbidities: links and risks. Clin Cosmet Investig Dermatol. 2014;7:119-132. doi:10.2147/CCID.S44843
5. Loft ND, Vaengebjerg S, Skov L. Cancer risk in patients with psoriasis: should we be paying more attention? Expert Rev Clin Immunol. 2020;16(5):479-492. doi:10.1080/1744666X.2020.1754194
6. Bu J, Ding R, Zhou L, Chen X, Shen E. Epidemiology of psoriasis and comorbid diseases: a narrative review. Front Immunol. 2022;13:880201. doi:10.3389/fimmu.2022.880201
7. Butrón-Bris B, Daudén E, Rodríguez-Jiménez P. Psoriasis therapy and skin cancer: a review. Life (Basel). 2021;11(10):1109. doi:10.3390/life11101109
8. Monks G, Rivera-Oyola R, Lebwohl M. The psoriasis decision tree. J Clin Aesthet Dermatol. 2021;14(4):14–22.
9. Oliveira M de FSP de, Rocha B de O, Duarte GV. Psoriasis: classical and emerging comorbidities. An Bras Dermatol. 2015;90(1):9-20. doi:10.1590/abd1806-4841.20153038
