Do Psoriasis Therapies Increase the Risk of Skin Cancer? Mark Lebwohl, MD Sol and Clara Kest Professor And Chairman Department of Dermatology The Mount Sinai School of Medicine
Disclosure Mark Lebwohl is an employee of Mount Sinai which receives research funds from: Abbvie, Amgen, Boehringer Ingelheim, Celgene, Eli Lilly, Janssen / Johnson & Johnson, Kadmon, Medimmune/Astra Zeneca, Novartis, Pfizer, Valeant and ViDac. Dr. Lebwohl is also a consultant for Allergan, Aqua Leo-pharma,and Promius.
The risk of cancer in patients with psoriasis: A population-based cohort study in the Health Improvement Network. Chiesa Fuxench ZC, et al. JAMA Dermatol. 2016;152(3):282-90.
Mild Severe ** Cancer(ѲNMSC)HR: 1.06 (1.02-1.09) 1.08(0.96-1.22)* Lymphoma: 1.31(1.15-1.49)* 1.89(1.25-2.86)* NMSC: 1.09(1.05-1.13)* 1.61(1.42-1.84)* Lung cancer: 1.12(1.01-1.25)* 1.62(1.16-2.28)* No association with breast, colon, prostate,or leukemia **Includes patients with systemic therapy Chiesa Fuxench ZC, et al. JAMA Dermatol. 2016;152(3):282-90.
The risk of melanoma and hematologic cancers inpatients with psoriasis. Reddy SP, Martires K, Wu JJ. J Am Acad Dermatol. 2017; 76:639-47. Patients with psoriasis had 1.53 times the risk of melanoma and hematologic cancers
UVB Narrowband UVB PUVA MTX Retinoids Cyclosporine Biologics Apremilast
UVB doses in maintenance psoriasis phototherapy versus solar UVB exposure. Schothorst AA, et al Photodermatol. 1985;2:213-20. The cumulative incidence among patients who received maintenance phototherapy for several decades was calculated to be a factor of 2.5 to 7.5 higher than the incidence among individuals with an outdoor occupation.
Skin Cancer In Patients With Psoriasis Treated With Coal Tar A 25-Year follow-up study Pittelkow MR, Perry HO, Muller SA, Maughan WZ, O'Brien PC. Arch Dermatol 1981; 117(8): 465-8.
Phototherapy is adminstered in a controlled manner, with slowly increasing increments. Typical phototherapy burn is often only a little higher than the MED. Blistering sunburns are often several times the MED. UV spectrum of phototherapy is not identical to that of sunlight.
The photocarcinogenic risk of narrowband (TL-01) phototherapy: early follow-up data Man I, Crombie IK, Dawe RS et al. Br J Dermatol 2005;152:755-757. 1908 pts.04 14 years (median 4) 1-199 NB treatments (median 23) 30-284,415 mj/cm 2 (median 13,337)
No increase SCC or MM 10 BCC vs. 4.7 expected, 9 on face Patients under regular dermatological follow-up are more likely to have skin cancers detected. Man I et al.
Carcinogenic risks of psoralen UV-A therapy and narrowband UV-B therapy in chronic plaque psoriasis: a systematic literature review. Archier E, et a;l. J Eur Acad Dermatol Venereol. 2012;26 Suppl 3:22-31. No increased risk of skin cancer was evidenced in the four studies specifically assessing the potential carcinogenic risk of NB-UVB.
Nonmelanoma skin tumors in long-term photochemotherapy treatment of psoriasis. An 8-year follow-up study. Tanew A et al. J Am Acad Dermatol. 1986;15(5 pt 1):960-965.
Malignant melanoma in patients treated for psoriasis with methoxsalen (psoralen) and ultraviolet A radiation (PUVA). The PUVA Follow-Up Study. Stern RS, Nichols KT, Vakeva LH. N Engl J Med. 1997; 336(15): 1041-5. relative risk 5.4, beginning 15 yrs. after 1 st treatment risk with number of treatments
Incidence of melanoma and other malignancies among rheumatoid arthritis patients treated with methotrexate. Buchbinder R et al. Arthritis & Rheumatism. 2008;59:794-99. RA pts started on MTX pre 1986 State cancer registry (not NMSC) 4,145 person-years (avg.9.3 yrs)
MTX associated with: 50% risk of malignancy 3-fold in melanoma 5-fold in nonhodgkins lymphoma 3-fold in lung ca. Buchbinder R et al. Arthritis & Rheumatism. 2008;59:794-99.
Prevention of skin cancer and reduction of keratotic skin lesions during acitretin therapy in renal transplant recipients: a double-blind, placebo-controlled study. Bavinck JN et al. J Clin Oncol. 1995;13:1933-1938. Acitretin 30 mg/d 2/19 2 SCCs vs 9/19 18 SCCs
Chemoprevention of skin cancer in xeroderma pigmentosum. Kraemer KH et al. J Dermatol. 1992;19:715-718. 121 BCCs or SCCs in 5 patients 2 years prior to Rx Isotretinoin 2 mg/kg/d 25 tumors over 2 years of Rx
Incidence and prediction of nonmelanoma skin cancer post-renal transplantation: a prospective study in Queensland, Australia. Carroll RP et al. Am J Kidney Dis. 2003;41:676-683. 18.8%, <5 years 24.8%, 5-10 years 33.3%, 10-20 years 47.1%, >20 years
Skin Cancer in Organ Transplant Patients Immunosuppressive Drugs Cyclosporine A Tacrolimus Berg and Otley, JAAD 47:1-17, 2002
Risk of malignancies in psoriasis patients treated with cyclosporine: a 5 y cohort study. Paul CF et al. J Invest Dermatol. 2003;120:211-216. 1252 patients for up to 5 years (average 1.9) 6-fold skin cancer No nonskin cancer
Cutaneous malignant melanoma occurring after cyclosporin A therapy. Arellano F, Krupp PF. Br J Dermatol. 1991;124:611. Cutaneous malignant melanomas occurring under cyclosporin A therapy: a report of two cases. Mérot Y, et al. Br J Dermatol. 1990;123:237-9.
Metastatic melanoma after solid organ transplantation: An interdisciplinary, institution-based review of management with systemic and targeted therapies. Tripathi SV, Morris CR, Alhamad T, Fields RC, Linette GP, Cornelius LA. J Am Acad Dermatol. 2018;78:184-185. Invasive Melanomas 2 fold M:F ratio 14:1
Withdrawal of immunosuppression contributing to the remission of malignant melanoma: a case report. Hodi FS et al. Cancer Immun. 2005;5:7.
TNF blockers Key Cells and Mediators in Psoriasis Natural killer T cell Innate immunity INF-γ Plasmacytoid dendritic cell Keratinocyte TNF-α INF-γ Macrophage IL-1β IL-6 TNF-α Myeloid dendritic cell TNF-α Adaptive immunity IL-12 Activation Adalimumab Etanercept Infliximab Certlizumab Adapted from Nestle FO, et al. N Engl J Med. 2009;361:496-509. IL-20 Th17 cell Th1 cell Th22 cell Innate immunity Antimicrobial peptides IL-1β TNF-α IL-6 INF-γ TNF-α S100 IL-20 CXCL8 CXCL9 CXCL10 Keratinocyte CXCL11 IL-22 CCL20 IL-17A IIL-17F IL-17R
Rapid onset of cutaneous squamous cell carcinoma in patients with rheumatoid arthritis after starting tumor necrosis factor alpha receptor IgG1-Fc fusion complex therapy. Smith KJ, Skelton HG. J Am Acad Dermatol. 2001;45:953-6.
Multiple squamous cell carcinomas in the setting of psoriasis treated with etanercept: A report of four cases and review of the literature. Brewer JD, et al. Int J Dermatol 2011;50:1555.
The rapid onset of multiple squamous cell carcinomas during etanercept treatment for psoriasis. Ly L, et al. Br J Dermatol. 2007;157(5):1076-8.
Rapid onset and fatal outcome of two squamous cell carcinomas of the genitalia in a patient treated with etanercept for cutaneous psoriasis. Comte C, et al. Dermatology. 2008;217(3):284-5.
Multiple and fulminant cutaneous squamous cell carcinomas in a Crohn's disease patient treated with immunosuppressants and adalimumab. Nancey S, et al. Inflamm Bowel Dis. 2011;17(4):1060-1.
[Long term treatment of psoriasis with TNF-alpha antagonists. Occurrence of malignant melanoma]. Kowalzick L et al. Hautarzt. 2009;60:655-7.
Metastatic melanoma in a young woman treated with TNF-α inhibitor for psoriatic arthritis: a case report. Marasini B,et al. Curr Drug Saf. 2011;6(4):275-6.
Eruptive latent metastatic melanomas after initiation of antitumor necrosis factor therapies. Fulchiero GJ Jr, et al. JAmAcadDermatol. 2007;56(5Suppl):S65-7.
Cutaneous melanoma in patients in treatment with biological therapy: review of the literature and case report. Manganoni AM, et al. Dermatol Online J. 2011;17(8):12.
Development of two primary malignant melanomas after treatment with adalimumab: a case report and review of the possible link between biological therapy with TNF-alpha antagonists and melanocytic proliferation. Katoulis AC, Kanelleas A, Zambacos G, Panayiotides I, Stavrianeas NG. Dermatology. 2010;221:9-12.
Melanoma at a dysplastic nevus excision site in a patient on etanercept. Hacard F, et al. Ann Dermatol Venereol. 2010;137(3):230-2.
Primary cutaneous melanoma: a complication of infliximab treatment? Khan I, et al. Clin Exp Dermatol. 2009;34(4):524-6..
Multiple basal cell carcinomas after etanercept treatment for psoriasis. Maire C, et al. Ann Dermatol Venereol. 2009;136(4):355-9.
Merkel cell carcinoma in a patient treated with adalimumab: case report. Krishna SM, et al. Cutis. 2011;87(2):81-4.
Malignancy rates in a large cohort of patients with systemically treated psoriasis in a managed care population. Maryam M. Asgari, et al. JAAD. Available online 3 February 2017 (In press). age, gender, race & comorbidity adjusted HR Any cancer (except NMSC) 0.86 (0.66-1.13) cscc 1.81 (1.23-2.67) BCC 1.23 (0.91-1.66) MM 1.57 (0.61-4.09) Lymphoma 1.01 (0.38-2.70)
Rate per 100 PY (95% CI) Cumulative Rates of NMSC Through 5 Years of Follow-up 47 patients reported NMSCs (3 patients reported both SCC and BCC) 40 had BCC (21 on 45 mg and 19 on 90 mg) 10 had SCC (5 on 45 mg and 5 on 90 mg) 4.0 3.0 BCC:SCC = 3:1 BCC:SCC = 4:1 2.0 1.0 1.13 (0.14, 4.09) 0.49 (0.01, 2.75) 0.98 (0.12, 3.55) 0.74 (0.15, 2.16) 0.70 (0.43, 1.09) 0.53 (0.33, 0.82) 0.61 (0.43, 0.82) 0.64 (0.41, 0.95) 0.44 (0.28, 0.66) 0.52 (0.39, 0.70) 0.0 Controlled Period 2010 Analyses 2011 Analyses n 732 790 792 1582 1319 1992 3117 1319 2001 3117 PY f/u 176 203 203 406 2846 3925 6770 3745 5220 8965 # patients 2 1 2 3 20 21 41 24 23 47 Placebo UST 45 mg UST 90 mg UST Combined ACCEPT data were not included in the Controlled Period rates since it did not include a placebo comparator. For PHOENIX 2, patients who were dose adjusted from 45 mg to 90 mg were switched to the corresponding column following dose adjustment.
Rate per 100 PY (95% CI) Rates of NMSC by Year Through 5 Years of Follow-up 4.0 Year 1 Year 2 Year 3 Year 4 Year 5 3.0 2.0 1.0 0.80 1.06 0.94 0.26 0.68 0.98 0.49 0.40 0.00 0.91 0.11 0.42 0.29 0.09 0.16 0.0 48 Weeks > 48 to 96 Weeks > 96 to 144 Weeks > 144 to 192 Weeks UST 45 mg UST 90 mg UST Combined > 192 Weeks n 1319 1798 3117 1009 1245 2145 718 1012 1671 621 987 1588 577 947 1516 PY f/u 1128 1412 2540 762 883 1644 613 890 1503 551 881 1432 700 1164 1864 # patients 9 15 24 2 6 8 6 0 6 5 1 6 2 1 3 PHOENIX 2 patients who were dose adjusted from 45 mg to 90 mg were switched to the corresponding column following dose adjustment.
Unadjusted Rates (n=no. of Events) of Malignancies per 100 PY (95% CI) 43 Results: Unadjusted Cumulative Rates of Malignancies (excluding NMSC) per 100 Patient- Years (PY) for Any Exposure to Therapy (Figure 1) PSOLAR 1.0 0.8 0.64 (0.42, 0.93) 0.74 (0.60, 0.91) 0.81 (0.59, 1.08) 0.68 (0.59, 0.77) 0.6 0.51 (0.37, 0.68) 0.4 0.2 0.0 n=45 Ustekinumab (N=8870 PY) n=27 n=98 n=45 n=215 Infliximab/ Golimumab* (N=4205 PY) ADA/ETN** (N=13167 PY) No Biologic (N=5576 PY) All (N=31818 PY) *Sponsor biologics, other than ustekinumab, approved for PsO &/or PsA; includes almost exclusively infliximab patients (n=1400); few patients were exposed to golimumab (n=35). **95% (n=4374) are adalimumab &/or etanercept patients, with the remainder exposed to efalizumab, alefacept, or other non-sponsor biologic. Fiorentino D, et al. AAD 2014. P8155.
Inborn errors of human IL-17 immunity underlie chronic mucocutaneous candidiasis. Puel A, et al. Allergy Clin Immunol. 2012;12:616-22.
IL-17 Mediated Inflammation Promotes Tumor Growth and Progression in the Skin D. He, et al PLoS ONE 2012; 7: 1-9 IL-23 IL-17 tumor growth Could blocking IL-17 be protective against cancer?
Secukinumab PUBMED search 1/10/18 NO MALIGNANCIES
Ixekizumab PUBMED search 1/10/18 NO MALIGNANCIES
Brodalumab PUBMED search 1/10/18 NO MALIGNANCIES
Guselkumab PUBMED search 1/10/18 NO MALIGNANCIES
PUBMED search 1/10/18
apremilast mode of action camp IL-23 IL-17 Apremilast T N F P D E- 4
Recurrence of Melanoma after Starting Apremilast for Psoriasis. Salopek TG. Case Rep Dermatol. 2017;9:108-111. h/o 2 melanomas: 2009-1.53mm Clark IV 2012-0.9mm Clark IV 2015 started apremilast >4mos. later recurrence near first MM
Association with Skin Cancer Sunlight strong association PUVA strong association Cyclosporine strong association Phototherapy UVB, narrowband UVB No clear association Methotrexate association Retinoids protective TNF blockers association Ustekinumab no association IL-17 blockers no association too new IL-23 blockers no association too new Apremilast no association too new
ARS question Which therapies have been associated with an increase in skin cancers? 1) Methotrexate 2) Apremilast 3) Ustekinumab 4) Anti-IL-17 antibodies 5) Anti-IL-23 antibodies
Sildenafil use and increased risk of incident melanoma in US men: A prospective cohort study. Li WQ et al. JAMA Intern Med. 2014;Apr 7. doi: 10.1001/jamainternmed.2014.594. [Epub ahead of print]