Sex differences in factors associated with switch between systemic agents among individuals with psoriasis: A retrospective cohort study in Quebec, Canada

To the Editor: Conventional systemic agents (CSAs) are indicated in moderate-to-severe psoriasis. CSA switch to another CSA and/or a biologic agent including a tumor necrosis factor inhibitor and ustekinumab (TNFi/UST) may be an indication of dissatisfaction with treatment.1Canadian Psoriasis Guidelines Addendum Committee2016 addendum to the Canadian guidelines for the management of plaque psoriasis 2009.J Cutan Med Surg. 2016; 20: 375-431Crossref PubMed Scopus (23) Google Scholar Discontinuation of CSA treatment has been previously studied in psoriasis, but switches between agents and the differences between sexes have not received much attention.2Mason K.J. Williams S. Yiu Z.Z.N. et al.Persistence and effectiveness of nonbiologic systemic therapies for moderate-to-severe psoriasis in adults: a systematic review.Br J Dermatol. 2019; 181: 256-264Crossref PubMed Scopus (6) Google Scholar, 3Higa S. Devine B. Patel V. Baradaran S. Wang D. Bansal A. Psoriasis treatment patterns: a retrospective claims study.Curr Med Res Opin. 2019; 35: 1727-1733Crossref PubMed Scopus (2) Google Scholar, 4Bergqvist C. Mezzarobba M. Weill A. Sbidian E. Persistence of treatment with conventional systemic agents for patients with psoriasis: a real-world analysis of 73 168 new users from the French National Health Insurance database.Br J Dermatol. 2020; 182: 1483-1484Crossref PubMed Scopus (1) Google Scholar We examined sex differences in factors associated with CSA treatment switch among patients with psoriasis. We conducted a retrospective cohort study using the Quebec health administrative databases. We considered new patients with psoriasis aged ≥20 years who were enrolled in the public drug plan (aged ≥65 years or <65 years with no private drug plan or receiving social assistance) in 2002-2015. New patients were those with no psoriasis diagnosis in the prior 3 years and no psoriasis treatment (phototherapy, CSA, or a biologic agent) in the prior year. We included those initiated on a CSA (methotrexate, cyclosporine, acitretin, and sulfasalazine)1Canadian Psoriasis Guidelines Addendum Committee2016 addendum to the Canadian guidelines for the management of plaque psoriasis 2009.J Cutan Med Surg. 2016; 20: 375-431Crossref PubMed Scopus (23) Google Scholar and followed them until the first date of a switch, CSA discontinuation (no supply for any CSA for ≥60 days), death, or the end of public drug plan enrollment. A switch was a prescription for another CSA or TNFi/UST during the days supplied for the initial CSA or a 60-day grace period. Cox regression models with the least absolute shrinkage and selection operator method identified factors associated with switch in male and female patients, separately.5Kumar S. Attri S.D. Singh K.K. Comparison of Lasso and stepwise regression technique for wheat yield prediction.J Agrometeorol. 2019; 21: 188-192Google Scholar In sensitivity analyses: (1) sulfasalazine was not considered among the CSAs prescribed for psoriasis (sulfasalazine is prescribed when other CSAs are contraindicated and in those with other immune-mediated conditions) and (2) both prevalent and incident psoriasis patients were studied. We included 1644 patients with psoriasis who initiated a CSA (55.7% females: mean age ±SD 61.4 ± 15.1 years vs 58.9 ± 15.7 years for males). Most patients initiated methotrexate, followed by acitretin, sulfasalazine, and cyclosporine (57.4%, 34.7%, 4.8%, and 3.1%, respectively) with no difference between sexes (Table I). Most methotrexate, acitretin, and cyclosporine prescriptions were by a dermatologist (48.5%, 91.1%, and 76.5%, respectively) and 65.8% of sulfasalazine prescriptions were by a rheumatologist.Table IBaseline characteristics by the initial conventional systemic agent receivedPatient characteristicsMethotrexateN = 944 (57.4)CyclosporineN = 51 (3.1)AcitretinN = 570 (34.7)SulfasalazineN = 79 (4.8)P valueǁChi-square test or exact Fisher test for statistical significance.Mean duration of follow-up in years (SD)1.83 (2.37)0.98 (1.26)0.92 (1.33)0.96 (1.58)—Median duration of follow-up in years (Q1, Q3)0.83 (0.38, 2.22)0.50 (0.31,1.09)0.49 (0.26, 0.95)0.35 (0.25, 0.65)—Sociodemographic variables, N (%) Age<.00120-45 y166 (17.6)21 (41.2)82 (14.4)12 (15.2)45-64 y332 (35.2)20 (39.2)248 (43.5)26 (32.9)65-74 y274 (29.0)7 (13.7)148 (26.0)26 (32.9)≥75 y172 (18.2)3 (5.9)92 (16.1)15 (19.0) Sex (male vs female)408 (43.2)26 (51.0)254 (44.6)40 (50.6).44 Area of residency (urban vs rural)754 (79.9)43 (84.3)456 (80.0)67 (84.8).64 Income (Low vs high income)∗Income (high vs low) was based on the type of drug plan the patients had with those receiving partial or total subsidies classified as low income.567 (60.1)37 (72.5)314 (55.1)45 (57.0).04Variables related to CSA and other psoriasis treatments, N (%) Year of cohort entry (≥2009-2015 vs 2002-2008)564 (59.7)28 (54.9)363 (63.7)38 (48.1).04 Psoriasis duration†Time from first psoriasis diagnosis until the first CSA prescription fill.<.0010-2.99 mo243 (25.7)18 (35.3)182 (31.9)15 (19.0)3-12 mo162 (17.2)13 (25.5)127 (22.3)13 (16.5)>12 mo539 (57.1)20 (39.2)261 (45.8)51 (64.6) Specialty of the first CSA prescriber<.001Dermatologist458 (48.5)39 (76.5)519 (91.1)0 (0.0)Rheumatologist238 (25.2)0 (0.0)0 (0.0)52 (65.8)Others‡The others category included mostly general practitioners (63.9%) and internal medicine doctors (25.1%). Only 5 (1.8%) received their first CSA from a gastroenterologist.248 (26.3)12 (23.5)51 (8.9)27 (34.2) Use of topical agents in the prior year759 (80.4)43 (84.3)533 (93.5)54 (68.4)<.001 Use of phototherapy in the prior year85 (9.0)8 (15.7)112 (19.6)1 (1.3)<.001Comorbidities in the prior 2 years, N (%) Psoriatic arthritis176 (18.6)3 (5.9)38 (6.7)25 (31.6)<.001 Rheumatoid arthritis192 (20.3)0 (0.0)13 (2.3)28 (35.4)<.001 Inflammatory bowel diseases18 (1.9)1 (2.0)5 (0.9)3 (3.8).12 Ankylosing spondylitis14 (1.5)0 (0.0)3 (0.5)6 (7.6)<.001 Obesity42 (4.4)5 (9.8)25 (4.4)6 (7.6).17 Renal diseases22 (2.3)5 (9.8)21 (3.7)3 (3.8).02 Liver diseases29 (3.1)6 (11.8)13 (2.3)3 (3.8).01 Cancer§43 patients had nonmelanoma cancer: 22 female patients and 21 male patients had nonmelanoma skin cancer. With regards to the CSA received, 27 patients with methotrexate, 1 patient with cyclosporine, 11 patients with acitretin, and 4 patients with sulfasalazine had nonmelanoma skin cancer.109 (11.5)6 (11.8)64 (11.2)11 (13.9).92 Mental health disorders, N (%).03 No mental health disorder671 (71.1)32 (62.7)423 (74.2)65 (82.3) Anxiety and mood disorders208 (22.0)15 (29.4)124 (21.8)9 (11.4) Dissociative, somatoform, and adjustment disorders20 (2.1)0 (0.0)5 (0.9)3 (3.8) Other mental health disorders45 (4.8)4 (7.8)18 (3.2)2 (2.5) Drug and/or alcohol abuse42 (4.4)2 (3.9)25 (4.4)5 (6.3).87Drug use in the prior year, N (%) Antidepressants235 (24.9)11 (21.6)124 (21.8)12 (15.2).16 Benzodiazepines287 (30.4)18 (35.3)151 (26.5)22 (27.8).30 Antihypertensive agents472 (50.0)22 (43.1)262 (46.0)37 (46.8).40 Hypoglycemic agents148 (15.7)12 (23.5)88 (15.4)10 (12.7).40 Lipid-lowering drugs342 (36.2)10 (19.6)193 (33.9)24 (30.4).07 Platelet inhibitors266 (28.2)14 (27.5)171 (30.0)20 (25.3).78 Anticoagulants38 (4.0)3 (5.9)12 (2.1)6 (7.6).02 Nonsteroidal antiinflammatory drugs455 (48.2)11 (21.6)131 (23.0)61 (77.2)<.001 Oral corticosteroids301 (31.9)17 (33.3)76 (13.3)29 (36.7)<.001CI, Confidence interval; CSA, conventional systemic agent; Q1, first quartile; Q3, third quartile; ref, reference group; SD, standard deviation.∗ Income (high vs low) was based on the type of drug plan the patients had with those receiving partial or total subsidies classified as low income.† Time from first psoriasis diagnosis until the first CSA prescription fill.‡ The others category included mostly general practitioners (63.9%) and internal medicine doctors (25.1%). Only 5 (1.8%) received their first CSA from a gastroenterologist.§ 43 patients had nonmelanoma cancer: 22 female patients and 21 male patients had nonmelanoma skin cancer. With regards to the CSA received, 27 patients with methotrexate, 1 patient with cyclosporine, 11 patients with acitretin, and 4 patients with sulfasalazine had nonmelanoma skin cancer.ǁ Chi-square test or exact Fisher test for statistical significance. Open table in a new tab CI, Confidence interval; CSA, conventional systemic agent; Q1, first quartile; Q3, third quartile; ref, reference group; SD, standard deviation. In total, 312 patients switched their initial CSA (to a different CSA: 82.7% and to TNFi/UST: 17.3%) (Fig 1). Most switched to methotrexate (29.8%), followed by acitretin (21.1%), sulfasalazine (18.9%), cyclosporine (12.2%), adalimumab (6.7%), and etanercept (5.5%). In both sexes, higher age was associated with a decreased risk of switch whereas receiving sulfasalazine versus methotrexate was associated with an increased risk (Table II). In male patients, psoriatic arthritis and longer disease duration were associated with increased risks. In female patients, disease duration of 3 to 12 versus 0 to 2.99 months was associated with a 50% decreased risk of switch, and the presence of somatoform/dissociative/adjustment disorders and prior use of nonsteroidal antiinflammatory drugs were associated with an increased risk.Table IIPredictors of switch to either another CSA or a tumor necrosis factor inhibitor/usterkinumab among male and female patients with psoriasisPredictorsAll patients (N = 1644)Females (N = 916)Males (N = 728)aHR (95% CI)aHR (95% CI)aHR (95% CI)Age 20-54 yRefRefRef 55-64 y0.70 (0.52-0.93)0.68 (0.45-1.01)0.72 (0.48-1.11) 65-74 y0.46 (0.33-0.64)0.44 (0.28-0.70)0.47 (0.28-0.76) ≥75 y0.32 (0.21-0.50)0.35 (0.19-0.62)0.29 (0.14-0.59)Psoriasis duration 0-2.99 moRefRefRef 3-12 mo0.65 (0.45-0.94)0.50 (0.31-0.81)0.90 (0.49-1.65) >12 mo1.13 (0.87-1.48)0.89 (0.63-1.25)1.61 (1.03-2.53)First CSA received MethotrexateRefRefRef Cyclosporine1.29 (0.69-2.41)1.15 (0.42-3.19)1.69 (0.74-3.82) Acitretin1.17 (0.88-1.55)1.24 (0.85-1.81)1.16 (0.75-1.80) Sulfasalazine3.05 (2.07-4.49)3.06 (1.81-5.18)3.34 (1.84-6.05)Psoriatic arthritis1.28 (0.96-1.70)1.15 (0.77-1.69)1.52 (1.02-2.31)Mental health disorders No mental health disorderRefRefRef Anxiety and mood disorders1.03 (0.76-1.38)0.90 (0.62-1.32)1.20 (0.74-1.95) Dissociative, somatoform, and adjustment disorders1.82 (0.95-3.49)2.18 (1.04-4.57)NA∗In male patients, only 7 patients had dissociative, somatoform, and adjustment disorders; therefore, they were combined with those who had anxiety and mood disorders. Other mental health disorders1.56 (0.97-2.51)1.83 (0.91-3.72)1.37 (0.72-2.60)Prior use of NSAIDS1.30 (1.02-1.66)1.50 (1.09-2.06)1.14 (0.78-1.65)Performance measures for internal validation Harrel's C index (95% CI)0.63 (0.59-0.66)0.61 (0.59-0.62)0.61 (0.55-0.67) Calibration slope0.810.660.77Bold denotes significant associations.aHR, Adjusted hazard ratio; CI, confidence interval; CSA, conventional systemic agent; Harrel's C index, Harrel's Concordance index; NA, not applicable; NSAIDS, nonsteroidal antiinflammatory drugs; ref, reference group.∗ In male patients, only 7 patients had dissociative, somatoform, and adjustment disorders; therefore, they were combined with those who had anxiety and mood disorders. Open table in a new tab Bold denotes significant associations. aHR, Adjusted hazard ratio; CI, confidence interval; CSA, conventional systemic agent; Harrel's C index, Harrel's Concordance index; NA, not applicable; NSAIDS, nonsteroidal antiinflammatory drugs; ref, reference group. The results of the sensitivity analyses were consistent with those of the main analysis (data not shown), although a higher proportion of patients switched to TNFi/UST when sulfasalazine was not considered (29.8% vs 17.3%). In this study, physical comorbidities increased the risk of switch in male patients, whereas in female patients, mental health disorders increased that risk. Raymond Milan holds a doctoral training award from the Fonds de Recherche du Québec – Santé (FRQS). Ivan Litvinov is supported by a Junior I Clinician Scientist award from the FRQS and has received consulting fees from Novartis, Janssen, Galderma and Bristol-Myers Squibb in the course of unrelated studies. Elham Rahme has received funds and consulting fees from Janssen in the course of an unrelated study. Jacques LeLorier, Marie-Josée Brouillette, and Anne Holbrooke have no conflicts of interest to declare. CorrectionJAAD InternationalVol. 5PreviewMilan R, LeLorier J, Brouillette M-J, Holbrook A, Litvinov IV, Rahme E. Sex differences in factors associated with switch between systemic agents among individuals with psoriasis: A retrospective cohort study in Quebec, Canada. JAAD Int. 2021;4:79-83. Full-Text PDF Open Access

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