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Impact of season and other factors on initiation, discontinuation and switching of systemic drug therapy in patients with psoriasis – a retrospective study

Open AccessPublished:November 15, 2022DOI:https://doi.org/10.1016/j.xjidi.2022.100171

      Abstract

      Impact of season and other factors on initiation, discontinuation and switching in systemic drug therapy in patients with psoriasis – a retrospective study
      This study investigated whether systemic drug prescribing for psoriasis varies by season and other exacerbating factors. Eligible patients with psoriasis were assessed for each season for initiation, discontinuation and switching of systemic drugs. A total of 360,787 patients were at risk of initiating any systemic drugs in 2016-2019; 39,572 patients and 35,388 patients were at risk of drug discontinuation or switching for a biologic vs a non-biologic systemic drug, respectively. The initiation of biologic therapy in 2016-2019 peaked in spring (1.28%), followed by summer (1.11%), fall (1.08%) and winter (1.01%). Non-biologic systemic drugs followed a similar pattern. Those with age 30-39 years, male, with psoriatic arthritis, those who live in South region, lower altitude, and lower humidity had higher initiation with the same seasonality pattern. Discontinuation of biologic drugs peaked in summer and switching of biologics was highest in spring. Season is associated with initiation, discontinuation and switching, though seasonality pattern is less clear for nonbiologic systemic drug. Approximately 14,280 more patients with psoriasis in the US are estimated to initiate a biologic in spring than in other seasons and over 840 more biologic users switched in spring than in winter. The findings may provide evidence for healthcare resources planning in psoriasis management.

      Key words

      Abbreviations:

      US (United States), CED (cohort entry date), CI (confidence interval)

      Introduction

      Psoriasis is a chronic systemic inflammatory disease affecting over 7.5 million adults and 0.9 million children in the United States (US). (
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      ) The objectives of this study were to explore seasonal patterns in the initiation, discontinuation and switching from systemic drugs among patients with psoriasis and to assess whether the change in systemic drugs vary by patient characteristics and other potentially exacerbating factors. The study findings may provide real-world evidence in use of systemic drugs for psoriasis and help with psoriasis management and healthcare resources planning.

      Results

      Patient Population

      Patient flow chart for each cohort is presented in Figure 1. A total of 360,787 patients with psoriasis were at risk of initiating any systemic drugs in 2016-2019 (see Table 1). They were on average 54.2 years (SD 18.2), 52.5% female and 6.4% had psoriatic arthritis at cohort entry. The South region of the US had the most patients (44.9%), followed by the Midwest (22.3%), West (19.1%) and Northeast regions (13.4%). Two-thirds came from latitude ≥39.85 °N; over 60% were from states with average annual relative humidity less than 77.1%. A total of 39,572 patients were at risk of discontinuing or switching from any biologics (see Table 1). They consisted of patients who initiated biologics or continued their existing biologics. Compared with 35,388 patients who were at risk of discontinuing or switching from any non-biologic systemic drugs, they were younger (mean 48.9 vs 56.6 years) and more likely to be male (52.8% vs 43.4%). Among biologic users, the ratio of patients who were at risk of discontinuing or switching from TNFα inhibitors, IL-12/23 inhibitor, IL-17 inhibitors, and IL-23 inhibitors was roughly 7:3:2:1, highest for those that entered the market earliest, lowest for the newest drug class.
      Figure thumbnail gr1
      Figure 1Patients flow chart (source: AETION® Evidence Platform)
      Table 1Demographics and characteristics of patients with psoriasis on systemic therapy in 2016-2019
      At risk of initiationA risk of discontinuing or switching from
      Non-biologic systemic therapyAny biologic therapyTNF-alpha inhibitorIL-17 inhibitorsIL-12/23 inhibitorsIL-23 inhibitors
      N360,78735,38839,57225,4857,59610,4533,439
      Age (years)
      mean (SD)54.2 (18. 2)56. 6 (15.3 )48. 9 (14.2 )49.4 (14.3 )50.6 (13.2 )47. 7 (14.3 )47.9 (13.4 )
      < 2013,720 (3.8)414 (1.2)776 (2.0)526 (2.1)40 (0.5)270 (2.6)37 (1.1)
      20-2925,016 ( 7. 0)1,465 (4.2)3,138 (7.9)1,878 (7.4)427 (5.6)930 (8.9)297 (8.6)
      30-3942,605 (11.8)3,404 (9.6)6,688 (16.9)4,088 (16.0)1,199 (15.8)1,904 (18.2)639 (18.6)
      40-4954,705 (15.2)5,518 (15.6)8,947 (22.6)5,663 (22.2)1,774 (23.4)2,425 (23.2)857 (24.9)
      50-5968,905 (19.2 )8,233 (23.3)10,561 (26.7)6,838 (26.8)2,194 (28.9)2,723 (26.0)904 (26.3)
      60 - 6974,811 (20. 8)8,692 (24.6)6,860 (17.3)4,692 (18.4)1,375 (18.1)1,591 (15.2)545 (15.8)
      ≥ 7079,983 (22.2)7,555 (21.4)2,597 (6.6)1,795 (7.0)587 (7.7)610 (5.8)160 (4.7)
      Missing1,042755000
      Sex
      Male170,946 (47.4)15,301 (43.4)20,913 (52. 9)13,428 (52.7)3,823 (50.3)5,419 (51.8)1,893 (55.0)
      Female189,545 (52. 6)19,984 (56.6)18,656 (47.1)12,054 (47.3)3,773 (49.7)5,034 (48.2)1,546 (45.0)
      Unknown/Missing296333000
      Region
      Northeast48,413 (13. 5)3,847 (10.9)3,940 (10.0)2,349 (9.2)666 (8.8)1,225 (11.7)384 (11.2)
      Midwest80,595 (22. 4)7,969 (22.6)9,223 (23.3)6,234 (24.5)1,686 (22.2)2,344 (22. 5)696 (20. 3)
      South162,079 ( 45. 0)16,895 (47.9)19,848 (50.2)12,705 (49.9)3,971 (52.3)5,062 (48. 5)1,795 (52.2)
      West68,829 (19.1)6,528 (18.5)6,509 (16. 5)4,161 (16. 4)1,268 (16.7)1,807 (17.3)562 (16. 4)
      Other/Missing8714952365152
      Humidity
      ≥77.1%138,633 (38. 5)13,079 (37.1)14,354 (36.3)9,391 (36. 9)2,623 (34.5)3,865 (37.0)1,185 (34.5)
      <77.1%221,283 (61. 5)22,175 (62. 9)25,188 (63.7)16,074 (63.1)4,969 (65. 5)6,577 ( 63. 0)2,253 (65.5)
      Missing8713430204111
      Latitude
      <39.85°N238,273 (66. 2)24,105 (68. 4)27,175 (68.7)17,434 (68. 5)5,372 (70. 8)7,068 (67. 7)2,394 (69.6)
      ≥39.85°N121,652 (33. 8)11,149 (31.6)12,367 (31.3)8,031 (31.5)2,220 (29.2)3,374 (32.3)1,044 (30.4)
      Missing8623430204111
      Psoriatic arthritis
      Yes23,212 (6.4)11,694 (33.1)14,350 (36.3)10,918 (42.8)3,454 (45.5)2,919 (27.9)821 (23.9)
      No337,575 (93.7)23,694 (79.9)25,222 (63.7)14,467 (57.2)4142 (54.5)7,534 (72.1)2,618 (76.1)
      Note: data presented as frequency (percentage) unless otherwise specified.

      Impact of season on initiation of systemic drugs

      Figure 2 shows the impact of season on initiation of systemic drugs in patients with psoriasis in 2016-2019. Initiation of biologics is on average higher than that of non-biologic systemic drugs (0.9%-1.4% vs 0.8%-1.1%). The initiation of non-biologic systemic drugs peaked in spring (0.9%-1.1%). The initiation of any biologic followed a similar pattern as that of non-biologic systemic drugs, with the incidence highest in spring (ranging from 1.1% to 1.4%) and lower in other seasons (ranging from 1.0% to 1.3%). Table 2 presents the incidence and 95% confidence intervals (CI) of initiation of biologic therapy and stratified by different factors in patients with psoriasis in 2016-2019. The mean incidence of initiation of biologic therapy (95% CI) in 2016-2019 was highest in spring (1.28% [1.25%-1.30%]), followed by summer (1.11% [1.08%-1.13%], fall (1.08% [1.06%-1.10%] and winter (1.01% [0.99%-1.03%]). Figure 3 demonstrates that biologics initiation by drug class also peaked in spring. Among biologics, the incidence of initiation seemed to be highest for TNF-a inhibitors, followed by IL-12/IL-23 inhibitor, IL-17 inhibitors and IL-23 inhibitors. To account for the clustering within the data due to repeated measures in Table 2, the meta-regression analysis results in Table 3 confirmed that the incidence of initiation of biologics was the highest in spring among four seasons. Compared with spring, the incidence of initiating biologics overall was 13% lower in summer (relative rate [RR]: 0.87, 95% CI: 0.82–0.92), 16% lower in fall (RR: 0.84, 95% CI: 0.84–0.95), and 21% lower in winter (RR: 0.79, 95% CI: 0.69–0.91). The initiation trend was consistent by biologic class and patient characteristics (sex, age, and PsA status).
      Figure thumbnail gr2
      Figure 2The impact of season on initiation of systemic drugs in patients with psoriasis in Optum claims databases in 2016-2019
      Table 2Incidence (%) and 95% confidence intervals of initiation of biologic therapy stratified by different factors in patients with psoriasis in 2016-2019
      Winter, 2016-2019Spring, 2016-2019Summer,2016-2019Fall, 2016-2019Mean, 2016-2019
      All1.01 (0.99, 1.03)1.28 (1.25, 1.30)1.11 (1.08, 1.13)1.08 (1.06, 1.10)1.12 (1.10, 1.14)
      Biologic class
      TNF-ai0.58 (0.57, 0.60)0.69 (0.67, 0.70)0.58 (0.56, 0.60)0.54 (0.52, 0.56)0.60 (0.58, 0.61)
      IL-17i0.18 (0.17, 0.19)0.25 (0.24, 0.26)0.22 (0.21, 0.23)0.23 (0.22, 0.24)0.22 (0.21, 0.23)
      IL-12/23i0.27 (0.25, 0.28)0.34 (0.33, 0.35)0.30 (0.29, 0.32)0.28 (0.27, 0.29)0.30 (0.28, 0.31)
      IL-23i0.08 (0.07, 0.09)0.19 (0.18, 0.20)0.12 (0.11, 0.13)0.17 (0.16, 0.18)0.14 (0.13, 0.15)
      Sex
      Male1.16 (1.12, 1.19)1.45 (1.41, 1.49)1.25 (1.21, 1.29)1.23 (1.20, 1.27)1.27 (1.2, 1.31)
      Female0.88 (0.85, 0.91)1.12 (1.09, 1.15)0.98 (0.95, 1.01)0.94 (0.91, 0.97)0.98 (0.9, 1.01)
      Age (years)
      <200.54 (0.44, 0.63)0.65 (0.55, 0.76)0.71 (0.60, 0.82)0.72 (0.60, 0.83)0.65 (0.5, 0.76)
      20-291.41 (1.29, 1.54)1.97 (1.83, 2.12)1.72 (1.59, 1.86)1.65 (1.52, 1.79)1.69 (1.6, 1.82)
      30-391.83 (1.73, 1.93)2.51 (2.39, 2.63)2.07 (1.97, 2.18)2.09 (1.98, 2.20)2.12 (2.0, 2.23)
      40-491.76 (1.68, 1.85)2.27 (2.18, 2.37)2.01 (1.92, 2.10)1.98 (1.89, 2.07)2.00 (1.9, 2.09)
      50-591.59 (1.52, 1.66)1.96 (1.88, 2.04)1.72 (1.65, 1.79)1.69 (1.62, 1.76)1.74 (1.7, 1.81)
      60-690.90 (0.85, 0.94)1.11 (1.05, 1.16)0.95 (0.90, 1.00)1.00 (0.95, 1.05)0.99 (0.9, 1.04)
      ≥700.22 (0.21, 0.24)0.27 (0.25, 0.29)0.23 (0.21, 0.25)0.24 (0.22, 0.25)0.24 (0.2, 0.26)
      PsA
      Yes4.25 (4.10, 4.39)5.10 (4.94, 5.26)4.47 (4.32, 4.61)4.19 (4.05, 4.33)4.49 (4.3, 4.64)
      No0.78 (0.76, 0.80)0.99 (0.96, 1.01)0.85 (0.83, 0.87)0.84 (0.82, 0.86)0.86 (0.8, 0.89)
      Region
      Northeast0.71 (0.65, 0.76)0.89 (0.83, 0.95)0.87 (0.81, 0.93)0.80 (0.74, 0.85)0.82 (0.8, 0.87)
      Midwest1.14 (1.08, 1.19)1.30 (1.25, 1.36)1.11 (1.06, 1.16)1.10 (1.05, 1.15)1.16 (1.1, 1.21)
      South1.16 (1.12, 1.20)1.52 (1.48, 1.56)1.30 (1.26, 1.34)1.25 (1.21, 1.29)1.31 (1.3, 1.35)
      West0.76 (0.72, 0.80)1.00 (0.95, 1.04)0.86 (0.82, 0.91)0.88 (0.84, 0.93)0.88 (0.8, 0.92)
      Latitude
      ≥39.85°N0.93 (0.88, 0.97)0.95 (0.92, 0.99)1.12 (1.07, 1.16)0.98 (0.95, 1.02)1.00 (1.0, 1.04)
      <39.85°N1.13 (1.10, 1.17)1.04 (1.01, 1.07)1.36 (1.33, 1.39)1.17 (1.14, 1.20)1.18 (1.1, 1.21)
      Humidity
      ≥77.1%0.93 (0.89, 0.97)0.94 (0.91, 0.97)1.12 (1.08, 1.15)0.97 (0.94, 1.01)0.99 (1.0, 1.03)
      <77.1%1.15 (1.11, 1.19)1.06 (1.03, 1.09)1.39 (1.35, 1.42)1.20 (1.17, 1.23)1.20 (1.2, 1.23)
      Figure thumbnail gr3
      Figure 3The impact of season on initiation of systemic drugs by biologic drug class in patients with psoriasis in 2016-2019
      Table 3Relative risk and 95% CI for initiation of biologic therapy: Meta-regression analysis using robust variance estimation method and aggregate data from 16 seasons in 2016-2019
      Winter vs SpringSummer vs SpringFall vs Spring
      All0.79 (0.69-0.91)0.87 (0.82-0.92)0.84 (0.84-0.85)
      Biologic class
      TNF-ai0.85 (0.83-0.87)0.85 (0.8-0.9)0.79 (0.78-0.79)
      IL-17i0.75 (0.59-0.96)0.83 (0.77-0.9)0.82 (0.76-0.9)
      IL-12/23i0.78 (0.67-0.92)0.9 (0.81-0.99)0.82 (0.8-0.84)
      IL-23i0.32 (0.25-0.39)0.23 (0.01-5.9)0.58 (0.44-0.75)
      Sex
      Male0.78 (0.78-0.78)0.86 (0.86-0.86)0.85 (0.85-0.85)
      Female0.78 (0.71-0.87)0.88 (0.83-0.93)0.84 (0.83-0.85)
      Age(years)
      <200.83 (0.44-1.58)1.08 (1.05-1.1)1.1 (1.08-1.12)
      20-29NANANA
      30-390.72 (0.13-4.02)0.83 (0.31-2.19)0.83 (0.25-2.71)
      40-490.77 (0.71-0.85)0.88 (0.8-0.97)0.87 (0.86-0.88)
      50-590.8 (0.55-1.16)0.88 (0.43-1.8)0.86 (0.51-1.46)
      60-69NANANA
      ≥700.81 (0.49-1.34)NANA
      PsA
      Yes0.83 (0.76-0.91)0.88 (0.85-0.9)0.82 (0.81-0.83)
      No0.79 (0.7-0.9)0.86 (0.81-0.93)0.86 (0.85-0.86)
      Region
      NortheastNANANA
      MidwestNANANA
      South0.76 (0.04-13.6)NANA
      WestNANANA
      Latitude
      ≥39.85°NNANANA
      <39.85°N0.76 (0.7-0.83)0.86 (0.83-0.9)0.84 (0.83-0.84)
      Humidity
      ≥77.1%NA0.87 (0.7-1.09)0.86 (0.53-1.4)
      <77.1%0.76 (0.7-0.83)0.87 (0.82-0.92)0.83 (0.82-0.85)
      Note: Robust variance estimation was used to estimate the covariance matrix of the correlated coefficients in the meta-regression accounting for the clustering within the data due to repeated measures (

      Fisher; Z, Tipton; E, Hou Z. Robumeta: Robust Variance Meta-Regression. Available at URL https://cran.r-project.org/web/packages/robumeta/index.html Updated 29 May 2017. Accessed 8 August 2022. 2017.

      )
      The meta-regression model was fitted with the incidence transformed into natural logarithmic scale and season as a fixed effect.
      For IL-17i, only the data from 2018 and 2019 are used to minimize the effect of multiple new product launch in 2015 and 2016.
      Figure 4, Figure 5, Figure 6, Figure 7, Figure 8, Figure 9 showed that when stratified by sex, age, diagnosis of psoriatic arthritis, and US region, latitude, and humidity, the peak in the initiation of any biologic therapy was spring, followed by summer, and fall or winter. The mean incidence of initiation of systemic drugs was higher in males than females in all seasons (1.16%-1.45% in males versus 0.88%-1.12% in females), with seasonal difference quite similar in males and females. When stratified by age, the incidence of initiation of systemic drugs was highest in those aged 30-39 years, followed by those 40-49 years, 20-29 years, 50-59 years, 60-69 years, <20 years and ≥70 years. The seasonal pattern is very clear in all age subgroups except those <20 years, who had higher initiation in summer and fall. Patients with psoriatic arthritis are at least five times more likely to initiate any biologics compared with those without (mean incidence 4.19%-5.10% in psoriatic arthritis versus 0.78%-0.99% in non-psoriatic arthritis). The seasonal pattern is more obvious in patients with psoriatic arthritis than in those without, with seasonal difference ranging from 0.3%-1.2% in psoriatic arthritis and from 0.1%-0.2% in those without psoriatic arthritis. The incidence of any biologic initiation appeared to be higher in patients in South and Midwest region than that in West and Northeast region (mean incidence 1.16%-1.52% in South vs 1.10%-1.30% in Midwest vs 0.76%-1.00% in West vs 0.71%-0.89% in Northeast). Initiation of biologics appeared to be higher in latitude <39.85 °N compared with latitude ≥39.85 °N (1.0%-1.5% vs 0.8%-1.4%) and in lower (<77.1%) vs higher (≥77.1%) humidity region.
      Figure thumbnail gr4
      Figure 4The impact of season on initiation of biologics stratified by sex in patients with psoriasis in 2016-2019
      Figure thumbnail gr5
      Figure 5The impact of season on initiation of biologics stratified by age in patients with psoriasis in 2016-2019
      Figure thumbnail gr6
      Figure 6The impact of season on initiation of biologics stratified by psoriatic arthritis in patients with psoriasis in 2016-2019
      Figure thumbnail gr7
      Figure 7The impact of season on initiation of biologics stratified by region in patients with psoriasis in 2016-2019
      Figure thumbnail gr8
      Figure 8The impact of season on initiation of biologics stratified by latitude in patients with psoriasis in 2016-2019
      Figure thumbnail gr9
      Figure 9The impact of season on initiation of biologics stratified by humidity in patients with psoriasis in 2016-2019

      Impact of season on discontinuation of systemic drugs

      Figure 10 shows the impact of season on discontinuation of systemic drugs in patients with psoriasis in 2016-2019. The incidence of discontinuation was lower for biologics (ranging from 11.3% to 15.0%) than for non-biologic systemic drugs (ranging from 14.9% to 19.2%) across seasons, with the incidence difference between non-biologic systemic drugs and biologics largest in spring. The peak of discontinuation was inconsistent for biologics or non-biologic systemic drugs, discontinuation peaked in two winters for non-biologic systemic drugs, and in two summers for biologics. Further analysis of biologic discontinuation by drug class based on four-season mean showed that discontinuation for TNF-a inhibitors and IL-17 inhibitors appeared to be highest in winter, and discontinuation for IL-12/IL-23 inhibitor appeared to be highest in summer (see Table 4). The mean incidence of discontinuation of biologics seemed to be highest in summer overall and in stratified analyses, except for patients aged 60 years and over and patients with psoriatic arthritis, who had highest discontinuation rate in the winter (see Table 4). The incidence of discontinuation of biologic drugs does not seem to differ by sex but seems lower in patients with psoriatic arthritis, patients in West and Midwest region, patients in latitude ≥39.85 °N, and in patients in higher humidity region. In addition, the incidence of discontinuation of biologics among adults aged ≥20 years decreases with increasing age, lowest in those who were ≥70 years old (see Table 4). For nonbiologic systemic therapy, both the mean incidence of discontinuation and stratified analyses seemed to be higher in spring and summer (data not shown). In Table 5, the results from meta-regression analysis showed that compared with spring, the incidence of discontinuation of biologics overall was 7% higher in summer (RR: 1.07, 95% CI: 1.07–1.07) but was not significantly different in fall (RR: 0.99, 95% CI: 0.93–1.06) and winter (RR: 1.00, 95% CI: 0.90–1.12). The discontinuation trend was consistent by biologic class and patient characteristics (sex, age, and PsA status).
      Figure thumbnail gr10
      Figure 10The impact of season on discontinuation of systemic drugs in patients with psoriasis in 2016-2019
      Table 4Incidence (%) and 95% confidence intervals of discontinuation of biologic therapy stratified by different factors in patients with psoriasis in 2016-2019
      Winter, 2016-2019Spring, 2016-2019Summer,2016-2019Fall, 2016-2019Mean, 2016-2019
      All12.7 (12.4, 13.1)12.5 (12.2, 12.9)13.4 (13.0, 13.7)12.5 (12.1, 12.8)12.8 (12.4, 13.1)
      Biologic class
      TNF-ai9.8 (9.4, 10.2)9.2 (8.9, 9.6)9.4 (9.0, 9.8)9.0 (8.6, 9.3)9.4 (9.0, 9.7)
      IL-17i10.5 (9.6, 11.4)8.4 (7.6, 9.2)10.1 (9.3, 10.8)9.2 (8.5, 9.9)9.5 (8.7, 10.3)
      IL-12/23i21.5 (20.5, 22.4)23.1 (22.1, 24.1)23.4 (22.4, 24.3)21.6 (20.6, 22.5)22.4 (21.4, 23.3)
      Sex
      Male12.7 (12.2, 13.2)12.5 (12.0, 13.0)13.6 (13.2, 14.1)12.2 (11.8, 12.7)12.8 (12.3, 13.2)
      Female12.7 (12.2, 13.2)12.5 (12.0, 13.0)13.1 (12.6, 13.6)12.7 (12.8, 13.2)12.8 (12.3, 13.3)
      Age
      <20 y14.8 (11.5, 18.2)15.3 (12.0, 18.6)18.4 (15.2, 21.7)14.3 (11.1, 17.4)15.8 (12.6, 19.1)
      20-29 y19.7 (17.8, 21.6)18.8 (17.0, 20.6)21.7 (20.0, 23.5)19.9 (18.1, 21.7)20.1 (18.3, 21.9)
      30-39 y16.0 (14.9, 17.0)16.6 (15.6, 17.6)18.5 (17.5, 19.5)17.6 (16.6, 18.7)17.2 (16.2, 18.3)
      40-49 y14.3 (13.5, 15.0)14.3 (13.5, 15.1)15.5 (14.7, 16.3)14.7 (13.9, 15.5)14.7 (13.9, 15.5)
      50-59 y11.6 (10.9, 12.2)11.8 (11.1, 12.4)12.2 (11.5, 12.8)11.7 (11.1, 12.3)11.8 (11.2, 12.4)
      60-69 y10.7 (10.0, 11.4)9.2 (8.5, 9.8)9.4 (8.7, 10.0)9.1 (8.5, 9.8)9.6 (8.9, 10.2)
      ≥70 y8.8 (7.8, 9.7)8.6 (7.6, 9.5)7.6 (6.7, 8.5)7.1 (6.3, 7.8)7.9 (7.1, 8.8)
      PsA
      Yes11.3 (10.9, 11.8)10.7 (10.2, 11.2)10.9 (10.4, 11.3)10.4 (10.0, 10.8)10.8 (10.4, 11.3)
      No14.0 (13.6, 14.5)14.0 (13.6, 14.5)15.2 (14.7, 15.6)14.1 (13.7., 14.6)14.3 (13.9, 14.8)
      Region
      Northeast13.0 (11.8, 14.1)13.0 (11.8, 14.1)13.3 (12.2, 14.4)12.1 (11.1, 13.1)12.8 (11.7, 13.9)
      Midwest12.0 (11.3, 12.7)12.0 (11.3, 12.7)12.5 (11.9, 13.2)12.0 (11.4, 12.7)12.2 (11.5, 12.8)
      South13.3 (12.8, 13.8)12.9 (12.4, 13.4)14.2 (13.8, 14.7)13.1 (12.6, 13.5)13.4 (12.9, 13.9)
      West11.7 (10.9, 12.5)11.9 (11.1, 12.7)12.1 (11.3, 12.8)11.5 (10.7, 12.3)11.8 (11.0, 12.6)
      Latitude
      ≥39.85°N12.2 (11.6, 12.8)12.2 (11.6, 12.9)12.4 (11.8, 13.0)11.9 (11.3, 12.4)12.2 (11.6, 12.8)
      <39.85°N12.9 (12.5, 13.3)12.6 (12.2, 13.0)13.8 (13.4, 14.3)12.7 (12.3, 13.1)13.0 (12.6, 13.5)
      Humidity
      ≥77.1%11.8 (11.2, 12.3)12.1 (11.5, 12.6)12.4 (11.9, 13.0)11.7 (11.2, 12.3)12.0 (11.5, 12.5)
      <77.1%13.2 (12.8, 13.7)12.8 (12.3, 13.2)13.9 (13.5, 14.4)12.9 (12.5, 13.3)13.2 (12.8, 13.7)
      Table 5Relative risk and 95% CI for discontinuation of biologic therapy: Meta-regression analysis using robust variance estimation method and aggregate data from 16 seasons in 2016-2019
      Winter vs SpringSummer vs SpringFall vs Spring
      All1.00 (0.90-1.12)1.07 (1.07-1.07)0.99 (0.93-1.06)
      Biologic class
      TNF-aiNA1.02 (0.99-1.04)0.97 (0.67-1.41)
      IL-17i1.28 (1.27-1.3)1.20 (1.18-1.22)1.11 (0.98-1.27)
      IL-12/23iNANA0.91 (0.72-1.16)
      IL-23i1.15 (0.54-2.45)1.17 (0.74-1.86)1.02 (0.77-1.35)
      Sex
      Male1.00 (0.87-1.15)1.09 (1.09-1.09)0.97 (0.92-1.03)
      Female1.01 (0.93-1.09)1.04 (1.04-1.04)1.01 (0.94-1.09)
      Age(years)
      <20NANA0.93 (0.17-4.96)
      20-29NANANA
      30-390.96 (0.92-1)1.11 (1.1-1.12)1.05 (0.96-1.16)
      40-490.98 (0.89-1.09)1.08 (1.04-1.12)1.02 (0.96-1.08)
      50-590.97 (0.66-1.43)1.04 (0.57-1.88)0.99 (0.75-1.29)
      60-691.15 (1.1-1.21)1.02 (0.91-1.16)0.98 (0.87-1.1)
      ≥700.99 (0.63-1.55)0.87 (0.75-1.01)0.82 (0.76-0.87)
      PsA
      Yes1.05 (1.03-1.06)1.02 (0.59-1.76)NA
      No0.99 (0.86-1.14)1.08 (1.07-1.08)1.00 (0.93-1.08)
      Region
      NortheastNA1.01 (0.81-1.25)0.91 (0.74-1.14)
      MidwestNANANA
      SouthNA1.11 (0.95-1.28)1.01 (0.78-1.3)
      West0.98 (0.93-1.03)1.01 (1.01-1.02)0.96 (0.81-1.13)
      Latitude
      ≥39.85°NNA1.01 (0.7-1.46)0.95 (0.67-1.36)
      <39.85°N1.01 (0.94-1.09)1.09 (1.08-1.11)1.00 (0.96-1.05)
      Humidity
      ≥77.1%0.96 (0.54-1.7)1.03 (0.59-1.77)NA
      <77.1%NANANA
      Note: Robust variance estimation was used to estimate the covariance matrix of the correlated coefficients in the meta-regression accounting for the clustering within the data due to repeated measures (

      Fisher; Z, Tipton; E, Hou Z. Robumeta: Robust Variance Meta-Regression. Available at URL https://cran.r-project.org/web/packages/robumeta/index.html Updated 29 May 2017. Accessed 8 August 2022. 2017.

      )
      The meta-regression model was fitted with the incidence transformed into natural logarithmic scale and season as a fixed effect.
      For IL-17i, only the data from 2018 and 2019 are used to minimize the effect of multiple new product launch in 2015 and 2016.

      Impact of season on switching of systemic drugs

      Figure 11 showed that the incidence of switching was higher for biologics (ranging from 0.03% to 0.15%) than for non-biologic systemic drugs (ranging from 0% to 0.10%) across all seasons. The switching of non-biologic drug therapy seemed lack of clear pattern, with a tendency of being lower in winter and higher in spring and summer. The switching of biologics appeared to be lower in winter and higher in spring. Stratified analyses by season did not show clear seasonality and the incidence of switching was not different by any stratifying variables, except that switching appeared to be higher in psoriatic arthritis than non-psoriatic arthritis (data not shown). The mean incidence of switching from biologic therapy (95% CI) in 2016-2019 in winter was 0.07% (95% CI 0.04%-0.09%) as opposed to 0.12% (95% CI 0.09%-0.15%) in spring and 0.08% (95% CI 0.06%-0.11%) in summer and fall. (see Table 6) Stratified analysis clearly showed that the mean incidence of switching from biologics appeared highest in spring, except for those aged <20 and ≥70 years. The incidence of switching from TNF-a inhibitors and IL-17 inhibitors appeared to be higher than that of switching from IL-12/IL-23 inhibitor. The results of meta-regression analysis in Table 7 did not indicate a statistically significant seasonal effect on the incidence of switching for biologics, though the point estimate indicated a trend of higher switching in summer. The highest incidence of switching in spring (see Table 6) supported the peak in the initiation of biologic drug in spring.
      Figure thumbnail gr11
      Figure 11The impact of season on switching from systemic drugs in patients with psoriasis in 2016-2019
      Table 6Incidence (%) and 95% confidence intervals of switching of biologic therapy stratified by different factors in patients with psoriasis in 2016-2019
      Winter, 2016-2019Spring, 2016-2019Summer,2016-2019Fall, 2016-2019Mean, 2016-2019
      All0.07 (0.04, 0.09)0.12 (0.09, 0.15)0.08 (0.06, 0.11)0.08 (0.06, 0.11)0.09 (0.06, 0.12)
      Biologic class
      TNF-ai0.07 (0.04, 0.10)0.13 (0.09, 0.17)0.09 (0.05, 0.12)0.08 (0.04, 0.11)0.09 (0.06, 0.13)
      IL-17i0.13 (0.03, 0.23)0.15 (0.05, 0.26)0.11 (0.03, 0.19)0.13 (0.04, 0.21)0.13 (0.04, 0.22)
      IL-12/23i0.02 (0.0, 0.05)0.05 (0.01, 0.10)0.04 (0.00, 0.08)0.04 (0.00, 0.08)0.04 (0.00, 0.08)
      Sex
      Male0.06 (0.03, 0.09)0.08 (0.05, 0.12)0.09 (0.05, 0.13)0.07 (0.04, 0.10)0.07 (0.04, 0.11)
      Female0.08 (0.04, 0.12)0.17 (0.11, 0.22)0.08 (0.04, 0.12)0.10 (0.06, 0.15)0.11 (0.06, 0.15)
      Age (years)
      <200 (0, 0)0.19 (0, 0.55)0.31 (0, 0.75)0 (0, 0)0.13 (0, 0.44)
      20-290 (0, 0)0.09 (0, 0.21)0 (0, 0)0.04 (0, 0.13)0.03 (0, 0.11)
      30-390.03 (0, 0.08)0.23 (0.11, 0.36)0.11 (0.03, 0.19)0.11 (0.03, 0.19)0.12 (0.03, 0.21)
      40-490.08 (0.02, 0.14)0.12 (0.05, 0.19)0.10 (0.04, 0.16)0.07 (0.02, 0.12)0.09 (0.03, 0.15)
      50-590.09 (0.03, 0.14)0.12 (0.06, 0.18)0.06 (0.01, 0.10)0.09 (0.04, 0.15)0.09 (0.04, 0.14)
      60-690.08 (0.02, 0.15)0.10 (0.03, 0.16)0.08 (0.02, 0.14)0.09 (0.03, 0.16)0.09 (0.03, 0.15)
      ≥700.03 (0, 0.08)0 (0, 0)0.12 (0.02, 0.23)0.04 (0.0, 0.10)0.05 (0, 0.12)
      PsA
      Yes0.11 (0.06, 0.15)0.17 (0.11, 0.22)0.11 (0.06, 0.15)0.09 (0.05, 0.13)0.12 (0.07, 0.16)
      No0.03 (0.01, 0.05)0.09 (0.05, 0.12)0.07 (0.04, 0.10)0.08 (0.05, 0.11)0.07 (0.04, 0.10)
      Region
      Northeast0.07 (0, 0.16)0.05 (0, 0.12)0.11 (0.01, 0.21)0.15 (0.04, 0.26)0.10 (0, 0.19)
      Midwest0.03 (0, 0.06)0.08 (0.02, 0.13)0.11 (0.05, 0.18)0.12 (0.05, 0.18)0.09 (0.03, 0.14)
      South0.08 (0.04, 0.12)0.15 (0.10, 0.21)0.08 (0.04, 0.12)0.07 (0.03, 0.10)0.10 (0.05, 0.14)
      West0.06 (0, 0.11)0.12 (0.04, 0.21)0.04 (0, 0.08)0.04 (0, 0.08)0.06 (0.01, 0.12)
      Latitude
      ≥39.85°N0.05 (0.01, 0.09)0.06 (0.02, 0.10)0.11 (0.06, 0.17)0.11 (0.06, 0.16)0.09 (0.04, 0.13)
      <39.85°N0.07 (0.04, 0.10)0.15 (0.10, 0.19)0.07 (0.04, 0.10)0.07 (0.04, 0.10)0.09 (0.06, 0.12)
      Humidity
      ≥77.1%0.06 (0.02, 0.10)0.10 (0.05, 0.15)0.08 (0.04, 0.12)0.09 (0.04, 0.13)0.08 (0.04, 0.12)
      <77.1%0.07 (0.04, 0.10)0.13 (0.09, 0.18)0.09 (0.05, 0.12)0.08 (0.05, 0.11)0.09 (0.06, 0.13)
      Table 7Relative risk and 95% CI for switching of biologic therapy: Meta-regression analysis using robust variance estimation method and aggregate data from 16 seasons in 2016-2019
      Winter vs SpringSummer vs SpringFall vs Spring
      All0.47 (0.00-49.85)0.73 (0.42-1.25)0.71 (0.12-4.29)
      Biologic class
      TNF-aiNANANA
      IL-17i0.84 (0.31-2.28)0.81 (0.3-2.19)0.51 (0.19-1.35)
      IL-12/23iNANANA
      IL-23iNANANA
      Sex
      Male0.80 (0.34-1.85)1.08 (0.44-2.64)0.78 (0.35-1.75)
      Female0.47 (0.38-0.58)0.5 (0.45-0.56)0.63 (0.57-0.71)
      Age(years)
      <20NANANA
      20-29NANA1.21 (0.55-2.63)
      30-390.32 (0.11-0.97)0.46 (0.43-0.49)0.65 (0.33-1.31)
      40-490.82 (0.29-2.31)0.9 (0.28-2.85)0.62 (0.16-2.31)
      50-59NANANA
      60-69NANANA
      ≥70NANANA
      PsA
      YesNANANA
      No0.47 (0.09-2.53)0.82 (0.54-1.22)0.89 (0.75-1.06)
      Region
      NortheastNANANA
      Midwest0.56 (0.15-2.02)NANA
      SouthNANANA
      WestNANANA
      Latitude
      ≥39.85°N0.65 (0.44-0.95)1.42 (0.37-5.45)1.35 (0.77-2.34)
      <39.85°N0.41 (0.24-0.7)0.5 (0.5-0.5)0.45 (0.35-0.59)
      Humidity
      ≥77.1%NA0.81 (0.28-2.35)0.93 (0.11-8.19)
      <77.1%NANANA
      Note: Robust variance estimation was used to estimate the covariance matrix of the correlated coefficients in the meta-regression accounting for the clustering within the data due to repeated measures (

      Fisher; Z, Tipton; E, Hou Z. Robumeta: Robust Variance Meta-Regression. Available at URL https://cran.r-project.org/web/packages/robumeta/index.html Updated 29 May 2017. Accessed 8 August 2022. 2017.

      )
      The meta-regression model was fitted with the incidence transformed into natural logarithmic scale and season as a fixed effect.
      For IL-17i, only the data from 2018 and 2019 are used to minimize the effect of multiple new product launch in 2015 and 2016.

      Discussion

      This study found that the initiation of systemic drugs for psoriasis peaked in spring and then declined in summer and fall. This pattern was consistent for all biologics and for non-biologic systemic drugs and within strata of potentially exacerbating factors for psoriasis. The incidence of initiation of any biologic was much higher in males than in females, highest in those aged 30-39 years compared with other age groups; those with comorbid psoriatic arthritis were more likely to receive systemic drugs. The incidence of any biologic initiation appeared to be higher in South and Midwest region, low latitude region and low humidity region compared with other regions. In addition, this study found that discontinuation of systemic drugs peaked in winter or summer and that switching from systemic drugs tended to be lower in winter and higher in spring and summer.
      No previous studies were identified that evaluated seasonality and environmental factors in relation to initiation and discontinuation of systemic therapies for psoriasis. Several studies, however, have reported a seasonal relationship to psoriasis in general. (
      • Hancox J.G.
      • Sheridan S.C.
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      Seasonal variation of dermatologic disease in the USA: a study of office visits from 1990 to 1998.
      ,
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      Seasonal variations in dermatologic and dermatopathologic diagnoses: a retrospective 15-year analysis of dermatopathologic data.
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      Psoriasis and seasonal variation: A systematic review on reports from Northern and Central Europe-Little overall variation but distinctive subsets with improvement in summer or wintertime.
      ,
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      Seasonal variation in the internet searches for psoriasis.
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      ) Two studies reported that the frequency of Google search data for the term “psoriasis” and related terms peaked in the late winter/early spring and troughed in the late summer/early fall.(
      • Kardes S.
      Seasonal variation in the internet searches for psoriasis.
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      Seasonality and global public interest in psoriasis: an infodemiology study.
      ) Our study found the initiation of systemic drugs peaked in spring, which was supported another study. (
      • Hancox J.G.
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      • Feldman S.R.
      • Fleischer Jr., A.B.
      Seasonal variation of dermatologic disease in the USA: a study of office visits from 1990 to 1998.
      ) Hancox et al. in 2004 reported that there is seasonal utilization of dermatologic care in the US (
      • Hancox J.G.
      • Sheridan S.C.
      • Feldman S.R.
      • Fleischer Jr., A.B.
      Seasonal variation of dermatologic disease in the USA: a study of office visits from 1990 to 1998.
      ) and that dermatologic office visits peaked in spring and troughed in fall (33.8% vs 20.3% of annual visit). (
      • Hancox J.G.
      • Sheridan S.C.
      • Feldman S.R.
      • Fleischer Jr., A.B.
      Seasonal variation of dermatologic disease in the USA: a study of office visits from 1990 to 1998.
      )
      Several studies identified a seasonal association with worsening of psoriasis symptoms. One study from India reported that 42% of patients with psoriasis worsened in winter vs 8% in summer while 43% improved in the summer and only 7% in winter.(
      • Kaur I.
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      • Kumar B.
      Natural history of psoriasis: a study from the Indian subcontinent.
      ) An online survey of adults with psoriasis from 15 countries reported that 77% respondents reported seasonal variation of psoriasis exacerbation most notably in winter (67.1%) as compared to 23.8% in summer, 7% in spring and 2.1% in autumn.(
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      • et al.
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      ) A nationwide survey of over 12000 patients with psoriasis in China found that season change was the most frequently reported cause of relapse or aggravation (60.2%). Nearly half reports about weather as aggravating factor were related to winter season (48.8%), followed by spring (23.1%), autumn (17.1%), and summer (8.4%).(
      • Chen K.
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      • Zheng M.
      • et al.
      Clinic characteristics of psoriasis in China: a nationwide survey in over 12000 patients.
      ) A retrospective study of 2270 patients with psoriasis in China found a total of 53.2% reported the seasonal pattern of disease, with psoriasis exacerbation in fall/winter.(
      • Zheng X.
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      Seasonal Variation of Psoriasis and Its Impact in the Therapeutic Management: A Retrospective Study on Chinese Patients.
      ) An oral or biologic treatment may be initiated if psoriasis is too extensive for topical therapy, or refractory to topical therapy and phototherapy.(
      • Menter A.
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      • Gordon K.B.
      • et al.
      Guidelines of care for the management of psoriasis and psoriatic arthritis: section 4. Guidelines of care for the management and treatment of psoriasis with traditional systemic agents.
      ) Winter season, with the shorter daylight compared with other seasons, is an aggravating factor for patients with psoriasis.(
      • Chen K.
      • Wang G.
      • Jin H.
      • Xu J.
      • Zhu X.
      • Zheng M.
      • et al.
      Clinic characteristics of psoriasis in China: a nationwide survey in over 12000 patients.
      ) Our study found the highest initiation rate in the South region. South region in the US has been associated with highest proportion of patients with obesity and very severe psoriasis (body surface area>20%) in the US Corrona Psoriasis Registry, (
      • Enos C.
      • O'Connell K.
      • Harrison R.
      • McLean R.
      • Dube B.
      • Van Voorheers A.
      Psoriasis severity, comorbidities and treatment response differ among geographic regions in the united states.
      ) which reported that psoriasis severity and comorbidities differed among United States geographic regions. (
      • Enos C.
      • O'Connell K.
      • Harrison R.
      • McLean R.
      • Dube B.
      • Van Voorheers A.
      Psoriasis severity, comorbidities and treatment response differ among geographic regions in the united states.
      )
      Our finding of seasonal variation in initiation of systemic drugs for psoriasis has not been reported in the literature and has important implications. A recent systematic review of 13 studies reported that about 50% of psoriasis patients were stable and showed no seasonal difference between seasons and that approximately 30% improved in summer, and 20% performed better in winter. (
      • Jensen K.K.
      • Serup J.
      • Alsing K.K.
      Psoriasis and seasonal variation: A systematic review on reports from Northern and Central Europe-Little overall variation but distinctive subsets with improvement in summer or wintertime.
      ) Guidelines on management of psoriasis are suggested to add seasonality so that treatment and patient education may be considered to prevent disease worsening. Although the relative seasonal change for the initiation of systemic drugs appeared small in this study (0.1%-0.4% for biologics, and 0.1%-0.3% for non-biologic systemic drugs), the mean reduction for biologic initiation from 1.28% in spring to 1.11% in summer could lead to an estimated decrease in the number of biologic initiators for over 14,280 patients, considering there are over 7.5 million adults and 0.9 million children with psoriasis in the US.(
      • Armstrong A.W.
      • Mehta M.D.
      • Schupp C.W.
      • Gondo G.C.
      • Bell S.J.
      • Griffiths C.E.M.
      Psoriasis Prevalence in Adults in the United States.
      ,
      • Paller A.S.
      • Singh R.
      • Cloutier M.
      • Gauthier-Loiselle M.
      • Emond B.
      • Guerin A.
      • et al.
      Prevalence of Psoriasis in Children and Adolescents in the United States: A Claims-Based Analysis. Journal of drugs in dermatology.
      ) Therefore, although the relative seasonal change is small, the absolute seasonal change has clinical significance as the findings provide evidence for healthcare resources planning in psoriasis management. In addition, we found the mean incidence of biologic switching appeared to be highest in spring. This change in systemic drugs use may not reflect the disease severity as patients’ behaviours around wanting to be 'free of psoriasis' and able to wear short sleeves / swim in warmer months may impact their use of systemic drugs. However, the initiation of systemic drug in the study was determined based on the date of systemic drug dispense or administration. It is typically related to a clinical visit or a medical claim with a psoriasis diagnosis. The timing of initiation of a new systemic drug may indicate a potential psoriasis flare for the patient. Whether a higher proportion of patients discontinued biologics due to psoriasis improvement in the summer is unknown. Thus, the findings from this study may be used for hypothesis generating and further patient-level based research is needed.
      Our finding that the incidence of the initiation of biologic drug peaks in spring is supported by the higher incidence of discontinuation and switching from non-biologic systemic drugs in spring and the higher incidence of switching from biologics in spring. Although 95% CI overlapped, the mean increase for biologic switching from 0.07% in winter to 0.12% in spring would result in an estimated increase in the number of biologic switchers for over 840 patients, considering a US psoriasis population of approximately 8.4 million(
      • Armstrong A.W.
      • Mehta M.D.
      • Schupp C.W.
      • Gondo G.C.
      • Bell S.J.
      • Griffiths C.E.M.
      Psoriasis Prevalence in Adults in the United States.
      ,
      • Paller A.S.
      • Singh R.
      • Cloutier M.
      • Gauthier-Loiselle M.
      • Emond B.
      • Guerin A.
      • et al.
      Prevalence of Psoriasis in Children and Adolescents in the United States: A Claims-Based Analysis. Journal of drugs in dermatology.
      ) and about 20% are moderate or severe (
      • Menter A.
      • Gottlieb A.
      • Feldman S.R.
      • Van Voorhees A.S.
      • Leonardi C.L.
      • Gordon K.B.
      • et al.
      Guidelines of care for the management of psoriasis and psoriatic arthritis: Section 1. Overview of psoriasis and guidelines of care for the treatment of psoriasis with biologics.
      ). We found the mean incidence of biologics discontinuation appeared to be highest in summer, except for those aged 60 years and over and those with psoriatic arthritis. Switching or discontinuation from biologics could be due to primary ineffectiveness, secondary loss of response, side effects, patient preferences, comorbidities, and economic burden.(
      • Bayaraa B.
      • Imafuku S.
      Sustainability and switching of biologics for psoriasis and psoriatic arthritis at Fukuoka University Psoriasis Registry.
      ,
      • Florek A.G.
      • Wang C.J.
      • Armstrong A.W.
      Treatment preferences and treatment satisfaction among psoriasis patients: a systematic review.
      ) Treatment switch is frequent in psoriasis, with 50% of traditional systemic-treated patients switching to a biologic; the age of these patients tended be younger. Conversely, 25% of the biologic group transitioned to traditional oral systemic therapy; these patients tended to be older, have a longer duration of disease.(
      • Tabolli S.
      • Giannantoni P.
      • Paradisi A.
      • Abeni D.
      The 'switcher' patient profile in psoriasis treatment: from traditional to biological and from biological to traditional systemic drugs.
      )
      This study found initiation of any biologics varied by patient characteristics. Patients’ preferences for certain treatments may depend on age, sex, comorbidities, disease duration, and prior treatments.(
      • Florek A.G.
      • Wang C.J.
      • Armstrong A.W.
      Treatment preferences and treatment satisfaction among psoriasis patients: a systematic review.
      )
      The higher incidence of initiation of any biologics in males than females may reflect patient preference and that men with psoriasis are more likely to have severe psoriasis compared with women.(
      • Florek A.G.
      • Wang C.J.
      • Armstrong A.W.
      Treatment preferences and treatment satisfaction among psoriasis patients: a systematic review.
      ,
      • Hagg D.
      • Eriksson M.
      • Sundstrom A.
      • Schmitt-Egenolf M.
      The higher proportion of men with psoriasis treated with biologics may be explained by more severe disease in men.
      ) In addition, men with psoriasis have been found to be more concerned about efficacy than women.(
      • Kromer C.
      • Schaarschmidt M.L.
      • Schmieder A.
      • Herr R.
      • Goerdt S.
      • Peitsch W.K.
      Patient Preferences for Treatment of Psoriasis with Biologicals: A Discrete Choice Experiment.
      ) The highest incidence of initiation of systemic drugs occurred in patients aged 30-39 years is also supported by the literature.(
      • Bayaraa B.
      • Imafuku S.
      Sustainability and switching of biologics for psoriasis and psoriatic arthritis at Fukuoka University Psoriasis Registry.
      ,
      • Florek A.G.
      • Wang C.J.
      • Armstrong A.W.
      Treatment preferences and treatment satisfaction among psoriasis patients: a systematic review.
      ,
      • Geale K.
      • Henriksson M.
      • Schmitt-Egenolf M.
      Evaluating equality in psoriasis healthcare: a cohort study of the impact of age on prescription of biologics.
      ,
      • Gorelick J.
      • Shrom D.
      • Sikand K.
      • Renda L.
      • Burge R.
      • Dworkin C.
      • et al.
      Understanding Treatment Preferences in Patients with Moderate to Severe Plaque Psoriasis in the USA: Results from a Cross-Sectional Patient Survey.
      ) Psoriasis impacts the patients’ self-esteem and quality of life.(
      • Kubanov A.A.
      • Bakulev A.L.
      • Fitileva T.V.
      • Novoderezhkina E.
      • Gilloteau I.
      • Tian H.
      • et al.
      Disease Burden and Treatment Patterns of Psoriasis in Russia: A Real-World Patient and Dermatologist Survey.
      ,
      • Nazik H.
      • Nazik S.
      • Gul F.C.
      Body Image, Self-esteem, and Quality of Life in Patients with Psoriasis.
      ,
      • Pariser D.
      • Schenkel B.
      • Carter C.
      • Farahi K.
      • Brown T.M.
      • Ellis C.N.
      A multicenter, non-interventional study to evaluate patient-reported experiences of living with psoriasis.
      )At least 90% of young patients with psoriasis value clear skin, sustained response, and rapid onset of action.(
      • Gorelick J.
      • Shrom D.
      • Sikand K.
      • Renda L.
      • Burge R.
      • Dworkin C.
      • et al.
      Understanding Treatment Preferences in Patients with Moderate to Severe Plaque Psoriasis in the USA: Results from a Cross-Sectional Patient Survey.
      ) As people age, patients with psoriasis have fewer opportunities to access biological medications.(
      • Geale K.
      • Henriksson M.
      • Schmitt-Egenolf M.
      Evaluating equality in psoriasis healthcare: a cohort study of the impact of age on prescription of biologics.
      )
      This study has several strengths. First, the exposure season is clearly defined. This study assessed treatment patterns using data from all four years and similar patterns were observed. In addition, seasonal pattern in initiation of systemic drugs is supported by the discontinuation and switching data. Second, effect modifiers were stratified to assess the association between seasons and treatment patterns of systemic drugs and similar patterns held after stratification. Third, study findings may not only inform healthcare providers and patients in their decision-making in patient disease management but also generate new research ideas.
      A few limitations need to be mentioned. First, although a clear association has been identified between seasons and initiation, discontinuation and switching of systemic drugs in patients with psoriasis, no causal relationship can be made. Second, patients with rheumatoid arthritis, ankylosing spondylitis, inflammatory bowel disease, and other conditions for which certain biologics may be indicated for were not excluded from the study. Therefore, there might be some misclassification in initiation, discontinuation and switching of certain biologics. However, the impact could be minimal given the prevalence of these conditions are less common. Third, the association between season and outcomes was not assessed in a mixed-effect regression model, where the season can be a fixed effect and a patient can be a random effect to derive the seasonal percentages while accounting for the correlation among repeated measures. Future study may be conducted to assess whether the findings from this study are true in patient-level drug utilization studies in psoriasis population (which will allow patients to be followed up without interruption of season end) and whether season is an independent factor to predict change in systemic therapy while controlling for other factors. Lastly, Patients in this database are covered by commercial insurance. Healthcare insurance coverage may affect treatment patterns as well.(
      • Armstrong A.W.
      • Koning J.W.
      • Rowse S.
      • Tan H.
      • Mamolo C.
      • Kaur M.
      Under-Treatment of Patients with Moderate to Severe Psoriasis in the United States: Analysis of Medication Usage with Health Plan Data.
      ) The study findings may not be generalizable to those without health care insurance or covered by a different healthcare insurance.
      In summary, a seasonal pattern of initiation of systemic drug therapies for psoriasis is identified in this study. However, this finding needs to be interpreted with caution as initiation of a systemic therapy does not indicate a reactive response to a loss of disease control and increased symptoms. Discontinuing ineffective drugs and switching to alternative systemic drugs among individuals who use medications in reaction to psoriasis symptoms might be a key component in reducing the risk of psoriasis worsening. Future research may focus on specific systemic drug survival rate and switching patterns among patients with certain comorbidities.

      Methods

      Study Design

      The study is a retrospective ecological study of individuals with psoriasis identified in the Optum™ Clinformatics™ Data Mart (CDM). Two cohorts were generated for each season of 2016 to 2019: patients with psoriasis who were eligible for initiating a systemic drug and those with psoriasis who were prevalent users of a systemic drug. Three outcomes were the incidence of initiation of a systemic drug in each season, the incidence of switching from or discontinuing a systemic drug. They were assessed separately for each season. Different cohorts were used to assess the association of season and other factors and the use of systemic drugs for psoriasis.

      Study Setting

      The Optum™ CDM is commercially available in the United States. It contains longitudinal commercial and Medicare Advantage health plan data from 50 US states since 2000. The claims data include member eligibility, medical and pharmacy claims, and inpatient confinements. It covered approximately 16 million annual lives associated with United Healthcare plans for over 80 million unique lives. Based on the Health Insurance Portability and Accountability Act in the Unites States, all personal identifiers for patients are anonymized by applying specific algorithms. For example, patient names, social security number, 5-digit zip code were removed from the databases. Date of birth was converted to year of birth before data release. Thus, Institutional Review Board review was unnecessary.

      Study population

      The study population included patients with psoriasis, defined as one diagnosis of psoriasis (ICD-9-CM: 696.1, ICD-10-CM: L40.0) at any time in their medical history before December 31, 2019 and were enrolled in Optum™ CDM between January 1, 2016 and December 31, 2019. Two diagnoses codes for psoriasis were not required because: (1) A patient may initiate a new treatment after one diagnosis of psoriasis. Requiring two diagnoses codes would arbitrarily ignore the initiating date of the treatment between two diagnoses codes, which made the initiating date of the treatment inaccurate. (2) For patients who were eligible to discontinue a systemic drug or eligible to switched from a systemic drug, one diagnosis of psoriasis plus a prescription claim for a systemic drug were used to identify psoriasis cohort, which has been reported to have a positive predictive value of 78.4%.(
      • Lee H.
      • He M.
      • Cho S.K.
      • Bessette L.
      • Tong A.Y.
      • Merola J.F.
      • et al.
      Validation of claims-based algorithms to identify patients with psoriasis.
      )
      Denominator cohorts consisted of patients with psoriasis who were eligible for initiating, switching from or discontinuing a systemic drug and were assessed separately by season. The denominator cohorts were determined on the first date of each season (cohort entry date, CED) using treatment data 6 months before the CED . A total of sixteen denominator cohorts were created for patients with psoriasis who were eligible for initiating a non-biologic systemic drug during the study period.

      Eligibility of denominator cohorts

      Patients were eligible for initiating a drug if they had psoriasis and were at risk of initiating the systemic drug. For example, only patients who had not initiated the drug of interest in the 180 days before January 2016 were considered “at risk” of initiating the drug on January 1, 2016. “Person-time at risk” referred to person-time in 2016-2019 that a patient contributed after a psoriasis diagnosis and before the systemic drug initiation. Patients who had a psoriasis diagnosis and continuously used a systemic agent were eligible for discontinuing or switching from the systemic drug. Only person-time that met these criteria were considered “at risk” of discontinuation or switching. In evaluating initiation, discontinuation, and switching of systemic drugs, a 30-day gap was allowed between prescription refills. If the same drug has multiple prescriptions with overlapping periods, the treatment duration was the sum of those periods. An at-risk patient was followed until the earliest occurrence of initiating, switching from, or discontinuing a systemic agent, death, disenrollment, end of study, and ceased contributing person-time. Numerators cohorts came from the denominator cohorts and were patients who initiated, switched from or discontinued a systemic drug during the season of interest and were also assessed separately for season of interest. The numerator cohorts were determined using treatment data at least 6 months before the season and treatment data during each season in 2016-2019. Figure 12 presents how denominators and numerators for initiation, discontinuation and switching are estimated in each season.
      Figure thumbnail gr12
      Figure 12Denominators and numerators for initiation, discontinuation and switching

      Exposures

      The exposure was periods of seasons and defined as winter (December – February), spring (March – May), summer (June – August), and fall (September – November) (
      • Trenberth K.
      What are the seasons?.
      ) in 2016-2019, except for winter 2016, only January and February data were used.

      Outcomes

      The outcomes were incidence of initiating, switching from, and discontinuing a systemic drug, first assessed for each drug of interest, and then grouped by drug classes.
      Specifically, initiation of a systemic drug was defined as the first date of that drug dispensing or administration in the season under study. To determine initiation, the use of systemic medications was assessed using data 180 days before CED. Switching from a systemic drug to another was defined as the first date for a prescription stream for alternative drug that occurred within 30 days before a patient exhausted or discontinued his initial therapy. Discontinuation of a systemic drug was defined as the last day of a therapy stream, which required at least 30 days free of any biologic or nonbiologic therapy after the end of the therapy stream. 22 For all these outcomes, the first event for drug initiation, discontinuation, and switching was assessed in each season, ranging from 90 to 92 days. It is less likely that a clinician would change a patient’s systemic therapy for two times in such a short time window. Torres et al. in 2021 reported that at 12 months IL-23 inhibitors had over 90% cumulative probability of drug survival whereas an IL-17 inhibitor had the lowest cumulative probability of 85.5% for drug survival.(
      • Torres T.
      • Puig L.
      • Vender R.
      • Lynde C.
      • Piaserico S.
      • Carrascosa J.M.
      • et al.
      Drug Survival of IL-12/23, IL-17 and IL-23 Inhibitors for Psoriasis Treatment: A Retrospective Multi-Country, Multicentric Cohort Study.
      ) However, patients who received the second or third biologic, etc. for 180 days in the following seasons would qualify to be assessed for further initiation, switching or discontinuation.
      The systemic drug classes assessed comprised tumor necrosis factor (TNF) alpha inhibitors, interleukin (IL)-12 and IL-23 inhibitor, IL-17 inhibitors, IL-23 inhibitors, any biologics, and non-biologic systemic immunosuppressants. The Table 8 presents the generic names for systemic medications and their use frequencies and prescription length. Number of days covered with each biologic was captured based on its mode of administration. Self-administered biologics dispensed at the pharmacy was identified from prescription claims using National Drug Codes and days of supply was used to calculate the number of days covered by each prescription. Biologics which required infusion under supervision of medical professionals were identified from medical claims using the Healthcare Common Procedure Coding System codes. The administration date and the assigned days’ supply for each administration based on recommended dosage regimen were used to calculate the estimated medication end date. For biologics that were found in both prescriptions claims and medical claims, medication end date was estimated using prescription fill date and days of supply or administration date and assigned days of supply.
      Table 8Biologic and non-biologic systemic treatment in the study
      Type of treatmentApproval dateDrug substanceMechanism of actionHalf-life in daysMaintenance dosing interval, rout of administrationStandard duration of prescriptions (days of service)
      Biologic: IL-23 inhibitors4/23/2019RisankizumabIL-23A28150 mg every 12 weeks, sc84
      7/13/2017GuselkumabIL-23A18100 mg every 8 weeks, sc56
      3/21/2018TildrakizumabIL-23A23100 mg every 12 weeks, sc84
      Biologic: IL-17 inhibitors1/21/2015SekukinumabIL-17A27300 mg every 4 weeks, sc28
      3/22/2016IxekizumabIL-17A1380 mg every 4 weeks, sc28
      2/15/2017BrodalumabIL-17RA11210 mg every 2 weeks, sc14
      Biologic biosimilars4/5/2016IFX-DYYBTNF-α inhibitor9.55 mg/kg every 8 weeks, iv56
      4/21/2017IFX-ABDBTNF-α inhibitor9.55 mg/kg every 8 weeks, iv56
      12/13/2017IFX-QBTXTNF-α inhibitor9.55 mg/kg every 8 weeks, iv56
      8/30/2016ETA-SZZSTNF-α inhibitor350 mg once a week, sc7
      Biologic: IL-12/23 inhibitor9/25/2009UstekinumabIL-12/IL-232145/90 mg every 12 weeks, sc/iv84b
      Biologic: TNF-α inhibitors4/30/2004EtanerceptTNF-α inhibitor350 mg once a week, sc7
      9/26/2006InfliximabTNF-α inhibitor9.55 mg/kg every 8 weeks, iv56
      1/18/2008AdalimumabTNF-α inhibitor1440 mg every 2 weeks, sc14
      5/29/2018CertolizumabTNF-α inhibitor14200 mg every 2 weeks, sc14
      Non-biologic systemic drugsNAAcitretinRetinoid/unknown2daily31
      NACyclosporineImmunosuppressive8.4 hours2.5 to 4.0 mg/kg/day for 6 to 16 weeks, oral31
      NAMethotrexateAntimetabolite6.5 hours10 to 25 mg per week, po, sc7
      9/23/2014ApremilastDPE-4 inhibitor30 g twice daily, po31
      Note: All prescription claims were allocated a minimum duration of 31 day

      Covariates

      Age on CED, sex, and region of residence were demographics variables.
      Patient level data included sex (male vs female), age subgroups (<20, 20-29, 30-39, 40-49, 50-59, 60-69, and ≥70 years) and status of comorbid psoriatic arthritis, which was identified based on one diagnosis code of ICD (ICD-9-CM 696.0 or ICD-10-CM L40.50, L40.51, L40.52, L40.53, L40.54, L40.59) using data before CED. Prescribers were classified into dermatologist and non-dermatologist (physician assistant, general practitioner/internist, rheumatologist and other), identified based on the provider information on medical claims and the National Uniform Claim Committee provider taxonomy codes in the provider file. Based on the state a patient resided, US geographic regions (Northeast, Midwest, West and South), low and high latitude (<39.85 °N vs ≥39.85 °N) and humidity (<77.1% vs ≥77.1%) were derived based on the median of all states (see Table 9). These variables were considered possible effect modifiers.
      Table 9Classification of region, latitude, and humidity in the United States
      CategoryUS states
      Region
      Region was classified based on the US census region.
      NortheastConnecticut, Maine, Massachusetts, New Hampshire, Rhode Island, Vermont, New Jersey, New York, Pennsylvania
      MidwestIndiana, Illinois, Michigan, Ohio, Wisconsin, Iowa, Nebraska, Kansas, North Dakota, Minnesota, South Dakota, Missouri
      SouthDelaware, District of Columbia, Florida, Georgia, Maryland, North Carolina, South Carolina, Virginia, West Virginia, Alabama, Kentucky, Mississippi, Tennessee, Arkansas, Louisiana, Oklahoma, Texas
      WestArizona, Colorado, Idaho, New Mexico, Montana, Utah, Nevada, Wyoming, Alaska, California, Hawaii, Oregon, Washington
      Latitude
      Latitude was classified based on the median latitude of US states.
      Latitude <39.85 °NWest Virginia, Texas, Kansas, Mississippi, Delaware,

      Arkansas, Missouri State, Florida, Georgia, Hawaii, Tennessee, Virginia, New Jersey, Kentucky, Oklahoma

      Utah, Colorado, Alabama, New Mexico, South Carolina

      Arizona, Maryland, California, North Carolina, Louisiana
      Latitude ≥ 39.85 °NWisconsin, Vermont, South Dakota, Rhode Island,

      Oregon, New York, New Hampshire, Nebraska,

      Illinois, Connecticut, Indiana, Nevada, Maine, Michigan

      Alaska, North Dakota, Minnesota, Montana,

      Washington, Ohio, Iowa, Pennsylvania, Massachusetts

      Idaho, Wyoming
      Humidity
      Humidity was classified based on median humidity of US states.
      Humidity

      <77.1%
      Florida, North Carolina, Texas, Illinois, Arkansas, Vermont, VA, Oklahoma, New Mexico, Alabama, Kentucky, Indiana, Georgia, Mississippi, Louisiana, New York, Tennessee, Massachusetts, Utah, Michigan, Hawaii, South Carolina, Maryland, Delaware, New Jersey
      Humidity

      ≥ 77.1%
      Iowa, New Hampshire, Alaska, Maine, North Dakota, MN, South Dakota, Montana, California, Colorado, Oregon, Idaho, Wyoming, Arizona, Kansas, Connecticut, Washington, Nebraska, West Virginia, Nevada, Pennsylvania, Missouri, Ohio, District of Columbia, Rhode Island, Wisconsin
      1 Region was classified based on the US census region.
      2 Latitude was classified based on the median latitude of US states.
      3 Humidity was classified based on median humidity of US states.

      Data analysis

      A patient flow chart was generated for each study cohort. Patient demographics were summarized with descriptive statistics. The incidence of initiating a systemic drug was calculated using the number of patients who initiated a systemic drug during the season divided by the number of patients with psoriasis who were eligible for initiating a systemic drug on CED. Similarly, the incidence of switching from or discontinuing a systemic drug was calculated using the number of patients who switched from or discontinued a systemic drug during the season divided by the number of patients with psoriasis who used the systemic drug before CED. The incidence of initiation, discontinuation and switching and 95% CIs were calculated separately for all seasons in 2016-2019 (Of note, the winter 2016 was from 1 Jan 2016- 29 Feb 2016. Thus, the incidence for winter 2016 needs to be interpreted with caution.). In addition, the mean incidence and 95% CI for winter through fall season in 2016-2019 were also calculated. To determine a seasonal trend, we compared the 95% CIs for the incidence of initiation, discontinuation and switching for each season. If the 95% CIs among seasons do not overlap, then the two incidences are considered statistically different. To account for the clustering within the data due to repeated measures, meta-regression analyses with robust variance estimation was conducted for biologics. The robust variance estimation considers the covariances between outcomes from different studies and provides an estimation of covariance matrix. The estimates from each season are considered separate studies for initiation, discontinuation, and switching. Therefore, data from 16 studies (seasons) were used in each meta-regression analysis. Meta-regression models were fitted with all the incidence transformed to natural logarithmic scale and season as a fixed effect for the incidence of initiation, discontinuation, and switching for all biologics and stratified by patient characteristics, region, latitude, and humidity, respectively. Meta-regression analysis results were presented in Tables 3, 5, and 7. In addition, line graphics were used to show the seasonal trend for systemic drugs overall and the seasonal trend stratified by each covariate. Finally, to demonstrate clinical significance, the change in the number of biologic initiators from spring to summer in one year was estimated based on absolute difference in mean incidence of biologic initiation between spring and summer in 2016-2019 and estimated psoriasis population in the US; (
      • Armstrong A.W.
      • Mehta M.D.
      • Schupp C.W.
      • Gondo G.C.
      • Bell S.J.
      • Griffiths C.E.M.
      Psoriasis Prevalence in Adults in the United States.
      ,
      • Paller A.S.
      • Singh R.
      • Cloutier M.
      • Gauthier-Loiselle M.
      • Emond B.
      • Guerin A.
      • et al.
      Prevalence of Psoriasis in Children and Adolescents in the United States: A Claims-Based Analysis. Journal of drugs in dermatology.
      ) the change in the number of biologic switchers from winter to spring in one year was estimated based on absolute difference in mean incidence of biologic switching between winter and spring in 2016-2019 and estimated moderate to severe psoriasis population in the US. (
      • Armstrong A.W.
      • Mehta M.D.
      • Schupp C.W.
      • Gondo G.C.
      • Bell S.J.
      • Griffiths C.E.M.
      Psoriasis Prevalence in Adults in the United States.
      ,
      • Menter A.
      • Gottlieb A.
      • Feldman S.R.
      • Van Voorhees A.S.
      • Leonardi C.L.
      • Gordon K.B.
      • et al.
      Guidelines of care for the management of psoriasis and psoriatic arthritis: Section 1. Overview of psoriasis and guidelines of care for the treatment of psoriasis with biologics.
      ,
      • Paller A.S.
      • Singh R.
      • Cloutier M.
      • Gauthier-Loiselle M.
      • Emond B.
      • Guerin A.
      • et al.
      Prevalence of Psoriasis in Children and Adolescents in the United States: A Claims-Based Analysis. Journal of drugs in dermatology.
      )
      To assess the impact of season on initiation, switching, and discontinuation of systemic drugs, analyses were performed in AETION Evident Platform (AEP ®) , a cloud-based scientifically validated software that transforms real-world data into transparent, reliable, and replicable real-world evidence. (
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      ) All analyses were stratified by possible effect modifiers of the association between season and initiation, discontinuation and switching of systemic drugs. No patient-level datasets can be downloaded from the seasonality analysis module of AEP® so that mixed-effect regression analysis of the patient-level data is not feasible. However, RStudio v3.6.0 was used for entry of data from 16 seasons for biologic initiation, discontinuation and switching, respectively. Robumeta package in R was used for meta-regression analyses. (

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      Assessing work-related productivity loss and indirect costs of psoriasis across six countries. The British journal of dermatology 2020;183(3):e65–e90.

      .

      Acknowledgements

      The design, study conduct, and financial support for the study were provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the publication. The authors wish to thank the Editor and the Reviewers for their review and constructive comments.

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