Original Paper
Dermatology 2010;220:128–137
DOI: 10.1159/000275198
High Prevalence of Potential Drug-Drug
Interactions for Psoriasis Patients
Prescribed Methotrexate or Cyclosporine
for Psoriasis: Associated Clinical and
Economic Outcomes in Real-World Practice
a b
Jean-Hilaire Saurat Annie Guérin Andrew P. Yu
b b
Dominick Latremouille-Viau Eric Q. Wu Shiraz R.
c c c
Gupta Yanjun Bao Parvez M. Mulani
aHôpital Cantonal Universitaire de Genève, Geneva, Switzerland; Analysis Group, Inc., Boston, Mass., and
c
Abbott Laboratories, Abbott Park, Ill., USA
Key Words
Methotrexate Cyclosporine Psoriasis Tumor
necrosis factor Health care costs Drug interactions
Abstract
Background: Methotrexate (MTX) and cyclosporine (CYC)
may adversely interact with common medications in pa-tients
with psoriasis. Objective: Our purpose was to investi-gate the
prevalence and outcomes of MTX/CYC polyphar-macy.
Methods: We evaluated rates of events that may be
associated with drug-related toxicity, health care resource
utilization and costs for patients with psoriasis in the Inge-nix
Impact National Managed Care Database (1999–2007) who
were exposed or not exposed to potential drug-drug
interactions. Results: Among 4,583 (57.6%) exposed and
3,372 (42.4%) nonexposed patients, nonsteroidal anti-in-
flammatory drugs and antibiotics were the most common
drugs with potential interactions. The exposed patients had
significantly greater risks of developing renal [adjusted odds
ratio (OR): 2.58; p = 0.0145], gastrointestinal (OR: 1.36; p =
© 2010 S. Karger AG, Basel
Fax +41 61 306 12 34 1018–8665/10/2202–0128$26.00/0
E-Mail karger@karger.ch Accessible online at:
www.karger.com www.karger.com/drm
Received: October 4, 2009
Accepted after revision: January 5, 2010
Published online: February 3, 2010
b
b
0.0197) and pulmonary events (OR: 1.20; p = 0.0470), and
sig-nificantly greater health care resource utilization (e.g. OR
for inpatient and emergency department visits: 1.47; p !
0.0001) and costs (adjusted incremental cost: USD 1,722; p !
0.0001). Conclusions: MTX/CYC polypharmacy is prevalent
in pa-tients with psoriasis and associated with significant risks.
Copyright © 2010 S. Karger AG, Basel
Psoriasis is a chronic inflammatory skin disease
influ-enced by genetic and environmental characteristics
and worsened by factors such as stress, drugs, tobacco
and alcohol abuse [1–3]. Psoriasis can impair physical
and psychological well-being and decrease work
productiv-ity [4].
Conventional oral systemic therapies, including meth-
otrexate (MTX), cyclosporine (CYC) and oral retinoids,
are often used to treat patients with moderate to severe
psoriasis who are not responsive to topical therapies alone.
These systemic immunosuppressant medications have
risks for serious toxicities and adverse effects, in-
Jean-Hilaire Saurat, MD
Hôpital Cantonal Universitaire
Rue Micheli-du-Crest 24
CH–1211 Geneva (Switzerland)
Tel. +41 22 372 94 22, Fax +41 22 372 94 60, E-Mail jean.saurat @ medecine.unige.ch
cluding renal toxicity, hepatotoxicity, hematotoxicity
and gastrointestinal toxicity [5]. Thus, patients treated
with oral systemic therapies need to be monitored
regularly with laboratory tests of blood cell counts and
liver and renal function. Despite these toxicities, these
inexpensive therapies, namely MTX and CYC, have
been the main-stay for treating moderate to severe
psoriasis for de-cades.
MTX and CYC may interact with a number of com-
mon medications and this is of particular concern for
pa-tients with psoriasis because psoriasis is associated
with increased prevalence of several comorbidities [6–
10]. Concomitant use of these drugs to control chronic
condi-tions or comorbidities could alter or prolong the
blood concentrations of MTX/CYC and enhance their
toxici-ties, which can cause adverse effects and
compromise the treatment efficacy.
Little is known about the clinical and economic rami-
fications of these potential drug-drug interactions in the
real-world setting [11, 12]. Other researchers have inves-
tigated the topic of comedication due to comorbidities in
psoriasis patients and its interference with psoriasis treat-
ments. However, to our knowledge, no studies on this
topic have been conducted in a US psoriasis population of
all severities, and none have investigated the clinical and
economic ramifications of comedication. Given the
seriousness of toxicities associated with systemic thera-
pies and potential intensification of these toxicities by
drug-drug interactions, this study used a large claims da-
tabase to investigate the prevalence of real-world poly-
pharmacy of oral conventional systemic therapies, in
particular MTX and CYC, and drugs that may interact
with them. In addition, the rates of potential adverse
events were estimated, as well as the implications for
health care resource utilization and costs associated with
potential drug-drug interactions among psoriasis pa-tients
with conventional systemic therapies, MTX or CYC, as a
group.
Methods
Data Source
The study used the Ingenix Impact National Managed Care
Database from 1999 to 2007. This database includes the medical
and pharmacy history of 160 million patients from 46 health
plans from all census regions of the USA and contains informa-
tion on member eligibility, inpatient confinement, medical ser-
vices utilization and pharmacy claims.
Drug-Drug Interactions in Patients with
Psoriasis
Study Population and Study Period
Patients were included in the study if they met the following
criteria: (1) at least 1 diagnosis of psoriasis [based on Internation-al
Classification of Diseases, Ninth Revision, Clinical Modification
(ICD-9-CM) 696.1x codes] [13], (2) continuous insurance for at
least 6 months before and after the first prescription fill of an oral
conventional systemic therapy, including MTX or CYC (i.e. the
index date and also the index medication), and (3) at least 18 years
of age 6 months prior to the index date. Patients with both MTX and
CYC on the index date and no other interactions were ex-cluded
because MTX and CYC are known to interact with each other and
this analysis focuses on drug-drug interactions associ-ated with
comorbidity-related drugs instead of relationships be-tween
combinations of psoriasis therapies. However, the patients may have
initiated treatment on only MTX or CYC and later on used
combination therapy sometime during the study period. The baseline
period included 6 months prior to the index date, and the patients
were followed for 6 months after the index date (i.e. the study
period) for the outcomes evaluation.
Study Cohorts
The study population was separated into 2 mutually exclusive
groups. A list of drugs that could potentially interact with MTX or
CYC was first created using their respective product labels [6, 7].
All drugs that could potentially interact with MTX or CYC and lead
to an adverse event were included. However, drugs known to
decrease MTX or CYC concentration were not included. Patients
who were taking any drug that could interact with MTX or CYC 30
days before or 30 days after starting MTX or CYC were includ-ed in
the exposed cohort. The nonexposed cohort included pa-tients
without any potential drug-drug interaction 30 days prior to the
index date and 6 months following the index date.
Sensitivity Analysis
In a sensitivity analysis, the exposed cohort was restricted to
a subgroup of patients with potential drug-drug interactions
within 30 days before and after the index date. This subgroup
was intended to define potential drug-drug interactions with a
more stringent criterion by selecting patients who were taking a
poten-tially interactive drug and refilled their drug prescription
even after the initiation of MTX or CYC.
Statistical Analyses
Patient Characteristics. Patient characteristics were reported
2
for both the exposed and the nonexposed cohorts. x tests were
performed for categorical variables and Wilcoxon rank sum tests
were performed for continuous variables to test differences be-
tween the exposed and the nonexposed cohorts.
Potential Adverse Events. The prevalence of relevant events that
may be associated with drug-related toxicities, including pul-
monary, renal, hematologic, gastrointestinal and hepatic events, were
identified using diagnosis codes from all medical claims (e.g.
inpatient admissions, outpatient visits and emergency room visits)
(online suppl. table 1, for all supplementary materials see
www.karger.com/doi/10.1159/000275198). Psoriasis patients with
any of these events at baseline were excluded. The study period was
truncated at the first occurrence of a relevant event. Odds ratios
(ORs) from logistic regressions were reported.
Health Care Resource Utilization. The utilization measures in-
cluded inpatient admissions, emergency department (ED) visits,
Dermatology 2010;220:128–137 129
emergency care (inpatient and ED), outpatient visits and other
medical services (e.g. laboratory, radiology or other ancillary
ser-vices).
Incidence rate ratios (IRRs) and ORs were estimated between
cohorts using generalized linear model (GLM) regression
models with a log link function and negative binomial
distribution for IRRs and logistic regression models for ORs.
Health Care Costs. Health care costs were adjusted for inflation
and expressed in USD 2007. The cost components included phar-
macy, inpatient, ED, outpatient and other medical service costs.
Incremental costs between the cohorts were reported using
GLM models with a log link and a g-distribution or 2-part mod-
els, where the first part is a logistic model with a binomial distri-
bution and the second part is a GLM model with a log link and a
g-distribution, for cost components with a portion of 0 values
15%. The p values were estimated using a nonparametric boot-
strap resampling technique of 500 iterations.
Study events, health care resource utilization and cost were
compared between the exposed and nonexposed cohorts during
the 6-month study period. In addition, appropriate multivariate
regression models controlled for age, sex, comorbidities with a
prevalence 12%, health care resource utilization and psoriasis
treatment during the baseline period. Furthermore, ORs of po-
tential adverse events were also adjusted for the number of other
concomitant medications used during the 30 days before or 30
days after starting MTX or CYC.
Results
Sample Selection
Figure 1 shows the sample selection process. The study
included 7,955 psoriasis patients who were taking either
CYC or MTX; 3,372 patients (42.4%) comprised the non-
exposed cohort and 4,583 (57.6%) comprised the exposed
cohort. Among the exposed cohort, 3,629 patients (79.2%)
initiated on MTX and 954 patients (20.8%) on CYC.
The 2 study cohorts exhibited different
characteristics at baseline (table 1). The patients in the
exposed cohort were older (51.0 vs. 47.6 years; p !
0.0001) and a greater percentage were women (56 vs.
52%; p ! 0.0001). The prevalence of comorbidities was
generally greater in the exposed cohort and the 4 most
prevalent comorbidities were hypertension (30 vs. 16%;
p ! 0.0001), psoriatic ar-thritis (35 vs. 14%; p ! 0.0001),
hyperlipidemia (26 vs.19%, p ! 0.0001) and rheumatoid
arthritis (24 vs.10%; p ! 0.0001). The patients in both
cohorts had similar histo-ries of topical therapy use
during the baseline period, but more patients in the
exposed cohort used retinoids (15 vs. 7%; p ! 0.0001).
Among the drugs with potential interactions with MTX
or CYC, nonsteroidal anti-inflammatory drugs (NSAIDs)
and antibiotics were the 2 most common drug classes pre-
scribed to patients who were taking MTX or CYC. The
130 Dermatology 2010;220:128–137
Patients with psoriasis
n = 532,047
Methotrexate or cyclosporine users
n = 22,176
Continuously eligible for at least 180 days prior to the index
date and 180 days after the index date n = 9,379
Age < 18 years 6 months prior to the index date
n = 9,226
a
Studied patients
n = 7,955
b, c c, d
Nonexposed cohort Exposed cohort
n = 3,372 n = 4,583
a
Fig. 1. Sample selection process and study population. Patients
with drug-drug interactions between 30 days after the index date and
the end of the study period were included. The index date was
b
defined as the first prescription fill of MTX or CYC. The non-
exposed cohort included patients without drug-drug interactions 30
days prior to the index date or 6 months after the index date.
cDrug-drug interactions were defined as a combination of MTX
or CYC with any of the following drugs: for MTX, nonsteroidal
anti-inflammatory drugs, trimethoprim, salicylates, phenylbuta-
zone, sulfonamides, penicillins, azathioprine, retinol, tretinoin,
isotretinoin, alitretinoin, etretinate, acitretin, tazarotene, bexaro-
tene, adapalene, theophylline, chloramphenicol, phenytoin, tet-
racycline or cyclosporine; for CYC, nonsteroidal anti-inflamma-
tory drugs, gentamicin, tobramycin, vancomycin, trimethoprim,
clarithromycin, erythromycin, quinupristin, melphalan, ampho-
tericin, ketoconazole, fluconazole, itraconazole, diclofenac,
naproxen, sulindac, colchicine, cimetidine, ranitidine, tacrolim-
us, diltiazem, nicardipine, verapamil, methylprednisolone, allo-
purinol, bromocriptine, danazol, metoclopramide, amiodarone,
digoxin, lovastatin, methotrexate, HIV medications, potassium-
d
sparing diuretics, prednisolone or rifabutin. The exposed cohort
included patients with potential drug-drug interactions 30 days
prior to the index date or 30 days after the index date.
Saurat /Guérin /Yu /Latremouille-Viau /
Wu /Gupta /Bao /Mulani
Table 1. Baseline patient characteristics for all studied patients prevalence for each of the studied potential drug-drug
(n = 7,955) in-teractions is shown in supplementary table 2.
Characteristics Exposed Nonexposed p valuea
Adverse Event Rates
Patients 4,583(57.6) 3,372(42.4) The rate of occurrence of relevant adverse events dur-
b
Mean age 8 SD, years 51.0812.1 47.6813.0 <0.0001 ing the study period was greater in the exposed than in the
Female sex 2,587(56.4) 1,749(51.9) <0.0001 nonexposed cohort (tables 2 and 3). Compared with the
c
Comorbidity nonexposed cohort, the exposed cohort initiating on CYC
AIDS 3(0.1) 3(0.1) 0.7059 had significantly greater rates of gastrointestinal events
Anemia 266 (5.8) 128 (3.8) <0.0001 (OR: 2.83; p ! 0.0001) and pulmonary events (OR: 1.62; p
Cerebrovascular 86(1.9) 52(1.5) 0.2590
Congestive heart failure 81(1.8) 21(0.6) <0.0001 = 0.0017). The renal event rates were also greater in the
Chronic pulmonary disease 421 (9.2) 195 (5.8) <0.0001 exposed cohort initiating on CYC than in the non-exposed
Coagulopathy 46(1.0) 26(0.8) 0.2789 cohort (OR: 2.39; p = 0.1186). Similarly, the ex-posed
Cardiovascular disease 314 (6.9) 146 (4.3) <0.0001 cohort initiating on MTX had significantly greater rates of
Depression 333 (7.3) 203 (6.0) 0.0285 renal events (OR: 4.33; p = 0.0061), hematologic events
Diabetes 540 (11.8) 225 (6.7) <0.0001
Fluid electrolyte disease 117 (2.6) 52(1.5) 0.0020 (OR: 1.56; p = 0.0014) and pulmonary events (OR: 1.43; p
Hyperlipidemia 1,171(25.6) 646 (19.2) <0.0001 = 0.0005) compared with the nonexposed cohort.
Hypertension 1,382(30.2) 528 (15.7) <0.0001 When looking at all the study patients together, the
Hypothyroidism 362 (7.9) 172 (5.1) <0.0001 most frequent events in the exposed and nonexposed co-
Liver disease 69(1.5) 27(0.8) 0.0044 horts were pulmonary (11 vs. 8%), hematologic (5 vs. 4%)
Lymphoma 30(0.7) 22(0.7) 0.9906
Metastatic cancer 14(0.3) 11 (0.3) 0.8703 and gastrointestinal events (5 vs. 3%). After adjusting for
Obesity 159 (3.5) 54(1.6) <0.0001 covariates at baseline, 3 types of adverse event remained
Other neurological disease 82(1.8) 35(1.0) 0.0059 significant. Renal events were more than twice as likely to
Paralysis 10(0.2) 4(0.1) 0.2951 occur in the exposed than in the nonexposed cohort (OR:
Peptic ulcer 22(0.5) 9(0.3) 0.1316 2.58; p = 0.0145). The likelihood of developing a gas-
Peripheral vascular disease 96(2.1) 40(1.2) 0.0020
Psoriatic arthritis 1,620(35.3) 460 (13.6) <0.0001
trointestinal event was 36% greater in the exposed cohort
Psychoses 181 (3.9) 94(2.8) 0.0051 than in the nonexposed cohort (OR: 1.36; p = 0.0197), and
Rheumatoid arthritis 1,105(24.1) 344 (10.2) <0.0001 the likelihood of developing a pulmonary event was 20%
Renal failure 56(1.2) 18(0.5) 0.0016 greater (OR: 1.20; p = 0.0470). The differences between
Solid tumor 197 (4.3) 128 (3.8) 0.2632 the cohorts for rates of hepatic and hematologic events
Valvular disease 149 (3.3) 57(1.7) <0.0001
were not statistically significant (table 3).
Weight loss 12(0.3) 2(0.1) 0.0332
d
History of psoriasis treatment Health Care Resource Utilization
Topical therapy 2,550(55.6) 1,890(56.0) 0.7163
Phototherapy 242 (5.3) 237 (7.0) 0.0012 Utilization of health care resources was significantly
e
Systemic nonbiologic therapy 705 (15.4) 237 (7.0) <0.0001 greater among the exposed than the nonexposed patients
Biologic therapy 312 (6.8) 287 (8.5) 0.0044 (table 4). After controlling for confounding factors, the
Prior use of potential inter- rates of inpatient and ED visits were 61 and 31%
f
action drugs , n (%) 3,724(81.3) 793 (23.5) <0.0001 greater, respectively, for the exposed cohort compared
with the nonexposed one (inpatient IRR: 1.61, p !
a
Figures in parentheses are percentages. p values were calculated
2
0.0001; ED IRR: 1.31, p ! 0.0022). The adjusted odds of
using x tests for categorical variables and Wilcoxon tests for con- having an urgent care event during the study period
b
tinuous variables. Age was calculated 180 days prior to the index were also significant-ly greater among the exposed
c
date. Comorbidities were identified by International Classification
of Diseases, Ninth Revision, codes defined by the US Agency for
patients (OR: 1.47; p ! 0.0001).
Healthcare Research and Quality [14] and were calculated during
the 6-month baseline period. Only comorbidities with a prevalence Health Care Costs
of at least 2% will be considered as covariates in the multivariate
d
regres-sion models. During the 6-month baseline period. The exposed cohort experienced significantly greater
e f
Excluding meth-otrexate and cyclosporine. Defined as any health care costs for all categories of medical service con-
prescription filled for the potential drugs that interact with the index sidered (table 5). During the 6-month study period, the
drug during the first 5 months of baseline period.
average total cost for pharmacy and medical services per
patient was 59% greater for the exposed cohort compared

Drug-Drug Interactions in Patients with Dermatology 2010;220:128–137 131

Psoriasis
Table 2. Potential adverse event rates stratified by CYC and MTX users

Exposed Nonexposed b
Unadjusted odds ratios
study patients with study patients with crude ratios p value
a adverse events a adverse events
sample sample
CYC users
Pulmonary event 791 98(12.4) 1,123 90 (8.0) 1.62 [1.20, 2.20] 0.0017
Renal event 920 9(1.0) 1,217 5 (0.4) 2.39 [0.80, 7.17] 0.1186
Hematologic event 843 40(4.7) 1,154 46 (4.0) 1.20 [0.78, 1.85] 0.4099
Gastrointestinal event 859 58(6.8) 1,164 29 (2.5) 2.83 [1.80, 4.47] <0.0001
Hepatic event 910 23(2.5) 1,196 21 (1.8) 1.45 [0.80, 2.64] 0.2225
MTX users
Pulmonary event 3,183 335 (10.5) 1,981 151 (7.6) 1.43 [1.17, 1.74] 0.0005
Renal event 3,599 29(0.8) 2,135 4 (0.2) 4.33 [1.52, 12.33] 0.0061
Hematologic event 3,385 188 (5.6) 2,041 74 (3.6) 1.56 [1.19, 2.06] 0.0014
Gastrointestinal event 3,435 148 (4.3) 2,081 71 (3.4) 1.27 [0.96, 1.70] 0.0990
Hepatic event 3,555 73(2.1) 2,121 41 (1.9) 1.06 [0.72, 1.57] 0.7545

Figures in parentheses are percentages and values in square brackets represent 95% confidence limits.
b
a All patients with the studied disease during the baseline period were excluded. Estimated using logistic regression without con-
trolling for baseline characteristics.

Table 3. Potential adverse event rates

Toxicity Exposed Nonexposed b c

Unadjusted ORs Adjusted ORs
study patients with study patients with crude ratios p value adjusted ratios p value
a adverse events a adverse events
sample sample
Pulmonary event 3,974 433 (10.9) 3,104 241 (7.8) 1.45 [1.23, 1.71] <0.0001 1.20 [1.00, 1.43] 0.0470
Renal event 4,519 38(0.8) 3,352 9 (0.3) 3.15 [1.52, 6.52] 0.0020 2.58 [1.21, 5.52] 0.0145
Hematologic event 4,228 228 (5.4) 3,195 120 (3.8) 1.46 [1.17, 1.83] 0.0010 1.15 [0.90, 1.46] 0.2656
Gastrointestinal event 4,294 206 (4.8) 3,245 100 (3.1) 1.58 [1.24, 2.02] 0.0002 1.36 [1.05, 1.77] 0.0197
Hepatic event 4,465 96(2.2) 3,317 62 (1.9) 1.15 [0.84, 1.59] 0.3853 1.09 [0.77, 1.55] 0.6239

Figures in parentheses are percentages and values in square medications, baseline comorbidities and baseline psoriasis treat-
brackets represent 95% confidence limits. ments. Psoriasis treatments included topical therapy, biologic
a
All patients with the studied adverse event during the base- therapy, systemic nonbiologic therapy and phototherapy.
line period were excluded. Baseline comorbidities were: cardiovascular disease,
b
Estimated using logistic regression without controlling for hypothyroidism, psoriatic arthritis, rheumatoid arthritis, valvular
baseline characteristics. disease, depres-sion, fluid electrolyte disorders, hyperlipidemia,
c
Adjusted ratios were estimated using multivariate regression obesity, psycho-ses and solid tumor.
models controlling for age, gender, number of other concomitant

with the nonexposed cohort (USD 7,960 vs. 5,021, p !
0.0001). The adjusted incremental total costs for the ex-
posed cohort were USD 1,722, 28% greater compared
with the nonexposed cohort’s total costs (p ! 0.0001). The
adjusted incremental pharmacy (USD 711, p ! 0.0001) and
outpatient costs (USD 539, p ! 0.0001) comprised a
substantial portion of the total cost differential.
Sensitivity Analysis
The sensitivity analysis included a subgroup of 2,704
patients in the exposed cohort who refilled their prescrip-
tions for potentially interactive drugs after the initiation of
MTX or CYC. Compared with the nonexposed cohort, this
subgroup had an almost 3-fold greater risk of devel-oping
a renal event (OR: 2.82; p = 0.0138) and a 38% great-

132 Dermatology 2010;220:128–137 Saurat /Guérin /Yu /Latremouille-Viau /

Wu /Gupta /Bao /Mulani
Table 4. Health care resource utilization

Medical outcome a Unadjusted b

Outcomes Adjusted
exposed nonexposed crude rate ratios p value adjusted rate p value
(n = 4,593) (n = 3,362) ratios
Inpatient
c
IRR 574 184 2.30 (1.86, 2.84) <0.0001 1.61 (1.30, 1.99) <0.0001
d
OR 375 144 2.00 (1.64, 2.43) <0.0001 1.55 (1.25, 1.93) <0.0001
ED
c
IRR 1,094 512 1.57 (1.32, 1.87) <0.0001 1.31 (1.10, 1.56) 0.0022
d
OR 574 288 1.53 (1.32, 1.78) <0.0001 1.39 (1.18, 1.64) <0.0001
Emergency care (inpatient and ED)
c
IRR 1,668 696 1.76 (1.53, 2.04) <0.0001 1.40 (1.21, 1.62) <0.0001
d
OR 825 385 1.70 (1.50, 1.94) <0.0001 1.47 (1.28, 1.70) <0.0001
Outpatient
c
IRR 52,860 29,296 1.41 (1.32, 1.52) <0.0001 1.22 (1.13, 1.32) <0.0001
e
Other medical services
c 10,780 5,613 1.33 (1.28, 1.37) <0.0001 1.16 (1.13, 1.20) <0.0001
IRR
Figures in parentheses are 95% confidence limits. pothyroidism, psoriatic arthritis, anemia, rheumatoid arthritis,
a
Total number of patients for OR and total number of visits valvular disease, depression, fluid electrolyte disorders, hyperlip-
for IRR. idemia, obesity, psychoses and solid tumor.
b c
Adjusted ratios were estimated using multivariate regression IRR refers the number of visits/hospitalizations during the
models controlling for age, gender, baseline comorbidities, base-line study period.
d
health care utilization and baseline psoriasis treatments, in-cluding OR refers to the probability of having at least 1 visit/hospi-
topical therapy, biologic therapy, systemic nonbiologic therapy and talization during the study period.
e
phototherapy. Baseline comorbidities were cardio-vascular disease, Including laboratory, radiology or other ancillary services.
chronic pulmonary disease, hypertension, hy-

Table 5. Health care costs

a Unadjusted cost difference b

Costs Adjusted cost difference
exposed nonexposed incremental p value incremental p value
costs costs
Pharmacy 2,89683,274 2,15383,028 743 <0.0001 711 <0.0001
Medical services
Emergency care (inpatient and ED) 1,661812,108 70584,962 956 <0.0001 105 0.5030
Outpatient 2,95486,156 1,92084,262 1,034 <0.0001 539 <0.0001
Other medical services 44882,092 24381,145 205 <0.0001 103 0.0040
Total (pharmacy + medical services) 7,960816,038 5,02187,820 2,938 <0.0001 1,722 <0.0001
aValues are means 8 standard deviation in 2007 USD. ism, psoriatic arthritis, anemia, rheumatoid arthritis, valvular
b Adjusted costs were estimated using multivariate regression disease, depression, fluid electrolyte disorders, hyperlipidemia,
models controlling for age, sex, baseline comorbidities, baseline
health care utilization and baseline psoriasis treatments, includ- obesity, psychoses and solid tumor. Cost differences were esti-
ing topical therapy, biologic therapy, systemic nonbiologic thera- mates using 2-part models for cost components with >5% of pa-
py and phototherapy. Baseline comorbidities were cardiovascular tients having 0 costs (e.g. inpatient, ED), and GLM regression
disease, chronic pulmonary disease, hypertension, hypothyroid- models with a log-link and a g-distribution were used for the
oth-er cost components (e.g. outpatient, total).

Drug-Drug Interactions in Patients with Dermatology 2010;220:128–137 133

Psoriasis
Table 6. Sensitivity analysis of adverse event rates

Toxicity Exposed Nonexposed b c

Unadjusted ORs Adjusted ORs
study patients with study patients with crude ratios p value adjusted ratios p value
a adverse event a
sample sample adverse event
Pulmonary event 2,340 269 (11.5) 3,104 241 (7.8) 1.54 [1.29, 1.85] <0.0001 1.16 [0.94, 1.43] 0.1557
Renal event 2,653 26(1.0) 3,352 9 (0.3) 3.68 [1.72, 7.86] 0.0008 2.82 [1.24, 6.44] 0.0138
Hematologic event 2,467 137 (5.6) 3,195 120 (3.8) 1.51 [1.17, 1.94] 0.0014 1.12 [0.84, 1.48] 0.4346
Gastrointestinal event 2,522 124 (4.9) 3,245 100 (3.1) 1.63 [1.24, 2.13] 0.0004 1.38 [1.02, 1.86] 0.0377
Hepatic event 2,629 59(2.2) 3,317 62 (1.9) 1.21 [0.84, 1.73] 0.3097 1.11 [0.74, 1.68] 0.6135

Figures in parentheses are percentages and values in square
brackets represent 95% confidence limits.
a
All patients with the studied adverse event during the base-
line period were excluded.
b
Estimated using logistic regression without controlling for
baseline characteristics.
c
Adjusted ratios were estimated using multivariate regression
models controlling for age, sex, number of other concomitant
medications, baseline comorbidities and baseline psoriasis treat-
ments. Psoriasis treatments included topical therapy, biologic
therapy, systemic nonbiologic therapy and phototherapy.
Baseline comorbidities were: cardiovascular disease,
hypothyroidism, psoriatic arthritis, rheumatoid arthritis, valvular
disease, depres-sion, fluid electrolyte disorders, hyperlipidemia,
obesity, psycho-ses and solid tumor.

er likelihood of developing a gastrointestinal event (OR:
1.38; p = 0.0377; table 6).
The sensitivity analysis also demonstrated greater to-
tal incremental health care costs for the exposed cohort
compared with the nonexposed cohort (table 7). The ad-
justed incremental total costs were USD 1,905 greater
per person over a 6-month period in the exposed than in
the nonexposed cohort (p ! 0.0001). This value
represents USD 400 more per year than the original
analysis, in which the total incremental costs for the
exposed cohort were USD 1,722 (p ! 0.0001).
Discussion
This study investigated the prevalence of potential
drug-drug interactions between the conventional system-ic
therapies, MTX and CYC, and various drugs typically
taken by patients with psoriasis. In addition, we evaluated
the outcomes of potential drug-drug interactions, such as
adverse events, healthcare resource utilization and costs,
by comparing the patients exposed to drug-drug interac-
tions with those who were not exposed. The study did not
aim to determine which immunosuppressant was better in
terms of safety or tolerability. The study looked at all
events that may be caused by toxicities related to these 2
oral conventional systemic therapies. These analyses were
performed using a large, US managed-care database that
included, but was not limited to, patients with psoriasis.
The results demonstrated that more than half of the
patients treated with MTX or CYC also received prescrip-
tions for interacting drugs at the time of MTX/CYC ini-
tiation. Compared with the patients who were not taking
interacting drugs, these patients experienced significant-ly
greater risks of pulmonary, renal and gastrointestinal
events and incurred substantially greater costs for re-
source utilization and treatment. A sensitivity analysis that
used more stringent inclusion criteria for selecting exposed
patients was confirmatory, with results that were robust
and more pronounced than for the initial exposed cohort,
especially for renal events.
Even at recommended dosages of MTX or CYC, there
is a risk of renal or gastrointestinal toxicity when MTX or
CYC are coadministered with compounds that increase
their blood concentration and/or decrease their clearance
[15, 16]. In this study, the exposed patients experienced
greater risks of these particular adverse events, consistent
with the known clinical consequences of those drug-drug
interactions. Furthermore, coadministration of drugs that
may interact with MTX or CYC and that could be deemed
high-risk interactions, based on information available in
the product labels [6, 7], was relatively frequent.
The most commonly used drugs with potential to in-
teract with both MTX and CYC in the exposed cohort
were NSAIDs and sulfonamides. NSAIDs are often used
to treat acute or chronic pain and inflammatory condi-
tions, such as rheumatoid arthritis and psoriatic arthritis.
The interaction of NSAIDs with MTX elevates and the

134 Dermatology 2010;220:128–137 Saurat /Guérin /Yu /Latremouille-Viau /

Wu /Gupta /Bao /Mulani
Table 7. Sensitivity analysis of health care costs

a Unadjusted cost difference b

Costs Adjusted cost difference
exposed nonexposed incremental p value incremental p value
costs costs
Pharmacy 3,20283,309 2,15383,028 1,048 <0.0001 1,087 <0.0001
Medical services
Emergency care (inpatient and ED) 1,63988,379 70584,962 933 <0.0001 18 0.9022
Outpatient 3,01085,279 1,92084,262 1,090 <0.0001 430 <0.0001
Other medical services 44182,051 24381,145 197 <0.0001 105 <0.0001
Total (pharmacy + medical services) 8,291812,454 5,02187,820 3,269 <0.0001 1,905 <0.0001
aValues are means 8 standard deviation in 2007 USD. ism, psoriatic arthritis, anemia, rheumatoid arthritis, valvular
b Adjusted costs were estimated using multivariate regression disease, depression, fluid electrolyte disorders, hyperlipidemia,
models controlling for age, sex, baseline comorbidities, baseline
health care utilization, and baseline psoriasis treatments, includ- obesity, psychoses and solid tumor. Cost differences were esti-
ing topical therapy, biologic therapy, systemic nonbiologic thera- mates using 2-part models for cost components with >5% of the
py and phototherapy. Baseline comorbidities were cardiovascular patients having 0 costs (e.g. inpatient, ED), and GLM regression
disease, chronic pulmonary disease, hypertension, hypothyroid- models with a log-link and a g-distribution were used for the
oth-er cost components (e.g. outpatient, total).

prolongs serum concentrations of MTX and increases the
risk of aplastic anemia, bone marrow suppression and
gastrointestinal toxicity [6, 17]. Concomitant administra-
tion of CYC and NSAIDs can be associated with a more
pronounced decrease in renal function than that seen with
either agent alone and is linked to renal toxicity [7, 18].
When taken alone, NSAIDs may lead to renal or gas-
trointestinal effects, particularly in patients with pre-ex-
isting chronic renal disease or with decreased effective
circulating fluid volume [19–21]. Most guidelines for pso-
riasis treatment do not recommend nonbiologic systemic
therapies, especially high doses of MTX, for patients who
are already at risk of renal and gastrointestinal toxicity
events or who have uncontrolled hypertension [6, 8, 22].
Sulfonamides are also frequently used to treat patients
with psoriasis and can potentially interact with MTX or
CYC. Sulfonamides are synthetic antimicrobial agents and
are also applied in the treatment of inflammatory bowel
disease. Sulfonamides can diminish renal tubular transport
of MTX, thus increasing MTX concentrations and the risk
of toxicities, including renal toxicity, hepato-toxicity and
bone marrow suppression [23–25]. Penicillin is often used
as treatment for guttate psoriasis, which is usually a
streptococcal (bacterial) infection that may be responsible
for chronic plaque psoriasis [26–28].
The patients in the exposed cohort experienced sig-
nificantly greater health care costs than those in the non-
exposed cohort. The baseline characteristics showed that
the exposed patients had greater prior resource use and
more extensive comorbidity profiles compared with the
nonexposed cohort. To control for selection bias, we
also controlled for baseline healthcare resource
utilization (inpatient, ED, outpatient), a comprehensive
list of co-morbidities and history of psoriasis treatments
prior to initiation of MTX/CYC systemic therapy.
Because of the risk of toxicities with conventional
sys-temic therapies, their use requires comprehensive
and regular laboratory monitoring, which can increase
the total costs [29, 30]. A lack of efficacy with these
immuno-suppressant agents may lead to dose titration
or use of combination therapies [31, 32]. Poor response
and issues related to drug safety and tolerability may
result in either worsening of the disease or an adverse
effect and poten-tial hospitalization.
Although claims data are a rich source for examining
health care utilization and costs, there are some inherent
limitations in any study conducted with claims data. This
investigation is based on administrative claims data in
which patients’ psoriasis severity, adverse event severity
and comorbidities could not be directly observed. There-
fore, despite the comprehensive list of covariates used in
the study, selection bias may still remain. In addition,
pharmacy claims data do not provide information on
whether drugs dispensed were actually taken according to
prescribed instructions. Thus, the study determined
potential drug-drug interactions under the assumption that
patients took their medicine as prescribed. This lim-itation
was overcome to a certain extent in the sensitivity

Drug-Drug Interactions in Patients with Dermatology 2010;220:128–137 135

Psoriasis
analysis, in which stricter criteria were used. Another
drawback is that the study was limited to prescribed
med-ication and did not considerer over-the-counter
products that could also be associated with drug-drug
interac-tions; thus, the findings may have
underestimated the impact of drug-drug interactions.
In addition, with claims data, it is not possible to be
certain that an adverse event is related to a drug-drug in-
teraction. The adverse event rates reported in this study
were based on the emergence of specific ICD-9 diagnosis
codes in patients’ medical claims that were used in the
definition of potential drug-related toxicities. These rates
represent all patients who experienced the studied toxic-ity
during the follow-up period in the case and control
cohorts. Patients with the studied conditions at baseline
were excluded from the analysis. Based on the temporal
relationship between concomitant drug use and the emer-
gence of these ICD-9 codes, one could infer that at least
some of the diagnoses were due to drug interactions.
However, the conditions identified by the ICD-9 diagno-
sis codes may not have solely resulted from drug use. For
example, conditions may have developed irrespective of a
drug interaction with MTX or CYC because of patients’
lifestyle factors (e.g. tobacco use), environmental factors
or family histories; information about such factors was not
available in the claims data.
To minimize the impact of factors that could not be
controlled for in our analysis of claims data, the same
definition of toxicity was applied to both cohorts. The
results, therefore, show that in a relative sense, exposed
patients were more likely to experience a studied
toxicity than nonexposed patients. The study findings
are based on relative risks. Events that were not directly
related to drug toxicities should have been as frequent
in both co-horts and, therefore, would not have had an
impact on the relative risk.
Previous studies have shown that patients with psoria-
sis have an increased prevalence of multiple comorbidi-
ties [9, 10]. This study found that, overall, 50% of the pa-
tients treated with conventional oral systemic therapies
(MTX or CYC) may experience potential drug-drug in-
teractions due to comedication with interacting drugs. The
total impact of these interactions (increased toxicity risk,
healthcare resource use and overall costs) is substan-tial.
Caution should be exercised when prescribing con-
ventional systemic therapies to patients with psoriasis be-
cause of the likelihood and potential effects of interac-
tions with concurrent medication use. Both the drug and
the patient’s unique characteristics need to be considered
when making treatment decisions to promote optimal
outcomes, even if that means selecting more costly thera-
pies. As has been previously demonstrated, certain agents
may have safer treatment profiles and promote better ad-
herence that ultimately offset a psoriasis patient’s total cost
of care [33].
Acknowledgment
The authors thank Arbor Communications, Inc., Ann Arbor,
Mich., USA, for editorial assistance on behalf of Abbott Labora-
tories. This analysis was supported by Abbott Laboratories.
Disclosures
J.-H.S. has served as a consultant for Abbott Laboratories and
has participated in continuing medical education events support-
ed by unrestricted educational grants from Abbott Laboratories.
The work reported here was performed under contract for Ab-
bott Laboratories by Analysis Group. A.P.Y. and E.Q.W., A.G.
and D.L.-V. are employees of Analysis Group. S.R.G., Y.B. and
P.M.M. are employees of Abbott Laboratories.

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