Research

Original Investigation

Risk of Serious Infection With Biologic and Systemic

Treatment of Psoriasis
Results From the Psoriasis Longitudinal Assessment
and Registry (PSOLAR)
Robert E. Kalb, MD; David F. Fiorentino, MD, PhD; Mark G. Lebwohl, MD; John Toole, MD, FRCPC; Yves Poulin, MD;
Arnon D. Cohen, MD; Kavitha Goyal, MD; Steven Fakharzadeh, MD, PhD; Stephen Calabro, MS; Marc Chevrier, MD, PhD;
Wayne Langholff, PhD; Yin You, MS; Craig L. Leonardi, MD

Supplemental content at
IMPORTANCE The efficacy of treatment for psoriasis must be balanced against potential jamadermatology.com
adverse events.

OBJECTIVE To determine the effect of treatment on the risk of serious infections in patients
with psoriasis.

DESIGN, SETTING, AND PARTICIPANTS A multicenter, longitudinal, disease-based registry

(Psoriasis Longitudinal Assessment and Registry [PSOLAR]) at dermatology centers.
Participants were adult patients with psoriasis who were receiving or were eligible to receive
conventional systemic or biologic agents. The registry opened on June 20, 2007, and data
included herein were collected through August 23, 2013.

EXPOSURES Patients were prescribed psoriasis therapies as in standard clinical practice.

Patients will be followed for up to 8 years. Data were collected and serious adverse events
(including serious infections) were assessed at regular intervals.

MAIN OUTCOMES AND MEASURES Cohort characteristics are described based on evaluation at
entry into the registry. The cumulative incidence rates of serious infections are reported
across treatment cohorts, including ustekinumab, infliximab, adalimumab, etanercept, and
nonbiologics (with or without methotrexate). A multivariate analysis using a Cox proportional
hazards regression model was used to identify predictors of the time to the first serious
infection using the nonmethotrexate/nonbiologics cohort as the reference.

RESULTS Data were analyzed from 11 466 patients with psoriasis (22 311 patient-years).
Differences in patient characteristics were found between the biologics and
nonmethotrexate/nonbiologics cohorts (eg, age, sex, body mass index, and disease
characteristics), as well as among the individual biologic groups (eg, a higher prevalence of
psoriatic arthritis in the infliximab cohort). The cumulative incidence rate of serious infections
was 1.45 per 100 patient-years (n = 323) across treatment cohorts, and the rates were 0.83,
1.47, 1.97, and 2.49 per 100 patient-years in the ustekinumab, etanercept, adalimumab, and
infliximab cohorts, respectively, and 1.05 and 1.28 per 100 patient-years in the
nonmethotrexate/nonbiologics and methotrexate/nonbiologics cohorts, respectively. The
most commonly reported types of serious infections across the registry were pneumonia and
cellulitis. Increasing age, diabetes mellitus, smoking, significant infection history, infliximab
exposure, and adalimumab exposure were each associated with an increased risk of serious
infection. Author Affiliations: Author
affiliations are listed at the end of this
CONCLUSIONS AND RELEVANCE Results from PSOLAR suggest a higher risk of serious article.

infections with adalimumab and infliximab compared with nonmethotrexate and nonbiologic Corresponding Author: Robert E.
Kalb, MD, Department of
therapies. No increased risk was observed with ustekinumab or etanercept. Dermatology, School of Medicine and
Biological Sciences, State University
TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00508547 of New York at Buffalo, Ste 210, 325
JAMA Dermatol. doi:10.1001/jamadermatol.2015.0718 Essjay Rd, Buffalo, NY 14221
Published online May 13, 2015. ([email protected]).

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 Research Original Investigation Risk of Serious Infection With Biologic and Systemic Treatment of Psoriasis

P
soriasis is a chronic immune-mediated disorder that of- cians prescribed treatments based on usual clinical practice and
ten requires long-term treatment, including conven- standard of care. The use of commercially available medica-
tional systemic therapy (eg, methotrexate) and bio- tions was not restricted. The planned duration of observa-
logic therapies (eg, tumor necrosis factor [TNF] and interleukin tion for each patient is 8 years, which permits the capture of
12/23 antagonists). Although biologic therapy offers new treat- long-term exposure outcomes over the course of registry par-
ment options with high levels of efficacy and convenience, ticipation. A total of 93 institutional review boards or ethics
these treatments (along with conventional systemic thera- committees (ie, 41 in North America, 37 in Europe and the
pies) have immunomodulatory or immunosuppressive ef- Middle East, and 15 in Latin America) approved the registry pro-
fects that may predispose patients to potential adverse tocol, and all patients provided written informed consent be-
events.1-4 Therefore, understanding the long-term safety pro- fore study procedures were initiated. The registry opened on
file of such therapy, particularly with regard to events such as June 20, 2007, and data included herein were collected through
serious infections, is crucial. August 23, 2013.
Biologic and conventional systemic agents used for treat-
ing psoriasis may be associated with an increased risk of seri- Data Collection
ous infection; however, these treatments may confer differ- Data were collected at entry into the registry and approxi-
ent degrees of risk.5-7 Much of the available data regarding mately every 6 months thereafter, whereas serious adverse
susceptibility to infection with biologic therapy derives from events were submitted and evaluated on a real-time basis. All
studies8-10 in inflammatory diseases other than psoriasis, such adverse event reports were reviewed. When provided by the
as rheumatoid arthritis and Crohn’s disease. However, these investigative site, hospital records were assessed by the study
patients may have a higher incidence of infection compared physician to verify reported events. Events were identified as
with patients with psoriasis due to differences in the under- infections if they were coded to terms in the “Infections and
lying disease state.11 In addition, the approach for treating pso- Infestations” System organ class of the Medical Dictionary for
riasis may differ from that for other inflammatory diseases be- Regulatory Activities (version 16.0). Per the study protocol, in-
cause patients with rheumatoid arthritis or Crohn’s disease may fections were defined as serious if they were associated with
be more commonly treated with higher doses of concomitant 1 or more of the following: (1) death, (2) a life-threatening con-
immunomodulating therapies (eg, systemic corticosteroids, dition, (3) persistent or significant disability or incapacita-
methotrexate, or other systemic therapies), which may in- tion, (4) a cause or prolongation of hospitalization, or (5) an-
crease the risk of infection. other medically important condition. Medically important
The Psoriasis Longitudinal Assessment and Registry (PSO- conditions included infections that, based solely on the clini-
LAR) is a large intercontinental, prospective, psoriasis-based cal judgment of the study investigator, may not be immedi-
registry and is designed to capture adverse events (including ately life threatening or result in death or hospitalization but
serious infections) across the spectrum of therapies com- may jeopardize the patient or may require intervention to pre-
monly used to treat psoriasis.12 This study evaluates the inci- vent one of the other conditions included in the definition of
dence of serious infections among patients with psoriasis ex- serious infections. For this analysis, serious infections were
posed to different biologic therapies in a real-world setting and summarized as specific types of infection for further catego-
compares the risk with these individual therapies to the risk rization, where relevant. For example, pneumonia pneumo-
with nonbiologic treatments. Based on the standard defini- coccal and pneumonia staphylococcal were combined into the
tion promulgated by the US Food and Drug Administration, a infection type of pneumonia, whereas nonspecific terms, such
serious infection was defined as any infection that results in as localized infection, were not categorized.
death, is life threatening, requires inpatient hospitalization or
prolongs existing hospitalization, causes persistent or signifi- Study Populations and Treatment Cohorts
cant disability or incapacitation, or may jeopardize the pa- Patients receiving each biologic (ie, infliximab, adalimumab,
tient or require intervention to prevent one of these out- ustekinumab, and etanercept) were included in separate co-
comes. The cumulative rates of serious infections across horts. As in all observational studies, treatment dosing was de-
treatment cohorts and the most frequently reported types of termined by the treating physician. The sample sizes for other
infections are summarized, and potential predictors of the time biologics that were either not indicated in major markets for
to the first serious infection are evaluated in a multivariate psoriasis currently (eg, golimumab, abatacept, and certoli-
analysis. zumab pegol), no longer commercially available (eg, efali-
zumab, alefacept), or investigational in nature (eg, bria-
kinumab, secukinumab, and brodalumab) were not large
enough to allow for feasible statistical analyses at this time.
Methods Consequently, results for the other biologics cohort were not
Patients and Study Design included in these analyses (but are reflected in the overall popu-
The study design and the inclusion and exclusion criteria for lation). Nonbiologic therapies included (but were not limited
study enrollment have been presented elsewhere.12 Briefly, eli- to) methotrexate, systemic retinoids, psoralen plus UV-A, and
gible adult patients had an established diagnosis of psoriasis UV-B, which may also impact infection risk in different ways
for which they were actively receiving (or were eligible to re- and to different degrees. The incidences of serious infections
ceive) systemic therapies, including biologic agents. Physi- in the biologic cohorts were compared with the incidence in a

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 Risk of Serious Infection With Biologic and Systemic Treatment of Psoriasis Original Investigation Research

standard reference group (the subset of patients exposed to .05) across biologics, pairwise comparisons were conducted be-
only therapies other than methotrexate and biologics), as well tween individual biologics using Bonferroni multiplicity adjust-
as a sensitivity analysis comparison with those exposed to ment for multiple comparisons. For comparisons of the number
methotrexate, which is the most commonly prescribed non- of prior biologics used, the 2 nonbiologics cohorts were ex-
biologic systemic therapy for psoriasis.13 Patients receiving cy- cluded. The numbers of serious infection were summarized by
closporine were not included in the nonbiologics cohort so that type, and the rate per 100 patient-years and 95% CIs were cal-
biologic therapies could be directly compared with the non- culated for each treatment cohort.
methotrexate/nonbiologics and methotrexate/nonbiologics co- A multivariate analysis using a Cox proportional hazards
horts in the absence of any contribution of risk from cyclo- regression model was performed to identify risk factors for se-
sporine. Data are presented for the following biologic treatment rious infection. The distribution of continuous baseline vari-
cohorts: ustekinumab, infliximab, adalimumab, and etaner- ables was rescaled to facilitate clinical interpretation (eg, age
cept. These biologic cohorts did not exclude methotrexate or and duration of disease were transformed to age divided by
cyclosporine use. Data are also presented for the 2 nonbiolog- 10 and duration of disease divided by 5). Adjusted hazard ra-
ics cohorts of nonmethotrexate/nonbiologics and methotrex- tios (HRs), 95% CIs, and corresponding P values (Wald χ2 test)
ate/nonbiologics (excluding cyclosporine). were calculated for each clinical characteristic compared with
Three populations (ie, overall, incident, and bionaive) a defined reference group. Missing values for covariates in the
within the registry were evaluated to assess the risk of seri- Cox proportional hazards regression model were imputed (ie,
ous infections. The overall population is the broadest group means for continuous factors and medians for categorical fac-
and includes patients who started receiving a biologic agent tors). Covariables (predefined based on clinical relevance by
before (prevalent population), at the time of, or after (inci- the coauthors) included the following: age, sex, race/
dent population) enrolling in the registry. The incident popu- ethnicity, body mass index (calculated as weight in kilograms
lation represents the subset of patients who initiated a bio- divided by height in meters squared), duration of psoriasis, di-
logic agent at the time of or after enrolling in the registry but agnosis of psoriatic arthritis, diagnosis of diabetes mellitus, his-
may have been exposed to a different biologic previously. The tory of immunomodulator use, number of biologic therapies
bionaive population is the subset of incident patients who re- used historically, history of significant infection (defined as in-
ceived their first biologic agent at the time of or after enroll- fections requiring treatment within 3 years before registry en-
ing in the registry and had never had any prior biologic expo- rollment), Physician’s Global Assessment score at baseline,
sure. The primary analysis was focused on the incidence of smoking status at enrollment, and alcohol use status at en-
serious infections in patients in the overall population, includ- rollment. In addition, individual use of ustekinumab, inflixi-
ing incident and prevalent biologic users, and sensitivity analy- mab, adalimumab, and etanercept was included in the model,
ses were performed for the narrower incident and bionaive and the reference group for comparison was the nonmetho-
populations. The following 2 nonbiologics cohorts included all trexate/nonbiologics cohort. As a sensitivity analysis, the mul-
patients who had never been exposed to any biologic: (1) those tivariate analysis was also performed using the methotrexate/
who had not received methotrexate (nonmethotrexate/ nonbiologics cohort as the reference group.
nonbiologics) (primary comparison) and (2) those who had re-
ceived methotrexate (methotrexate/nonbiologics). Exposure
for each biologic group started at exposure to the first bio-
logic therapy in the registry. For prevalent users, exposure be-
Results
gan at the registry start date; however, exposure began at the The overall population consisted of 11 466 patients (22 311 pa-
first dose in the registry for incident and bionaive users. End tient-years): 9154 had received a biologic agent, 490 had re-
of exposure for all groups occurred at the earlier of (1) 90 days ceived methotrexate (and possibly other nonbiologics), and
after discontinuation of that treatment, (2) the initiation of a 1610 had received therapy other than methotrexate and bio-
different biologic, (3) discontinuation from the study, or (4) the logics during the registry (Table 1 and Figure). The incident
data cutoff date (August 23, 2013). Infections that occurred be- population included approximately half of the patients in the
fore the start of exposure to the first biologic or after that ex- overall population (5609 patients [10 560 patient-years]), and
posure ended were not included in this analysis. All cohorts the bionaive population comprised more than half of the in-
within each population analysis were mutually exclusive. cident population (3274 patients [6858 patient-years]). Most
patients in PSOLAR were enrolled in North America (74.3% in
Statistical Analysis the United States and 15.7% in Canada). Just over half of the
Demographic, disease, and social characteristics, as well as PSOLAR population was male (6321 patients [55.1%]), and the
medical history and prior treatments, were summarized mean age at enrollment was 48.5 years (Table 2). Of 11 466 pa-
using descriptive statistics. To detect differences between tients in the overall population, 8192 (71.4%) had received at
combined biologics (ustekinumab, infliximab, etanercept, and least 1 biologic agent before entering the registry. Notable dif-
adalimumab) and the reference (nonmethotrexate/nonbiolog- ferences in patient and disease characteristics at entry into the
ics) cohort and differences across biologic cohorts, correspond- registry (Table 3) were found between the biologics groups and
ing P values were calculated based on the overall F test from an the nonmethotrexate/nonbiologics cohort, as expected. Some
analysis of variance for continuous variables or a χ2 test for cat- potentially clinically relevant findings were also observed in
egorical variables. For statistically significant differences (P ≤ statistical comparisons between biologic groups. Body mass

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 Research Original Investigation Risk of Serious Infection With Biologic and Systemic Treatment of Psoriasis

Table 1. Number of Patients and Patient-years of Follow-up by Population and Treatment Cohort Among Patients Enrolled in PSOLAR
Nonmethotrexate/ Methotrexate/
Variable Ustekinumab Infliximab Etanercept Adalimumab Nonbiologicsa Nonbiologicsa Totalb
c
Overall Population
No. 3474 1151 1854 2675 1610 490 11 466
Patient-years 5923 2253 3750 5173 3800 1246 22 311
Duration of follow-up, median, y 1.60 1.62 1.82 1.72 2.27 2.52 1.75
Incident Populationc
No. 1519 246 461 1157 1610 490 5609
Patient-years 2489 324 715 1887 3800 1246 10 560
Duration of follow-up, median, y 1.42 0.93 1.10 1.26 2.27 2.52 1.65
Bionaive Populationc
No. 376 64 298 412 1610 490 3274
Patient-years 585 97 501 614 3800 1246 6858
Duration of follow-up, median, y 1.37 1.21 1.22 1.21 2.27 2.52 1.91
b
Abbreviation: PSOLAR, Psoriasis Longitudinal Assessment and Registry. The total number also includes 212 patients who received other biologics that
a
The nonmethotrexate/nonbiologics cohort includes patients who have never were not indicated in major markets for psoriasis (eg, golimumab, abatacept,
received a biologic or methotrexate, while the methotrexate/nonbiologics and certolizumab), no longer commercially available (eg, efalizumab,
cohort includes those who have never received a biologic but have received alefacept), or investigational (eg, briakinumab, secukinumab, and
methotrexate. Nonbiologic therapies included systemic retinoids, psoralen brodalumab).
c
plus UV-A, and UV-B. The populations are described in the Figure caption.

dition, patients in the ustekinumab cohort had a longer duration

Figure. Cumulative Incidence Rates of Serious Infections of Interest
per 100 Patient-years of disease and a higher prevalence of alcohol use and smoking.
Findings for the incident and bionaive populations were gen-
4
Overall population a
erally similar to those reported for the overall population.
Incident population b In the overall population, 323 serious infections were re-
ported during the registry follow-up period. For 287 events
Events per 100 Patient-years

Bionaive population c
3
(88.9%), the study investigator considered the infection to be
serious because it caused or prolonged hospitalization. The cu-
2 mulative unadjusted incidence rate of serious infections was
1.45 per 100 patient-years (Table 4). The rates in the incident
and bionaive populations were 1.35 and 1.12 per 100 patient-
1 years, respectively. In the overall population, the rates of se-
rious infection were 0.83, 1.47, 1.97, and 2.49 per 100 patient-
years in the ustekinumab, etanercept, adalimumab, and
0
UST IFX ETN ADA Other Non-MTX/ MTX/ infliximab cohorts, respectively, and 1.05 and 1.28 per 100 pa-
Bio d Non-Bio Non-Bio
tient-years in the nonmethotrexate/nonbiologics and metho-
Cohort
trexate/nonbiologics cohorts, respectively (Figure and Table 4).
Data are shown by treatment cohort in the overall, incident, and bionaive Compared with the overall population, the trend was similar
populations. ADA indicates adalimumab; ETN, etanercept; IFX, infliximab; across the 4 biologic cohorts in the incident and bionaive popu-
MTX/non-Bio, methotrexate/nonbiologics; non-MTX/non-Bio, lations (ie, lowest rates for the ustekinumab or etanercept co-
nonmethotrexate/nonbiologics; and UST, ustekinumab.
horts, followed by either the infliximab or adalimumab co-
a
The overall population includes patients who received a biologic agent before
hort) (Figure). The most commonly reported types of serious
(prevalent population) or after (incident population) enrolling in the registry.
b infections across the registry were pneumonia and cellulitis
The incident population, a subset of the overall population, includes patients
who received a biologic agent at or after enrolling in the registry but may have (Table 4). The single most frequently reported serious infec-
been exposed to a different biologic previously. tion was cellulitis. There were isolated reports of necrotizing
c
The bionaive population is a further subset of the incident population and fasciitis (n = 4), tuberculosis (n = 2), histoplasmosis (n = 2),
includes patients who received their first biologic agent at or after enrolling in hepatitis C (n = 1), and Salmonella bacteremia (n = 1). In the
the registry and had never received prior biologic exposure.
d
overall population, 6 patients (0.1% [0.03 per 100 patient-
The other biologics cohort includes patients who received alefacept,
efalizumab, golimumab, and other investigational biologic agents.
years]) had serious infections that resulted in death.
Results of the multivariate analysis for the overall popu-
lation showed that increasing age (HR, 1.37; 95% CI, 1.24-1.52;
index was significantly higher and medical comorbidities (eg, P < .001), presence of diabetes mellitus (HR, 1.70; 95% CI, 1.25-
psoriatic arthritis, cardiovascular disease) and history of sig- 2.32; P < .001), and history of significant infections before reg-
nificant infections were significantly more prevalent in the in- istry entry (HR, 1.67; 95% CI, 1.28-2.18; P < .001) were each
fliximab cohort compared with the other biologic groups. In ad- found to be a significant predictor of serious infection (eTable

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 Risk of Serious Infection With Biologic and Systemic Treatment of Psoriasis Original Investigation Research

Table 2. Demography, Social Characteristics, and Medical History at Entry Into the Registry Among the Overall Population
Nonmethotrexate/ Methotrexate/
Ustekinumab Infliximab Etanercept Adalimumab Nonbiologics Nonbiologics Total
Variable (n = 3474) (n = 1151) (n = 1854) (n = 2675) (n = 1610)a P Valueb (n = 490)a (N = 11 466)c,d
Demography
Age, mean (SD), y 47.2 (13.1) 48.5 (13.5) 48.7 (13.7) 47.6 (13.3) 50.1 (15.8) <.001 55.1 (13.8) 48.5 (13.8)
Male sex, No. (%) 1999 (57.5) 655 (56.9) 1038 (56.0) 1505 (56.3) 830 (51.6) <.001 207 (42.2) 6321 (55.1)
White 3002 (86.4) 966 (83.9) 1482 (80.0) 2138 (79.9) 1357 (84.3) .15 395 (80.6) 9508/
race/ethnicity, 11 465 (82.9)
No. (%)
BMI, mean (SD) 31.3 (7.2) 32.2 (8.2) 30.4 (7.1) 31.0 (7.0) 29.9 (6.9) <.02 30.1 (7.0) 30.9 (7.2)
Obesity class, (n = 3420) (n = 1126) (n = 1820) (n = 2635) (n = 1594) <.001 (n = 484) (n = 11 291)
No./total No. (%)e
Underweight/ 587 (17.2) 194 (17.2) 401 (22.0) 476 (18.1) 372 (23.3) NA 117 (24.2) 2186 (19.4)
normal
Overweight/class 1973 (57.7) 593 (52.7) 1032 (56.7) 1509 (57.3) 913 (57.3) NA 269 (55.6) 6406 (56.7)
I
Obesity class 860 (25.1) 339 (30.1) 387 (21.3) 650 (24.7) 309 (19.4) NA 98 (20.2) 2699 (23.9)
II-III
Social Characteristics, No./Total No. (%)
Current alcohol use 2430/3461 749/1145 1167/1853 1703/2673 1029/1602 .12 233 (47.6) 7444/11 435
(69.9) (65.1) (62.9) (63.7) (63.9) (65.0)
Current smoking 939/3464 265/1147 375/1853 603/2675 373/1605 .64 113 (23.1) 2706/11 445
(27.1) (23.1) (20.2) (22.5) (23.2) (23.6)
Medical History, No./Total No. (%)
Psoriatic arthritis 1134 (32.6) 601 (52.2) 785 (42.3) 1112 (41.6) 237/1610 <.001 140 (28.6) 4098/11 461
(14.7) (35.7)
Cardiovascular 1320 (38.0) 499 (43.4) 686/1852 1006/2674 582/1608 .09 219 (44.7) 4395/11 461
(37.0) (37.6) (36.2) (38.3)
Pulmonary 451 (13.0) 185 (16.1) 284/1852 374/2674 233/1608 .77 82 (16.7) 1645/11 461
(15.3) (14.0) (14.5) (14.4)
Hepatic 133 (3.8) 61 (5.3) 88/1852 110/2674 58/1608 .18 13 (2.7) 477/11 461
(4.7) (4.1) (3.6) (4.2)
Skin cancer 157 (4.5) 62 (5.4) 125/1852 147/2674 137/1608 <.001 33 (6.7) 686/11 461
(6.7) (5.5) (8.5) (6.0)
Other cancers 88 (2.5) 31 (2.7) 67/1852 74/2674 105/1608 <.001 36 (7.3) 408/11 461
(3.6) (2.8) (6.5) (3.6)
Diabetes mellitus 440 (12.7) 161 (14.0) 221/1852 331/2674 204/1608 .98 70 (14.3) 1459/11 461
(11.9) (12.4) (12.7) (12.7)
Significant 802/3463 350/1146 467 (25.2) 660/2674 337/1606 <.001 116 (23.7) 2791/11 444
infectionsf (23.1) (30.5) (24.7) (21.0) (24.4)
d
Abbreviations: BMI, body mass index (calculated as weight in kilograms divided The number of patients for selected parameters varied somewhat across
by height in meters squared); NA, not applicable. treatment cohorts based on data availability; differences are noted.
a e
The nonmethotrexate/nonbiologics and methotrexate/nonbiologics cohorts Obesity class is based on the National Heart, Lung, and Blood Institute Obesity
are described in the Table 1 footnotes. Education Initiative (http://www.nhlbi.nih.gov/health/public/heart/obesity
b
P values for comparisons between combined biologic cohorts and the /lose_wt/bmi_dis.html). Underweight/normal is a BMI less than 25.0,
nonmethotrexate/nonbiologics cohort (reference) were calculated based on overweight/class I is a BMI between 25.0 and 35.0, and obesity class II-III is a
the overall F test from an analysis of variance for continuous variables or a χ2 BMI 35.0 or greater.
f
test for categorical variables. Significant infections are defined as infections requiring treatment within 3
c
The total number is defined in the Table 1 footnotes. The number of patients years before registry enrollment.
for selected parameters varied across treatment cohorts based on data
availability.

in the Supplement). The presence of psoriatic arthritis was not ated with serious infection. Predictors for the incident popu-
associated with serious infection (HR, 1.14; 95% CI, 0.88- lation were similar to those for the overall population, except
1.49; P = .33). Current smoking status (HR, 1.43; 95% CI, 1.08- that only adalimumab (and not infliximab) was significantly
1.88; P = .01) was associated with an increased risk of serious associated with the risk of serious infection. In the bionaive
infection; however, patients who reported current alcohol use population, increasing age was found to be associated with an
were less likely to develop serious infection compared with elevated risk of serious infection, while alcohol use was asso-
those who never used alcohol (HR, 0.68; 95% CI, 0.51-0.93; ciated with a lower risk. No other significant associations were
P = .01). In addition, exposure to infliximab (HR, 2.51; 95% CI, observed, although the number of patients was low in this sub-
1.45-4.33; P < .001) and exposure to adalimumab (HR, 2.13; 95% population. Results of the sensitivity multivariate analysis
CI, 1.33-3.41; P = .002) during the registry were indepen- using the methotrexate/nonbiologics cohort as the reference
dently associated with the risk of serious infection, whereas group were similar to those obtained using the nonmethotrex-
treatment with ustekinumab or etanercept was not associ- ate/nonbiologics cohort as the reference group.

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 Research Original Investigation Risk of Serious Infection With Biologic and Systemic Treatment of Psoriasis

Table 3. Disease Characteristics and Prior Medication Use at Entry Into the Registry Among the Overall Population
Nonmethotrexate/ Methotrexate/
Ustekinumab Infliximab Etanercept Adalimumab Nonbiologics Nonbiologics Total
Variable (n = 3474) (n = 1151) (n = 1854) (n = 2675) (n = 1610)a P Valueb (n = 490)a (N = 11 466)c,d
Disease Characteristics, Mean (SD)
Physician’s Global 2.0 (1.3) 1.8 (1.2) 1.9 (1.1) 1.9 (1.2) 2.3 (1.1) <.001 2.1 (1.2) 2.0 (1.2)
Assessment score
Duration of 19.4 (12.8) 18.4 (12.7) 17.4 (13.35) 17.2 (13.1) 14.3 (14.6) <.001 14.3 (14.8) 17.5 (13.4)
disease, y
Prior Treatment, No./Total No. (%)
Systemic 735/3470 346/1148 408/1848 666/2670 307/1606 <.001 121 (24.7) 2640/11 444
corticosteroids (21.2) (30.1) (22.1) (24.9) (19.1) (23.1)
Immunomodulators 1969/3470 795/1148 813/1848 1254/2670 132/1606 <.001 384 (78.4) 5462/11 444
(56.7) (69.3) (44.0) (47.0) (8.2) (47.7)
Cyclosporine 831/3470 288/1148 204/1848 379/2670 16/1606 <.001 10 (2.0) 1776/11 444
(23.9) (25.1) (11.0) (14.2) (1.0) (15.5)
Methotrexate 1652/3470 682/1148 712/1848 1077/2670 101/1606 <.001 379 (77.3) 469/11 444
(47.6) (59.4) (38.5) (40.3) (6.3) (41.1)
No. of biologics
before study entry
0 376/3470 64/1148 298/1848 412/2670 1610 (100) NA 490 (100) 3274/11 444
(10.8) (5.6) (16.1) (15.4) (28.6)
1 1262/3470 484/1148 1204/1848 1313/2670 0/1606 NA 0 4352/11 444
(36.3) (42.1) (64.9) (49.1) (38.0)
2-3 1546/3470 536/1148 338/1848 907/2670 0/1606 NA 0 3399/11 444
(44.5) (46.6) (18.2) (33.9) (29.6)
4-7 290/3470 67/1148 14/1848 43/2670 0/1606 NA 0 441/11 444
(8.3) (5.8) (0.8) (1.6) (3.8)
c
Abbreviations: BMI, body mass index (calculated as weight in kilograms divided The total number is defined in the Table 1 footnotes. The number of patients
by height in meters squared); NA, not applicable. for selected parameters varied across treatment cohorts based on data
a
The nonmethotrexate/nonbiologics and methotrexate/nonbiologics cohorts availability.
d
are described in the Table 1 footnotes. The number of patients for selected parameters varied somewhat across
b
P values for comparisons between combined biologic cohorts and the treatment cohorts based on data availability; differences are noted.
nonmethotrexate/nonbiologics cohort (reference) were calculated based on
the overall F test from an analysis of variance for continuous variables or a χ2
test for categorical variables.

ciated with an increased risk of serious infection in the smaller

Discussion subset of bionaive patients. Adalimumab and infliximab are
monoclonal antibodies that share a similar mechanism of
Our findings from the prospective, diseased-based PSOLAR (in action.19 In contrast, etanercept (a TNF receptor fusion pro-
which more than 11 000 patients were enrolled) better char- tein) was not associated with the risk of serious infections for
acterize the relative risks of serious infection among patients any of the evaluated populations. This finding is consistent with
treated with various systemic therapies for psoriasis. The cu- observations of a difference in infection risk between pa-
mulative unadjusted rates of serious infection in the overall tients with rheumatoid arthritis exposed to etanercept and
population were 0.83, 1.47, 1.97, and 2.49 per 100 patient- those treated with other anti-TNF agents.19 Analyses of all 3
years for the ustekinumab, etanercept, adalimumab, and in- populations showed that the use of ustekinumab (an interleu-
fliximab cohorts, respectively, and 1.05 and 1.28 per 100 patient- kin 12/23 antagonist) was not associated with an increased risk
years in the 2 nonbiologics cohorts (without methotrexate and of serious infection compared with the use of nonbiologic
with methotrexate, respectively). The most common types of therapies (with and without methotrexate).
serious infection in the overall population were pneumonia and As expected, increasing age, diabetes mellitus, history of
cellulitis, as is typical of hospitalized patients in general14,15 and significant infection, and the use of tobacco were also signifi-
patients enrolled in clinical trials and other registries.1-4,16,17 cantly associated with serious infections in the modeled analy-
The association between TNF inhibitor use and serious in- sis for the overall population. All of these variables have been
fection risk in the treatment of psoriasis and other inflamma- identified previously as risk factors for serious infection in the
tory diseases has been well documented in the literature.6,8,9,18 population with psoriasis.20 Concurrent psoriatic arthritis was
Multivariate analyses of PSOLAR data confirmed that the use not associated with serious infections. The use of alcohol re-
of adalimumab and infliximab was associated with serious in- ported at registry entry appeared to be associated with a lower
fection compared with nonbiologic therapy (with and with- likelihood of developing a serious infection. However, the rea-
out methotrexate) for the overall patient population. This find- sons underlying this finding are unclear, and details on the
ing was replicated for adalimumab (but not for infliximab) in quantity of intake were not captured.
the patients initiating biologic therapy at the time of or after Some limitations inherent to observational studies should
entry into the registry; however, neither treatment was asso- be considered when interpreting these data, including treat-

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 Risk of Serious Infection With Biologic and Systemic Treatment of Psoriasis Original Investigation Research

Table 4. Cumulative Incidence of Serious Infections per 100 Patient-years and Number of Patients by Type of Infection Among the Overall Populationa

No. (%) [95% CI]

Nonmethotrexate/ Methotrexate/
Ustekinumab Infliximab Etanercept Adalimumab Nonbiologicsb Nonbiologicsb Total
Infection or (5923 (2253 (3750 (5173 (3800 (1246 (22 311
Infestation Patient-years) Patient-years) Patient-years) Patient-years) Patient-years) Patient-years) Patient-years)
Overall 49 (0.83) 56 (2.49) 55 (1.47) 102 (1.97) 40 (1.05) 16 (1.28) 323 (1.45)
[0.61-1.09] [1.88-3.23] [1.10-1.91] [1.61-2.39] [0.75-1.43] [0.73-2.09] [1.29-1.61]
Pneumonia 11 (0.19) 10 (0.44) 10 (0.27) 20 (0.39) 8 (0.21) 2 (0.16) 61 (0.27)
[0.09-0.33] [0.21-0.82] [0.13-0.49] [0.24-0.60] [0.09-0.41] [0.02-0.58] [0.21-0.35]
Cellulitis 11 (0.19) 9 (0.40) 14 (0.37) 10 (0.19) 5 (0.13) 3 (0.24) 53 (0.24)
[0.09-0.33] [0.18-0.76] [0.20-0.63] [0.09-0.36] [0.04-0.31] [0.05-0.70] [0.18-0.31]
Sepsis 2 (0.03) 4 (0.18) 1 (0.03) 7 (0.14) 6 (0.16) 2 (0.16) 23 (0.10)
[0.00-0.12] [0.05-0.45] [0.00-0.15] [0.05-0.28] [0.06-0.34] [0.02-0.58] [0.07-0.15]
Diverticulitis 1 (0.02) 5 (0.22) 4 (0.11) 5 (0.10) 1 (0.03) 1 (0.08) 17 (0.08)
[0.00-0.09] [0.07-0.52] [0.03-0.27] [0.03-0.23] [0.00-0.15] [0.00-0.45] [0.04-0.12]
Urinary tract 3 (0.05) 1 (0.04) 3 (0.08) 4 (0.08) 3 (0.08) 0 (0.00) 15 (0.07)
infection [0.01-0.15] [0.00-0.25] [0.02-0.23] [0.02-0.20] [0.02-0.23] [0.00-0.24] [0.04-0.11]
Abscess 3 (0.05) 3 (0.13) 3 (0.08) 5 (0.10) 0 (0.00) 0 (0.00) 14 (0.06)
[0.01-0.15] [0.03-0.39] [0.02-0.23] [0.03-0.23] [0.00-0.08] [0.00-0.24] [0.03-0.11]
Skin 4 (0.07) 4 (0.18) 0 (0.00) 3 (0.06) 1 (0.03) 1 (0.08) 14 (0.06)
[0.02-0.17] [0.05-0.45] [0.00-0.08] [0.01-0.17] [0.00-0.15] [0.00-0.45] [0.03-0.11]
Bronchitis 2 (0.03) 2 (0.09) 3 (0.08) 4 (0.08) 1 (0.03) 1 (0.08) 13 (0.06)
[0.00-0.12] [0.01-0.32] [0.02-0.23] [0.02-0.20] [0.00-0.15] [0.00-0.45] [0.03-0.10]
Pyelonephritis 0 (0.00) 3 (0.13) 0 (0.00) 6 (0.12) 2 (0.05) 0 (0.00) 11 (0.05)
[0.00-0.05] [0.03-0.39] [0.00-0.08] [0.04-0.25] [0.01-0.19] [0.00-0.24] [0.02-0.09]
Colitis 2 (0.03) 1 (0.04) 0 (0.00) 2 (0.04) 4 (0.11) 0 (0.00) 9 (0.04)
[0.00-0.12] [0.00-0.25] [0.00-0.08] [0.00-0.14] [0.03-0.27] [0.00-0.24] [0.02-0.08]
Gastroenteritis 1 (0.02) 1 (0.04) 2 (0.05) 3 (0.06) 1 (0.03) 1 (0.08) 9 (0.04)
[0.00-0.09] [0.00-0.25] [0.01-0.19] [0.01-0.17] [0.00-0.15] [0.00-0.45] [0.02-0.08]
Appendicitis 2 (0.03) 0 (0.00) 1 (0.03) 3 (0.06) 0 (0.00) 2 (0.16) 8 (0.04)
[0.00-0.12] [0.00-0.13] [0.00-0.15] [0.01-0.17] [0.00-0.08] [0.02-0.58] [0.02-0.07]
Osteomyelitis 1 (0.02) 1 (0.04) 3 (0.08) 0 (0.00) 1 (0.03) 0 (0.00) 6 (0.03)
[0.00-0.09] [0.00-0.25] [0.02-0.23] [0.00-0.06] [0.00-0.15] [0.00-0.24] [0.01-0.06]
Wound 1 (0.02) 0 (0.00) 4 (0.11) 0 (0.00) 1 (0.03) 0 (0.00) 6 (0.03)
infection [0.00-0.09] [0.00-0.13] [0.03-0.27] [0.00-0.06] [0.00-0.15] [0.00-0.24] [0.01-0.06]
Influenza 0 (0.00) 0 (0.00) 1 (0.03) 3 (0.06) 1 (0.03) 0 (0.00) 5 (0.02)
[0.00-0.05] [0.00-0.13] [0.00-0.15] [0.01-0.17] [0.00-0.15] [0.00-0.24] [0.01-0.05]
Meningitis 0 (0.00) 1 (0.04) 0 (0.00) 3 (0.06) 0 (0.00) 0 (0.00) 5 (0.02)
[0.00-0.05] [0.00-0.25] [0.00-0.08] [0.01-0.17] [0.00-0.08] [0.00-0.24] [0.01-0.05]
Necrotizing 0 (0.00) 1 (0.04) 1 (0.03) 2 (0.04) 0 (0.00) 0 (0.00) 4 (0.02)
fasciitis [0.00-0.05] [0.00-0.25] [0.00-0.15] [0.00-0.14] [0.00-0.08] [0.00-0.24] [0.00-0.05]
Viral 0 (0.00) 1 (0.04) 0 (0.00) 3 (0.06) 0 (0.00) 0 (0.00) 4 (0.02)
[0.00-0.05] [0.00-0.25] [0.00-0.08] [0.01-0.17] [0.00-0.08] [0.00-0.24] [0.00-0.05]
Herpes zoster 0 (0.00) 1 (0.04) 1 (0.03) 2 (0.04) 0 (0.00) 0 (0.00) 4 (0.02)
[0.00-0.05] [0.00-0.25] [0.00-0.15] [0.00-0.14] [0.00-0.08] [0.00-0.24] [0.00-0.05]
a b
Serious infections displayed here are those that occurred at least 4 times The nonmethotrexate/nonbiologics and methotrexate/nonbiologics cohorts
across treatment cohorts. are described in the Table 1 footnotes.

ment selection and patient participation biases due to the lack tional study given the lack of randomization of patients to treat-
of randomization. Treatments are chosen solely by the pre- ment groups, clinical characteristics were included in the Cox
scriber, and only patients with access to participating sites were proportional hazards regression modeling analyses of PSO-
represented. Patients were enrolled based on broad enroll- LAR data.
ment criteria, and participation was voluntary. It may some-
times be impossible to validate diagnoses and outcomes. In this
analysis, the use of methotrexate (which carries its own risk
of infection) was not excluded from the biologic comparator
Conclusions
cohorts, which may have affected some outcomes. Finally, Among 9154 patients treated with biologic agents in PSOLAR,
based on statistical testing, some differences were noted in pa- our results indicate that the risk of serious infection varies
tient characteristics across biologic cohorts at entry into the across treatments. Specifically, adalimumab and infliximab ap-
registry. However, due to the large sample sizes, the statisti- pear to carry a higher risk of serious infection compared with
cal tests were sensitive enough to detect small differences be- nonmethotrexate and nonbiologic therapies, whereas etaner-
tween groups, even in cases in which numerical differences cept and ustekinumab do not. Continued follow-up of PSO-
were not apparent. Therefore, statistical significance may not LAR patients will provide increasingly robust data and may al-
necessarily connote clinical relevance. Nonetheless, because low for assessment of the risk of infection in other treatment
such variables would be expected to differ in an observa- cohorts, such as those treated with combination or sequen-

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 Research Original Investigation Risk of Serious Infection With Biologic and Systemic Treatment of Psoriasis

tial therapy. The risk of serious infection associated with data,24,25 provide real-world evidence of serious infection
TNF inhibitors is noted in current international guidelines risk with specific biologic treatments, thereby providing
for treating patients with psoriasis, but the risk is not differ- physicians with important guidance regarding the potential
entiated across individual biologic therapies.21-23 The find- for serious infections when choosing treatment for patients
ings reported herein, and in other safety analyses of PSOLAR with psoriasis.

ARTICLE INFORMATION advisory board for AbbVie, Dexcel, Janssen 5. Rustin MH. Long-term safety of biologics in the
Accepted for Publication: March 3, 2015. Biotech, Medison, Neopharm, Novartis, Perrigo, treatment of moderate-to-severe plaque psoriasis:
Pfizer, and Rafa and reported being an investigator review of current data. Br J Dermatol. 2012;167(suppl
Published Online: May 13, 2015. for AbbVie, Janssen Biotech, Medison, and 3):3-11.
doi:10.1001/jamadermatol.2015.0718. Novartis. Dr Leonardi reported serving as a 6. Garcia-Doval I, Carretero G, Vanaclocha F, et al.
Author Affiliations: Department of Dermatology, consultant for AbbVie, Amgen, Dermira, Janssen Risk of serious adverse events associated with
School of Medicine and Biological Sciences, State Biotech, Boehringer-Ingleheim, Eli Lilly, Leo biologic and nonbiologic psoriasis systemic therapy:
University of New York at Buffalo (Kalb); Pharma, Sandoz, UCB Pharma, and Pfizer; reported patients ineligible vs eligible for randomized
Department of Dermatology, Stanford University being an investigator for AbbVie, Amgen, Anacor, controlled trials. Arch Dermatol. 2012;148(4):463-
School of Medicine, Stanford, California Celgene, Coherus, Eli Lilly, Galderma, Janssen 470.
(Fiorentino); Department of Dermatology, Mount Biotech, Merck, Pfizer, Sandoz, Stiefel, Leo Pharma,
Sinai Medical Center, New York, New York Novartis, and Tolmar; and reported serving on a 7. Tan X, Balkrishnan R, Feldman SR. Infections
(Lebwohl); Dermadvances Research, University of speakers bureau for AbbVie. Drs Goyal, associated with the use of tumor necrosis factor-α
Manitoba, Winnipeg, Canada (Toole); Laval Fakharzadeh, Chevrier, and Langholff; Mr Calabro; inhibitors in psoriasis. J Drugs Dermatol. 2013;12(3):
University and Centre de Dermatologique du and Ms You are employees of Janssen e41-e45.
Quebec Metropolitain, Quebec City, Quebec, pharmaceutical companies of Johnson & Johnson 8. Dommasch ED, Abuabara K, Shin DB, Nguyen J,
Canada (Poulin); Siaal Research Center for Family and own stock in Johnson & Johnson. No other Troxel AB, Gelfand JM. The risk of infection and
Medicine and Primary Care, Ben-Gurion University disclosures were reported. malignancy with tumor necrosis factor antagonists
of the Negev, Beer-Sheva, Israel (Cohen); Janssen Funding/Support: This study was sponsored by in adults with psoriatic disease: a systematic review
Scientific Affairs, LLC, Horsham, Pennsylvania Janssen Scientific Affairs, LLC. and meta-analysis of randomized controlled trials.
(Goyal, Fakharzadeh, Calabro); Janssen Research & J Am Acad Dermatol. 2011;64(6):1035-1050.
Development, LLC, Horsham and Spring House, Role of the Funder/Sponsor: The sponsor had a
role in the design and conduct of the study; 9. Galloway JB, Hyrich KL, Mercer LK, et al; BSRBR
Pennsylvania (Chevrier, Langholff, You); Control Centre Consortium; British Society for
Department of Dermatology, Saint Louis University collection, management, analysis, and
interpretation of data; preparation, review, or Rheumatology Biologics Register. Anti-TNF therapy
School of Medicine, St Louis, Missouri (Leonardi). is associated with an increased risk of serious
approval of the manuscript; and decision to submit
Author Contributions: Drs Kalb and Goyal had full the manuscript for publication. infections in patients with rheumatoid arthritis
access to all the data in the study and take especially in the first 6 months of treatment:
responsibility for the integrity of the data and the Additional Contributions: Cynthia Arnold, BS, updated results from the British Society for
accuracy of the data analysis. Samantha Simpson, BS, and Kristin Ruley Sharples, Rheumatology Biologics Register with special
Study concept and design: Kalb, Lebwohl, Poulin, PhD (Janssen Scientific Affairs, LLC), provided emphasis on risks in the elderly. Rheumatology
Fakharzadeh, Calabro, Chevrier. editorial assistance and writing support for the (Oxford). 2011;50(1):124-131.
Acquisition, analysis, or interpretation of data: All manuscript. Kezhen L. Tang, PhD (Janssen
Research & Development, LLC) provided statistical 10. Van Assche G, Lewis JD, Lichtenstein GR, et al.
authors. The London position statement of the World
Drafting of the manuscript: Kalb, Poulin, Cohen, support. Joel Gelfand, MD, MSCE (Hospital of the
University of Pennsylvania, Philadelphia), and the Congress of Gastroenterology on Biological
Goyal, Fakharzadeh, Langholff. Therapy for IBD with the European Crohn’s and
Critical revision of the manuscript for important PSOLAR Scientific Advisory Committee provided
critical review of the analytical plan for the Colitis Organisation: safety. Am J Gastroenterol.
intellectual content: All authors. 2011;106(9):1594-1602.
Statistical analysis: Langholff, You. manuscript. None of these individuals received
Obtained funding: Calabro, Chevrier. financial compensation for their services outside 11. Burmester GR, Panaccione R, Gordon KB,
Administrative, technical, or material support: their usual salaries. McIlraith MJ, Lacerda AP. Adalimumab: long-term
Goyal, Calabro, Chevrier. safety in 23 458 patients from global clinical trials in
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