J AM ACAD DERMATOL
VOLUME 78, NUMBER 3
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1. Kubica AW, Brewer JD. Melanoma in immunosuppressed
patients. Mayo Clin Proc. 2012;87:991-1003.
2. Pratt G, Goodyear O, Moss P. Immunodeficiency and immu-
notherapy in multiple myeloma. Br J Haematol. 2007;138:
563-579.
3. Yang J, Terebelo HR, Zonder JA. Secondary primary malig-
nancies in multiple myeloma: an old NEMESIS revisited. Adv
Hematol. 2012;2012:801495.
4. Dong C, Hemminki K. Second primary neoplasms among 53
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den, 1958-1996: a search for common mechanisms. Br J
Cancer. 2001;85:997-1005.
5. Mailankody S, Pfeiffer RM, Kristinsson SY, et al. Risk of acute
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tiple myeloma and its precursor disease (MGUS). Blood. 2011;
118:4086-4092.
https://doi.org/10.1016/j.jaad.2017.10.014
A comparison of apremilast
monotherapy and combination therapy
for plaque psoriasis in clinical practice: A
Canadian multicenter retrospective study
To the Editor: Apremilast is approved for treatment of
moderate-to-severe plaque psoriasis (PP) as a mono-
therapy (MT). In clinical practice, it is sometimes
used in combination therapy (CT) to manage resid-
ual PP that cannot be controlled with 1 agent alone.
However, there are scant data comparing the real-
world efficacy and safety of apremilast MT with those
of CT.
We conducted a retrospective review of 148
patients at 2 academic centers in Toronto, Canada,
to compare the real-world efficacy and safety of
apremilast MT with those of CT. The study was
approved by the research ethics board at Women’s
College Hospital and Sunnybrook Health Sciences
Centre. The inclusion criteria were patients with PP
who (1) used apremilast and (2) were at least
18 years old. CT was defined as apremilast treatment
with phototherapy, systemic therapy, or biologic
therapy. Patients receiving CT were screened to
ensure that therapy other than apremilast had been
used for at least 12 weeks before initiation of
apremilast therapy to mitigate confounding efficacy
and safety outcomes. Patients whose CT changed
after addition of apremilast were excluded. All
patients were permitted to use topicals. Efficacy
(Psoriasis Area and Severity Index score of 75 or
Physician Global Assessment score of 0 or 1) and
safety (reported adverse events [AEs]) were assessed
from baseline to week 16 (discontinuations were
considered nonresponse). The Pearson chi-square
test and Fisher’s exact test were used to compare
proportions, 2-tailed t tests were used to compare
Research Letters 623
means, and logistic regression was used to compare
efficacy and safety end points per the MT and CT
cohorts, with a P value of 0.05 or less considered
significant.
Baseline demographics (Table I) and efficacy and
safety outcomes were summarized (Table II).
Although not statistically significant, a greater pro-
portion of patients receiving MT achieved a response
than those patients receiving CT (26 of 59 who
received MT [44.1%] vs 33 of 89 who received CT
[37.1%] [P ¼ .396]). This may be explained because
patients receiving CT presented with more chal-
lenging psoriasis, as reflected by the higher propor-
tion of patients with diabetes in their cohort
(P ¼ .013), which is associated with systemic treat-
ment resistance and increased psoriasis severity.1
Significantly more patients receiving CT had failed
prior conventional systemic or biologic therapy
(P\.001), further supporting their challenging pre-
sentation. The CT cohort also reported a significantly
greater proportion of patients with psoriatic arthritis
(P\.001) because apremilast is used in CT for both
residual PP and for management of psoriatic
arthritis.2 Overall, both groups reported a propor-
tionately appreciable clinical response compared
with the 28.8% to 33.1% success rate of the ESTEEM
clinical trials.3,4
Similar proportions of patients receiving MT and
patients receiving CT experienced 1 or more AEs
(37 of 59 who received MT [62.7%] vs 55 of 89
who received CT [61.8%] [P ¼ .911]). Subgroup
analysis of commonly reported AEs showed no
significant difference between cohorts: headache
(P ¼ .075), diarrhea (P ¼ .796), nausea (P ¼ .210),
and weight loss (P ¼ .486). Many common AEs
were reported in similar proportions within clinical
trials, with the exception of upper respiratory tract
infection and nasopharyngitis, which were not
actively elicited at our centers.3,4 One patient
receiving CT experienced a severe AE and was
admitted to the emergency department on account
of significant acute weight loss; the weight loss
stabilized and the patient continued treatment.
These findings suggest that apremilast results in
equally safe real-world outcomes, whether used as
MT or used in CT.
Despite being limited by its retrospective nature,
this real-world multicenter study suggests that apre-
milast can result in clinically significant reduction of
PP, with primarily mild-to-moderate AEs, when it is
used in clinical practice both as MT and in CT.
Physicians may consider using apremilast as MT to
control chronic PP or in CT to reduce residual PP that
624 Research Letters J AM ACAD DERMATOL
MARCH 2018

Table I. Population demographics and baseline characteristics of study cohort

Combination
Monotherapy therapy All patients
Variable (n = 59) (n = 89) (n = 148) P value
Male sex, n (%) 34 (57.6) 51 (57.3) 85 (57.4) .969
Mean age (SD), y 54.1 (12.0) 51.5 (11.9) 52.5 (12.0) .193
Mean disease duration (SD), y 19.1 (14.2) 20.7 (12.8) 20.0 (13.4) .598
Comorbidities, n (%)
Psoriatic arthritis 17 (28.8) 51 (57.3) 68 (45.9) \.001
Hypertension 18 (30.5) 32 (36.0) 50 (33.8) .493
Dyslipidemia 12 (20.3) 30 (33.7) 42 (28.4) .077
Diabetes 6 (10.2) 24 (27.0) 30 (20.3) .013
History of malignancy 15 (25.4) 11 (12.4) 26 (17.6) .066
Liver disease 8 (13.6) 16 (18.0) 24 (16.2) .475
Psychiatric disorder 9 (15.3) 14 (15.7) 23 (15.5) .938
Gastrointestinal symptoms 5 (8.5) 8 (9.0) 13 (8.8) .914
Hypothyroidism 4 (6.8) 8 (9.0) 12 (8.1) .763*
Previously failed nontopical therapies, mean (SD) 2.1 (1.6) 3.6 (2.0) 3.0 (2.0) \.001
Failed therapies before apremilast, n (%)
Phototherapy 43 (72.9) 58 (65.2) 101 (68.2) .324
Methotrexate 30 (50.8) 64 (71.9) 94 (63.5) .009
Acitretin 20 (33.9) 44 (49.4) 64 (43.2) .062
Etanercept 9 (15.3) 44 (49.4) 53 (35.8) \.001
Adalimumab 7 (11.9) 32 (36.0) 39 (26.4) .001
Ustekinumab 6 (10.2) 27 (30.3) 33 (22.3) .004
Infliximab 6 (10.2) 13 (14.6) 19 (12.8) .429
Cyclosporine 2 (3.4) 17 (19.1) 19 (12.8) .005
Alefacept 2 (3.4) 7 (7.9) 9 (6.1) .317*
Efalizumab 0 (0.0) 2 (2.2) 2 (1.4) .517*
Prior conventional systemic and/or biologic therapy, n (%) 43 (72.9) 84 (94.4) 127 (85.8) \.001
Prior conventional systemic therapy, n (%) 39 (66.1) 74 (83.1) 113 (76.4) .017
Prior biologic therapy, n (%) 13 (22.0) 60 (67.4) 73 (49.3) \.001
Combination therapies per patient, mean (SD) — 1.2 (0.4) — —
Combination therapies used by patients, n (%)
Methotrexate — 19 (21.3) — —
Etanercept — 18 (20.2) — —
Ustekinumab — 14 (15.7) — —
Adalimumab, methotrexate — 8 (9.0) — —
Infliximab — 7 (7.9) — —
Adalimumab — 5 (5.6) — —
Secukinumab — 3 (3.4) — —
Cyclosporine — 3 (3.4) — —
Ustekinumab, acitretin — 3 (3.4) — —
Phototherapy — 2 (2.2) — —
Infliximab, methotrexate — 2 (2.2) — —
Sulfasalazine — 2 (2.2) — —

Proportions were compared by using the Pearson chi-square test or Fisher’s exact test. Means were compared using a 2-tailed independent
samples t test. Only comorbidities reported in at least 10 of all patients were listed. Only combination therapies reported in at least 2 of all
patients were listed. Patients were permitted to be treated with combinations of biologics and apremilast because some health insurance
plans in Canada cover this type of CT. In other cases, patients received compassionate doses of apremilast through Celgene Canada.
Boldface indicates statistical significance.
SD, Standard deviation.
*Fisher’s exact test was conducted instead of the Pearson chi-square test.
J AM ACAD DERMATOL Research Letters 625
VOLUME 78, NUMBER 3

Table II. Comparison of efficacy and safety outcomes in patients receiving apremilast monotherapy and
combination therapy
Monotherapy Combination therapy All patients
Variable (n = 59) (n = 89) (n = 148) P value; OR (95% CI)
Efficacy end point: PASI-75 or PGA 26 (44.1) 33 (37.1) 59 (39.9) .396; 0.748 (0.383-1.462)
0/1, n (%)
Baseline PASI, mean (SD) 13.2 (6.5) 11.3 (6.0) 12.2 (6.2)
16-wk PASI, mean (SD) 5.0 (5.7) 5.5 (8.2) 5.3 (7.2)
Safety end point: $1 AE, n (%) 37 (62.7) 55 (61.8) 92 (62.2) .911; 0.962 (0.488-1.897)
Reported AEs, n (%)
Headache 14 (23.7) 11 (12.4) 25 (16.9) .075; 0.453 (0.190-1.083)
Diarrhea 9 (15.3) 15 (16.9) 24 (16.2) .796; 1.126 (0.457-2.772)
Nausea 11 (18.6) 10 (11.2) 21 (14.2) .210; 0.552 (0.218-1.398)
Weight loss 4 (6.8) 9 (10.1) 13 (8.8) .486; 1.547 (0.454-5.275)
Nonspecific gastrointestinal 2 (3.4) 10 (11.2) 12 (8.1) .106; 3.608 (0.761-17.098)
symptoms
Loose stool 6 (10.2) 5 (5.6) 11 (7.4) .308; 0.526 (0.153-1.809)
Abdominal pain 4 (6.8) 7 (7.9) 11 (7.4) .805; 1.174 (0.328-4.201)
Fatigue 5 (8.5) 2 (2.2) 7 (4.7)
Vomiting 2 (3.4) 5 (5.6) 7 (4.7)
Migraine 3 (5.1) 2 (2.2) 5 (3.4)
Sleep disturbance 3 (5.1) 2 (2.2) 5 (3.4)
Dizziness 2 (3.4) 2 (2.2) 4 (2.7)
Upper respiratory tract infection 1 (1.7) 3 (3.4) 4 (2.7)
Appetite (decreased) 3 (5.1) 0 (0.0) 3 (2.0)
Bloating 3 (5.1) 0 (0.0) 3 (2.0)
Back pain 2 (3.4) 1 (1.1) 3 (2.0)
Ophthalmologic concerns: 2 (3.4) 1 (1.1) 3 (2.0)
blurry vision
(2 cases) and iritis (1 case)
Arthralgia 1 (1.7) 2 (2.2) 3 (2.0)
Increased bowel movements 1 (1.7) 2 (2.2) 3 (2.0)
Flatulence 2 (3.4) 0 (0.0) 2 (1.4)
Leg pain 0 (0.0) 2 (2.2) 2 (1.4)
Depression 2 (3.4) 0 (0.0) 2 (1.4)
Mood change 0 (0.0) 2 (2.2) 2 (1.4)
Swollen face 1 (1.7) 1 (1.7) 2 (1.4)
Reported AEs per subject, n (%)
0 22 (37.3) 34 (38.2) 56 (37.8)
1 13 (22.0) 22 (24.7) 35 (23.6)
2 9 (15.3) 14 (15.7) 23 (15.5)
3 4 (6.8) 12 (13.5) 16 (10.8)
$4 11 (18.6) 7 (7.9) 18 (12.2)
Reported AEs per subject, mean 1.5 (1.6) 1.3 (1.4) 1.4 (1.5) t test: .368
(SD)

Binary logistic regression was used to compare outcomes in the monotherapy and combination therapy cohorts. Mean numbers of reported
AEs per subject were compared by using a 2-tailed independent samples t test. Only AEs reported in at least 2 of all patients are listed.
AE, Adverse event; CI, confidence interval; OR, odds ratio; PASI, Psoriasis Area and Severity Index; PGA, Physician Global Assessment; SD,
standard deviation.

is not adequately controlled with another treatment
alone.
Arvin Ighani, BMSc,a Jorge R. Georgakopoulos,
BSc,b Scott Walsh, MD, FRCPC,c,d,e Neil H.
Shear, MD, FRCPC,c,d,e and Jensen Yeung, MD,
FRCPCc,d,e,f
Faculty of Medicinea and Division of Dermatology,
Department of Medicine, University of Toronto,
Toronto, Ontario, Canadac; Schulich School of
Medicine and Dentistry, Western University,
London, Ontario, Canadab; Sunnybrook Health
Sciences Centre, Toronto, Ontario, Canadad;
Women’s College Hospital, Toronto, Ontario,
626 Research Letters
Canadae; and Probity Medical Research Inc,
Waterloo, Ontario, Canadaf
Funding sources: None.
Disclosure: Dr Yeung has been a speaker and/or
consultant and/or investigator for AbbVie, Aller-
gan, Amgen, Astellas, Boehringer Ingelheim,
Celgene, Centocor, Coherus, Dermira, Eli Lilly,
Forward, Galderma, Janssen, Leo, Medimmune,
Merck, Novartis, Pfizer, Regeneron, and Takeda.
Dr Shear has been a consultant and/or speaker
for AbbVie, Actelion, Amgen, Celgene, Hospira,
Janssen, Janssen Biotech, Lilly, Novartis, Sanofi,
Genzyme, and Takeda. Dr Walsh has been a
consultant for AbbVie, Amgen, Celgene, Janssen,
and Lilly. Mr Georgakopoulos and Mr Ighani
have no conflicts of interest to declare.
Reprints not available from the authors.
Correspondence to: Arvin Ighani, BMSc, Depart-
ment of Dermatology, Faculty of Medicine,
J AM ACAD DERMATOL
MARCH 2018
University of Toronto, 1 King’s College Circle,
Toronto, ON, Canada M5S 1A8
E-mail: arvin.ighani@mail.utoronto.ca
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2. Deeks ED. Apremilast: a review in psoriasis and psoriatic
arthritis. Drugs. 2015;75(12):1393-1403.
3. Paul C, Cather J, Gooderham M, et al. Efficacy and safety of
apremilast, an oral phosphodiesterase 4 inhibitor, in patients
with moderate-to-severe plaque psoriasis over 52 weeks: a
phase III, randomized controlled trial (ESTEEM 2). Br J Dermatol.
2015;173(6):1387-1399.
4. Papp K, Reich K, Leonardi CL, et al. Apremilast, an oral phospho-
diesterase 4 (PDE4) inhibitor, in patients with moderate to severe
plaque psoriasis: results of a phase III, randomized, controlled trial
(Efficacy and Safety Trial Evaluating the Effects of Apremilast in
Psoriasis [ESTEEM] 1). J Am Acad Dermatol. 2015;73(1):37-49.
https://doi.org/10.1016/j.jaad.2017.09.060