Clinical Review & Education

Review

Combining Biologic Therapies With Other Systemic

Treatments in Psoriasis
Evidence-Based, Best-Practice Recommendations From the
Medical Board of the National Psoriasis Foundation
April W. Armstrong, MD, MPH; Jerry Bagel, MD; Abby S. Van Voorhees, MD; Andrew D. Robertson, PhD;
Paul S. Yamauchi, MD

IMPORTANCE While monotherapy with biologic agents is effective for many patients with
psoriasis, some patients require combination therapy. Evidence-based recommendations on
combination therapy provide guidance for treating appropriately selected patients with
psoriasis.

OBJECTIVE To make evidence-based, best-practice recommendations regarding combining

biologics with other systemic treatments, including phototherapy, oral medications, or other
biologics, for psoriasis treatment.

EVIDENCE REVIEW We searched the MEDLINE database for studies from January 1, 1946, to
June 18, 2013, that evaluated therapies combining biologics with phototherapy, oral
medications, or other biologic agents. The Medical Board of the National Psoriasis Foundation
arrived at best-practice recommendations through group discussion and voting.

FINDINGS Few trials evaluated the efficacy and safety of combination therapies in moderate
to severe psoriasis. Combining biologics, such as etanercept or adalimumab, with
phototherapy likely results in greater reduction in disease severity than either alone.
Etanercept and methotrexate combination is more effective than monotherapy with either
medication. A combination of infliximab with methotrexate results in greater efficacy than
infliximab alone. With concomitant use of acitretin, the dosing of etanercept can be reduced
to maintain similar levels of efficacy. Short-term cyclosporine use has been combined with
etanercept or adalimumab to control psoriasis flares. Based on the expert opinion of the
Medical Board of the National Psoriasis Foundation, the preferred order for combining a
second modality with biologics is biologic and methotrexate combination, biologic and
acitretin combination, and then biologic and phototherapy combination. In the psoriasis
literature, there are overall insufficient data on combining biologics with acitretin,
cyclosporine, or a second biologic.

CONCLUSIONS AND RELEVANCE Among appropriately selected patients with psoriasis,

carefully chosen combinations may result in greater efficacy, while minimizing toxicity. Author Affiliations: Department of
Dermatology, University of Colorado
Denver (Armstrong); currently in
private practice in East Windsor, New
Jersey (Bagel); Department of
Dermatology, University of
Pennsylvania School of Medicine,
Philadelphia (Van Voorhees); National
Psoriasis Foundation, Portland,
Oregon (Robertson); Department of
Dermatology, David Geffen School of
Medicine at UCLA, Los Angeles,
California (Yamauchi).
Corresponding Author: April W.
Armstrong, MD, MPH, Department of
Dermatology, University of Colorado
Denver, 12801 E 17th Ave, Mail Stop
JAMA Dermatol. doi:10.1001/jamadermatol.2014.3456 8127, Aurora, CO 80045
Published online December 17, 2014. (aprilarmstrong@post.harvard.edu).

E1

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 Clinical Review & Education Review Biologic Therapies and Other Psoriasis Treatments

P
soriasis is a chronic inflammatory disease that affects 2% to
4% of the world’s population.1 It is associated with cardio-
metabolic, rheumatologic, and psychiatric comorbidities,
and patients with psoriasis experience significantly reduced qual-
ity of life.2 Before the advent of biologic therapies, common treat-
ments for moderate to severe psoriasis included phototherapy and
systemic oral agents such as methotrexate, acitretin, and cyclospor-
ine. Since the mid-2000s, biologic agents, such as etanercept, adali-
mumab, infliximab, and ustekinumab, have been used widely to treat
moderate to severe psoriasis. While monotherapy with photo-
therapy, conventional systemic agents, or biologics can be effec-
tive for many patients, some patients continue to experience inad-
equate response on approved dosages. Although continually
increasing the dosage of the monotherapy is one management op-
tion, this option may be limited by concerns of accumulating toxic-
ity and expense.
Specifically, various monotherapies at escalating dosages carry
unique dose-related toxicities. For example, high-dose photo-
therapy is associated with increased risk of burning, and long-term
use is associated with increased skin cancer risk, especially with
UV-A.3 Some investigators recommend limiting lifetime psoralen–
UV-A (PUVA) treatments to fewer than 200 sessions.4 Data are in-
sufficient regarding the maximum number of phototherapy ses-
sions allowable for patients with darker skin types. Methotrexate use
has been associated with bone marrow suppression, immunosup-
pression, and liver toxicities. While cyclosporine is helpful in man-
aging flares, it is associated with immunosuppression, hyperten-
sion, and nephrotoxicity, especially when used long term. Acitretin
may cause cheilitis, dyslipidemia, and hair loss.5
Owing to different pharmacodynamics, pharmacokinetics, and
toxicities associated with various psoriasis treatments, carefully se-
lected combination therapies may lead to greater efficacy while mini-
mizing toxicity. A combination approach is often adopted in the treat-
ment of psoriatic arthritis to improve overall treatment response.
Physicians and physician extenders typically reserve combina-
torial approaches for treating challenging patients with psoriasis, but
rigorously conducted clinical investigations on combination sys-
temic therapies are scarce.6,7 One time-honored combination ap-
proach to treating moderate to severe psoriasis is the use of a reti-
noid in combination with phototherapy.8-12 Combination therapy
with a retinoid and PUVA has been shown to clear psoriasis more
rapidly than PUVA alone.8,11,13 Combination treatment of a retinoid
with UV-B results in greater improvement than either treatment as
monotherapy.9,13 However, not all combinations are desired; for ex-
ample, combination treatment with cyclosporine and PUVA may lead
to increased skin cancer risk.14
While the approved biologic medications are highly effective in
most patients with psoriasis, some patients lack a complete re-
sponse to biologic monotherapy and require combination ap-
proaches for disease control. Biologics have the potential to act syn-
ergistically in combination with other systemic treatments,15 and each
has a distinctive safety profile compared with oral medications.15 To
date, no evidence-based recommendations exist for the use of bio-
logics in combination with other systemic therapeutic modalities in
the United States. In this article, we discuss combining biologic agents
with other treatment modalities, including phototherapy, oral medi-
cations, or another biologic agent, and we make recommendations
on biologic combinations based on the available evidence.
Methods
To provide evidence-based treatment recommendations, we per-
formed a literature search of primary studies on the use of biolog-
ics in combination with other systemic agents in psoriasis. We
searched the MEDLINE database to identify clinical trials, case re-
ports, and abstracts concerning such combination therapies from
January 1, 1946, to June 18, 2013. We used the following search terms:
psoriasis, treatment, combination therapy, biologics, photo-
therapy, UV-B therapy, nbUV-B, psoralen UV-A therapy, PUVA, ex-
cimer laser, methotrexate, acitretin, cyclosporine, etanercept, inflix-
imab, adalimumab, and ustekinumab. Efalizumab and alefacept were
not included in the primary search owing to their discontinuation un-
less they appear in combination with other biologics approved by
the Food and Drug Administration. Because of the limited availabil-
ity of randomized clinical trials evaluating combination therapy with
systemic medications, observational studies assessing the effi-
cacy, benefits, or risks associated with the combination therapies
were also evaluated. For the selected studies, we performed evi-
dence grading based on the grading recommendations and evi-
dence quality by Robinson et al16 (Table 1).
Results
Biologics and Phototherapy
Recommendations for Combining Biologics and Phototherapy
While most physicians and physician extenders will prescribe biologic
monotherapy first before considering combination therapy in prac-
tice, they may consider combining biologics with phototherapy for
patients not responding to biologic monotherapy. Rigorously con-
ducted comparative effectiveness studies are lacking that compare

Table 1. Grading for Recommendation and Evidencea

Strength of Grading for Level of Quality of
Recommendation Recommendation Evidence Supporting Evidence
1 Strong recommendation; A Systematic review or meta-analysis,
high-quality, patient-oriented randomized clinical trials with consistent
evidence findings, all-or-none observational study
2A Weak recommendation; B Systematic review or meta-analysis of
limited-quality, patient- lower-quality clinical trials or studies with
oriented evidence limitations and inconsistent findings,
lower-quality clinical trial, cohort study,
case-control study
2B Weak recommendation, C Consensus guidelines, usual practice, a
The grading scale was adapted from
low-quality evidence expert opinion, case series
the study by Robinson et al.16

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 Biologic Therapies and Other Psoriasis Treatments
Table 2. Strength of Recommendations for the Use of Biologics
in Combination With Phototherapy for Psoriasis Treatment
Strength of Level of
Agent Recommendation Evidence Source
Etanercept and 2A B Kircik et al,21 2008;
phototherapy Gambichler et al,17 2011;
Park et al,18 2013;
De Simone et al,22 2011;
Wolf et al,23 2009;
Lynde et al,24 2012
Adalimumab and 2A B Bagel,25 2011;
phototherapy Wolf et al,19 2011
Ustekinumab and 2B C Wolf et al,20 2012
phototherapy
treatments combining biologics plus phototherapy vs monotherapy
with either modality. The results of small controlled studies and ob-
servational studies17-20 appear to suggest that combination therapy
with phototherapy and biologics may result in greater efficacy than
monotherapy with biologics for patients with moderate to severe pso-
riasis. Specifically, patients treated concomitantly with narrowband
UV-B (nbUV-B) and biologic agents, such as etanercept and adali-
mumab, may experience greater efficacy compared with mono-
therapy with etanercept or adalimumab. However, in obese patients
treated with etanercept, 3 months of adjunctive nbUV-B may not re-
sult in significant benefit. Concomitant use of nbUV-B may acceler-
ate the therapeutic response of patients treated with ustekinumab.
Studies evaluating the long-term safety of combination treatments
using biologic agents and nbUV-B are needed.
Evidence Evaluation for Combining Biologics and Phototherapy
Six studies17,18,21-24 examined the effectiveness of etanercept com-
bined with nbUV-B in patients with moderate to severe psoriasis.
Two studies19,25 evaluated the combination of nbUV-B and adali-
mumab. One study20 assessed combination therapy of nbUV-B and
ustekinumab.
Etanercept and Phototherapy | Table 2 summarizes the articles re-
viewed for combining etanercept and phototherapy in the treatment
of psoriasis.17,18,21-24 For example, Kircik et al21 evaluated the efficacy
and safety of a combination of etanercept and nbUV-B in 86 patients
with moderate to severe psoriasis (Psoriasis Area and Severity Index
[PASI], ⱖ15; mean body surface area [BSA] affected, 28%). These pa-
tients received etanercept (50 mg twice weekly) and nbUV-B (thrice
weekly) for 12 weeks. At week 12, it was found that 85% of patients
had achieved at least 75% improvement on the PASI; 58% had
achieved a PASI of 90, and 26% had achieved a PASI of 100. Approxi-
mately 75% of patients had achieved a rating of clear or almost clear
on the Physician Global Assessment (PGA). The mean BSA affected
was reduced by 84%. Common adverse events were erythema and
injection-site reactions. Overall, etanercept and nbUV-B combination
therapy was well tolerated.21
Park et al18 conducted a randomized clinical trial to assess the
efficacy and safety of etanercept plus nbUV-B therapy compared
with etanercept monotherapy in 30 patients with moderate to se-
vere psoriasis. During the initial 12 weeks, all patients received etaner-
cept (50 mg twice weekly), which resulted in 48% of patients achiev-
ing a PASI of 75. From week 12 through week 24, the patients were
randomized to receive a combination of etanercept (50 mg weekly)
and nbUV-B (thrice weekly) or etanercept monotherapy.18 At week
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24, it was found that 53% of patients in the combination group had
achieved a PASI of 75 compared with 47% of patients in the etaner-
cept monotherapy group. Park et al noted that the addition of
nbUV-B did not significantly enhance the efficacy of etanercept in
patients who were obese.
Lynde et al24 studied the combination of nbUV-B with etaner-
cept therapy in 75 patients who had failed to achieve a PASI of 90
after receiving 12 weeks of etanercept monotherapy. These pa-
tients were randomized to etanercept monotherapy (50 mg/wk) or
to etanercept combined with thrice-weekly nbUV-B. At week 24, a
PASI of 90 had been achieved in 16% of patients in the combina-
tion group compared with 16% of patients in the etanercept mono-
therapy group (P > .99). However, among the patients random-
ized to receive combination therapy, only 22% had achieved
adherence of at least 80% for nbUV-B treatments. Among pa-
tients with high adherence, 43% in the combination group had
achieved a PASI of 90 compared with 3% in the monotherapy group
(P = .02) at week 16.
In a single-arm, open-label study, De Simone et al22 evaluated
the efficacy and safety of etanercept and nbUV-B combination
therapy. Thirty-three patients with moderate to severe psoriasis re-
ceived etanercept (50 mg weekly) and nbUV-B (thrice weekly) for
8 weeks, followed by etanercept monotherapy for 4 weeks. After
weeks 8 and 12, it was found that 67% and 82% of patients, respec-
tively, had achieved a PASI of 75; 15% and 58%, respectively, had
achieved a PASI of 90. De Simone et al concluded that combination
treatment with etanercept and nbUV-B was safe and effective.
Adalimumab and Phototherapy | The studies19,25 evaluating the
combination of adalimumab and phototherapy in psoriasis treat-
ment are summarized in Table 2. For example, in a single-center,
open-label study, Bagel25 evaluated the combination of adali-
mumab and nbUV-B in 20 patients with greater than 10% BSA
affected by psoriasis. Patients received adalimumab (80 mg at
week 0 and then 40 mg every other week) starting at week 1. In
addition, nbUV-B was given 3 times a week. At week 12, patients
had experienced a mean of 95% improvement in their PASI from
baseline. Specifically, 95% of patients had achieved a PASI of 75,
75% had achieved a PASI of 90, and 55% had achieved a PASI of
100. Overall, 55% of patients had achieved a PGA rating of clear,
and 30% had achieved a PGA rating of almost clear. Between
weeks 12 and 24, these patients had received no systemic treat-
ment or phototherapy. At week 24, it was found that 65% of
patients had maintained a PASI of 75. The most frequent adverse
event was erythema. Adalimumab and nbUV-B combination
therapy was well tolerated among study participants.25
Ustekinumab and Phototherapy | Wolf et al20 conducted a small, ran-
domized, intraindividual, half-body trial to determine the effects of
311-nm nbUV-B with ustekinumab therapy. Ten patients with mod-
erate to severe psoriasis were treated with ustekinumab at weeks
0 and 4, as well as concurrent 311-nm nbUV-B phototherapy thrice
weekly, to a randomly selected body half for 6 weeks. In the body
half treated with 311-nm nbUV-B, there was an 82% mean PASI re-
duction compared with a 54% mean PASI reduction in the nonirra-
diated body half (P < .05) at week 6. Therefore, treatment with
311-nm nbUV-B appears to accelerate the therapeutic response in
patients treated with ustekinumab.
JAMA Dermatology Published online December 17, 2014 E3
 Clinical Review & Education Review Biologic Therapies and Other Psoriasis Treatments

Biologics and Methotrexate Table 3. Strength of Recommendations for the Use of Biologics
Recommendations for Combining Biologics and Methotrexate in Combination With Traditional Oral Systemic Medications for
Of the biologics approved by the Food and Drug Administration, Psoriasis Treatment
etanercept and methotrexate combination therapy is the most well Strength of Level of
studied, and this combination is more effective than either etaner- Agent Recommendation Evidence Source
cept or methotrexate used alone. Therefore, etanercept combined Biologics and Methotrexate in Combination Therapy
with methotrexate can be used when desired efficacy is not achieved Etanercept and 1 A Zachariae et al,26 2008;
methotrexate Gottlieb et al,27 2012;
with monotherapy with either medication. A combination of inflix- Driessen et al,29 2008
imab and methotrexate or a combination of adalimumab and metho- Infliximab and 2A B Dalaker and
trexate may result in additional efficacy beyond biologic mono- methotrexate Bonesrønning,28 2009;
Goedkoop et al,30 2004;
therapy, but data on these particular combinations are limited. The Kavanaugh et al,31
dosage of methotrexate used in combination with biologics varied 2007
widely among the studies reviewed, and the ideal dosage of metho- Adalimumab and 2B C De Groot et al,32 2008
methotrexate
trexate is unknown to date; methotrexate dosage likely depends on Biologics and Acitretin in Combination Therapy
a multitude of factors, including the type of concurrent biologic agent Etanercept and 2A, etanercept plus B Gisondi et al,34 2008;
and patient factors. acitretin acitretin similar Smith et al,35 2008
efficacy to
etanercept alone
Evidence Evaluation for Combining Biologics and Methotrexate Infliximab and 2B, favors C Smith et al,35 2008
Seven studies26-32 examined the efficacy of biologics combined with acitretin combination
methotrexate for the treatment of plaque psoriasis. Two random- Adalimumab and 2B, favors C Smith et al,35 2008
acitretin combination
ized clinical trials and 1 retrospective review examined the effective-
Biologics and Cyclosporine in Combination Therapy
ness of combining etanercept and methotrexate for the treatment of
Etanercept and 2B C Yamauchi and
moderate to severe psoriasis26,27,29; two studies30,31 examined the cyclosporine Lowe,36 2006;
combined use of infliximab with methotrexate in patients with pso- Lee et al,37 2010

riasis. Another study32 evaluated the cellular effects of adalimumab
in combination with methotrexate in lesional and nonlesional psori-
atic skin. Concomitant use of biologics with methotrexate may have
beneficial effects of reducing the formation of antidrug antibodies
compared with biologic monotherapy.33 No studies to date have ex-
amined synergistic effects beyond the additive effects of combining
biologic therapy with methotrexate. To our knowledge, no long-
term data exist regarding liver toxicity when combining tumor necro-
sis factor (TNF) inhibitors with methotrexate use.
Etanercept and Methotrexate | Table 3 (top) summarizes the ar-
ticles that were reviewed for combining etanercept and methotrex-
ate for psoriasis treatment.26,27,29 For example, Gottlieb et al27 evalu-
ated the efficacy of etanercept plus methotrexate combination
therapy vs etanercept monotherapy in patients with moderate to
severe plaque psoriasis. Patients with an affected BSA of 10% or
greater and a PASI of 10 or higher who had not failed prior metho-
trexate or TNF inhibitor therapy were included in the study. In total,
478 patients with psoriasis were randomized to receive methotrex-
ate (7.5-15 mg/wk) in combination with etanercept (n = 239) or
etanercept monotherapy (n = 239). All patients received etaner-
cept (50 mg twice weekly for the initial 12 weeks, followed by 50
mg once weekly for the remaining 12 weeks). Patients in the com-
bination therapy group also received methotrexate (7.5 mg/wk for
weeks 1 and 2, 10 mg/wk for weeks 3 and 4, and 15 mg/wk or the
maximum tolerated dosage for weeks 5-24). At week 24, it was found
that 77% of patients receiving combination therapy had achieved a
PASI of 75 compared with 60% of patients receiving etanercept
monotherapy (P < .001). Adverse events were reported in 75% of
the combination therapy group and in 60% in the monotherapy
group.
In a randomized open-label study, Zachariae et al26 assessed the
efficacy of etanercept and methotrexate combination in patients
with psoriasis who had inadequate response to prior methotrexate
Adalimumab and 2B C Gattu et al,38 2009
cyclosporine
monotherapy. Fifty-nine patients with psoriasis (PASI, ⱖ8 and BSA
affected, ⱖ10%) with inadequate response to 3 months of metho-
trexate use (mean dosage, 13.7 mg/wk) were randomized to re-
ceive (1) etanercept with methotrexate tapered or discontinued dur-
ing a 4-week period (n = 28) or (2) etanercept with continuous
methotrexate (n = 31). Patients in both groups received etaner-
cept (50 mg twice weekly for 12 weeks and then 25 mg twice weekly
for the remaining 12 weeks). At week 24, it was found that 67% of
patients receiving combination therapy with continuous metho-
trexate dosing had achieved a PGA rating of clear or almost clear com-
pared with 37% of patients receiving etanercept or methotrexate
taper (P = .03). Safety data were similar between both groups.
Infliximab and Methotrexate | Articles regarding infliximab and
methotrexate combination therapy that were reviewed are sum-
marized in Table 3 (top).28,30,31 In the Infliximab Multinational Pso-
riatic Arthritis Controlled Trial (IMPACT 2),31 a subanalysis evalu-
ated concomitant use of methotrexate (ⱕ25 mg/wk) and infliximab.
Psoriasis activity was assessed in patients with greater than 3% BSA
involvement at baseline. Among 100 patients receiving infliximab
(5 mg/kg), 47 patients received concomitant methotrexate (mean
[SD] dosage, 16.2 [5.2] mg/wk) at baseline. At week 54, it was found
that 53% of patients receiving methotrexate in combination with in-
fliximab had achieved a PASI of 75 compared with 48% of patients
not receiving methotrexate at baseline (no P value was reported).
The study design does not allow for interpretation of whether metho-
trexate has an additive or synergistic effect with infliximab. The in-
cidence of adverse events was similar between patients receiving
concomitant methotrexate (88%) and patients not receiving metho-
trexate (83%) at baseline.

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 Biologic Therapies and Other Psoriasis Treatments
In a prospective open-label study, Goedkoop et al30 evaluated
11 patients with psoriasis and psoriatic arthritis who had received in-
fliximab infusions (3 mg/kg) at weeks 0, 2, 6, 14, and 22 with con-
comitant methotrexate (range, 5-20 mg/wk). At week 16, the mean
(SD) PASI had decreased from 2.3 (2.4) at baseline to 1.8 (0.4)
(P ⱕ .02).
Adalimumab and Methotrexate | To date, no studies exist regarding
the clinical efficacy of adalimumab and methotrexate combination
therapy. De Groot et al32 examined the effect of adalimumab and
methotrexate combination on inflammatory cells within psoriatic skin.
After 4 weeks of treatment, adalimumab and methotrexate combi-
nation resulted in a decrease in the inflammatory markers CD3, CD68,
CD161, elastase, BDCA-2, and TNF. Adalimumab and methotrexate
combination appears to be more effective in reducing inflammatory
cell numbers in lesional psoriatic skin than either drug alone.
Data are limited on the risk of developing malignancies and
infections during treatments combining biologics with methotrex-
ate or other oral agents.39,40 The ideal databases for such investi-
gations are prospective disease registries, for which patients are
not selected for their likelihood of developing outcomes of inter-
est and thereby selection bias is minimized. For example, data
from almost 8000 patients with rheumatoid arthritis in North
America showed no elevated infectious risk when combining
methotrexate with a TNF antagonist.41 While synthesis of pub-
lished case reports can be helpful, publication bias and selection
bias must be considered.39,40
Biologics and Acitretin
Recommendations for Combining Biologics and Acitretin
Controlled studies regarding the combined use of biologics and
acitretin are limited. However, among patients with refractory
psoriasis in whom other treatments have failed, acitretin may be
combined with etanercept to achieve positive results. With con-
comitant use of acitretin, the dosing of etanercept can be
reduced to maintain similar levels of efficacy. It is the opinion of
the Medical Board of the National Psoriasis Foundation that the
addition of acitretin to biologics may be marginally beneficial to
increase efficacy, but controlled trials are necessary to determine
the combined efficacy.
Evidence Evaluation for Combining Biologics and Acitretin
Acitretin is a traditional systemic treatment for psoriasis with anti-
proliferative and immunomodulatory properties.42 Although the ex-
act mechanism is unclear, acitretin reduces proliferative activity and
favors the differentiation of epidermal keratinocytes. Acitretin acts,
at least in part, by inhibiting interleukin 6–driven induction of helper
T cells (subtype 17), which has a major role in the pathogenesis of
psoriasis.42 Acitretin may contribute to additive effectiveness when
combined with a biologic and could be considered in patients for
whom immunosuppression is not desirable.34
Table 3 (middle) summarizes the articles that were reviewed for
combining biologics and acitretin to treat psoriasis.34,35 In the study
by Gisondi et al,34 for example, 60 patients were randomized to re-
ceive either a combination of etanercept (25 mg once weekly) plus
oral acitretin (0.4 mg/kg daily) (n = 18), etanercept monotherapy (25
mg twice weekly) (n = 22), or oral acitretin (0.4 mg/kg daily) (n = 20).
At week 24, a PASI of 75 had been achieved by 44% of patients re-
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ceiving combination therapy, by 45% of patients receiving etaner-
cept monotherapy, and by 30% of patients receiving acitretin mono-
therapy (P = .001 for both comparing combination therapy and
acitretin alone and comparing etanercept monotherapy and acitre-
tin monotherapy). The mean BSA improvement at week 24 was 78%
in the combination group, 80% in the etanercept group, and 46%
in the acitretin group. Results indicate that combination treatment
with etanercept (25 mg once weekly) plus acitretin (0.4 mg/kg daily)
was not significantly different from results of etanercept mono-
therapy (25 mg twice weekly). Both treatment regimens that in-
cluded etanercept were more effective than acitretin alone. All 3
groups had similar safety profiles. Four patients in the acitretin group
withdrew from the study owing to lack of efficacy, whereas no pa-
tients withdrew from the other 2 groups (P < .05).
Biologics and Cyclosporine
Recommendations for Combining Biologics and Cyclosporine
Limited controlled data exist regarding concomitant use of cyclo-
sporine and biologics in the treatment of psoriasis. Published case
reports have indicated possible increased effectiveness of combin-
ing etanercept and cyclosporine compared with monotherapy with
cyclosporine or etanercept.36,37 Short-term cyclosporine and adali-
mumab combination has been used as a transition to long-term adali-
mumab therapy. Long-term therapy with high doses of cyclospor-
ine is not recommended because of the adverse effects on the
renovascular system.43 To date, no study has examined the effects
of combining cyclosporine with infliximab or ustekinumab in the
population with psoriasis.
Evidence Evaluation for Combining Biologics and Cyclosporine
Etanercept and Cyclosporine | Two studies36,37 have examined the
combined use of biologics with cyclosporine (Table 3 [bottom]). Case
reports have focused on using a biologic and cyclosporine combi-
nation as a transition to long-term biologic use.36,38 For example,
Yamauchi and Lowe36 evaluated etanercept and cyclosporine com-
bination in 8 patients with severe plaque psoriasis. All patients re-
ceived cyclosporine (200 mg twice daily) until they had achieved a
PASI of 50, at which point etanercept (50 mg weekly) was initiated
while cyclosporine was tapered. The patients were tapered off cy-
closporine every 2 to 4 weeks until maintenance on 100 mg/d for
at least 2 to 4 weeks before discontinuation. Etanercept and cyclo-
sporine combination maintained disease clearance throughout the
tapering period and up to 12 weeks after cyclosporine discontinua-
tion. The authors suggested that etanercept and cyclosporine com-
bination may be helpful during the transition period to prevent pso-
riasis rebound and flares.
Adalimumab and Cyclosporine | In a case series that examined a tran-
sition from cyclosporine to adalimumab, 5 patients with psoriasis re-
ceived combined cyclosporine and adalimumab therapy as a cyclo-
sporine-tapering regimen that ranged from 6 to 11 weeks.38 The
patients were able to transition to adalimumab after the cyclospor-
ine taper without flare in the short term.
Available data on the risk of malignancies and infections for com-
bining biologics and cyclosporine are limited.39,40 However, it is im-
portant to exercise caution, monitor regularly, and actively manage
the development of any adverse events.
JAMA Dermatology Published online December 17, 2014 E5
 Clinical Review & Education Review Biologic Therapies and Other Psoriasis Treatments

Table 4. Strength of Recommendations for the Use of a Biologic

in Combination With Another Biologic for Psoriasis Treatment Discussion
Strength of Level of
Agent Recommendation Evidence Source Fifteen members of the Medical Board of the National Psoriasis Foun-
Etanercept and 2B C Cuchacovich et al,48 dationwereaskedtoprovidetheirpreferenceforcombinationtherapy
ustekinumab 2012; Heinecke et al,49
2013
in a hypothetical clinical case. In this case, a patient with psoriasis with-
Etanercept and 2B C Krell,50 2006 out psoriatic arthritis had experienced unsatisfactory skin response
alefacept when receiving biologic monotherapy despite dosage escalation and
Etanercept and 2B C Hamilton,45 2008; switching of biologic agents. In selecting combination therapy for the
efalizumab Adişen et al,46 2008;
Kitamura et al,47 2009 next 6 months, the members expressed the highest preference for
Adalimumab 2B C Heinecke et al,49 2013 combining a biologic medication with methotrexate. This regimen is
and followed by decreasing preferences for biologic and acitretin com-
ustekinumab
Infliximab and 2B C Lowes et al,44 2005;
bination and then biologic and phototherapy combination. Most
efalizumab Hamilton,45 2008 members do not recommend biologic and cyclosporine combination
or biologic and biologic combination for 6 months.

Biologic and Biologic Combination

Literature is lacking for evaluating the effectiveness of combining 2
biologics for the treatment of psoriasis and psoriatic arthritis.44-48 Few
case reports and case series have described biologic and biologic com-
binations to treat recalcitrant psoriasis (Table 4).44-50 More studies
assessing biologic and biologic combinations are necessary before evi-
dence-based recommendations can be made. Owing to the scarcity
of literature on biologic and biologic combinations, safety data are
largely unknown with these combinations.39,40 However, signifi-
cant theoretical risks may exist with respect to potential infectious and
malignancy concerns. Therefore, careful patient selection and dili-
gent monitoring of adverse events are critical to minimize treatment
risks.
Conclusions
When considering combination therapies, physicians and physi-
cian extenders need to be aware of the pharmacodynamics, phar-
macokinetic properties, and toxicities associated with each com-
ponent of the combination. Selection of combination therapy
depends on disease severity, previous treatment, existing comor-
bidities, and adverse effects. In appropriately selected patients, care-
fully chosen combinations may result in greater efficacy while mini-
mizing toxicity. Rigorously conducted trials and observational studies
evaluating the efficacy and safety of combination therapy are nec-
essary to guide clinical decisions.

ARTICLE INFORMATION
Accepted for Publication: August 23, 2014.
Published Online: December 17, 2014.
doi:10.1001/jamadermatol.2014.3456.
Author Contributions: Dr Armstrong had full
access to all the data in the study and takes
responsibility for the integrity of the data and the
accuracy of the data analysis.
Study concept and design: All authors.
Acquisition, analysis, or interpretation of data: All
authors.
Drafting of the manuscript: All authors.
Critical revision of the manuscript for important
intellectual content: Armstrong.
Statistical analysis: All authors.
Administrative, technical, or material support:
Armstrong.
Study supervision: Armstrong.
Conflict of Interest Disclosures: Dr Armstrong
reported serving as an investigator for or consultant
to AbbVie, Lilly, Janssen, Amgen, Merck, and Pfizer.
Dr Bagel reported serving as a consultant, speaker,
and investigator for Amgen and AbbVie. Dr Van
Voorhees reported serving as an advisor for Amgen,
AbbVie, Janssen, LEO Pharma, and Warner Chilcott.
She reported receiving grants from Amgen and
AbbVie. She reported serving as a consultant for
Amgen and as a speaker for Amgen, AbbVie, and
Janssen. Dr Robertson reported being employed by
the National Psoriasis Foundation, which receives
unrestricted financial support from companies that
make products used to treat psoriasis and psoriatic
arthritis, including AbbVie, Amgen, Celgene
Corporation, Lilly, Galderma Laboratories, Janssen,
LEO Pharma, Novartis, Pfizer Inc, and Stiefel, a GSK
company. No other disclosures were reported.
Additional Contributions: Negar Foolad and Julie
Wu provided formatting and administrative
assistance during the preparation of the
manuscript. The following members of the Medical
Board of the National Psoriasis Foundation
reviewed the manuscript and participated in the
ranking exercise: Lakshi M. Aldredge, Erin E. Boh,
Sylvia Hsu, Arthur Kavanaugh, John Koo, Gerald
Krueger, Mark Lebwohl, Ronald Prussick, Abrar
Qureshi, Jeffrey Weinberg, and Jashin Woo.
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