PIIS019096222030284X
PIIS019096222030284X
PIIS019096222030284X
Psoriasis is a chronic inflammatory disease involving multiple organ systems and affecting approximately
2% of the world’s population. In this guideline, we focus the discussion on systemic, nonbiologic
medications for the treatment of this disease. We provide detailed discussion of efficacy and safety for the
most commonly used medications, including methotrexate, cyclosporine, and acitretin, and provide
recommendations to assist prescribers in initiating and managing patients on these treatments. Additionally,
we discuss newer therapies, including tofacitinib and apremilast, and briefly touch on a number of other
medications, including fumaric acid esters (used outside the United States) and therapies that are no longer
widely used for the treatment of psoriasis (ie, hydroxyurea, leflunomide, mycophenolate mofetil,
thioguanine, and tacrolimus). ( J Am Acad Dermatol 2020;82:1445-86.)
From Baylor Scott and White, Dallasa; the University of Pennsyl- Medicine, Atlantaw; Central Connecticut Dermatology, Crom-
vania Perelman School of Medicineb; University of Alabama, wellx; Yale University, New Haveny; Michigan Medicine, Univer-
Birminghamc; University of Southern California, Los Angelesd; sity of Michigan, Ann Arborz; San Antonio Uniformed Services
the Department of Dermatology, University of California, San Health Education Consortium, Joint-Base San Antonioaa;
Francisco School of Medicinee; Mayo Clinic, Rochesterf; Medical Dermatology Research and Education Foundation, Irvinebb;
College of Wisconsin, Milwaukeeg; the Department of Derma- and the American Academy of Dermatology, Rosemont.cc
tology, Icahn School of Medicine at Mt. Sinai, New Yorkh; Funding sources: None.
University of Pittsburghi; University of California, San Diegoj; Conflicts of interest: Listed in text.
Patient Advocate, National Psoriasis Foundation, Portlandk; IRB approval status: Not applicable.
University Hospitals Cleveland Medical Centerl; Massachusetts Accepted for publication February 14, 2020.
General Hospital, Bostonm; Icahn School of Medicine at Mount Reprints not available from the authors.
Sinai, New Yorkn; Central Dermatology, St Louiso; Department Correspondence to: Vidhya Hariharan, PhD, AAD, 9500 W Bryn
of Dermatology, Henry Ford Hospital, Detroitp; National Heart Mawr Ave, Suite 500, Rosemont, IL 60018. E-mail: vhariharan@
Lung and Blood Institute, National Institutes of Health, Bethes- aad.org.
daq; Northwestern University Feinberg School of Medicine, Published online February 28, 2020.
Chicagor; Dermatology and Skin Surgery, Sumters; Colorado 0190-9622/$36.00
Permanente Medical Group, Centennialt; University of Okla- Ó 2020 by the American Academy of Dermatology, Inc. Published
homa Health Sciences Center, Oklahoma Cityu; Pediatric by Elsevier Inc. All rights reserved.
Dermatology Society Alliancev; Emory University School of https://doi.org/10.1016/j.jaad.2020.02.044
1445
1446 Menter et al J AM ACAD DERMATOL
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Key words: Clinical guidelines for psoriasis; dermatology; nonbiologic systemic; psoriasis; psoriasis
guidelines; skin disease.
cells.13 Instead, low-dose methotrexate (\25 mg per methotrexate group compared with 10% of the
week) decreases proliferation of lymphoid cells, and placebo group (relative risk, 3.93; 95% confidence
this direct immunosuppressive effect is considered to interval [CI], 1.31-11.81; P = .0026).20 Subcutaneous
be the mechanism by which methotrexate improves methotrexate was well tolerated, with no patient
psoriatic disease.13,14 deaths and no reported malignancies, serious in-
fections, or major adverse cardiovascular events.20
Dosing Parenteral methotrexate solution can be
For psoriasis, methotrexate is typically adminis- administered orally: 0.6 mL of (25 mg/mL)
tered in doses ranging from 7.5 mg to 25 mg weekly methotrexate is equal to six 2.5-mg tablets and is
as 1 dose or divided into 3 dosages over 24 hours. In less expensive. Although the drug labels for subcu-
a direct comparison study, 10 mg weekly dosing was taneous and oral routes of administration report
slower acting than 25 mg weekly dosing but with different bioavailabilities,21 the bioavailability of
fewer severe adverse effects.15 Daily dosing (2.5 mg parenteral solution when taken orally is thought to
daily for 6 days of the week) showed less benefits be similar to that of oral formulations (expert
than weekly dosing (15 mg divided into 3 doses consensus).
every 8 hours over a 24-hour period) and was also
more likely to cause elevation in liver enzymes.16 In
Folate supplementation
some patients, the gastrointestinal (GI) adverse
Concomitant supplementation with folic acid is
effects of methotrexate were better tolerated when
recommended to decrease the rate of adverse effects
the dose was divided into 3 doses, given every
associated with methotrexate therapy. Folate is
12 hours. This split-dosing schedule (3 divided doses
typically given daily, except for the days in which
given every 12 hours each week) was based on
methotrexate is given, to avoid influencing
‘‘current knowledge concerning the epidermal cell
efficacy.18 Folic acid or folinic acid has been reported
proliferation kinetics of psoriasis and chemotherapy
to decrease hepatic laboratory abnormalities and GI
with cell-cycle specific drugs.’’17 Because psoriatic
adverse effects in patients with rheumatoid
keratinocytes traverse the cell cycle in approximately
arthritis.22 Whether there is a lower incidence of
7 days, the rationale for the prolonged dosing period
hematologic adverse effects with folic acid
was to attempt to interfere with a prolonged S phase
supplementation is uncertain (expert consensus).
of the cell cycle.
There is no difference in efficacy between folinic
Methotrexate is usually given orally, although a
acid and folic acid, but folic acid is less expensive.22
parenteral preparation is available for weekly
The influence of folate supplementation on the
subcutaneous or intramuscular administration.
efficacy of methotrexate therapy could not be
Some physicians prefer to start with a test dose of
analyzed due to variations across pooled studies,
2.5 to 5 mg, followed by a complete blood count
but folinic acid may slightly decrease methotrexate
(CBC) 5 to 7 days after the test dose to gauge
efficacy in psoriasis.18,23,24
individual susceptibility to bone marrow
suppression (expert consensus). Alternatively, it is
reasonable to begin at a therapeutic dose, such as Efficacy
15 mg weekly, with subsequent laboratory Methotrexate was FDA approved in 1972 at a time
evaluation, using test doses only for patients with when randomized clinical trials were not
an increased risk of having adverse effects (potential required for regulatory approval. As such, there
drug interactions, diabetes, decreased kidney were few large, high-quality studies analyzing the
function, or other significant comorbidities).18,19 safety and efficacy of methotrexate. Nonetheless,
The methotrexate dose can be adjusted as needed several studies have demonstrated the benefit of
to achieve adequate skin clearance while minimizing methotrexate in psoriasis.25,26
adverse effects. Dosage changes frequently take at One study randomized 868 methotrexate-na€ıve
least a month for a clinical response. patients (3:1) to receive infliximab, 5 mg/kg, at
Subcutaneous administrations of methotrexate weeks 0, 2, 6, 14, and 22, or methotrexate, 15 mg
may be particularly useful for patients receiving weekly, with a dose increase to 20 mg weekly at
higher doses that increase the risk of GI adverse week 6 if the PASI response was \25%.27 After
effects when taken orally. In a randomized 16 weeks of treatment with methotrexate, 42%
controlled trial with 120 patients with psoriasis achieved PASI 75, and 38% of patients were clear
receiving subcutaneous methotrexate weekly or almost clear; however, this study did not include a
(n = 91) or placebo (n = 29), a PASI 75 score was placebo group and thus may overestimate clinical
achieved in 41% (n = 37) of the subcutaneous response. The efficacy of methotrexate in this study
J AM ACAD DERMATOL Menter et al 1449
VOLUME 82, NUMBER 6
was significantly lower compared with biologic between the 2 groups. A systematic review
therapy. concluded that etanercept plus methotrexate was
A large randomized clinical trial compared more beneficial than etanercept monotherapy (PASI
methotrexate (n = 110) to adalimumab (n = 108) 75; relative risk [RR], 1.28; 95% CI, 1.14-1.45).36 There
and placebo (n = 53), with PASI 75 serving as the was an increased rate of adverse effects with
primary end point after 16 weeks of treatment.28 combination therapy (RR, 1.25; 95% CI, 1.10-1.42),
Methotrexate group performed significantly better but its overall safety profile remained acceptable.
than placebo (35.5% of patients achieved PASI 75 Methotrexate has also been used with NB-UVB
compared with 18.9%) but was less effective than phototherapy. This combination results in
adalimumab (79.6% with PASI 75). Of concern in this increased efficacy and more rapid skin clearing at
study is the high PASI 75 rate seen in the placebo lower cumulative doses of methotrexate and
group (18.9%). Adalimumab cleared 16.7% of UVB compared with monotherapy with either
patients compared with 7.3% with methotrexate treatment.37-39 The long-term effects of this
and 1.9% with placebo. On the basis of direct combination on photocarcinogenesis remains to be
comparison studies, infliximab, adalimumab, determined.
etanercept, ustekinumab, and narrowband
ultraviolet B (NB-UVB) are more effective than
methotrexate.26,27,29,30 Toxicity
Although not FDA approved for this indication, Common toxicities of methotrexate tend to occur
methotrexate is a disease-modifying drug for shortly after the medication is initiated and
psoriatic arthritis. Further studies are needed to include fatigue, anorexia, nausea, and stomatitis.40
assess both in terms of efficacy disease activity and Alterations in the dose, route, or frequency of
prevention of radiographic progression. A recent administration (eg, oral to subcutaneous or
randomized controlled trial found no evidence intramuscular routes or from single weekly dose to
that methotrexate improves synovitis in psoriatic three divided doses over 24-hour period) can help
arthritis and failed to demonstrate significant mitigate these effects. Taking the medication with
treatment effects for a number of end points, food can also be helpful.40 Given the immunosup-
including tender and swollen joint counts, Health pressive nature of methotrexate, treatment may
Assessment Questionnaire scores, pain, erythrocyte increase the risk of infection and reactivation of
sedimentation rate, and C-reactive protein.31 The latent tuberculosis, hepatitis, and lymphoma (espe-
study has been criticized because it may not have cially Epstein-Barr viruseassociated B-cell lym-
had adequate statistical power. A more recent study phoma). These conditions have been reported in
did find statistically significant improvements in the patients with psoriasis treated with methotrexate,
number of patients with dactylitis (62.7% reduction) supporting the importance of regular laboratory
and enthesitis (25.7% reduction) and American monitoring and the need to maintain a high level of
College of Rheumatology (ACR) outcomes, with suspicion for these complications.41-44 Hepatitis B
ACR20 achieved in 40.8%, ACR50 in 18.8%, and and C screening and baseline tuberculosis testing
ACR70 in 8.6%.32 Skin disease also improved, with (purified protein derivative, T-Spot [Oxford
27.2% attaining PASI 75 after 12 weeks. Immunotec USA, Inc, Marlborough, MA],45 or
Combination therapy with methotrexate and QuantiFERON Gold [Qiagen, Germantown, MD]46)
tumor necrosis factor inhibitors results in improved should be considered, depending on the individual
efficacy over methotrexate monotherapy for the patient’s risk factors.
treatment of psoriasis.33,34 A large randomized study Other methotrexate adverse events include
of 239 patients demonstrated that the addition of pneumonitis, myelosuppression, epidermal necrol-
methotrexate to etanercept was associated with a ysis, and hepatotoxicity.47 Although pneumonitis is a
better clinical response than etanercept alone.35 At potentially devastating consequence, it is more
24 weeks, PASI 75 was achieved in 77.3% on the commonly seen in rheumatoid arthritis and rarely
combination therapy compared with 60.3% treated occurs in psoriasis.48 A systematic review and
with etanercept monotherapy, and 71.8% of patients meta-analysis including 7 studies found 504
were ‘‘clear’’ or ‘‘almost clear’’ with combination respiratory events occurred in 1630 participants
therapy compared with 54.3% with etanercept and concluded that methotrexate was not associated
monotherapy. Adverse events were slightly more with a significant increase in the risk of respiratory
common in the combination group (74.9% vs 59.8%), infections, adverse respiratory events, and noninfec-
but there was no difference in the proportion of tious respiratory events (RR 1.03, 95% CI 0.90-1.17).
patients experiencing serious adverse events In addition, no pulmonary deaths occurred.49
1450 Menter et al J AM ACAD DERMATOL
JUNE 2020
d Nursing
d Alcoholism
d Immunodeficiency syndromes
d Hypersensitivity to methotrexate
Relative contraindications
d Abnormalities in renal function
d Active infection
51
Risk factors for methotrexate-associated hepatotoxicity
d History of or current use of greater than moderate alcohol consumption
d Diabetes mellitus
d Obesity
d Hyperlipidemia
50
Baseline/ongoing monitoring
d History and physical examination
d Pretreatment test for latent TB (PPD, T-Spot [Oxford Immunotec USA, Inc,
d Monitor CBC and LFT every 3-6 months assuming no abnormal laboratory results
CBC, Complete blood count; LFT, liver function test; PPD, purified protein derivative; TB, tuberculosis.
*Supplemental information is expert consensus and not part of evidence-based recommendations.
y
Greater potential for methotrexate toxicity.
However, patients on methotrexate should be still risk factors (Table II50,51 and Figs 1 and 2). In
monitored for rare, serious lung reactions. addition, drug-drug interactions, especially
The risk of hematologic and hepatic adverse involving sulfonamides, can significantly increase
effects is determined by patient characteristics and the likelihood of methotrexate toxicity. Thus, an
J AM ACAD DERMATOL Menter et al 1451
VOLUME 82, NUMBER 6
Fig 1. Monitoring for hepatotoxicity in patients on methotrexate without risk factors for
hepatotoxicity (baseline liver biopsy not recommended). The following is a link to a Fibrosis-4
(FIB-4) Index for Liver Fibrosis online calculator (https://www.mdcalc.com/fibrosis-4-fib-4-
index-liver-fibrosis). GI, Gastrointestinal; LFT, liver function test; MTX, methotrexate.
1452 Menter et al J AM ACAD DERMATOL
JUNE 2020
Fig 2. Monitoring for hepatotoxicity in patients on methotrexate with risk factors for
hepatotoxicity (baseline liver biopsy not recommended). The following is a link to a
Fibrosis-4 (FIB-4) Index for Liver Fibrosis online calculator (https://www.mdcalc.com/
fibrosis-4-fib-4-index-liver-fibrosis). BMI, Body mass index; GI, gastrointestinal; LFT, liver
function test; MTX, methotrexate.
J AM ACAD DERMATOL Menter et al 1453
VOLUME 82, NUMBER 6
ongoing review of patient medications is important High cumulative doses of methotrexate may be
to identify potential drug interactions that may associated with an increased risk of liver damage.
increase methotrexate toxicity (Table II). Cumulative methotrexate doses of 1 to 2 grams
Hematologic toxicity is more likely seen in were less associated with clinically significant
patients with renal insufficiency, advanced age, hepatotoxicity, but inflammation and fibrosis
methotrexate dosing errors, drug interactions, were seen with cumulative doses of 3 to 4 grams.57
hypoalbuminemia, and greater than moderate Although prior AAD guidelines recommended
alcohol intake.* Most literature concerning myelo- consideration of liver biopsy after 3.5 to 4 cumu-
suppression by methotrexate reports studies that lative grams of methotrexate, reliable noninvasive
were conducted in the rheumatoid arthritis popula- options to evaluate the severity of liver disease are
tion. Whether this information can be extrapolated to now available, including serologic tests and liver
psoriasis is uncertain. Methotrexate-induced myelo- stiffness assessment by transient elastography.
suppression is a rare adverse effect in psoriasis as Serologic tests include the Fibrosis-4 (FIB-4), an
long as there are no other risk factors and there is algorithm based on liver enzymes, platelet count
appropriate monitoring.40,52,53 and age (available online), and other patented tests
A test dose should be considered in patients with such as FibroTest/FibroSure (BioPredictive, Paris,
risk factors for developing complications, such as France), FibroMeter (Echosens, Waltham, MA), and
decreased kidney function. If there is no evidence of Hepascore (Quest Diagnostics, Wilmington, DE).
signs and symptoms of myelosuppression or FibroScan (Echosens, Waltham, MA) is a vibration-
hepatotoxicity, then the weekly dose can be controlled transient elastography and the most
increased as needed. Pancytopenia can result after used to assess liver stiffness. A combination of
even a single dose of methotrexate and can occur at FibroTest and FibroScan or other elastography with
any time during treatment, typically in patients with additional measurement of type III serum
at least 1 risk factor (see Table II). Close laboratory procollagen has been proposed as the ideal
monitoring is recommended after each methotrexate method for monitoring hepatotoxicity with metho-
dose increase, because pancytopenia can occur as trexate use. However, type III procollagen is not
late as 6 weeks.54 Regular laboratory monitoring widely available in the United States, and these
(CBC and liver function tests) should be performed tests have not been proven to eliminate the risk of
every 3 to 6 months, assuming no abnormalities in serious liver complications due to chronic metho-
laboratory test results. Periodic renal monitoring trexate use.58 Magnetic resonance elastography is a
should be considered in patients with poor renal more accurate technique that should be considered
function. if there is a technical failure with vibration-
Hepatotoxicity is an important adverse event controlled transient elastography or in patients
of methotrexate therapy and is more common with a particularly high risk of such failure
in psoriasis than in rheumatoid arthritis.48 Patients (ie, body mass index $40 kg/m2).
with obesity, diabetes, and hyperlipidemia are at The algorithm for methotrexate hepatotoxicity
increased risk for nonalcoholic fatty liver disease and screening differs depending on whether patients
thus are more likely to experience methotrexate- do not (Fig 1) or do have risk factors (Fig 2). A
induced hepatotoxicity. Nonalcoholic steatohepatitis noninvasive baseline liver fibrosis assessment is
is also a common comorbidity of psoriasis, which recommended before starting treatment with
can be aggravated by methotrexate treatment.55,56 methotrexate. Baseline liver biopsy is not
Other risk factors for methotrexate-induced recommended, regardless of the presence of risk
hepatotoxicity include greater than moderate factors. Abnormal laboratory results or risk factors
alcohol use,* persistent abnormal liver function test for hepatic fibrosis should prompt consideration of
results, chronic liver disease, such as hepatitis B and a GI or hepatology specialist referral or imaging
C, prior exposure to other hepatotoxic drugs or with vibration-controlled transient elastography, or
chemicals, and family history of inheritable liver both. Methotrexate can be continued only if risk of
disease (eg, Wilson disease, hemochromatosis, and cirrhosis is low. Annual GI/hepatology referral or
a-1 antitrypsin deficiency).40 vibration-controlled transient elastography, or
both, should be performed if methotrexate is
continued despite abnormal baseline liver
*Moderate alcohol use: [1 alcoholic drink for women per day (or fibrosis laboratory results. Because liver fibrosis is a
binge drinking of [7 drink equivalents per week) and [2
alcoholic drinks per day for men (or binge drinking of 14 drink
process that typically takes years to develop,
equivalents per week) is considered harmful. Drink equivalent is screening more frequently than annually is not
1 shot liquor = 12 oz beer = 5 to 6 oz wine. generally necessary.
1454 Menter et al J AM ACAD DERMATOL
JUNE 2020
Liver function test monitoring is recommended Methotrexate has been detected in human milk.
every 3 to 6 months, assuming there are no There is potential risk for serious adverse reactions
laboratory abnormalities in the results. Abnormal in breast-fed infants. Methotrexate is therefore
elevations should prompt a repeat laboratory check contraindicated in nursing mothers.
in 2 to 4 weeks. For persistent elevations, a GI referral Male fertility. Although methotrexate is not
is recommended. For patients with risk factors for mutagenic, findings are conflicting about whether
hepatotoxicity, it may be reasonable to consider an it affects spermatogenesis.61 Some studies have
alternative therapy to methotrexate. If methotrexate demonstrated reversible oligospermia in men taking
is chosen, recommended hepatotoxicity monitoring methotrexate, whereas others have found no
is similar to that in low-risk individuals, except changes in sperm count.62-64 Data are lacking
noninvasive hepatic specific serology should be regarding the teratogenicity of methotrexate when
performed at baseline and annually thereafter, used by the father. Given the mixed data and level of
irrespective of total cumulative dose. uncertainty, it is reasonable for men to wait 3 months
Details about less common adverse effects of after discontinuing the medication before attempting
methotrexate are not well defined.54 Hair loss has to father a child, because the average cycle of
been seen rarely in patients using methotrexate.59 spermatogenesis lasts 74 days, and the presumed
However, its mechanism of action is unknown. Rare effects of methotrexate on the sperm should
cases of photosensitivity have been reported in theoretically be cleared by that time.
patients treated with methotrexate.60
Contraindications
Pregnancy and lactation Given the risk of potential serious hematologic
Methotrexate use is contraindicated during preg- and hepatic adverse effects, methotrexate is
nancy. It is essential for women of child-bearing age contraindicated in patients with cirrhosis, significant
to be on contraception while taking methotrexate. thrombocytopenia, leukopenia or anemia, in
Fetal abnormalities have been reported after expo- pregnancy, and while nursing. Relative contraindi-
sure to methotrexate at all gestational ages, but the cations (Table II) include concomitant use of sulfa
critical period for its teratogenic effects appears to be drugs and acitretin, although this combination may
within the first 6 to 8 weeks of pregnancy. If a female be used if necessary, especially in palmar-plantar
patient wishes to become pregnant after metho- psoriasis, as long as there is appropriate hepatic
trexate therapy, she should wait at least 3 months monitoring. Recommendations for the use of
after discontinuation to ensure that methotrexate is methotrexate are outlined in Table III. Practitioners
fully cleared from her liver and other tissues.54 should carefully consider who should receive
J AM ACAD DERMATOL Menter et al 1455
VOLUME 82, NUMBER 6
methotrexate treatment
37-39
Combination therapy 1.8 I
d Methotrexate and NB-UVB
methotrexate, because it requires regular laboratory randomized 844 patients to receive apremilast
monitoring and lifestyle modifications, such as 30 mg twice daily (n = 562) or placebo (n = 282).86
reduction in alcohol consumption and avoidance At week 16, the placebo group was switched to
of pregnancy. Patients must be reliable and willing to receive apremilast until week 52. At week 32, 154
adhere to instruction to ensure safety. Levels of patients from the apremilast group who
evidence of methotrexate therapy in psoriasis are achieved PASI 75 were rerandomized to continue
outlined in Table IV,z and supporting statements for apremilast or switch to placebo until week 52. The
methotrexate associated hepatotoxicity are available PASI 75 rate at week 16 was higher in the apremilast
in Table V.58,70-85 group compared with the placebo group (33.1% vs
5.3%, P \ .001). Of the 77 patients who were
APREMILAST rerandomized at 32 weeks to receive apremilast,
Apremilast was approved by the FDA in 2014 and 61.0% maintained PASI 75 at week 52. Of the 77
is the first oral medication for psoriasis in decades. It patients who were rerandomized to receive placebo
inhibits phosphodiesterase 4, resulting in an at 32 weeks, 83.11% lost PASI 75 response and
increased level of intracellular cyclic adenosine reinitiated apremilast, and only 11.7% achieved
monophosphate, with subsequent downregulation PASI 75 by week 52. Between week 0 and 16, there
of inflammatory responses involving T helper 1, were reports of 1 or more adverse events in 69.3% of
T helper 17, and type 1 interferon pathways.86 patients treated with apremilast compared with
The additional ability to modulate the levels of 55.7% of those in the placebo group. Apremilast is
anti-inflammatory cytokines, such as IL-10, further effective for psoriasis, especially for scalp and
enables apremilast to improve the inflammatory palmar-plantar involvement, with a promising safety
profile underlying psoriasis. profile.
Apremilast is also effective in psoriatic arthritis. A
large randomized controlled trial (n = 504) evaluated
Dosing
ACR20 scores and found that dosages of 20 mg twice
The maintenance dosing for apremilast is 30 mg
a day and 30 mg twice a day were significantly more
twice daily by mouth, with an initial dose of 10 mg
effective than placebo at 16 weeks (30.4% and 38.1%
daily that is titrated up by 10 mg per day over the first
compared with 19.0%, respectively), with even
5 days to minimize the risk of GI adverse effects. For
greater proportions of patients with ACR20 response
patients with severe renal impairment (creatinine
after 52 weeks of continuous therapy (63.0% of 119
clearance \30 mL/min), the dose of apremilast
patients on 20 mg twice a day and 54.6% of 130
should be reduced to 30 mg once daily. (Refer to
patients on 30 mg twice a day).8,88 There are no data
Table VI87 for dosing schedule.)
to date on the impact of apremilast in the prevention
of radiologic damage in psoriatic arthritis.
Efficacy High-quality data supporting the use of apremilast
The Efficacy and Safety Trial Evaluating the Effects in combination with other systemic or phototherapy
of Apremilast in Psoriasis (ESTEEM) 1 trial evaluated treatments are lacking, but multiple case reports and
the efficacy of apremilast in psoriasis. The trial small case series have found benefit of apremilast
when used in conjunction with other treatments,
z
References15,16,18-20,22,23,27,28,31-33,35,37-39,65-69. including biologic agents such as adalimumab.89-91
1456 Menter et al J AM ACAD DERMATOL
JUNE 2020
Toxicity Contraindications
In the ESTEEM 1 trial, the most common adverse The safety profile of apremilast is a positive
effects were diarrhea, nausea, upper respiratory tract feature. It can be used in a wide variety of patients,
infection, nasopharyngitis, tension headache, and including those with complex medical issues in
headache.86 In those experiencing GI adverse which other systemic agents are contraindicated.
effects, 70% to 80% occurred within the first 2 weeks, Although severe renal impairment is not a
75% to 80% were mild in severity, and 60% to 65% contraindication, it does warrant a dose decrease to
resolved within the first month. Depression was 30 mg daily instead of twice daily. For any individual
reported in approximately 1% of patients. experiencing weight loss ([5% from baseline) due
Appropriate discussion and patient counseling are to apremilast, consideration should be given to its
thus recommended before apremilast therapy discontinuation. Patients prone to dehydration
initiation to prevent worsening of pre-existing (eg, the elderly) should be aware that GI adverse
depression or suicidality. Decreases of 5% to 10% effects may be more severe and could result in
in body weight occurred in 12% of patients treated hospitalization. There have been no significant
with apremilast compared with 5% treated with studies evaluating the effect of apremilast on human
placebo.87,92 pregnancies.87
J AM ACAD DERMATOL Menter et al 1457
VOLUME 82, NUMBER 6
randomized to receive placebo or cyclosporine at side effects of chronic hypertension, but also kidney
1.5 or 3.0 mg/kg/d.115 While the placebo and damage.127 If hypertension is observed on 2 separate
1.5 mg/kg/day groups showed a median time to occasions, then the dose of cyclosporine should be
relapse of 6 weeks, median relapse time was not decreased using the same approach recommended
observed for the 3.0 mg/kg/d group during the above. If the blood pressure does not normalize
24-week trial because \50% of patients relapsed. (\140/90 mm Hg) after decreasing the dose multiple
Of those who received the 3.0 mg/kg/d dosage, times, then the medication should be discontinued.
58% maintained improvement through the entire Alternatively, cyclosporine can be continued if
24-week trial. Laboratory abnormalities observed elevated blood pressure can be adequately treated
during the induction phase tended to partially or with antihypertensive medication. Because the
completely normalize throughout the maintenance hypertensive effects of cyclosporine are thought to
phase of treatment, demonstrating the increased result from renal arteriole vasoconstriction, calcium
tolerability at lower doses. channel blockers are the preferred choice due to
The simultaneous administration of cyclosporine their ability to relax vascular smooth muscle.
and NB-UVB phototherapy is contraindicated due to Some of the more common but less severe
the increase risk of photocarcinogenesis,116-118 but adverse effects include headache, paresthesia,
this combination is efficacious when used and musculoskeletal pain, which occur in
sequentially.119 A low dose of cyclosporine at approximately 15%, 7%, and 5% of patients,
3 mg/kg/d for 4 weeks, followed by a rapid taper respectively. Approximately 6% of patients
and initiation of NB-UVB phototherapy, showed experience hypertrichosis, with the most noticeable
faster resolution of pruritus, reduced number of change typically arising in women with dark hair.128
NB-UVB treatments, and reduced cumulative Gingival hyperplasia is more commonly seen at
amount of UVB needed to obtain equivalent PASI higher doses as used for transplant patients but has
compared with NB-UVB monotherapy.119 been reported in patients with psoriasis.129
Neurologic sequelae include fatigue, tremor, and
Toxicity asthenia. Seizures have also been reported,
Nephrotoxicity and hypertension are the most particularly in patients with a history of seizures.130
common adverse effects of cyclosporine. Even with Cyclosporine can lower an individual’s seizure
close monitoring, patients will often experience threshold.131 A few cases of pseudotumor cerebri
adverse effects on renal function, with reversible have been reported in young patients receiving
nephrotoxicity developing in 19% to 24% during cyclosporine; however, these are not psoriasis
short-term treatment.109,110 If treatment is continued cases.132-135 (The risk of pseudotumor cerebri
for more than 2 years, the risk of fibrosis and development in patients using cyclosporine is based
irreversible kidney damage increases substantially. on extrapolation.) GI adverse effects tend to be mild
In one study, 71% of patients treated with and short-lived, including abdominal pain, diarrhea,
cyclosporine for an average of 4.5 years were found nausea, and vomiting.128 Approximately 5% of
to have serum creatinine level of [30% above patients will experience respiratory effects such as
baseline.120 The serum creatinine levels in most of dyspnea, cough, and rhinitis.131 Hyperuricemia and
these patients did not return to normal after the hypomagnesemia can also occur.
cyclosporine dose was decreased.120 In a larger
systematic review, $50% of patients demonstrated Pregnancy
an increase in serum creatinine over 30% of baseline The data regarding the use of cyclosporine in
when treated with cyclosporine for longer than pregnancy are derived primarily from studies in
2 years.109,110,112,121 Even though the data suggest organ transplant recipients. In contrast to psoriasis
that the duration of treatment is the major factor patients, cyclosporine in organ transplant recipients
determining renal sequelae, continuous treatment is usually prescribed in conjunction with other
poses a higher risk than does as-needed intermittent medications, such as azathioprine or mycophenolate
treatment with repeated 12-week courses.122-125 mofetil, making it difficult to attribute the observed
Hypertension is most likely to develop in elderly effects specifically to cyclosporine. The complex
patients taking cyclosporine but is typically medical history of these patients, including often
reversible after the medication is discontinued.126 numerous comorbidities, further obfuscates the
Because elevations in blood pressure often precede conclusions about pregnancy risk of cyclosporine.
increases in creatinine, it is important to monitor On the basis of animal studies, there is no impair-
blood pressure regularly to avoid not only the ment of fertility from cyclosporine. In a study of 67
1460 Menter et al J AM ACAD DERMATOL
JUNE 2020
d Dose adjustments downward (by 0.25-1.0 mg/kg) when clearance of psoriasis is achieved or
5. Contraindications
d Prior PUVA treatment (especially [200 treatments) or radiation therapy
d Uncontrolled hypertension
d Malignancy
d Hypersensitivity to cyclosporine
6. Baseline monitoring
d History and physical examination
d BP 32
d Urinalysis
Ongoing monitoring
d Monitor BP (early morning resting BP), BUN, creatinine every other week during first 3 months
7. Toxicity
d Renal impairment
B Acute
B Chronic (increasing glomerular fibrosis with increasing duration of treatment and/or with
higher dosages)
d Hypertension
d Malignancies
B Cutaneous
B Lymphoproliferative
d Headache, tremor, and paresthesia
d Hypertrichosis
d Gingival hyperplasia
d Worsening acne
d Myalgias
d Flu-like symptoms
d Lethargy
d Hypertriglyceridemia
d Hyperkalemia
d Hyperbilirubinemia
Continued
J AM ACAD DERMATOL Menter et al 1461
VOLUME 82, NUMBER 6
d Grapefruit juice
9. Pregnancy
d Lower birth weight and shorter duration of pregnancy reported in patients with transplantation;
BP, Blood pressure; BUN, blood urea nitrogen; CBC, complete blood count; LFTs, liver function tests; PUVA, psoralen plus ultraviolet A.
*Supplemental information is expert consensus and not part of evidence-based recommendations.
pregnancies after renal transplantation and blockers, and warfarin. In a case of concomitant
cyclosporine-containing regimens, the preterm labor cyclosporine and statin therapy, severe rhabdomyol-
rate was [40%, with the most frequent complica- ysis was reported.138 Increased nephrotoxicity can
tions in the mother being hypertension, anemia, be seen when other nephrotoxic medications,
urinary tract infections, and preeclampsia.136 such as aminoglycosides and nonsteroidal anti-
In rabbits, in utero exposure to cyclosporine inflammatory medications, are used in conjunction
10 mg/kg/d between days 14 and 18 of gestation with cyclosporine. Potassium-sparing diuretics can
produced offspring with reduced nephron counts potentiate potassium elevation with concomitant
and associated renal dysfunction at birth, progressive cyclosporine treatment, possibly leading to
hypertension, and worsening renal insufficiency hyperkalemia.
with age. There is no evidence that maternal Although cyclosporine can affect the levels of
cyclosporine use during pregnancy can have any numerous other medications, other drugs can
renal sequelae on children.137 On the basis of the interfere with cyclosporine levels. Excessive alcohol
available evidence, treatment with cyclosporine has consumption can increase levels of cyclosporine,
yielded increased rates of prematurity in human whereas mild-to-moderate intake* does not appear
studies. Additionally, animal studies have shown to have a major effect.139 Table IX105,106,140 highlights
decreased fetal weight and increased prenatal and a number of clinically relevant drug interactions
postnatal mortality. between cyclosporine and other medications.
Cyclosporine contains ethanol and has been Owing to the degree of immunosuppression
found in human breast milk; therefore, ethanol will associated with cyclosporine therapy, vaccinations
be orally absorbed by the nursing infant. A decision may be less beneficial, as has been seen in transplant
should be made whether to discontinue nursing or patients on cyclosporine who experienced variable
cyclosporine based on the benefit of therapy to the efficacy with the influenza vaccine.141-143 Even so,
patient. vaccinations are highly recommended in these
patients, because their immunosuppression places
Drug interactions
Cyclosporine is metabolized primarily by the
*Moderate alcohol use: [1 alcoholic drink for women per day (or
cytochrome P450 3A4 subtype (CYP3A4).
binge drinking of [7 drink equivalents per week) and [2
Therefore, cyclosporine use can increase or decrease alcoholic drinks per day for men (or binge drinking of 14 drink
the levels of other medications that are metabolized equivalents per week) is considered harmful. Drink equivalent is
by CYP3A4, such as statins, calcium channel 1 shot liquor = 12 oz beer = 5 to 6 oz wine.
1462 Menter et al J AM ACAD DERMATOL
JUNE 2020
them at risk for severe infections. Live attenuated The package insert also recommends monthly
vaccinations, however, should not be administered CBC, potassium, uric acid, lipids, magnesium, serum
to these patients. bilirubin, and liver enzymes checks.130 Despite these
official recommendations, many physicians gauge
Baseline and ongoing monitoring their patients’ response with biweekly early morning
Patients should be screened with a thorough blood pressure, creatinine, and blood urea nitrogen
history and physical examination, including checks over the first 6 to 8 weeks and then monthly
establishment of baseline blood pressure, hepatitis, monitoring if no persistent abnormalities are
and tuberculosis status, and family history of renal identified.104,128,131 Before starting therapy, women
disease. Because of its potential interactions with should be informed of the risks associated with
prescription and nonprescription medications as cyclosporine during pregnancy.
well as supplements, it is important to take a Patients should regularly monitor their blood
thorough medication history. Factors that increase pressure to avoid chronic hypertension as well as
the risk of nephrotoxicity, such as obesity, advanced kidney damage.127 Early morning resting blood
age, diabetes, and use of other nephrotoxic drugs, pressure is a more sensitive indicator of early neph-
should be considered.126,144 Laboratory monitoring rotoxicity than elevated creatinine.145 If hypertension
at baseline should include urinalysis, serum is observed on 2 separate occasions, the dose of
creatinine, blood urea nitrogen, CBC, potassium, cyclosporine should be decreased using the approach
magnesium, uric acid, lipids, bilirubin, and liver recommended for elevated creatinine levels. If blood
enzymes. pressure does not normalize (\140/90 mm Hg) after
Renal function should be monitored regularly to multiple dose reductions, then the cyclosporine
avoid potential permanent kidney damage. Baseline should be discontinued. Alternatively, elevated blood
and biweekly blood urea nitrogen and creatinine pressure can be adequately treated with antihyper-
monitoring are recommended during the first tensive medications. Because the hypertensive effects
3 months of treatment and then monthly of cyclosporine results from renal arteriole
thereafter.130 There should be an annual estimation vasoconstriction, calcium channel blockers are the
of the glomerular filtration rate for patients who have antihypertensive of choice due to their ability to relax
been treated with cyclosporine for more than 1 year. vascular smooth muscles. Isradipine does not interact
According to the package insert, a 25% increase in with cyclosporine metabolism. b-Blockers can also be
creatinine over baseline, as measured on 2 separate used for blood pressure control. It is best to
occasions at least 2 weeks apart, should prompt a avoid thiazide diuretics, because they enhance
25% to 50% reduction in dose, with monitoring of nephrotoxicity. Potassium-sparing diuretics should
creatinine every other week for 1 month also not be used, because cyclosporine can induce
thereafter.130 If creatinine does not decrease to hyperkalemia.
within 25% of baseline, another dose reduction of Regular monitoring of cyclosporine blood levels
25% to 50% should be performed with biweekly is not necessary at the doses used for the treatment of
laboratory monitoring for another month. If the psoriasis, but certain conditions may warrant
creatinine is not within 25% of baseline after this, closer attention. For instance, patients taking
cyclosporine should be discontinued. An alternative medications that might interfere with cyclosporine
approach is with a 30% increase in creatinine over metabolism or those with liver disease may require
baseline, a gradual, stepwise decrease in the closer monitoring. Those on doses greater than
cyclosporine dose by 1 mg/kg/d until creatinine 3 mg/kg/day for an extended period of time may
falls closer to baseline or, if unobtainable, to also require blood levels or consultation with a
discontinue it. nephrologist, or both.
J AM ACAD DERMATOL Menter et al 1463
VOLUME 82, NUMBER 6
d General pustular
d Palmoplantar
d Pustular
Combination therapy
d Acitretin 1 PUVA
154,155,174-177
4.3 I-II
d Acitretin 1 BB-UVB
170,171
4.4 I-II
elevated triglycerides, there may also be an increased metabolism of acitretin. Drugs that compete for
risk of atherosclerosis. plasma-binding proteins, such as phenytoin, may
Elevation in transaminases is another laboratory also affect plasma concentrations. Simultaneous use
abnormality and is seen in 13% to 16% of patients.180 of oral retinoids and vitamin A supplementation can
While major increases in liver function test results are increase the risk of hypervitaminosis A and should
uncommon, when they do occur, it could suggest the be avoided. Acitretin might interact with the glucose-
onset of acitretin-induced toxic hepatitis.184 lowering effect of glyburide (aka glibenclamide) and
This requires prompt discontinuation of the should be used with caution or avoided in patients
medication.185 taking this drug.
Other less common adverse effects of acitretin
therapy include pseudotumor cerebri-like symp-
Initiation and monitoring
toms, mood changes, decreased night and color
Patients should have a full history and physical
vision, and minor myalgia/arthralgia. Diffuse
examination before beginning acitretin. Baseline
idiopathic hyperostosis is a rarely reported adverse
laboratory studies should include fasting cholesterol
effect of systemic retinoids. It presents with skeletal
and triglycerides, renal and liver function tests, and
changes of the spine, including vertebral syndesmo-
pregnancy tests in women. If acitretin is used in
phytes, extraspinal bones with bone spurs, arthritis
women of child-bearing potential, baseline and
of the vertebral articulations, and degenerative
monthly pregnancy testing is essential.
spondylosis.186 In some cases, hyperostosis may be
After initiation of treatment, patients should be
severe and debilitating.187 Whether acitretin causes
closely monitored to avoid serious adverse effects.
osteoporosis is controversial. The risk appears to be
Fasting lipid profile and liver enzyme testing should
highest in patients receiving long-term, high-dose
be performed monthly for the first 3 months and then
retinoids.188,189 Although rare, systematic retinoids
every 3 months.
may cause premature epiphyseal growth plate
Triglyceride-lowering medications, such as a
closure in young patients.190
fibrate, may be necessary for elevated lipid levels.191
Because patients with psoriasis have an increased
Drug interactions risk of cardiovascular disease, physicians should
Drugs that interfere with the cytochrome P450 recommend lifestyle changes that reduce hyper-
pathway, such as cyclosporine, may affect the lipidemia in patients taking acitretin.
1466 Menter et al J AM ACAD DERMATOL
JUNE 2020
d Lower doses (#25 mg/d) are often used to minimize adverse effects, especially in combination regimens.
d When acitretin is added to phototherapy, the light dose should be reduced by 30%-50%.
2. Contraindications
d Women of childbearing potential cannot consider pregnancy up to 3 years after completion of treatment.
3. Baseline monitoring
d History and physical examination
Ongoing monitoring
d LFTs, lipid profile monthly for the first 3 months, then every 3 months
4. Toxicity
d Cheilitis
d Alopecia
d Xerosis
d Pruritus
d Xerophthalmia
d Night blindness
d Dry mouth
d Paronychia
d Paresthesia
d Headache
d Pseudotumor cerebri
d Nausea
d Abdominal pain
d Joint pain
d Myalgia
d Hypertriglyceridemia
d Abnormal LFTs
5. Drug interactions
d Etretinate can be formed with concurrent ingestion of acitretin and ethanol.
d Acitretin and methotrexate can both cause hepatotoxicity; therefore, they should be combined with
caution.
d Acitretin may reduce the protein binding of phenytoin.
d Acitretin and tetracyclines can both increase intracranial pressure; their combined use should be avoided.
d Concomitant administration of vitamin A and other oral retinoids with acitretin should be avoided.
6. Pregnancy
d Should not be used by patients who are pregnant or intend to become pregnant for at least 3 years after
discontinuation of therapy
Nursing
d Mothers receiving acitretin should not breast-feed.
Fertility
d Not a teratogen when used by male patients who are potentially fathering an infant
The strength of recommendations for the use of transducers and activators of transcription signaling
acitretin in the treatment of psoriasis is provided in pathway necessary for activity of several inflamma-
Table XII,192 the level of evidence for acitretin therapy tory cytokines involved in psoriasis, including inter-
in psoriasis is outlined in Table XIII,x and Table XIV is feron-a/-b, interferon-g, IL-2, IL-12, IL-20, IL-22, and
the supplementary table for acitretin therapy. IL-23.196 It is prescribed at doses of 5 or 10 mg twice
daily (expert consensus).
TOFACITINIB
Tofacitinib is an oral Janus kinase inhibitor Efficacy
approved by the FDA for the treatment of rheuma- Multiple large phase III clinical trials were
toid arthritis, psoriatic arthritis, and ulcerative coli- completed investigating the use of tofacitinib in
tis.194,195 It has shown beneficial effects in psoriasis psoriasis, including Oral treatment Psoriasis Trial
but is not currently approved for that indication. (OPT) Pivotal 1 (n = 901) and OPT Pivotal 2
Tofacitinib interrupts the Janus kinase/signal (n = 960).197 Across these 2 studies, 745 patients
received tofacitinib (5 mg), 741 received tofacitinib
x
References33,150,152,154-157,159,161,162,170,171,193. (10 mg), and 373 received placebo. At week 16, a
1468 Menter et al J AM ACAD DERMATOL
JUNE 2020
d Pregnancy
d Breast-feeding
4. Baseline monitoring
d History and physical examination
d Chemistry screen
d Urinalysis
Ongoing monitoring
d CBC and platelet count every other week for the first 2 months; monthly until 6 months; and bimonthly
thereafter
5. Toxicity
d Anaphylaxis/angioedema
d Flushing
d Malaise
d Fatigue
6. Drug interactions
d Other fumaric acid derivatives, methotrexate, cyclosporine, immunosuppressive, and cytostatic drugs may
potentiate toxicity
d Drugs that cause renal dysfunction
CBC, Complete blood count; GI, gastrointestinal; LFT, liver function test.
*Supplemental information is expert consensus and not part of evidence-based recommendations.
y
The information presented in the supplementary table is obtained from the previous 2009 American Academy of Dermatology Guidelines
of Care for the Management of Psoriasis and Psoriatic Arthritis.
z
Reprinted from Journal of the American Academy of Dermatology, 61(3), Menter A, Korman NJ, Elmets CA, et al., Guidelines of Care for the
Management of Psoriasis and Psoriatic Arthritis: Section 4. Guidelines of Care for the Management and Treatment of Psoriasis with
Traditional Systemic Agents, 451-485, Copyright (2009), with permission from Elsevier.
larger percentage of patients achieved Physician’s (OPT Pivotal 1, 6.2%; OPT Pivotal 2, 11.4%). Efficacy
Global Assessment responses of ‘‘clear’’ or ‘‘almost persisted through week 28, with PASI 75 rates of
clear’’ with tofacitinib 5 and 10 mg twice daily vs 55.6% and 68.8% in patients receiving tofacitinib
placebo (OPT Pivotal 1, 41.9% and 59.2% vs 9.0%; 5 mg and 10 mg twice daily, respectively, and the
OPT Pivotal 2, 46.0% and 59.1% vs 10.9%; all proportion of patients with goal Physician’s Global
P \ .001). Rates of PASI 75 were also higher among Assessment scores measuring 54.7% and 65.9%,
patients receiving tofacitinib (OPT Pivotal 1, 39.9% respectively. Most patients continued to experience
and 59.2%, respectively, for tofacitinib 5 and 10 mg benefit through 2 years of treatment, with serious
twice daily; OPT Pivotal 2, 46.0% and 59.6%, adverse events and discontinuations occurring in
respectively; all P \ .001) compared with placebo less than 11% of patients over 33 months. In a phase
J AM ACAD DERMATOL Menter et al 1469
VOLUME 82, NUMBER 6
2. Dosing
d Initial dose of 500 mg orally twice daily, increasing to 1.5 g/d as tolerated.
3. Contraindications
d Marked bone marrow suppression, including leukopenia, thrombocytopenia, or anemia
4. Baseline monitoring
d History and physical examination
d CBC
Ongoing monitoring
d Weekly CBC until a stable dose is achieved, then monthly
5. Toxicity
d Bone marrow suppression
d Dysuria (rare)
d Temporary impairment of renal tubular function accompanied by elevations in serum uric acid, BUN, and
creatinine
d Fever, chills, malaise, edema, asthenia
d Pulmonary fibrosis
d Fatal and nonfatal pancreatitis and hepatoxicity, and severe peripheral neuropathy have been reported in
7. Pregnancy/nursing
d Pregnancy and breast-feeding should be avoided during treatment and patients (including men) must use
adequate contraception.
d Fertility may be compromised in male patients.
BUN, Blood urea nitrogen; CBC, complete blood count; FDA, Food and Drug Administration; GI, gastrointestinal; NMSCs, nonmelanoma skin
cancers.
*Supplemental information is expert consensus and not part of evidence-based recommendations.
y
The information presented in the supplementary table is obtained from the previous 2009 American Academy of Dermatology Guidelines
of Care for the Management of Psoriasis and Psoriatic Arthritis.
z
Reprinted from Journal of the American Academy of Dermatology, 61(3), Menter A, Korman NJ, Elmets CA, et al., Guidelines of Care for the
Management of Psoriasis and Psoriatic Arthritis: Section 4. Guidelines of Care for the Management and Treatment of Psoriasis with
Traditional Systemic Agents, 451-485, Copyright (2009), with permission from Elsevier.
2. Dosing
d 1.0-1.5 g orally 2 times/d
3. Contraindication
d Hypersensitivity to mycophenolate mofetil (MMF) and mycophenolic acid
4. Baseline monitoring
d History and physical examination
d TB screen, LFTs
Ongoing monitoring
d CBC and platelet count weekly for 1 month; every 2 weeks thereafter for 2 months; then monthly thereafter
5. Toxicity
d GI adverse effects (diarrhea, nausea/vomiting, abdominal cramps); occur early and decrease with continued
use
d Hematologic (leukopenia is most common; anemia, thrombocytopenia)
d Headache, insomnia
d Peripheral edema
d Hypertension
d Patients taking MMF should not be given live attenuated virus vaccines
6. Drug interactions
d Antacids containing aluminum and magnesium
d Cholestyramine
d Phenytoin
d Xanthine bronchodilators
d Probenecid
7. Pregnancy/nursing
d Pregnancy and breast-feeding should be avoided during treatment, and patients (including men) must use
CBC, Complete blood count; CMP, comprehensive metabolic panel; FDA, Food and Drug Administration; LFTs, liver function tests; NMSCs,
nonmelanoma skin cancer.
*Supplemental information is expert consensus and not part of evidence-based recommendations.
y
The information presented in the supplementary table is obtained from the previous 2009 American Academy of Dermatology Guidelines
of Care for the Management of Psoriasis and Psoriatic Arthritis.
z
Reprinted from Journal of the American Academy of Dermatology, 61(3), Menter A, Korman NJ, Elmets CA, et al., Guidelines of Care for the
Management of Psoriasis and Psoriatic Arthritis: Section 4. Guidelines of Care for the Management and Treatment of Psoriasis with
Traditional Systemic Agents, 451-485, Copyright (2009), with permission from Elsevier.
groups (n = 5 vs 0). Overall, nasopharyngitis was the each of the 4 groups (tofacitinib 5 mg twice daily;
most common AE. In the etanercept comparison tofacitinib 10 mg twice daily; etanercept 50 mg
study, rates of adverse events were similar (;2%) in twice weekly, and placebo).199 Patients taking
J AM ACAD DERMATOL Menter et al 1471
VOLUME 82, NUMBER 6
2. Dosing
When thiopurine S-methyltransferase (TPMT) levels are used to guide dosing
Suggested daily schedule
d TPMT \5.0 U, do not use azathioprine
3. Contraindications
d Absolute
B Allergy to azathioprine
B Pregnancy or attempting pregnancy
B Clinically significant active infection
d Relative
B Concurrent use of allopurinol
B Prior treatment with cyclophosphamide or chlorambucil
4. Baseline monitoring
d History and physical examination
d LFTs, CBC and differential CMP, urinalysis, TB screen, hepatitis B and C screen
Ongoing monitoring
d CBC and differential every 2 weeks for the first 2 months, monthly for the next 2 months, every 2 months
thereafter
d LFTs monthly for the first 3 months then every 2 months thereafter
5. Toxicity
d Bone marrow suppression
d Malignancies
d Cutaneous SCCs
d Lymphoproliferative disorders
d Hypersensitivity syndrome
d Pancreatitis
d Hepatitis
6. Drug interactions
d Allopurinoldincreases risks of pancytopenia (if used concurrently, lower the azathioprine dose by 75%)
Continued
1472 Menter et al J AM ACAD DERMATOL
JUNE 2020
CBC, Complete blood count; CMP, comprehensive metabolic panel; FDA, Food and Drug Administration; GI, gastrointestinal;
LFTs, liver function tests; NMSCs, nonmelanoma skin cancers; SCCs, squamous cell carcinomas; TB, tuberculosis.
*Supplemental information is expert consensus and not part of evidence-based recommendations.
y
The information presented in the supplementary table is obtained from the previous 2009 American Academy of Dermatology Guidelines
of Care for the Management of Psoriasis and Psoriatic Arthritis.
z
Reprinted from Journal of the American Academy of Dermatology, 61(3), Menter A, Korman NJ, Elmets CA, et al., Guidelines of Care for the
Management of Psoriasis and Psoriatic Arthritis: Section 4. Guidelines of Care for the Management and Treatment of Psoriasis with
Traditional Systemic Agents, 451-485, Copyright (2009), with permission from Elsevier.
tofacitinib have experienced rare episodes of serious before starting tofacitinib. Vaccination with recom-
infections, such as tuberculosis (including dissemi- binant zoster vaccine (Shingrix, GlaxoSmithKline,
nated disease), opportunistic infections, and bacte- Research Triangle Park, NC) before initiation
rial, fungal, and viral infections. The most common of therapy should be considered. Baseline
serious infections include cellulitis, urinary tract laboratory studies, including CBC with differential,
infection, pneumonia, and herpes zoster. comprehensive metabolic profile, and lipid panel,
Malignancies, including lymphoma, have been re- should be performed at the initiation of treatment
ported; with the use of tofacitinib, Epstein Barr virus- and repeated 4 to 8 weeks later. There should be
associated post-transplant lymphoproliferative dis- regular monitoring every 12 weeks after that.
order was seen in renal transplant patients receiving Because of the small risk of bone marrow
simultaneous treatment with other immunosuppres- suppression with tofacitinib, patients who have low
sive medications.201,202 Lung and breast cancer were counts at baseline (absolute lymphocyte count
the most common nonhematologic malignancies.195 \500 cells/mm3, absolute neutrophil count
Rates of drug discontinuation due to adverse events \1000 cells/mm3, or hemoglobin \9 g/dL) should
were highest in the placebo group. Tofacitinib has a not be treated with tofacitinib. Dose interruption
box warning for increased risk of blood clots with is recommended for patients with normal
higher doses that are sometimes used in the treat- hematologic parameters at baseline who develop
ment of psoriasis.195 10 mg twice-daily dosing of lymphopenia, neutropenia, or anemia while on
tofacitinib has been associated with a higher risk of therapy (Table XV).
thromboembolic disease.195 Tofacitinib is metabolized in the liver and is
Tofacitinib may affect blood counts, liver excreted by the kidney; therefore, the dose should
enzymes, lipid, and creatinine levels. After 3 months be decreased to 5 mg once daily in patients with
of exposure, 0.04% of patients experienced a renal or hepatic impairment. Tofacitinib is not
decrease in absolute lymphocyte count to less than recommended in patients with severe hepatic
500 cells/mm3, and this was correlated with an impairment. Drug interactions can occur because
increased incidence of treated and serious infections. tofacitinib is metabolized by the CYP3A4 enzyme,
Increases in liver enzymes to more than 3 times the with a minor contribution from CYP2C19. Patients
upper limit of normal were also recorded in patients taking other medications that act as inhibitors of
treated with tofacitinib, as were dose-related these enzymes may need to be placed on the lower
elevations of serum creatinine and lipid parameters dose (5 mg daily) to avoid adverse effects from
(triglycerides and total cholesterol, low-density tofacitinib.
lipoprotein cholesterol, and high-density lipoprotein Tofacitinib is not recommended in patients with
cholesterol). The increase in cholesterol occurred active infections, and the risks and benefits of
after 1 month of therapy and subsequently remained treatment should be thoroughly considered and
stable.195 discussed with the patient before beginning treat-
ment. The medication should not be combined with
Monitoring other potent immunosuppressive drugs such as
Given the risk of infection, patients should be azathioprine, cyclosporine, or biologic agents,
screened for tuberculosis, hepatitis, and HIV although it may be used with methotrexate if
J AM ACAD DERMATOL Menter et al 1473
VOLUME 82, NUMBER 6
2. Dosing
d Loading dose of 100 mg/d for 3 days, followed by 20 mg/d thereafter
3. Contraindications
d Patients with hypersensitivity to leflunomide or its metabolites
4. Baseline monitoring
d History and physical examination
d LFTs
Ongoing monitoring
d Monthly CBC with differential and LFTs for the first 6 months and every 6-8 weeks thereafter
5. Toxicity
d Most common adverse effects include nausea, diarrhea, loss of appetite, weight loss, headache, dizziness
B May be fatal
B Most cases occur within 6 months of therapy and in patients with multiple risk factors for hepatotoxicity
d Rare reports of pancytopenia, agranulocytosis, and thrombocytopenia in patients treated with or who had
recently discontinued methotrexate or other immunosuppressive agents
6. Drug interactions
d No pharmacokinetic interaction between leflunomide and methotrexate, but coadministration of the 2
7. Pregnancy
d Should be avoided in pregnant patients
Nursing
d Leflunomide should not be used by nursing mothers.
CBC, Complete blood count; LFTs, liver function tests; FDA, Food and Drug Administration.
*Supplemental information is expert consensus and not part of evidence-based recommendations.
y
The information presented in the supplementary table is obtained from the previous 2009 American Academy of Dermatology Guidelines
of Care for the Management of Psoriasis and Psoriatic Arthritis.
z
Reprinted from Journal of the American Academy of Dermatology, 61(3), Menter A, Korman NJ, Elmets CA, et al., Guidelines of Care for the
Management of Psoriasis and Psoriatic Arthritis: Section 4. Guidelines of Care for the Management and Treatment of Psoriasis with
Traditional Systemic Agents, 451-485, Copyright (2009), with permission from Elsevier.
indicated. For further recommendations about the due strictly to their immunomodulatory actions.203
use of tofacitinib in psoriasis see Table XV. However, more recent studies have identified anti-
angiogenesis and antioxidant effects as well.203-205
FUMARIC ACID ESTERS In 2015, a Cochrane review investigated the use of
Fumaric acid esters (FAEs), also known as FAEs for psoriasis.206 The review included 6 studies
fumarates, are compounds of dimethyl fumarate (2 full reports, 2 abstracts, 1 brief communication,
along with monoethyl fumarate salts. While and 1 letter) with a total of 544 participants. All
frequently used in Europe for treatment of moderate studies reported a significant reduction in PASI
to severe psoriasis, fumarates are not currently scores with FAEs. A meta-analysis of 2 additional
approved by the FDA for psoriasis, although they studies with 247 participants showed superiority of
are approved in the United States for other FAEs in achieving PASI 50 over placebo (64% vs 14%;
indications, including psoriatic arthritis. Their RR, 4.55; 95% CI, 2.80-7.40). Treatment with FAEs
mechanism of action was originally thought to be resulted in a statistically significant improvement in
1474 Menter et al J AM ACAD DERMATOL
JUNE 2020
2. Dosage
d 0.05-0.15 mg/kg
3. Contraindications
d Patients with hypersensitivity to tacrolimus or its metabolites
d BP
d LFTs
d TB
d Serum chemistry
5. Drug interactions
d Numerous drug interactions due to its metabolization by the cytochrome P450 system
6. Pregnancy
d Can be used during pregnancy only if the potential benefit to mother justifies the potential risk to fetus.
Nursing
d Tacrolimus should not be used by nursing mothers.
Fertility
d Advise patients to use appropriate contraception before initiating therapy.
d On the basis of animal studies, female and male fertility may be compromised by treatment.
BP, Blood pressure; FDA, Food and Drug Administration; LFTs, liver function tests; TB, tuberculosis.
*Supplemental information is expert consensus and not part of evidence-based recommendations.
y
The information presented in the supplementary table is obtained from the previous 2009 American Academy of Dermatology Guidelines
of Care for the Management of Psoriasis and Psoriatic Arthritis.
z
Reprinted from Journal of the American Academy of Dermatology, 61(3), Menter A, Korman NJ, Elmets CA, et al., Guidelines of Care for the
Management of Psoriasis and Psoriatic Arthritis: Section 4. Guidelines of Care for the Management and Treatment of Psoriasis with
Traditional Systemic Agents, 451-485, Copyright (2009), with permission from Elsevier.
participants’ quality of life.203 The same studies also nausea, vomiting, esophageal, and stomach pain,
reported that more participants achieved PASI 75 can occur in up to two-thirds of patients.208 A modest
with FAEs. When a combination of methotrexate and lymphopenia is invariably present but does not
FAEs was compared with methotrexate alone, the appear to be of significant clinical concern.209
difference was not statistically significant after Increases in liver function test results, triglycerides,
adjustment for baseline disease severity.19 cholesterol, and creatinine are possible, necessi-
Adverse effects, mainly GI disturbance and tating regular laboratory monitoring. There are rare
flushing, were more prevalent in patients taking cases of renal disease that have been reported with
FAEs compared with placebo (76% vs 16%; RR, 4.72; FAEs, although this was not experienced in any
95% CI, 2.45-9.0).207 Similar findings have been randomized controlled trials and FAEs may not be
reported in other studies. GI complaints, including the cause.210 There have also been rare cases
J AM ACAD DERMATOL Menter et al 1475
VOLUME 82, NUMBER 6
2. Dosing
d Start at 80 mg 2 times/wk; increase by 20 mg every 2-4 weeks
3. Contraindications
d Pre-existing liver disease
d Immunosuppression
4. Baseline monitoring
d History and physical examination
Ongoing monitoring
d CBC and platelet count every 2-4 weeks; CMP every 3 months
5. Toxicity
d Myelosuppression
d Hyperuricemia
d Photodermatitis
d Taste changes
d Headache
d Nausea/vomiting
d Aphthous ulcers
d Fatigue
6. Drug interactions
d Aminosalicylate derivatives (olsalazine, mesalazine, or sulfasalazine) may inhibit thiopurine
methyltransferase.
7. Pregnancy
d Pregnancy and breast-feeding should be avoided during treatment, and patients (including men) must use
adequate contraception.
ALT, alanine aminotransferase; AST, aspartate aminotransferase; CBC, complete blood count; CMP, complete metabolic profile; FDA, Food and
Drug Administration; LFTs, liver function tests; NMSCs, nonmelanoma skin cancers; TB, tuberculosis.
*Supplemental information is expert consensus and not part of evidence-based recommendations.
y
The information presented in the supplementary table is obtained from the previous 2009 American Academy of Dermatology Guidelines
of Care for the Management of Psoriasis and Psoriatic Arthritis.
z
Reprinted from Journal of the American Academy of Dermatology, 61(3), Menter A, Korman NJ, Elmets CA, et al., Guidelines of Care for the
Management of Psoriasis and Psoriatic Arthritis: Section 4. Guidelines of Care for the Management and Treatment of Psoriasis with
Traditional Systemic Agents, 451-485, Copyright (2009), with permission from Elsevier.
OTHER TREATMENTS 15. Dogra S, Krishna V, Kanwar AJ. Efficacy and safety of systemic
Although rarely necessary for psoriasis, systemic methotrexate in two fixed doses of 10 mg or 25 mg orally
once weekly in adult patients with severe plaque-type
immunosuppressants and antimetabolites, including psoriasis: a prospective, randomized, double-blind, dose-
hydroxyurea (Table XVII), mycophenolate mofetil ranging study. Clin Exp Dermatol. 2012;37(7):729-734.
(Table XVIII), azathioprine (Table XIX), leflunomide 16. Radmanesh M, Rafiei B, Moosavi ZB, Sina N. Weekly vs. daily
(Table XX), tacrolimus (Table XXI), and thioguanine administration of oral methotrexate (MTX) for generalized
(Table XXII), may have value for this disease in plaque psoriasis: a randomized controlled clinical trial. Int J
Dermatol. 2011;50(10):1291-1293.
certain instances. These medications still have 17. Weinstein GD, Frost P. Methotrexate for psoriasis. A new
a place in the management of various other therapeutic schedule. Arch Dermatol. 1971;103(1):33-38.
autoimmune conditions. 18. Menting SP, Dekker PM, Limpens J, Hooft L, Spuls PI.
Methotrexate dosing regimen for plaque-type psoriasis: a
We thank our medical librarian Charniel McDaniels, MS, systematic review of the use of test-dose, start-dose, dosing
and our specialist David A. Castillo, BS, for helping scheme, dose adjustments, maximum dose and folic acid
with search strings, evidence table generation, as well as supplementation. Acta Derm Venereol. 2016;96(1):23-28.
with the manuscript publication process. During 19. Fallah Arani S, Neumann H, Hop W, Thio H. Fumarates vs.
the development of this guideline, Michael Siegel served methotrexate in moderate to severe chronic plaque psoriasis:
as a patient representative for the National Psoriasis a multicentre prospective randomized controlled clinical trial.
Foundation. Br J Dermatol. 2011;164(4):855-861.
20. Warren RB, Mrowietz U, von Kiedrowski R, et al. An intensified
dosing schedule of subcutaneous methotrexate in
REFERENCES patients with moderate to severe plaque-type psoriasis
1. Kaushik SB, Lebwohl MG. Psoriasis: which therapy for which (METOP): a 52 week, multicentre, randomised, double-blind,
patient: psoriasis comorbidities and preferred systemic placebo-controlled, phase 3 trial. Lancet. 2017;389(10068):
agents. J Am Acad Dermatol. 2019;80(1):27-40. 528-537.
2. Kaushik SB, Lebwohl MG. Psoriasis: which therapy for which 21. US Food and Drug Administration. REDITREX (methotrexate)
patient: focus on special populations and chronic infections. injection [package insert]. Available at: https://www.
J Am Acad Dermatol. 2019;80(1):43-53. accessdata.fda.gov/drugsatfda_docs/label/2019/210737
3. Menter A. Psoriasis and psoriatic arthritis overview. Am J s000lbl.pdf; 2019. Accessed February 12, 2020.
Manag Care. 2016;22(8 Suppl):s216-s224. 22. Prey S, Paul C. Effect of folic or folinic acid supplementation
4. Fredriksson T, Pettersson U. Severe psoriasisdoral on methotrexate-associated safety and efficacy in inflamma-
therapy with a new retinoid. Dermatologica. 1978;157(4): tory disease: a systematic review. Br J Dermatol. 2009;160(3):
238-244. 622-628.
5. Hawkes JE, Chan TC, Krueger JG. Psoriasis pathogenesis and 23. Chladek J, Simkova M, Vaneckova J, et al. The effect of folic
the development of novel targeted immune therapies. J acid supplementation on the pharmacokinetics and pharma-
Allergy Clin Immunol. 2017;140(3):645-653. codynamics of oral methotrexate during the remission-
6. Heidenreich R, Rocken M, Ghoreschi K. Angiogenesis drives induction period of treatment for moderate-to-severe plaque
psoriasis pathogenesis. Int J Exp Pathol. 2009;90(3):232-248. psoriasis. Eur J Clin Pharmacol. 2008;64(4):347-355.
7. Lowes MA, Suarez-Farinas M, Krueger JG. Immunology of 24. Cline A, Jorizzo JL. Does daily folic acid supplementation
psoriasis. Annu Rev Immunol. 2014;32:227-255. reduce methotrexate efficacy? Dermatol Online J. 2017;
8. Matthews DA, Alden RA, Bolin JT, et al. Dihydrofolate 23(11).
reductase: x-ray structure of the binary complex with 25. West J, Ogston S, Foerster J. Safety and efficacy of metho-
methotrexate. Science. 1977;197(4302):452-455. trexate in psoriasis: a meta-analysis of published trials. PLoS
9. Whittle SL, Hughes RA. Folate supplementation and metho- One. 2016;11(5):e0153740.
trexate treatment in rheumatoid arthritis: a review. Rheuma- 26. Sbidian E, Chaimani A, Garcia-Doval I, et al. Systemic
tology (Oxford). 2004;43(3):267-271. pharmacological treatments for chronic plaque psoriasis: a
10. Chan ES, Cronstein BN. Molecular action of methotrexate in network meta-analysis. Cochrane Database Syst Revs. 2017;12:
inflammatory diseases. Arthritis Res. 2002;4(4):266-273. CD011535.
11. Montesinos MC, Desai A, Delano D, et al. Adenosine A2A or 27. Barker J, Hoffmann M, Wozel G, et al. Efficacy and safety of
A3 receptors are required for inhibition of inflammation by infliximab vs. methotrexate in patients with moderate-to-
methotrexate and its analog MX-68. Arthritis Rheum. 2003; severe plaque psoriasis: results of an open-label, active-
48(1):240-247. controlled, randomized trial (RESTORE1). Br J Dermatol. 2011;
12. Morgan SL, Oster RA, Lee JY, Alarcon GS, Baggott JE. The 165(5):1109-1117.
effect of folic acid and folinic acid supplements on purine 28. Saurat JH, Stingl G, Dubertret L, et al. Efficacy and safety
metabolism in methotrexate-treated rheumatoid arthritis. results from the randomized controlled comparative study
Arthritis Rheum. 2004;50(10):3104-3111. of adalimumab vs. methotrexate vs. placebo in patients
13. Jeffes EW 3rd, McCullough JL, Pittelkow MR, et al. Metho- with psoriasis (CHAMPION). Br J Dermatol. 2008;158(3):558-
trexate therapy of psoriasis: differential sensitivity of prolif- 566.
erating lymphoid and epithelial cells to the cytotoxic and 29. Gelfand JM, Wan J, Callis Duffin K, et al. Comparative
growth-inhibitory effects of methotrexate. J Invest Dermatol. effectiveness of commonly used systemic treatments or
1995;104(2):183-188. phototherapy for moderate to severe plaque psoriasis in the
14. Saporito FC, Menter MA. Methotrexate and psoriasis in the clinical practice setting. Arch Dermatol. 2012;148(4):487-494.
era of new biologic agents. J Am Acad Dermatol. 2004;50(2): 30. Jabbar-Lopez ZK, Yiu ZZN, Ward V, et al. Quantitative
301-309. evaluation of biologic therapy options for psoriasis: a
J AM ACAD DERMATOL Menter et al 1477
VOLUME 82, NUMBER 6
systematic review and network meta-analysis. J Invest 48. Helliwell PS, Taylor WJ, Group CS. Treatment of psoriatic
Dermatol. 2017;137(8):1646-1654. arthritis and rheumatoid arthritis with disease modifying
31. Kingsley GH, Kowalczyk A, Taylor H, et al. A randomized drugsdcomparison of drugs and adverse reactions. J Rheu-
placebo-controlled trial of methotrexate in psoriatic arthritis. matol. 2008;35(3):472-476.
Rheumatology (Oxford). 2012;51(8):1368-1377. 49. Conway R, Low C, Coughlan RJ, O’Donnell MJ, Carey JJ.
32. Coates LC, Helliwell PS. Methotrexate efficacy in the tight Methotrexate use and risk of lung disease in psoriasis,
control in psoriatic arthritis study. J Rheumatol. 2016;43(2): psoriatic arthritis, and inflammatory bowel disease: system-
356-361. atic literature review and meta-analysis of randomised
33. Takeshita J, Wang S, Shin DB, et al. Comparative effectiveness controlled trials. BMJ. 2015;350:h1269.
of less commonly used systemic monotherapies and 50. Menter A, Korman NJ, Elmets CA, et al. Guidelines of care for
common combination therapies for moderate to severe the management of psoriasis and psoriatic arthritis: section 4.
psoriasis in the clinical setting. J Am Acad Dermatol. 2014; Guidelines of care for the management and treatment of
71(6):1167-1175. psoriasis with traditional systemic agents. J Am Acad
34. Zachariae C, Mork NJ, Reunala T, et al. The combination of Dermatol. 2009;61(3):451-485.
etanercept and methotrexate increases the effectiveness of 51. Kalb RE, Strober B, Weinstein G, Lebwohl M. Methotrexate
treatment in active psoriasis despite inadequate effect of and psoriasis: 2009 National Psoriasis Foundation
methotrexate therapy. Acta Derm Venereol. 2008;88(5):495-501. Consensus Conference. J Am Acad Dermatol. 2009;60(5):
35. Gottlieb AB, Langley RG, Strober BE, et al. A randomized, 824-837.
double-blind, placebo-controlled study to evaluate the addi- 52. Kivity S, Zafrir Y, Loebstein R, Pauzner R, Mouallem M,
tion of methotrexate to etanercept in patients with moderate Mayan H. Clinical characteristics and risk factors for low
to severe plaque psoriasis. Br J Dermatol. 2012;167(3):649-657. dose methotrexate toxicity: a cohort of 28 patients. Auto-
36. Busard C, Zweegers J, Limpens J, Langendam M, Spuls PI. immun Rev. 2014;13(11):1109-1113.
Combined use of systemic agents for psoriasis: a systematic 53. Boffa MJ, Chalmers RJ. Methotrexate for psoriasis. Clin Exp
review. JAMA Dermatol. 2014;150(11):1213-1220. Dermatol. 1996;21(6):399-408.
37. Al-Hamamy HR, Al-Mashhadani SA, Mustafa IN. Comparative 54. US Food and Drug Administration. Methotrexate (Otrexup)
study of the effect of narrowband ultraviolet B phototherapy [package insert]. Available at: https://www.accessdata.fda.
plus methotrexate vs. narrowband ultraviolet B alone and gov/drugsatfda_docs/label/2019/204824s009lbl.pdf; 2019.
methotrexate alone in the treatment of plaque-type psoria- Accessed August 26, 2019.
sis. Int J Dermatol. 2014;53(12):1531-1535. 55. Langman G, Hall PM, Todd G. Role of non-alcoholic steato-
38. Mahajan R, Kaur I, Kanwar AJ. Methotrexate/narrowband hepatitis in methotrexate-induced liver injury. J Gastroenterol
UVB phototherapy combination vs. narrowband UVB photo- Hepatol. 2001;16(12):1395-1401.
therapy in the treatment of chronic plaque-type psoriasisda 56. Rosenberg P, Urwitz H, Johannesson A, et al. Psoriasis
randomized single-blinded placebo-controlled study. J Eur patients with diabetes type 2 are at high risk of developing
Acad Dermatol Venereol. 2010;24(5):595-600. liver fibrosis during methotrexate treatment. J Hepatol. 2007;
39. Soliman A, Nofal E, Nofal A, El Desouky F, Asal M. Combination 46(6):1111-1118.
therapy of methotrexate plus NBUVB phototherapy is more 57. Carneiro SC, Cassia FF, Lamy F, Chagas VL, Ramos-e-Silva M.
effective than methotrexate monotherapy in the treatment of Methotrexate and liver function: a study of 13 psoriasis cases
chronic plaque psoriasis. J Dermatolog Treat. 2015;26(6):528-534. treated with different cumulative dosages. J Eur Acad
40. Ford AR, Siegel M, Bagel J, et al. Dietary recommendations for Dermatol Venereol. 2008;22(1):25-29.
adults with psoriasis or psoriatic arthritis from the medical 58. Montaudie H, Sbidian E, Paul C, et al. Methotrexate in
board of the National Psoriasis Foundation: a systematic psoriasis: a systematic review of treatment modalities,
review. JAMA Dermatol. 2018;154(8):934-950. incidence, risk factors and monitoring of liver toxicity. J Eur
41. Belzunegui J, Intxausti JJ, De Dios JR, et al. Absence of Acad Dermatol Venereol. 2011;25 Suppl 2:12-18.
pulmonary fibrosis in patients with psoriatic arthritis treated 59. Menter A, Cordoro KM, Davis DMR, et al. Joint American
with weekly low-dose methotrexate. Clin Exp Rheumatol. Academy of Dermatology-National Psoriasis Foundation
2001;19(6):727-730. guidelines of care for the management and treatment of
42. Brownell I, Strober BE. Folate with methotrexate: big benefit, psoriasis in pediatric patients. J Am Acad Dermatol. 2020;
questionable cost. Br J Dermatol. 2007;157(1):213. 82(1):161-201.
43. Kremer JM. Toward a better understanding of methotrexate. 60. Hoffmann K, Casetti F, Schempp C. Methotrexate-associated
Arthritis Rheum. 2004;50(5):1370-1382. photosensitization [in German]. Hautarzt. 2015;66(6):459-461.
44. MacDonald A, Burden AD. Noninvasive monitoring for 61. Morris LF, Harrod MJ, Menter MA, Silverman AK.
methotrexate hepatotoxicity. Br J Dermatol. 2005;152(3): Methotrexate and reproduction in men: case report
405-408. and recommendations. J Am Acad Dermatol. 1993;29(5 Pt
45. Haberman R, Perez-Chada LM, Merola JF, Scher J, Ogdie A, 2):913-916.
Reddy SM. Bridging the gaps in the care of psoriasis and 62. El-Beheiry A, El-Mansy E, Kamel N, Salama N. Methotrexate
psoriatic arthritis: the role of combined clinics. Curr Rheuma- and fertility in men. Arch Androl. 1979;3(2):177-179.
tol Rep. 2018;20(12):76. 63. Estop AM, Cieply K, Van Kirk V, Levison F, Buckingham R.
46. Perez-Chada LM, Cohen JM, Gottlieb AB, et al. Achieving Sperm chromosome studies in patients taking low dose
international consensus on the assessment of psoriatic methotrexate. Am J Hum Genet. 1992;51:A314.
arthritis in psoriasis clinical trials: an International Derma- 64. Sussman A, Leonard JM. Psoriasis, methotrexate, and oligo-
tology Outcome Measures (IDEOM) initiative. Arch Dermatol spermia. Arch Dermatol. 1980;116(2):215-217.
Res. 2018;310(9):701-710. 65. Akhyani M, Chams-Davatchi C, Hemami MR, Fateh S. Efficacy
47. Chen TJ, Chung WH, Chen CB, et al. Methotrexate-induced and safety of mycophenolate mofetil vs. methotrexate for
epidermal necrosis: a case series of 24 patients. J Am Acad the treatment of chronic plaque psoriasis. J Eur Acad
Dermatol. 2017;77(2):247-255.e242. Dermatol Venereol. 2010;24(12):1447-1451.
1478 Menter et al J AM ACAD DERMATOL
JUNE 2020
66. Barker J, Horn EJ, Lebwohl M, et al. Assessment and Roenigk classification in Asian patients with psoriasis:
management of methotrexate hepatotoxicity in psoriasis a retrospective study. Arch Dermatol Res. 2017;309(5):403-408.
patients: report from a consensus conference to evaluate 82. Bray AP, Barnova I, Przemioslo R, Kennedy CT. Liver fibrosis
current practice and identify key questions toward opti- screening for patients with psoriasis taking methotrexate: a
mizing methotrexate use in the clinic. J Eur Acad Dermatol cross-sectional study comparing transient elastography and
Venereol. 2011;25(7):758-764. liver biopsy. Br J Dermatol. 2012;166(5):1125-1127.
67. Ho SG, Yeung CK, Chan HH. Methotrexate versus traditional 83. Tapper EB, Castera L, Afdhal NH. FibroScan (vibration-
Chinese medicine in psoriasis: a randomized, placebo- controlled transient elastography): where does it stand in
controlled trial to determine efficacy, safety and quality of the United States practice. Clin Gastroenterol Hepatol. 2015;
life. Clin Exp Dermatol. 2010;35(7):717-722. 13(1):27-36.
68. Reich K, Signorovitch J, Ramakrishnan K, et al. Benefit-risk 84. Park CC, Nguyen P, Hernandez C, et al. Magnetic resonance
analysis of adalimumab versus methotrexate and placebo in elastography vs transient elastography in detection of
the treatment of moderate to severe psoriasis: comparison of fibrosis and noninvasive measurement of steatosis in pa-
adverse event-free response days in the CHAMPION trial. J tients with biopsy-proven nonalcoholic fatty liver disease.
Am Acad Dermatol. 2010;63(6):1011-1018. Gastroenterology. 2017;152(3):598-607. e592.
69. Revicki D, Willian MK, Saurat JH, et al. Impact of adalimumab 85. Hoganson DD, Chen J, Ehman RL, et al. Magnetic resonance
treatment on health-related quality of life and other patient- elastography for liver fibrosis in methotrexate treatment.
reported outcomes: results from a 16-week randomized Open J Rheumatol Autoimmune Dis. 2012;2(2):6-13.
controlled trial in patients with moderate to severe plaque 86. Papp K, Reich K, Leonardi CL, et al. Apremilast, an oral
psoriasis. Br J Dermatol. 2008;158(3):549-557. phosphodiesterase 4 (PDE4) inhibitor, in patients with mod-
70. Ogdie A, Grewal SK, Noe MH, et al. Risk of incident liver erate to severe plaque psoriasis: Results of a phase III,
disease in patients with psoriasis, psoriatic arthritis, and randomized, controlled trial (Efficacy and Safety Trial Evalu-
rheumatoid arthritis: a population-based study. J Invest ating the Effects of Apremilast in Psoriasis [ESTEEM] 1). J Am
Dermatol. 2018;138(4):760-767. Acad Dermatol. 2015;73(1):37-49.
71. van der Voort EA, Koehler EM, Nijsten T, et al. Increased 87. US Food and Drug Administration. Apremilast (Otezla) [package
prevalence of advanced liver fibrosis in patients with psori- insert]. Celgene Corporation. Available at: https://www.
asis: a cross-sectional analysis from the Rotterdam Study. accessdata.fda.gov/drugsatfda_docs/label/2017/205437s006lbl.
Acta Derm Venereol. 2016;96(2):213-217. pdf; 2017. Accessed May 2, 2019.
72. van der Voort EA, Koehler EM, Dowlatshahi EA, et al. Psoriasis 88. Kavanaugh A, Mease PJ, Gomez-Reino JJ, et al. Longterm
is independently associated with nonalcoholic fatty liver (52-week) results of a phase III randomized, controlled trial of
disease in patients 55 years old or older: results from a apremilast in patients with psoriatic arthritis. J Rheumatol.
population-based study. J Am Acad Dermatol. 2014;70(3):517- 2015;42(3):479-488.
524. 89. Danesh MJ, Beroukhim K, Nguyen C, Levin E, Koo J.
73. Robert M, Sofair AN, Thomas A, et al. A comparison of Apremilast and adalimumab: a novel combination therapy
hepatopathologists’ and community pathologists’ review of for recalcitrant psoriasis. Dermatol Online J. 2015;21(6).
liver biopsy specimens from patients with hepatitis C. Clin 90. AbuHilal M, Walsh S, Shear N. Use of apremilast in combina-
Gastroenterol Hepatol. 2009;7(3):335-338. tion with other therapies for treatment of chronic plaque
74. Intraobserver and interobserver variations in liver biopsy psoriasis: a retrospective study. J Cutan Med Surg. 2016;20(4):
interpretation in patients with chronic hepatitis C. The 313-316.
French METAVIR Cooperative Study Group. Hepatology. 91. Rothstein BE, McQuade B, Greb JE, Goldminz AM,
1994;20(1 Pt 1):15-20. Gottlieb AB. Apremilast and secukinumab combined therapy
75. Ratziu V, Charlotte F, Heurtier A, et al. Sampling variability of in a patient with recalcitrant plaque psoriasis. J Drugs
liver biopsy in nonalcoholic fatty liver disease. Gastroenter- Dermatol. 2016;15(5):648-649.
ology. 2005;128(7):1898-1906. 92. Zerilli T, Ocheretyaner E. Apremilast (Otezla): a new oral
76. Regev A, Berho M, Jeffers LJ, et al. Sampling error and treatment for adults with psoriasis and psoriatic arthritis. P T.
intraobserver variation in liver biopsy in patients with chronic 2015;40(8):495-500.
HCV infection. Am J Gastroenterol. 2002;97(10):2614-2618. 93. Gottlieb AB, Matheson RT, Menter A, et al. Efficacy, tolera-
77. Tapper EB, Lok AS. Use of liver imaging and biopsy in clinical bility, and pharmacodynamics of apremilast in recalcitrant
practice. N Engl J Med. 2017;377(8):756-768. plaque psoriasis: a phase II open-label study. J Drugs
78. Laharie D, Seneschal J, Schaeverbeke T, et al. Assessment of liver Dermatol. 2013;12(8):888-897.
fibrosis with transient elastography and FibroTest in patients 94. Nast A, Jacobs A, Rosumeck S, Werner RN. Efficacy and safety
treated with methotrexate for chronic inflammatory diseases: a of systemic long-term treatments for moderate-to-severe
case-control study. J Hepatol. 2010;53(6):1035-1040. psoriasis: a systematic review and meta-analysis. J Invest
79. Bauer B, Chyou PH, Stratman EJ, Green C. Noninvasive testing Dermatol. 2015;135(11):2641-2648.
for nonalcoholic steatohepatitis and hepatic fibrosis in 95. Papp K, Cather JC, Rosoph L, et al. Efficacy of apremilast in
patients with psoriasis receiving long-term methotrexate the treatment of moderate to severe psoriasis: a randomised
sodium therapy. JAMA Dermatol. 2017;153(10):977-982. controlled trial. Lancet. 2012;380(9843):738-746.
80. Maybury CM, Samarasekera E, Douiri A, Barker JN, Smith CH. 96. Paul C, Cather J, Gooderham M, et al. Efficacy and safety of
Diagnostic accuracy of noninvasive markers of liver fibrosis in apremilast, an oral phosphodiesterase 4 inhibitor, in patients
patients with psoriasis taking methotrexate: a systematic with moderate-to-severe plaque psoriasis over 52 weeks: a
review and meta-analysis. Br J Dermatol. 2014;170(6):1237- phase III, randomized controlled trial (ESTEEM 2). Br J
1247. Dermatol. 2015;173(6):1387-1399.
81. Rongngern P, Chularojanamontri L, Wongpraparut C, et al. 97. Strand V, Fiorentino D, Hu C, Day RM, Stevens RM, Papp KA.
Diagnostic performance of transient elastography for Improvements in patient-reported outcomes with apremilast,
detection of methotrexate-induced liver injury using an oral phosphodiesterase 4 inhibitor, in the treatment of
J AM ACAD DERMATOL Menter et al 1479
VOLUME 82, NUMBER 6
moderate to severe psoriasis: results from a phase IIb random- 115. Shupack J, Abel E, Bauer E, et al. Cyclosporine as mainte-
ized, controlled study. Health Qual Life Outcomes. 2013;11:82. nance therapy in patients with severe psoriasis. J Am Acad
98. Mueller W, Herrmann B. Cyclosporin A for psoriasis. N Engl J Dermatol. 1997;36(3 Pt 1):423-432.
Med. 1979;301(10):555. 116. Lebwohl M, Ali S. Treatment of psoriasis. Part 2. Systemic
99. Gottlieb AB, Grossman RM, Khandke L, et al. Studies of the therapies. J Am Acad Dermatol. 2001;45(5):649-661;quiz 662-
effect of cyclosporine in psoriasis in vivo: combined effects 644.
on activated T lymphocytes and epidermal regenerative 117. Naldi L. Malignancy concerns with psoriasis treatments using
maturation. J Invest Dermatol. 1992;98(3):302-309. phototherapy, methotrexate, cyclosporin, and biologics: facts
100. Prens EP, van Joost T, Hegmans JP, t Hooft-Benne K, and controversies. Clin Dermatol. 2010;28(1):88-92.
Ysselmuiden OE, Benner R. Effects of cyclosporine on 118. van de Kerkhof PC. Therapeutic strategies: rotational
cytokines and cytokine receptors in psoriasis. J Am Acad therapy and combinations. Clin Exp Dermatol. 2001;26(4):
Dermatol. 1995;33(6):947-953. 356-361.
101. Faerber L, Braeutigam M, Weidinger G, et al. Cyclosporine in 119. Calzavara-Pinton P, Leone G, Venturini M, et al. A compar-
severe psoriasis. Results of a meta-analysis in 579 patients. ative non randomized study of narrow-band (NB) (312 1/-2
Am J Clin Dermatol. 2001;2(1):41-47. nm) UVB phototherapy versus sequential therapy with oral
102. Amor KT, Ryan C, Menter A. The use of cyclosporine in administration of low-dose Cyclosporin A and NB-UVB
dermatology: part I. J Am Acad Dermatol. 2010;63(6):925-946; phototherapy in patients with severe psoriasis vulgaris. Eur
quiz 947-928. J Dermatol. 2005;15(6):470-473.
103. Christophers E, Mrowietz U, Henneicke HH, Farber L, 120. Markham T, Watson A, Rogers S. Adverse effects with long-
Welzel D. Cyclosporine in psoriasis: a multicenter dose- term cyclosporin for severe psoriasis. Clin Exp Dermatol. 2002;
finding study in severe plaque psoriasis. The German 27(2):111-114.
Multicenter Study. J Am Acad Dermatol. 1992;26(1):86-90. 121. Laburte C, Grossman R, Abi-Rached J, Abeywickrama KH,
104. Griffiths CE, Dubertret L, Ellis CN, et al. Ciclosporin in psoriasis Dubertret L. Efficacy and safety of oral cyclosporin A (CyA;
clinical practice: an international consensus statement. Br J Sandimmun) for long-term treatment of chronic severe
Dermatol. 2004;150(Suppl 67):11-23. plaque psoriasis. Br J Dermatol. 1994;130(3):366-375.
105. Shintani Y, Kaneko N, Furuhashi T, Saito C, Morita A. Safety 122. Soleymani T, Vassantachart JM, Wu JJ. Comparison of
and efficacy of a fixed-dose cyclosporin microemulsion (100 guidelines for the use of cyclosporine for psoriasis: a critical
mg) for the treatment of psoriasis. J Dermatol. 2011;38(10): appraisal and comprehensive review. J Drugs Dermatol. 2016;
966-972. 15(3):293-301.
106. Gisondi P, Del Giglio M, Di Francesco V, Zamboni M, 123. Ramirez-Fort MK, Levin AA, Au SC, Gottlieb AB. Continuous
Girolomoni G. Weight loss improves the response of obese versus intermittent therapy for moderate-to-severe psoriasis.
patients with moderate-to-severe chronic plaque psoriasis to Clin Exp Rheumatol. 2013;31(4 Suppl 78):S63-S70.
low-dose cyclosporine therapy: a randomized, controlled, 124. Chaidemenos GC, Mourellou O, Avgoustinaki N,
investigator-blinded clinical trial. Am J Clin Nutr. 2008;88(5): Papakonstantinou M, Karakatsanis G, Katsambas A. Intermit-
1242-1247. tent vs. continuous 1-year cyclosporin use in chronic
107. Berth-Jones J, Henderson CA, Munro CS, et al. Treatment of plaque psoriasis. J Eur Acad Dermatol Venerol. 2007;21(9):
psoriasis with intermittent short course cyclosporin (Neoral). 1203-1208.
A multicentre study. Br J Dermatol. 1997;136(4):527-530. 125. Ohtsuki M, Nakagawa H, Sugai J, et al. Long-term continuous
108. Ellis CN, Fradin MS, Messana JM, et al. Cyclosporine for versus intermittent cyclosporin: therapy for psoriasis. J
plaque-type psoriasis. Results of a multidose, double-blind Dermatol. 2003;30(4):290-298.
trial. N Engl J Med. 1991;324(5):277-284. 126. Lowe NJ, Wieder JM, Rosenbach A, et al. Long-term low-dose
109. Ho VC, Griffiths CE, Albrecht G, et al. Intermittent short cyclosporine therapy for severe psoriasis: effects on renal
courses of cyclosporin (Neoral(R)) for psoriasis unresponsive function and structure. J Am Acad Dermatol. 1996;35(5 Pt 1):
to topical therapy: a 1-year multicentre, randomized study. 710-719.
The PISCES Study Group. Br J Dermatol. 1999;141(2):283-291. 127. Silverman AK, Emmett M, Menter A. Can maintenance
110. Ho VC, Griffiths CE, Berth-Jones J, et al. Intermittent short cyclosporine be used in psoriasis without decreasing renal
courses of cyclosporine microemulsion for the long-term function? Semin Dermatol. 1992;11(4):302-312.
management of psoriasis: a 2-year cohort study. J Am Acad 128. Berth-Jones J. The use of ciclosporin in psoriasis. J Dermato-
Dermatol. 2001;44(4):643-651. log Treat. 2005;16(5-6):258-277.
111. Nast A, Kopp I, Augustin M, et al. German evidence-based 129. Salman BN, Vahabi S, Movaghar SE, Mahjour F. Proliferative
guidelines for the treatment of psoriasis vulgaris (short and inductive effects of Cyclosporine a on gingival
version). Arch Dermatol Res. 2007;299(3):111-138. fibroblast of child and adult. Dent Res J (Isfahan). 2013;
112. Maza A, Montaudie H, Sbidian E, et al. Oral cyclosporin 10(1):52-58.
in psoriasis: a systematic review on treatment modalities, 130. US Food and Drug Administration. SandimmuneÒ Oral
risk of kidney toxicity and evidence for use in non- Solution (cyclosporine oral solution, USP) [package insert].
plaque psoriasis. J Eur Acad Dermatol Venerol. 2011;25 Suppl Novartis. Available at: https://www.accessdata.fda.gov/
2:19-27. drugsatfda_docs/label/2015/050573s041,050574s051,050625
113. Ryan C, Amor KT, Menter A. The use of cyclosporine in s055lbl.pdf; 2015. Accessed January 7, 2020.
dermatology: part II. J Am Acad Dermatol. 2010;63(6):949-972. 131. Lebwohl M, Ellis C, Gottlieb A, et al. Cyclosporine consensus
quiz 973-944. conference: with emphasis on the treatment of psoriasis. J
114. Mrowietz U, Farber L, Henneicke-von Zepelin HH, Am Acad Dermatol. 1998;39(3):464-475.
Bachmann H, Welzel D, Christophers E. Long-term mainte- 132. Blasco Morente G, Tercedor Sanchez J, Garrido Colmenero C,
nance therapy with cyclosporine and posttreatment survey in Martinez Garcia E, Molina-Carballo A. Pseudotumor cerebri
severe psoriasis: results of a multicenter study. German associated with cyclosporine use in severe atopic dermatitis.
Multicenter Study. J Am Acad Dermatol. 1995;33(3):470-475. Pediatr Dermatol. 2015;32(2):237-239.
1480 Menter et al J AM ACAD DERMATOL
JUNE 2020
133. Costa KM, Almeida JB, Felix RH, Silva Junior MF. [Pseudotu- 151. Geiger JM, Czarnetzki BM. Acitretin (Ro 10-1670, etretin):
mor cerebri associated with cyclosporin use following renal overall evaluation of clinical studies. Dermatologica. 1988;
transplantation]. J Bras Nefrol. 2010;32(1):136-139. 176(4):182-190.
134. Somech R, Doyle J. Pseudotumor cerebri after allogeneic 152. Goldfarb MT, Ellis CN, Gupta AK, Tincoff T, Hamilton TA,
bone marrow transplant associated with cyclosporine a use Voorhees JJ. Acitretin improves psoriasis in a dose-dependent
for graft-versus-host disease prophylaxis. J Pediatr Hematol fashion. J Am Acad Dermatol. 1988;18(4 Pt 1):655-662.
Oncol. 2007;29(1):66-68. 153. Lassus A, Geiger JM, Nyblom M, Virrankoski T, Kaartamaa M,
135. Gonzalez Vicent M, Diaz MA, Madero L. ‘‘Pseudotumor Ingervo L. Treatment of severe psoriasis with etretin (RO 10-
cerebri’’ following allogeneic bone marrow transplantation 1670). Br J Dermatol. 1987;117(3):333-341.
(BMT). Ann Hematol. 2001;80(4):236-237. 154. Ling MR. Acitretin: optimal dosing strategies. J Am Acad
136. Ghanem ME, El-Baghdadi LA, Badawy AM, Bakr MA, Dermatol. 1999;41(3 Pt 2):S13-S17.
Sobhe MA, Ghoneim MA. Pregnancy outcome after renal 155. Lowe NJ, Lazarus V, Matt L. Systemic retinoid therapy for
allograft transplantation: 15 years experience. Eur J Obstet psoriasis. J Am Acad Dermatol. 1988;19(1 Pt 2):186-191.
Gynecol Reprod Biol. 2005;121(2):178-181. 156. Murray HE, Anhalt AW, Lessard R, et al. A 12-month
137. Cochat P, Decramer S, Robert-Gnansia E, Dubourg L, Audra P. treatment of severe psoriasis with acitretin: results of a
Renal outcome of children exposed to cyclosporine in utero. Canadian open multicenter study. J Am Acad Dermatol. 1991;
Transpl Proc. 2004;36(2 Suppl):208S-210S. 24(4):598-602.
138. Omar MA, Wilson JP, Cox TS. Rhabdomyolysis and HMG-CoA 157. Olsen EA, Weed WW, Meyer CJ, Cobo LM. A double-blind,
reductase inhibitors. Ann Pharmacother. 2001;35(9):1096- placebo-controlled trial of acitretin for the treatment of
1107. psoriasis. J Am Acad Dermatol. 1989;21(4 Pt 1):681-686.
139. Paul MD, Parfrey PS, Smart M, Gault H. The effect of ethanol 158. Torok L, Kadar L, Geiger JM. Acitretin treatment of severe
on serum cyclosporine A levels in renal transplant recipients. psoriasis. Acta Derm Venereol Suppl (Stockh). 1989;146:104-
Am J Kidney Dis. 1987;10(2):133-135. 106.
140. Colombo D, Cassano N, Altomare G, Giannetti A, Vena GA. 159. Gollnick H, Bauer R, Brindley C, et al. Acitretin versus
Psoriasis relapse evaluation with week-end cyclosporine A etretinate in psoriasis. Clinical and pharmacokinetic results
treatment: results of a randomized, double-blind, multicenter of a German multicenter study. J Am Acad Dermatol. 1988;
study. Ing J Immunopathol Pharmacol. 2010;23(4):1143-1152. 19(3):458-468.
141. Grekas D, Alivanis P, Kiriazopoulou V, et al. Influenza 160. Kragballe K, Jansen CT, Geiger JM, et al. A double-blind
vaccination on renal transplant patients is safe and comparison of acitretin and etretinate in the treatment of
serologically effective. Int J Clin Pharmacol Ther Toxicol. severe psoriasis. Results of a Nordic multicentre study. Acta
1993;31(11):553-556. Derm Venereol. 1989;69(1):35-40.
142. Soesman NM, Rimmelzwaan GF, Nieuwkoop NJ, et al. Efficacy 161. Geiger JM. Efficacy of acitretin in severe psoriasis. Skin Ther
of influenza vaccination in adult liver transplant recipients. J Lett. 2003;8(4):1-3, 7.
Med Virol. 2000;61(1):85-93. 162. Buccheri L, Katchen BR, Karter AJ, Cohen SR. Acitretin therapy is
143. Versluis DJ, Beyer WE, Masurel N, Wenting GJ, Weimar W. effective for psoriasis associated with human immunodeficiency
Impairment of the immune response to influenza vaccination virus infection. Arch Dermatol. 1997;133(6):711-715.
in renal transplant recipients by cyclosporine, but not 163. Ozawa A, Ohkido M, Haruki Y, et al. Treatments of general-
azathioprine. Transplantation. 1986;42(4):376-379. ized pustular psoriasis: a multicenter study in Japan. J
144. Powles AV, Hardman CM, Porter WM, Cook T, Hulme B, Fry L. Dermatol. 1999;26(3):141-149.
Renal function after 10 years’ treatment with cyclosporin for 164. Wolska H, Jablonska S, Bounameaux Y. Etretinate in severe
psoriasis. Br J Dermatol. 1998;138(3):443-449. psoriasis. Results of double-blind study and maintenance
145. Gilbert SC, Emmett M, Menter A, Silverman A, Klintmalm G. therapy in pustular psoriasis. J Am Acad Dermatol. 1983;9(6):
Cyclosporine therapy for psoriasis: serum creatinine mea- 883-889.
surements are an unreliable predictor of decreased renal 165. Sevrain M, Richard MA, Barnetche T, et al. Treatment for
function. J Am Acad Dermatol. 1989;21(3 Pt 1):470-474. palmoplantar pustular psoriasis: systematic literature review,
146. Altomare G, Ayala F, Bardazzi F, et al. Consensus on the evidence-based recommendations and expert opinion. J Eur
use of cyclosporine in dermatological practice. Italian Acad Dermatol Venerol. 2014;28(Suppl 5):13-16.
Consensus Conference. G Ital Dermatol Venereol. 2014; 166. Ozdemir M, Engin B, Baysal I, Mevlitoglu I. A randomized
149(5):607-625. comparison of acitretin-narrow-band TL-01 phototherapy
147. Ito T, Furukawa F, Iwatsuki K, et al. Efficacious treatment of and acitretin-psoralen plus ultraviolet A for psoriasis. Acta
psoriasis with low-dose and intermittent cyclosporin micro- Derm Venereol. 2008;88(6):589-593.
emulsion therapy. J Dermatol. 2014;41(5):377-381. 167. Yelverton CB, Yentzer BA, Clark A, et al. Home narrowband
148. Reich K, Mrowietz U, Radtke MA, et al. Drug safety of UV-B phototherapy in combination with low-dose acitretin in
systemic treatments for psoriasis: results from The German patients with moderate to severe psoriasis. Arch Dermatol.
Psoriasis Registry PsoBest. Arch Dermatol Res. 2015;307(10): 2008;144(9):1224-1225.
875-883. 168. Lebwohl M, Drake L, Menter A, et al. Consensus conference:
149. Vena GA, Galluccio A, Pezza M, Vestita M, Cassano N. acitretin in combination with UVB or PUVA in the treatment of
Combined treatment with low-dose cyclosporine and psoriasis. J Am Acad Dermatol. 2001;45(4):544-553.
calcipotriol/betamethasone dipropionate ointment for 169. Lebwohl M. Acitretin in combination with UVB or PUVA. J Am
moderate-to-severe plaque psoriasis: a randomized controlled Acad Dermatol. 1999;41(3 Pt 2):S22-S24.
open-label study. J Dermatolog Treat. 2012;23(4):255-260. 170. Lowe NJ, Prystowsky JH, Bourget T, Edelstein J, Nychay S,
150. van de Kerkhof PC, Cambazard F, Hutchinson PE, et al. The effect Armstrong R. Acitretin plus UVB therapy for psoriasis.
of addition of calcipotriol ointment (50 micrograms/g) to Comparisons with placebo plus UVB and acitretin alone. J
acitretin therapy in psoriasis. Br J Dermatol. 1998;138(1):84-89. Am Acad Dermatol. 1991;24(4):591-594.
J AM ACAD DERMATOL Menter et al 1481
VOLUME 82, NUMBER 6
171. Ruzicka T, Sommerburg C, Braun-Falco O, et al. Efficiency of 190. Luthi F, Eggel Y, Theumann N. Premature epiphyseal closure
acitretin in combination with UV-B in the treatment of severe in an adolescent treated by retinoids for acne: an unusual
psoriasis. Arch Dermatol. 1990;126(4):482-486. cause of anterior knee pain. Joint Bone Spine. 2012;79(3):314-
172. Iest J, Boer J. Combined treatment of psoriasis with acitretin 316.
and UVB phototherapy compared with acitretin alone and 191. Vahlquist A. Long-term safety of retinoid therapy. J Am Acad
UVB alone. Br J Dermatol. 1989;120(5):665-670. Dermatol. 1992;27(6 Pt 2):S29-S33.
173. Spuls PI, Rozenblit M, Lebwohl M. Retrospective study of the 192. Elmets CA, Lim HW, Stoff B, et al. Joint American
efficacy of narrowband UVB and acitretin. J Dermatolog Treat. Academy of Dermatology-National Psoriasis Foundation
2003;14(Suppl 2):17-20. guidelines of care for the management and treatment of
174. Lauharanta J, Geiger JM. A double-blind comparison of psoriasis with phototherapy. J Am Acad Dermatol. 2019;
acitretin and etretinate in combination with bath PUVA in 81(3):775-804.
the treatment of extensive psoriasis. Br J Dermatol. 1989; 193. Carpentieri A, Pacello L, De Marco IM, Loiacono A, Picconi O,
121(1):107-112. Loconsole F. Retrospective analysis of the effectiveness and
175. Saurat JH, Geiger JM, Amblard P, et al. Randomized double- costs of traditional treatments for moderate-to-severe psori-
blind multicenter study comparing acitretin-PUVA, asis: a single-center, Italian study. J Dermatolog Treat. 2016;
etretinate-PUVA and placebo-PUVA in the treatment of 27(5):399-405.
severe psoriasis. Dermatologica. 1988;177(4):218-224. 194. Singh JA, Guyatt G, Ogdie A, et al. Special Article: 2018
176. Tanew A, Guggenbichler A, Honigsmann H, Geiger JM, American College of Rheumatology/National Psoriasis Foun-
Fritsch P. Photochemotherapy for severe psoriasis without or dation Guideline for the Treatment of Psoriatic Arthritis.
in combination with acitretin: a randomized, double-blind Arthritis Rheumatol. 2019;71(1):5-32.
comparison study. J Am Acad Dermatol. 1991;25(4):682-684. 195. US Food and Drug Administration. XELJANZÒ (tofacitinib)
177. Nijsten TE, Stern RS. Oral retinoid use reduces cutaneous [package insert]. Available at: https://www.accessdata.fda.
squamous cell carcinoma risk in patients with psoriasis gov/drugsatfda_docs/label/2019/203214s025lbl.pdf; 2019.
treated with psoralen-UVA: a nested cohort study. J Am Accessed January 8, 2020.
Acad Dermatol. 2003;49(4):644-650. 196. Vijayakrishnan L, Venkataramanan R, Gulati P. Treating
178. David M, Hodak E, Lowe NJ. Adverse effects of retinoids. Med inflammation with the Janus kinase inhibitor CP-690,550.
Toxicol Adverse Drug Exp. 1988;3(4):273-288. Trends Pharmacol Sci. 2011;32(1):25-34.
179. US Food and Drug Administration. Acitretin (Soriatane) 197. Papp KA, Menter MA, Abe M, et al. Tofacitinib, an oral
[package insert]. Stiefel Laboratories, Inc. Available at: Janus kinase inhibitor, for the treatment of chronic
https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/ plaque psoriasis: results from two randomized, placebo-
019821s028lbl.pdf; 2017. Accessed August 26, 2019. controlled, phase III trials. Br J Dermatol. 2015;173(4):949-
180. Koo J, Nguyen Q, Gambla C. Advances in psoriasis therapy. 961.
Adv Dermatol. 1997;12:47-72. discussion 73. 198. Papp KA, Menter A, Strober B, et al. Efficacy and safety of
181. Yamauchi PSRD, Kormill T, Patnaik R, Lowe NJ. Systematic tofacitinib, an oral Janus kinase inhibitor, in the treatment of
Retinoids. In: Gottlieb GWaA, ed. Therapy of Moderate-to- psoriasis: a phase 2b randomized placebo-controlled dose-
Severe-Psoriasis. New York: Marcel Dekker, Inc.; 2003:137- ranging study. Br J Dermatol. 2012;167(3):668-677.
150. 199. Bachelez H, van de Kerkhof PC, Strohal R, et al. Tofacitinib
182. Malloy MJ, Kane JP. A risk factor for atherosclerosis: versus etanercept or placebo in moderate-to-severe chronic
triglyceride-rich lipoproteins. Adv Intern Med. 2001;47:111-136. plaque psoriasis: a phase 3 randomised non-inferiority trial.
183. Treewittayapoom C, Singvahanont P, Chanprapaph K, Lancet. 2015;386(9993):552-561.
Haneke E. The effect of different pulse durations in the 200. A One-Year Study To Evaluate The Efficacy And Safety Of CP-
treatment of nail psoriasis with 595-nm pulsed dye laser: a 690,550 For Patients With Moderate To Severe Chronic
randomized, double-blind, intrapatient left-to-right study. J Plaque Psoriasis. Pfizer. Available at: https://clinicaltrials.
Am Acad Dermatol. 2012;66(5):807-812. gov/ct2/show/NCT01309737?term=NCT01309737&draw
184. Roenigk HH Jr, Callen JP, Guzzo CA, et al. Effects of acitretin on =2&rank=1; 2014. Accessed January 9, 2020.
the liver. J Am Acad Dermatol. 1999;41(4):584-588. 201. Zand MS. Tofacitinab in renal transplantation. Transpl Rev
185. van Ditzhuijsen TJ, van Haelst UJ, van Dooren-Greebe RJ, van (Orlando). 2013;27(3):85-89.
de Kerkhof PC, Yap SH. Severe hepatotoxic reaction with 202. Vincenti F, Silva HT, Busque S, et al. Evaluation of the effect of
progression to cirrhosis after use of a novel retinoid tofacitinib exposure on outcomes in kidney transplant
(acitretin). J Hepatol. 1990;11(2):185-188. patients. Am J Transpl. 2015;15(6):1644-1653.
186. DiGiovanna JJ, Sollitto RB, Abangan DL, Steinberg SM, 203. Mrowietz U, Reich K, Spellman M. Efficacy, safety, and quality
Reynolds JC. Osteoporosis is a toxic effect of long-term of life effects of a novel oral formulation of dimethyl
etretinate therapy. Arch Dermatol. 1995;131(11):1263-1267. fumarate in patients with moderate to severe plaque
187. Vincent V, Zabraniecki L, Loustau O, et al. Acitretin-induced psoriasis: results of a phase 3 study. J Am Acad Dermatol.
enthesitis in a patient with psoriatic arthritis. Joint Bone Spine. 2006;54(3 Suppl):AB202.
2005;72(4):326-329. 204. Arbiser JL. Fumarate esters as angiogenesis inhibitors: key
188. Okada N, Nomura M, Morimoto S, Ogihara T, Yoshikawa K. to action in psoriasis? J Invest Dermatol. 2011;131(6):1189-1191.
Bone mineral density of the lumbar spine in psoriatic 205. Meissner M, Valesky EM, Kippenberger S, Kaufmann R.
patients with long term etretinate therapy. J Dermatol. Dimethyl fumarate-only an anti-psoriatic medication? J Dtsch
1994;21(5):308-311. Dermatol Ges. 2012;10(11):793-801.
189. Van Dooren-Greebe RJ, Lemmens JA, De Boo T, Hangx NM, 206. Atwan A, Ingram JR, Abbott R, et al. Oral fumaric acid
Kuijpers AL, Van de Kerkhof PC. Prolonged treatment with esters for psoriasis. Cochrane Database Syst Rev. 2015;(8):
oral retinoids in adults: no influence on the frequency CD010497.
and severity of spinal abnormalities. Br J Dermatol. 1996; 207. Altmeyer PJ, Matthes U, Pawlak F, et al. Antipsoriatic effect
134(1):71-76. of fumaric acid derivatives. Results of a multicenter
1482 Menter et al J AM ACAD DERMATOL
JUNE 2020
double-blind study in 100 patients. J Am Acad Dermatol. 213. Mrowietz U, Christophers E, Altmeyer P. Treatment of pso-
1994;30(6):977-981. riasis with fumaric acid esters: results of a prospective
208. Mrowietz U, Asadullah K. Dimethylfumarate for psoriasis: multicentre study. German Multicentre Study. Br J Dermatol.
more than a dietary curiosity. Trends Mol Med. 2005;11(1):43- 1998;138(3):456-460.
48. 214. Peeters AJ, Dijkmans BA, van der Schroeff JG. Fumaric acid
209. Kolbach DN, Nieboer C. Fumaric acid therapy in psoriasis: therapy for psoriatic arthritis. A randomized, double-blind,
results and side effects of 2 years of treatment. J Am Acad placebo-controlled study. Br J Rheumatol. 1992;31(7):502-504.
Dermatol. 1992;27(5 Pt 1):769-771. 215. Kimball AB, Gladman D, Gelfand JM, et al. National Psoriasis
210. Raschka C, Koch HJ. Longterm treatment of psoriasis using Foundation clinical consensus on psoriasis comorbidities and
fumaric acid preparations can be associated with severe recommendations for screening. J Am Acad Dermatol. 2008;
proximal tubular damage. Hum Exp Toxicol. 1999;18(12):738- 58(6):1031-1042.
739. 216. Ebell MH, Siwek J, Weiss BD, et al. Strength of recommen-
211. Bomprezzi R. Dimethyl fumarate in the treatment of dation taxonomy (SORT): a patient-centered approach to
relapsing-remitting multiple sclerosis: an overview. Ther Adv grading evidence in the medical literature. J Am Board Fam
Neurol Disord. 2015;8(1):20-30. Pract. 2004;17(1):59-67.
212. Gollnick H, Altmeyer P, Kaufmann R, et al. Topical calcipotriol 217. Administrative Regulation-Evidence-Based Clinical Practice
plus oral fumaric acid is more effective and faster acting than Guidelines. American Academy of Dermatology; 2014. Avail-
oral fumaric acid monotherapy in the treatment of severe able at: https://server.aad.org/Forms/Policies/Uploads/
chronic plaque psoriasis vulgaris. Dermatology. 2002;205(1): Members/AR%20-%20Evidence-Based%20Clinical%20Prac
46-53. tice%20Guidelines.pdf. Accessed March 27, 2020.
Dermira, Dr. Reddy, GlaxoSmithKline, Janssen USA, Inc, Teva, UCB, Valeant Pharmaceuticals
Pharmaceuticals, Inc, Menlo Therapeutics, Novartis International, Valeant Pharmaceuticals North
Pharmaceuticals Corp, Pfizer, Inc, Regeneron, Sanofi America LLC, XBiotech, and Xenoport, Inc,
US Services, UCB (DSMB), and Valeant receiving honoraria; as a consultant for Aclaris
Pharmaceuticals North America LLC receiving hon- Therapeutics, Inc, Avotres Inc, Merck & Co, Inc,
oraria; as a consultant for BMS receiving fees; as and XBiotech receiving no compensation; as a
speaker and/or faculty education for continuing speaker for AbbVie, Eli Lilly, and Janssen Biotech
medical education supported by Eli Lilly and receiving honoraria; as a principal investigator/
Company receiving fees; as a principal investigator investigator for Abbott Laboratories, AbbVie,
for AbbVie, Boehringer Ingelheim, Celgene, Eli Lilly Allergan, Amgen, Celgene Corporation, Coronado
and Company, Janssen Pharmaceuticals, Inc, Biosciences, Immune Control, Incyte Corporation,
Novartis Pharmaceuticals Corp, Ortho Janssen Biotech, Janssen-Ortho, Inc, LEO Pharma,
Dermatologics, Pfizer, Inc, Regeneron, and Sanofi/ Lerner Medical Devices, Inc, Lilly ICOS LLC, Merck
Sanofi US Services receiving grants/research fund- & Co, Inc, Novartis Pharmaceuticals Corp, Novo
ing; as an investigator for Sanofi receiving grants Nordisk A/S, Pfizer Inc, UCB, Xbiotech, and
and/or research funding; as an advisory board Xenoport, Inc, receiving grants/research funding;
member for Sanofi US Services receiving honoraria; as a principal investigator for Janssen-Ortho, Inc,
as a data safety monitoring board member for receiving honoraria; as an advisory board member
Coherus Biosciences and Merck & Co, Inc, receiving for Abbott Laboratories, Actelion, Allergan, Amgen,
honoraria; received payment for continuing medical Astellas Pharma US, Inc, Beiersdorf, Inc, BMS,
education work related to psoriasis that was sup- Celgene Corporation, Coronado Biosciences,
ported indirectly by Eli Lilly and Company, Ortho Dermira, Dr. Reddy, Genentech, Janssen-Ortho,
Dermatologics, and Novartis; in another role for Inc, Janssen Biotech, LEO Pharma US, Lilly ICOS
Elsevier, Inc, receiving no compensation; in another LLC, Novartis Pharmaceuticals Corp, Novo Nordisk
role for Eli Lilly and Company and UCB receiving A/S, Pfizer, Inc, UCB, and Valeant, receiving hono-
fees; and in another role for Resiquimod receiving raria; in another role for Amgen receiving grants
patent royalties or other compensation for intellec- and/or research funding; in another role for
tual rights. Crescendo Bioscience and Karyopharm
Kenneth B. Gordon,* MD, served as a consultant Therapeutics receiving no compensation; in
for AbbVie, Almirall, Amgen, Boehringer Ingelheim, another role (Data Safety) for Catabasis
Bristol-Myers Squibb, Demira, Dermavant Sciences, Pharmaceuticals, Inc, receiving honoraria; and in
Kyowa Hakko Kirin Pharma, Inc, LEO Pharma, another role for DermiPsor receiving honoraria.
Ortho Dermatologics, Sun Pharmaceuticals Ltd, and Daniel H. Kaplan, MD, PhD, served as a consul-
UCB receiving honoraria; as a consultant for tant for Eli Lilly and Company and Galderma
Genzyme receiving fees; as a principal investigator Laboratories, LP, receiving no compensation, and
for AbbVie, Amgen, Boehringer Ingelheim, Celgene as a member of the data safety monitoring board for
Corporation, Eli Lilly and Company, Janssen Hapten Sciences receiving fees.
Pharmaceuticals, Inc, Merck & Co, Inc, and Arthur Kavanaugh,* MD served as a principal
Novartis Pharmaceuticals Corp receiving grants investigator for AbbVie, Amgen, BMS, Celgene
and/or research funding; and as an advisory board Corporation, Eli Lilly and Company, Janssen
member for Celgene Corporation, Janssen Biotech, Novartis, Pfizer, Inc, and UCB receiving
Pharmaceuticals Inc, Lilly ICOS LLC, Novartis grants/research funding.
Pharmaceuticals Corp, and Pfizer, Inc, receiving Matthew Kiselica has no relationships to disclose.
honoraria. Dario Kivelevitch, MD, has a first-degree relative
Alice B. Gottlieb,* MD, PhD, served as a consul- employed by Boehringer Ingelheim.
tant for Abbott Laboratories, AbbVie, Akros Pharma, Neil J. Korman,* MD, PhD, served as a consultant
Inc, Allergan, Amgen, Amicus Therapeutics, Baxalta for Novartis Pharmaceuticals Corp receiving hono-
Inc, Bristol-Myers Squibb, Canfite, Celgene raria; as a consultant for Dr. Reddy’s Laboratory
Corporation, CSL Behring, Dermira, Dr. Reddy, receiving fees; as a speaker for AbbVie, Celgene, Eli
DUSA Pharmaceuticals, Inc, GlaxoSmithKline, Lilly, Genentech, Janssen, Novartis, Regeneron, and
Incyte Corporation, KPI Therapeutics, Lilly ICOS Sanofi receiving honoraria; as a principal investigator
LLC, Meiji Seika Pharma Co, Ltd, Merck & Co, Inc, for AbbVie, Amgen, Celgene Corporation, Chugai,
Mitsubishi Pharma, Novartis Pharmaceuticals Corp, Dermira, Eli Lilly and Company, Kyowa Hakko Kirin
Sanofi-Aventis, Sienna Biopharmaceuticals, Sun Pharma, Inc, LEO Pharma, Menlo Therapeutics,
Pharmaceutical Industries, Takeda Pharmaceuticals Merck, Pfizer, Prothena, Regeneron, Rhizen, Inc,
1484 Menter et al J AM ACAD DERMATOL
JUNE 2020
Syntimmune, Trevi, and UCB receiving grants and/or Henry W. Lim, MD, served as a principal or
research funding; as an advisory board member for coinvestigator for Beiersdorf, Inc, Estee Lauder,
Amgen, Celgene Corporation, Eli Lilly and Company, Ferndale Laboratories, Inc, Incyte, and Unigen
Genentech, GlaxoSmithKline, Janssen receiving grants and/or research funding; as a
Pharmaceuticals, Inc, Novartis Pharmaceuticals speaker and/or faculty education for Pierre Fabre
Corp, Pfizer, Inc, and Principia Biopharma receiving Dermatologie receiving honoraria; as a speaker/
honoraria; as an advisory board member for Dr. faculty education for Pierre Fabre Deramtolgie
Reddy’s Laboratory, Immune Pharmaceuticals, receiving grants/research funding; and as an advi-
Regeneron, Sanofi, Sun Pharma, and Valeant sory board member for Ferndale Laboratories and
receiving fees; as an advisory board member/consul- Galderma Laboratories, LP, receiving honoraria.
tant for AbbVie, Eli Lilly, GlaxoSmithKline, Pfizer Inc, Nehal N. Mehta,* MD, MSCE, is a full-time United
and Principa receiving honoraria/fees; and in States government employee and has served as a
another role for Janssen Pharmaceuticals, Inc consultant for Amgen, Eli Lilly, and LEO Pharma
receiving grants and/or research funding. receiving grants/other payments; as principal inves-
Daniela Kroshinsky, MD, MPH, has no relation- tigator and/or investigator for AbbVie, Celgene,
ships to disclose. Janssen Pharmaceuticals, Inc, and Novartis receiving
Mark Lebwohl,* MD, served as a consultant for grants and/or research funding; and as a principal
Allergan, Almirall, Arcutis, Inc, Boehringer Ingelheim, investigator for the National Institutes of Health
Bristol-Myers Squibb, Castle Biosciences, Inc, LEO receiving grants and/or research funding.
Pharma, Menlo Therapeutics, Mitsubishi Pharma, Alan Menter,* MD, served as a consultant for
Neuroderm Ltd, Pfizer, Inc, Promius/Dr. Reddy, Abbott Labs, AbbVie, Amgen, Eli Lilly and
Theravance Biopharma, and Verrica Pharmaceuticals Company, Galderma USA, Janssen Pharmaceuticals
Inc receiving honoraria; as a principal investigator or Inc, LEO Pharma US, Menlo Therapeutics, Novartis,
investigator for AbbVie, Amgen, Inc, AstraZeneca, Sienna Biopharmaceuticals, and Wyeth Labs
Boehringer Ingelheim, Celgene Corporation, Eli Lilly receiving honoraria; as a consultant for New
and Company, Incyte Corporation, Janssen Research Enterprise Associates, Promius Pharma LLC,
and Development LLC/Johnson & Johnson, LEO Spherix Global Insights US, UCB, and Valeant
Pharma, Medimmune, Novartis Pharmaceuticals Pharmaceuticals North America receiving fees; as a
Corp, Ortho-Dermatologics, Pfizer, Inc, SCIDerm, consultant for Afecta Pharmaceuticals receiving no
UCB, and ViDac Pharma receiving grants and/or compensation; as a speaker for Abbott Labs, AbbVie,
research funding; and in another role for Corrona, Amgen, Janssen Biotech, LEO Pharma US, Pfizer, Inc,
Inc, Facilitation of International Dermatology Promius Pharma LLC, Sienna Pharmaceuticals, UCB,
Education, and the Foundation for Research and and Wyeth Labs receiving honoraria; as a principal
Education in Dermatology receiving honoraria. investigator for AbbVie, Amgen, Boehringer
Craig L. Leonardi,* MD, served as a consultant/ Ingelheim, Celgene Corporation, Eli Lilly and
advisory board member for AbbVie, Amgen, Company, Janssen Pharmaceuticals, Inc,
Boehringer Ingelheim, Celgene Dermira, Eli Lilly Medimetriks Pharmaceuticals, Inc, Merck & Co, Inc,
and Company, Janssen Pharmaceuticals, Inc, LEO Novartis Pharmaceutical Corp, and Pfizer, Inc,
Pharma A/S, Ortho Dermatologics, Pfizer, Inc, receiving grant and/or research funding; as an
Sandoz (a Novartis Company), UCB, and Vitae investigator for Eli Lilly and Company and UCB
receiving honoraria; as a speaker for AbbVie, receiving honoraria; as an investigator for Abbott
Amgen, Celgene Corporation, Eli Lilly and Labs, LEO Pharma US, and Sienna
Company, Novartis, Sun Pharmaceuticals, Ltd, and Biopharmaceuticals receiving grants; as an advisory
UCB receiving honoraria; and as a principal investi- board member for Abbott Labs, AbbVie, Boehringer
gator for Actavis, Amgen, Boehringer Ingelheim, Ingelheim, Eli Lilly and Company, Janssen
Celgene Corporation, Cellceutix, Coherus Pharmaceuticals, Inc, LEO Pharma US, Medscape,
Biosciences, Corrona, Dermira, Eli Lilly and Pfizer, Inc, and Sienna Biopharmaceuticals receiving
Company, Galderma Laboratories, LP, Glenmark honoraria; as an advisory board member for Amgen
Generics, Inc, Janssen Pharmaceuticals, Inc, LEO receiving grant and/or research funding; as an
Pharma, Merck, Novartis, Novella, Pfizer, Inc, Sandoz advisory board member for Afecta Pharmaceuticals
(a Novartis Company), Sienna Biopharmaceuticals, receiving no compensation; and as an independent
Stiefel (a GSK company), UCB, and Warner Chillcott contractor for Prime Education receiving fees.
receiving other financial benefits (fee for service). Amy S. Paller,* MD, served as a consultant for
Jason Lichten, MD, has no relationships to Amgen, Amicus Therapeutics, Anacor
disclose. Pharmaceuticals, Inc, Aqua Pharmaceuticals,
J AM ACAD DERMATOL Menter et al 1485
VOLUME 82, NUMBER 6
Boehringer Ingelheim International GmbH, Corporation, Eli Lilly and Company, Galderma
BridgeBio Pharma, Castle Creek Pharma, Celgene Laboratories, LP, Janssen-Ortho, Inc, Merck & Co,
Corporation, Chameleon Communications, Pfizer, Inc, Sienna, and Sun Pharmaceutical
Dermavant Sciences, Dermira, Eli Lilly and Industries receiving no compensation; as an advisory
Company, Forte Biosciences, Galderma board member for AbbVie, Amgen, Bristol-Myers
Laboratories, LP, LEO Pharma, Genentech, Menlo Squibb, Celgene Corporation, Dermira, Eli Lilly and
Therapeutics, MorphoSys AG, Novartis Company, Janssen-Ortho, Inc, Novartis
Pharmaceuticals Corp, Pfizer Inc, Pierre Fabre Pharmaceuticals Corp, Pfizer, Inc, Sanofi-
Dermatologie, Proctor and Gamble, Regeneron, Regeneron, Sun Pharmaceuticals Industries, and
Sanofi, Scioderm, Shire, Sol-Gel Technologies, UCB receiving honoraria; as consultant/advisory
Stiefel (a GSK company), Target Pharma, board for AstraZeneca Pharmaceuticals LP receiving
Theravance Biopharma, UCB, Union Therapeutic, fees/honoraria; and in another role for AbbVie and
Valeant Pharmaceuticals North America LLC, Vitae Janssen-Ortho, Inc, receiving no compensation.
Pharmaceuticals, and Verrica receiving honoraria; as Elliot B. Tapper, MD served as a consultant for
a speaker/educator for Expanscience receiving hon- Allergan receiving fees; as a principal investigator for
oraria; as a principal investigator for AbbVie, Amgen, Gilead Sciences and Valeant Pharmaceuticals
Anacor Pharmaceuticals, Inc, AnaptysBio, Celgene International receiving grants and/or research fund-
Corporation, Eli Lilly and Company, Galderma ing; and as an advisory board member for
Laboratories, LP, Janssen Pharmaceuticals, Inc, LEO Mallinckrodt Pharmaceuticals and Valeant
Pharma, Regeneron, and Scioderm, receiving no Pharmaceuticals International receiving honoraria.
compensation; and as an advisory board member Emily B. Wong, MD, has no relationships to
for Menlo Therapeutics receiving honoraria. disclose.
Sylvia L. Parra, MD, has no relationships to Jashin J. Wu,* MD, served as a consultant for
disclose. AbbVie, Allergan, Almirall, Amgen, Bristol-Myers
Arun L. Pathy, MD, has no relationships to Squibb, Celgene, Dermira, Dr. Reddy’s
disclose. Laboratories, Eli Lilly and Company, Janssen
Elizabeth A. Farley Prater, MD, has no relation- Biotech, LEO Pharma, Novartis, Ortho
ships to disclose. Dermatologics, Pfizer, Inc, Promius Pharma,
Robert S. Rahimi, MD, MSCR served as a consul- Regeneron, Sun Pharmaceutical Industries, Ltd,
tant for Kaleido and Mallinckrodt Pharmaceuticals UCB, and Valeant Pharmaceuticals North America,
receiving honoraria; as a principal investigator for LLC, receiving fees and/or honoraria; as a speaker for
Mallinckrodt Pharmaceutical (formerly Ocera), and AbbVie, Celgene, Novartis, Regeneron, Sanofi
Valeant Pharmaceuticals North America LLC Genzyme, Sun Pharmaceutical Industries Ltd, UCB,
receiving grants and/or research funding; and as an and Valeant Pharmaceuticals North America, LLC,
independent contractor for M3 Global Research receiving honoraria; and as a principal/investigator
receiving honoraria. for AbbVie, Amgen, AstraZeneca, Boehringer
Reena N. Rupani, MD, served as speaker for Ingelheim, Coherus Biosciences, Dermira, Eli Lilly
Nutrafol receiving honoraria. and Company, Janssen Pharmaceuticals, Inc, Merck
Michael Siegel, PhD, has no relationships to & Co, Inc, Novartis, Pfizer, Inc, Regeneron, Sandoz (a
disclose. Novartis Company), and Sun Pharmaceutical
Benjamin Stoff, MD, MA, served as an investigator Industries Ltd, receiving research and/or grant
for Celtaxsys, Inc receiving fees. funding.
Bruce E. Strober,* MD, PhD, served as a consultant Vidhya Hariharan, PhD has no relationships to
for AbbVie, Almirall, Amgen, Boehringer Ingelheim, disclose.
Celgene Corporation, Dermira, Eli Lilly and
Company, GlaxoSmithKline, Janssen-Ortho, Inc, APPENDIX 1
LEO Pharma, Maruho Co, Ltd, Medac Pharma, Inc,
Menlo Therapeutics, Novartis Pharmaceuticals Corp, Method
Ortho Dermatologics, Pfizer, Inc, Sanofi-Regeneron, A multidisciplinary work group of recognized
Sun Pharmaceuticals Industries, and UCB receiving psoriasis experts, consisting of dermatologists
honoraria; as a consultant for Affibody, Arena, (including private practitioners), a rheumatolo-
Bristol-Myers Squibb, Dermavant, Meiji Seika gist, a cardiologist, and representatives from pa-
Pharma Co, Ltd, Sebela Pharmaceuticals, Sirtris, and tient advocacy organization, was convened to
UCB receiving fees; as a principal investigator for identify important clinical questions with regards
AbbVie, Boehringer Ingelheim, Celgene to psoriasis. Work group members completed a
1486 Menter et al J AM ACAD DERMATOL
JUNE 2020