PIIS019096222030284X

FROM THE ACADEMY
Joint American Academy of

DermatologyeNational Psoriasis
Foundation guidelines of care for the
management of psoriasis with systemic
nonbiologic therapies
Alan Menter, MD, (Co-Chair),a Joel M. Gelfand, MD, MSCE,b Cody Connor, MD,c
April W. Armstrong, MD, MPH,d Kelly M. Cordoro, MD,e Dawn M. R. Davis, MD,f Boni E. Elewski, MD,c
Kenneth B. Gordon, MD,g Alice B. Gottlieb, MD, PhD,h Daniel H. Kaplan, MD, PhD,i Arthur Kavanaugh, MD,j
Matthew Kiselica, BA/BS,k Dario Kivelevitch, MD,a Neil J. Korman, MD, PhD,l
Daniela Kroshinsky, MD, MPH,m Mark Lebwohl, MD,n Craig L. Leonardi, MD,o Jason Lichten, MD,k
Henry W. Lim, MD,p Nehal N. Mehta, MD, MSCE,q Amy S. Paller, MD,r Sylvia L. Parra, MD,s Arun L. Pathy, MD,t
Elizabeth Farley Prater, MD,u Robert S. Rahimi, MD, MSCR,a Reena N. Rupani, MD,n Michael Siegel, PhD,v
Benjamin Stoff, MD, MA,w Bruce E. Strober, MD, PhD,x,y Elliot B. Tapper, MD,z Emily B. Wong, MD,aa
Jashin J. Wu, MD,bb Vidhya Hariharan, PhD,cc and Craig A. Elmets, MD, (Co-Chair)c
Dallas and San Antonio, Texas; Philadelphia and Pittsburgh, Pennsylvania; Birmingham, Alabama; Los
Angeles, San Francisco, San Diego, and Irvine, California; Rochester, Minnesota; Milwaukee, Wisconsin;
New York, New York; Portland, Oregon; Cleveland, Ohio; Boston, Massachusetts; St Louis, Missouri;
Detroit and Ann Arbor, Michigan; Bethesda, Maryland; Chicago and Rosemont, Illinois; Sumter, South
Carolina; Centennial, Colorado; Oklahoma City, Oklahoma; Atlanta, Georgia; and Cromwell and New
Haven, Connecticut
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
JUNE 2020
Key words: Clinical guidelines for psoriasis; dermatology; nonbiologic systemic; psoriasis; psoriasis
guidelines; skin disease.
CONFLICT OF INTEREST STATEMENT other methods of care reasonably directed toward

The American Academy of Dermatology (AAD) obtaining the same results. The ultimate judgment
strives to produce clinical guidelines that reflect the regarding the propriety of any specific therapy must
best available evidence supplemented with the be made by the physician and the patient in light of
judgment of expert clinicians. Significant efforts are circumstances presented by the individual patient
taken to minimize the potential for conflicts and the known variability and biologic behavior of
of interest to influence guideline content. The the disease. Furthermore, the treatment dosages used
management of conflict of interest for this guideline in clinical trials may not be effective in certain cases,
complies with the Council of Medical Specialty and some patients may require shorter intervals
Societies’ ‘‘Code of Interactions with Companies.’’ between doses and/or higher treatment doses of a
Funding of guideline production by medical or particular treatment methodology. This guideline
pharmaceutical entities is prohibited, full disclosure reflects the best available data at the time the
is obtained and evaluated for all guideline guideline was prepared. The results of future studies
contributors throughout the guideline development may require revisions to the recommendations in
process, and recusal is used to manage identified this guideline to reflect new data.
relationships. The AAD conflict of interest policy
summary may be viewed at www.aad.org. SCOPE
The information below represents the author’s This guideline will cover the use of oral-systemic,
disclosed relationship with industry during guideline nonbiologic medication in the treatment of psoriasis.
development. Authors (listed alphabetically) with
relevant conflicts with respect to this guideline are METHOD
noted with an asterisk (*). In accordance with AAD For a full description of the methodology used
policy, a minimum 51% of workgroup members did herein, please refer to Appendix 1.
not have any relevant conflicts of interest.
Participation in one or more of the below-listed DEFINITION OF REVIEW
activities constitutes a relevant conflict: See section below for full definition statement
d Service as a member of a speaker bureau, (Table I).
consultant, advisory board, for pharmaceutical
companies on psoriasis disease state or psoriasis INTRODUCTION
drugs in development or United States Food and In the treatment of psoriasis, topical therapies,
Drug Administration (FDA) approved such as vitamin D analogues and corticosteroids,
d Sponsored research funding or investigator- may be effective and sufficient for managing limited
initiated studies with partial/full funding from disease and offer the additional benefit of fewer
pharmaceutical companies on psoriasis disease significant adverse effects due to the lack of systemic
state or psoriasis drugs in development or FDA exposure. Although helpful and important in most
approved psoriasis treatment regimens, topical therapies are
frequently inadequate to obtain and maintain
If a potential conflict was noted, the work group
skin clearance. Hence, phototherapy or systemic
member recused themselves from discussion and
treatments can be pursued. Many oral medications
drafting of recommendations pertinent to the topic
have been used for decades to treat psoriasis, each
area of interest. Complete group consensus was
with its own benefits and risks. Most work by
obtained for draft recommendations. Areas where
targeting the immune system, whereas others, such
complete consensus was not achieved are shown
as acitretin, work predominantly by decreasing
transparently in the guideline.
keratinocyte hyperproliferation, thus restoring the
normal epidermal differentiation.
DISCLAIMER The rapidity of onset is an important pharmaco-
Adherence to this guideline will not ensure suc- logic trait guiding treatment selection in many cases,
cessful treatment in every situation. Furthermore, particularly with inflammatory or erythrodermic
these guidelines should not be interpreted as setting a psoriasis, while in other cases, individual
standard of care, nor should they be deemed either patient circumstances and comorbidities, including
inclusive of all proper methods of care, or exclusive of concomitant obesity, psoriatic arthritis, inflammatory
J AM ACAD DERMATOL Menter et al 1447
VOLUME 82, NUMBER 6
Table I. Clinical questions

Abbreviations used:
AAD: American Academy of Dermatology What are the efficacy, effectiveness, adverse effects,
ACR: American College of Rheumatology contraindications, and recommended monitoring for oral
AE: adverse event systemic therapies used to treat psoriasis in adults?
BB-UVB: broadband ultraviolet B
BSA: body surface area 1. MethotrexatedFDA approval 1972
BUN: blood urea nitrogen 2. ApremilastdFDA approval 2014
CBC: complete blood count 3. CyclosporinedFDA approval 1997
CI: confidence interval 4. AcitretindFDA approval 1997
CYP3A4: cytochrome P450 3A4 subtype 5. TofacitinibdNot FDA approved for psoriasis
FAE: fumaric acid ester
FDA: Food and Drug Administration 6. Fumaric acid estersdNot FDA approved for
GI: gastrointestinal psoriasis
IL: interleukin 7. HydroxyureadNot FDA approved for psoriasis
NB-UVB: narrowband ultraviolet B 8. Mycophenolate mofetildNot FDA approved for
OPT: Oral treatment Psoriasis Trial
PASI: Psoriasis Area and Severity Index psoriasis
PUVA: psoralens with ultraviolet A 9. Azathioprined Not FDA approved for psoriasis
RR: relative risk 10. LeflunomidedNot FDA approved for psoriasis
UV: ultraviolet
UVA: ultraviolet A 11. TacrolimusdNot FDA approved for psoriasis
UVB: ultraviolet B 12. ThioguaninedNot FDA approved for psoriasis
FDA, Food and Drug Administration.

bowel disease, and infections, including viral hepa-
titis, latent tuberculosis, and HIV, may be potent Psoriasis is an immune-mediated condition
drivers toward or away from a specific medication.1,2 caused by inappropriate activation of T cells
Although the advent of biologic therapies has and dendritic cells with subsequent release of
changed the treatment landscape, the medications inflammatory cytokines including interleukin (IL)
discussed in this guideline are still widely used, 17, IL-23, and tumor necrosis factor-a.5 These
either as monotherapy or in combination with soluble mediators are responsible for keratinocyte
biologic medications. These therapies can benefit hyperproliferation, increased vascularity, and the
widespread psoriasis, have a comparatively low cost inflammatory infiltrate present in psoriatic plaques.6
(in the case of older medications), have increased These cytokines have also been implicated in a
availability, and ease of administration. number of psoriasis comorbidities, including
metabolic syndrome, heart disease, and arthritis.7
DEFINITIONS
Because psoriatic plaques have robust infiltration of
Psoriasis vulgaris is a chronic inflammatory skin
inflammatory cells, a number of systemic medica-
disease that typically presents with well-demarcated
tions that suppress inflammatory responses have
pink plaques with silvery scale, commonly involving
been evaluated.
the scalp, elbows, knees, and presacral region. Any
area of skin may be involved, including the palms
and soles, as well as the genital regions in up to 60% METHOTREXATE
of patients.3 The severity of psoriasis is generally Methotrexate was FDA approved in 1972 and has
defined by the total body surface area (BSA) been used for more than 4 decades in the treatment
involved, and BSAs of \3%, 3% to 10%, and [10% of psoriasis. It is a competitive inhibitor of
are considered as mild, moderate, and severe dihydrofolate reductase, decreasing folate cofactors
disease, respectively. The Psoriasis Area and required for the synthesis of nucleic acids.8 In
Severity Index (PASI) is a more specific means of addition, polyglutamate derivatives of methotrexate
quantifying the extent and severity of psoriasis. The are potent inhibitors of 5-aminoimidazole-4-
PASI takes into account not only the BSA but also carboxamide ribonucleotide transformylase, an
intensity of redness, scaling, and plaque thickness, effect that results in increased amounts of endoge-
ultimately producing a score from 0 (no disease) to nous adenosine, an anti-inflammatory molecule.9-12
72 (maximal disease severity).4 The PASI is an These inhibitory actions have a large effect on
important research tool but is used infrequently in rapidly dividing cells. In psoriasis, a theoretic
clinical practice. It is time consuming and provides inhibitory effect on keratinocytes was originally
little additional information about the individual suspected to be responsible for its therapeutic
patient that is not provided by the physician’s global benefit, but studies have since failed to show a
assessment or BSA estimate. significant influence of methotrexate on epidermal
JUNE 2020
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
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
JUNE 2020
Table II. Methotrexate supporting information*

Supporting statement References
50
Absolute contraindications
d Pregnancy
d Nursing
d Alcoholism
d Alcoholic liver disease or other chronic liver diseases
d Immunodeficiency syndromes
d Bone marrow hypoplasia, leukopenia, thrombocytopenia, or significant anemia
d Hypersensitivity to methotrexate
Relative contraindications
d Abnormalities in renal function
d Abnormalities in liver function
d Active infection
51
Risk factors for methotrexate-associated hepatotoxicity
d History of or current use of greater than moderate alcohol consumption
d Persistent abnormal liver function test findings
d History of liver disease including chronic hepatitis B or C
d Family history of inheritable liver disease
d Diabetes mellitus
d Obesity
d History of exposure to hepatotoxic drugs or chemicals
d Hyperlipidemia
50
Baseline/ongoing monitoring
d History and physical examination
d Hepatitis B and C (baseline monitoring)
d Pretreatment test for latent TB (PPD, T-Spot [Oxford Immunotec USA, Inc,
Marlborough, MA], or QuantiFERON Gold [Qiagen, Germantown, MD])

d Referral for a chest radiograph for a positive TB test
d Monitor CBC and LFT every 3-6 months assuming no abnormal laboratory results
d Additional monitoring recommended for patients with impaired kidney function
B Blood urea nitrogen and creatinine levels

B Check CBC 5 to 7 days after a test-dose
Medications that may increase the risk of methotrexate toxicity

Nonsteroidal anti-inflammatory drugs Antibiotics Others
Salicylates Trimethoprim/sulfamethoxazoley Barbiturates 50
Naproxen Sulfonamides Colchicine

Ibuprofen Penicillin Dipyridamole
Indomethacin Minocycline Ethanol
Phenylbutazone Ciprofloxacin Phenytoin
Sulfonylureas
Furosemide
Thiazide diuretics
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
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.
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.
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.
JUNE 2020
Table III. Strength of recommendation for methotrexate in psoriasis therapy

Recommendation Strength of
No. Recommendation recommendation
1.1 Methotrexate is recommended for the treatment of moderate to severe psoriasis in A
adults.
1.2 Methotrexate is less effective than adalimumab and infliximab for cutaneous psoriasis. A
1.3 Methotrexate is efficacious for treatment of psoriatic arthritis (peripheral arthritis, but not B
for axial involvement); in psoriatic arthritis, the efficacy of methotrexate is lower than
TNF-inhibitors.
1.4 Recommended methotrexate dosage typically ranges from 7.5 to 25 mg weekly. The B
dose can be given as a single dose or in 3 doses over 24 hours.
1.5 Methotrexate can be administered orally or subcutaneously. A
1.6 A test dose should be considered, especially in patients with impaired kidney function. B
1.7 Administration of folic acid or folinic acid is recommended to reduce the incidence of GI A
and hepatic adverse effects. Large folic acid and folinic acid doses may reduce the
efficacy of methotrexate.
1.8 Combination therapy with methotrexate and NB-UVB phototherapy can be considered B
for adult patients with generalized plaque psoriasis to enhance efficacy and lower
cumulative doses of both treatments.
GI, Gastrointestinal; TNF, tumor necrosis factor; NB-UVB, narrowband ultraviolet B.
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
VOLUME 82, NUMBER 6
Table IV. Level of evidence of methotrexate therapy in psoriasis

Recommendation Level of
Recommendation No. evidence Studies
19,27,28,33,35,37-39,65-69
d Methotrexate use in psoriasis patients 1.1 I-III
d Methotrexate less effective than ADA or IFX
27,28,33,68,69
1.2 I-II
d Methotrexate treatment for psoriatic arthritis
31,32
1.3 I
d Methotrexate weekly dosage
15,16,18,20,22,23
1.4-1.7 I, III
d Methotrexate taken orally or subcutaneously and expert
d Methotrexate test dose consensus (1.7)
d Folic acid and folinic acid use with
methotrexate treatment
37-39
Combination therapy 1.8 I
d Methotrexate and NB-UVB
ADA, Adalimumab; IFX, infliximab; NB-UVB, narrowband ultraviolet B.
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
JUNE 2020
Table V. Supporting statements for methotrexate associated hepatotoxicity*

Statement No. Statement References
70-72
1 Patients with psoriasis are at higher risk of developing fatty liver disease, fibrosis, and cirrhosis from
methotrexate than patients with other diseases commonly treated with methotrexate such as
rheumatoid arthritis.
56
2 The frequency of serious liver complications associated with methotrexate is lower than previously
reported. However, the risk of serious liver complications related to methotrexate treatment of
psoriasis is difficult to quantify accurately.
73-76
3 Liver biopsies are expensive, invasive, and associated with risk of serious complications such as
internal bleeding. Furthermore, inter-rater reliability is a limitation for liver biopsy.
77
4 Noninvasive blood tests have been developed to predict fibrosis in patients with nonalcoholic
steatohepatitis and viral hepatitis with a reasonable negative predictive value for cirrhosis (ie, a
normal test result accurately predicts low risk of cirrhosis). However, the negative predictive
value will depend on the pretest probability of cirrhosis. Testing (such as imaging techniques)
for most patients should be considered to lower the probability of fibrosis further. The positive
predictive value is less reliable, and thus, a positive test does not preclude use of methotrexate if
follow-up testing with imaging (vibration-controlled transient elastography) or liver biopsy are
reassuring.
78-80
5 There are limited data regarding the test characteristics of noninvasive blood tests in patients with
psoriasis treated with methotrexate compared with liver biopsy. Patients can be monitored with
noninvasive blood tests while minimizing use of liver biopsies.
56,81-83
6 Imaging with vibration-controlled transient elastography is a direct measure of liver fibrosis. Its use
has been validated in nonalcoholic steatohepatitis and viral hepatitis compared with liver
biopsy. Its limitations include operator experience, obesity, hepatic inflammation, cholestasis,
congestion (right-sided heart failure), and recent food intake (should be done fasting for at least
3 hours). Vibration-controlled transient elastography has been used to monitor fibrosis in
psoriasis patients treated with methotrexate and is useful in lowering the need for liver biopsy.
84,85
7 Elastography can also be performed using magnetic resonance imaging techniques. Compared
with vibration-controlled transient elastography, magnetic resonance elastography (MRE) is less
studied, with unclear generalizability between centers/radiologists. Both methods showed equal
benefit in excluding advanced fibrosis/cirrhosis; however, MRE appears to be more accurate
overall and is technically successful in patients with severe obesity. Given its high cost, it is an
option for patients who are not candidates for vibration-controlled transient elastography. MRE
has been studied in the evaluation of methotrexate-induced liver disease in a single-center
study.
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
VOLUME 82, NUMBER 6
Table VI. Supporting statements for apremilast in psoriasis

Statement No. Supporting statement Reference
87
1 Patients should initially start at a lower dose (10 mg), which is titrated up over 5 days to reduce the
risk of gastrointestinal adverse effects. Thereafter, apremilast is dosed 30 mg by mouth twice
daily.
Dosage titration schedule:
Day 1d10 mg (AM)
Day 2d10 mg (AM & PM)
Day 3d10 mg (AM); 20 mg (PM)
Day 5d20 mg (AM); 30 mg (PM)
87
2 The most common adverse effects of apremilast are diarrhea, nausea, upper respiratory tract
infections, and headache (those 65 and older are prone to experience dehydration and its
complications).
87
3 Apremilast may be associated with the emergence or worsening of depression. Discuss the risk of
depression with patients in advance of therapy.
87
4 Apremilast is metabolized in the liver by cytochrome P450. Use with strong inducers of
cytochrome P450 (eg, rifampin, phenobarbital, carbamazepine, phenytoin) may result in
decreased efficacy and is not recommended.
87
5 Apremilast should be reduced to 30 mg once daily in patients with severe renal impairment
(creatine clearance \30 mL/min).
87
6 A small percentage of patients may lose weight on apremilast. Weight should be monitored
regularly, and if weight loss occurs ([5% from baseline), discontinuation of apremilast should be
considered.
7 Routine laboratory screening and monitoring can be considered on an individual basis.*
8 There is currently no strong evidence to support the combined use of apremilast with other
systemic or phototherapy treatments for psoriasis.*
87
9 Pregnancy
Should only be used in pregnancy if benefit justifies potential risk to fetus.
Apremilast is metabolized in the liver by CYCLOSPORINE

cytochrome P450 and is thus susceptible to the forms Cyclosporine received FDA approval for psoriasis
of drug interactions that are typical of medications in 1997. It is a potent immunosuppressant
metabolized by this route. Use of apremilast in that functions by binding cyclophilin, which then
conjunction with strong inducers of cytochrome inhibits calcineurin and blocks proinflammatory
P450 (eg, rifampin, phenobarbital, carbamazepine, signaling.98-100 Several inflammatory cytokines,
and phenytoin) is not recommended, because this including interferon-g and IL-2, are consequently
combination may result in decreased efficacy. reduced, leading to decreased activation of
Dangerous drug interactions have not yet been T cells.99,100 Because of the long list of potential
reported, but medication lists should be serious adverse effects, cyclosporine is not used as
reviewed before initiating therapy and periodically a long-term treatment for psoriasis. Nevertheless, it
thereafter. does have an important role as a rapid-acting medi-
Overall, apremilast as monotherapy is beneficial cation for severe, recalcitrant disease, acute flares, and
to treat psoriasis and psoriatic arthritis. These erythroderma. It can also be used as a bridge therapy
benefits include oral administration and the lack of in the transition to a safer long-term treatment.
a requirement for laboratory monitoring. For patients
who would prefer to avoid frequent injections as
well as laboratory monitoring and are willing to Dosage
accept a slower onset of skin clearance and lower There are 2 main approaches in the use of
likelihood of clearing, apremilast is an appropriate cyclosporine for the treatment of psoriasis. Some
choice. Table VII provides the strength of clinicians prefer to start at an intermediate dose of
recommendation and Table VIII86,93-97 provides the 2.5 to 3.0 mg/kg/day given twice daily for
level of evidence for apremilast in psoriasis therapy. approximately 4 weeks before gradually increasing
JUNE 2020
Table VII. Strength of recommendation for the apremilast in psoriasis therapy

Recommendation No. Recommendation Strength of recommendation
2.1 Apremilast is recommended for the treatment of moderate to A
severe psoriasis in adults.
Table VIII. Level of evidence for apremilast in Efficacy

psoriasis therapy The demonstration that cyclosporine was an
Recommendation Level of
effective treatment was instrumental in establishing
Recommendation No. evidence Studies the role of aberrant T-cell activation in the
Apremilast and psoriasis 2.1 I 86,93-97 pathogenesis of psoriasis, rather than a sole
consequence of abnormal keratinocyte proliferation.
Cyclosporine is dosed at 2.5 to 5 mg/kg/d for 12 to
16 weeks and produces swift and dramatic
the dose by 0.5 mg/kg/day until adequate control is improvement in up to 80% to 90% of patients with
obtained. This method may be better for moderate psoriasis.98,101,107-110 At a dose of 3 mg/kg/d, 50% to
disease and identification of adverse effects as the 70% of patients with psoriasis achieved PASI 75 and
dose is increased. Alternatively, patients with severe 30% to 50% achieved PASI 90.111 In a large systematic
disease who require rapid improvement can be review that included 10 studies (randomized
started at a dose of up to 5 mg/kg/day and controlled trials, prospective studies, and case
subsequently tapered once improvement has been series), a cyclosporine dose of 5 mg/kg/d produced
achieved.50,101-104 Another consideration is the type PASI 75 rates between 50% and 97%, while
of preparation. In addition to the unmodified form, cyclosporine 2.5 mg/kg/d achieved PASI 75 in 28%
cyclosporine is available as a modified to 85% of patients.112
microemulsion that is more steadily absorbed and Cyclosporine-treated patients frequently relapse
is recommended in low (2-3 mg/kg/d) or ultralow after discontinuation (ie, ; 3 months), unless other
(1-2 mg/kg/d) doses.105 treatments are substituted. In 365 patients who
Obese patients are more effectively treated when achieved $90% clearance of plaque psoriasis after
dosed according to their actual body weight. In fact, intermittent short courses of cyclosporine, 2.5 mg/kg
weight loss in obese (body mass index $30 kg/m2) microemulsion formulation daily, abrupt cyclo-
patients with psoriasis treated with cyclosporine sporine termination led to slightly quicker relapse
can increase treatment efficacy, suggesting a (median time to relapse of 109 days) compared with
pharmacokinetic benefit of matching dose to actual gradual tapering of 1 mg/kg/d weekly (median
body weight.106 A study randomized 61 obese time to relapse of 113 days).109 Short courses of
patients to receive treatment with cyclosporine in cyclosporine were well tolerated, although 8%
combination with a low-calorie diet or without discontinued treatment due to adverse effects,
dietary intervention.106 At 24 weeks, the intervention primarily elevations in blood pressure and
group lost 7.0% 6 3.5% of body weight and creatinine.
two-thirds achieved PASI 75, whereas the control Lower doses of cyclosporine can be beneficial in
group lost only 0.2% 6 0.9% of body weight and only maintaining skin clearance in patients treated
29% achieved PASI 75. initially with higher-dose cyclosporine induction
Although evidence for dosing by weight is therapy for psoriasis.102,113 One trial with 217
available, one study sought to determine whether a patients used cyclosporine doses of 1.25, 2.5, or
fixed dose of cyclosporine regardless of weight 5.0 mg/kg/d over an extended course of 6 to
could be used.105 The study compared 2 different 30 months, and 12.5% of patients were successfully
fixed dosing schedules of the cyclosporine maintained at the 1.25 mg/kg/d dose without any
microemulsiond100 mg once daily or 50 mg twice apparent worsening of the disease.114 Adverse
daily.105 There were no statistically significant effects were less common during the maintenance
differences in the percentage of patients achieving phase. After eventual discontinuation, 55.5% expe-
PASI 75 and PASI 90 between the 2 groups.105 rienced worsening of their psoriasis, sufficient to
Improvement rates were 69.4% 6 4.8% in the require further therapy. In another study, 181 pa-
once-daily group and 73.4% 6 4.3% in the tients who achieved $70% BSA improvement after
twice-daily group.105 cyclosporine induction therapy at 5 mg/kg/d were
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
JUNE 2020
Table IX. Supporting statements for cyclosporine in psoriasis*

Statement No. Supporting statement Studies
105
1. Single daily dose of cyclosporine may yield similar treatment response to twice-daily dose when the
microemulsion formulation is used.
149
2. Patients who have achieved a clinical response to cyclosporine may have some benefit by using
cyclosporine on 2 consecutive days per week (5 mg/kg/d) compared with placebo over 24 weeks.
106
3. Weight loss may result in improvement in cyclosporine response in obese patients whose body mass
index is $30 kg/m2 but \45 kg/m2.
4. Dosage
d 2.5-5.0 mg/kg/d in 2 divided doses per day
d Dose adjustments downward (by 0.25-1.0 mg/kg) when clearance of psoriasis is achieved or
when hypertension or decreased renal function are observed

Duration of dosing
d Optimally used as interventional therapy; may be repeated at intervals after a rest period
5. Contraindications
d Prior PUVA treatment (especially [200 treatments) or radiation therapy
d Abnormal renal function
d Uncontrolled hypertension
d Malignancy
d Hypersensitivity to cyclosporine
d Live vaccinations should be avoided
d Caution with major infections and poorly controlled diabetes
6. Baseline monitoring
d BP 32
d BUN and creatinine
d Urinalysis
d Consider latent tuberculosis test
d LFTs, CBC, lipid profile, magnesium, uric acid, and potassium
d Pregnancy test if indicated
Ongoing monitoring
d Monitor BP (early morning resting BP), BUN, creatinine every other week during first 3 months
and then monthly monitoring if no persistent abnormalities are identified

d Monthly CBC, LFTs, lipid profile, magnesium, uric acid, and potassium
d Pregnancy testing if indicated
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 Nausea, vomiting, and diarrhea
d Myalgias
d Flu-like symptoms
d Lethargy
d Hypertriglyceridemia
d Hyperkalemia
d Hyperbilirubinemia
d Increased risk of infections
d May increase risk of cancer
Continued
VOLUME 82, NUMBER 6
Table IX. Cont’d

Statement No. Supporting statement Studies
8. Drug interactions
d Inducer/inhibitors of cytochrome P450 3A4
d St John’s Wort (decreases cyclosporine concentration)
d Cyclosporine may reduce clearance of digoxin, colchicine, prednisolone, and statins
d Potassium-sparing diuretics (may cause hyperkalemia)
d Thiazide diuretics (increased nephrotoxicity)
d Killed and/or recombinant vaccines
d Grapefruit juice
d Nonsteroidal anti-inflammatory drugs
9. Pregnancy
d Lower birth weight and shorter duration of pregnancy reported in patients with transplantation;
appears not to be teratogenic in patients with transplantation.

Nursing
d Cyclosporine contains ethanol and has been found in human breast milk; therefore, ethanol will
be orally absorbed by the nursing infant

d A decision should be made whether to discontinue nursing or cyclosporine based on benefit of
therapy to the patient.

Fertility
d On the basis of animal studies, there is no effect on fertility.
BP, Blood pressure; BUN, blood urea nitrogen; CBC, complete blood count; LFTs, liver function tests; PUVA, psoralen plus ultraviolet A.
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.
JUNE 2020
Table X. Strength of recommendation for cyclosporine therapy in psoriasis

3.1 Cyclosporine is recommended for patients with severe, recalcitrant psoriasis. A
3.2 Cyclosporine can be recommended for the treatment of erythrodermic, generalized B
pustular, and/or palmoplantar psoriasis.
3.3 Cyclosporine can be recommended as short-term interventional therapy in patients who C
flare up while on a pre-existing systemic therapy.
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.
VOLUME 82, NUMBER 6
Table XI. Level of evidence for cyclosporine in psoriasis therapy

Recommendation Recommendation No. Level of evidence Studies
33,105,112,146-149
Cyclosporine for psoriasis treatment 3.1 I-III
112
Cyclosporine treatment in different types of psoriasis 3.2 I
d Erythrodermic
d General pustular
d Palmoplantar
Cyclosporine for psoriasis flare 3.3 III Expert consensus
Contraindications slow-acting medication that can take 3 to 6 months

Caution should be taken when considering for full treatment response.
the use of cyclosporine in elderly or pregnant
patients or those with immunodeficiency disorders.
Contraindications to cyclosporine therapy include Efficacy
a history of systemic malignancy (excluding Acitretin is less beneficial than other common
nonmelanoma skin cancer), renal insufficiency, systemic psoriasis medications, although head-to-
hypertension, prior psoralen plus ultraviolet A head comparison studies are lacking. The effects of
(PUVA) treatment, uncontrolled infections, and acitretin are dose-dependent, and a number of
hypersensitivity to cyclosporine. Caution should be different dosing schedules have been used.151-158
taken when prescribing cyclosporine in patients In one study, 23% of patients treated with acitretin
taking other medications that can interact with 50 mg/d achieved PASI 75 after 8 weeks of therapy,
CYP3A4. Live vaccinations are contraindicated in with some patients experiencing complete clearance
patients using cyclosporine. of skin disease.159 In another trial, patients treated
Cyclosporine should be avoided in patients with with acitretin 40 mg daily for 4 weeks and then
poor health and in those with risk factors for continued on with an individually adjusted dose for
developing severe adverse effects.112 the next 8 weeks, had a mean PASI improvement of
Recommendations for the use of cyclosporine 75.8%.160 A different study started patients on 20 mg
are outlined in Table X, and the level of daily, followed by 10 mg dose increases every
evidence of these recommendations is reported in 2 weeks, with a maximum dose of 70 mg.
Table XI.33,50,105,112,146-149 Maintenance therapy with acitretin was beneficial,
with 75% of patients achieving PASI 50 after 6 months
ACITRETIN of treatment and 88% achieving PASI 50 after
The oral retinoid, acitretin, is a vitamin A 12 months.161
derivative, and the active metabolite, etretinate, is Because acitretin is not immunosuppressive, it is
an oral retinoid that was initially used for psoriasis in often used in patients with psoriasis on highly active
the early 1980s. Acitretin was approved for treatment antiretroviral therapy treatment of HIV.162 Severe
of psoriasis by the FDA in 1997. The mechanism psoriasis variants, such as erythrodermic psoriasis,
of action of retinoids, such as acitretin, is not generalized pustular psoriasis, and palmoplantar
entirely understood. It does modulate epidermal psoriasis, have been successfully treated with
differentiation and proliferation and also has acitretin or in the past with etretinate. One study
anti-inflammatory and immunomodulatory effects. reported improvement in 84% of patients with
Unlike most systemic psoriasis treatments, acitretin is pustular psoriasis after treatment with acitretin.163
not immunosuppressive. Another study of etretinate found it to be effective in
both erythrodermic and pustular psoriasis.164 The
Dosage response of pustular psoriasis, both generalized and
Acitretin is administered for psoriasis in doses palmoplantar, to systemic retinoids can be quite
ranging from 10 to 50 mg daily. One study set a rapid and remarkable.165
maximum dose of 70 mg daily, which was reached Acitretin is of value in hyperkeratotic (plaque-
after gradual upward titration toward the desired type) palmoplantar psoriasis, as monotherapy or in
clinical effect.150 The major element in dosing combination with other treatment modalities, such
acitretin is balancing efficacy with the individual as NB-UVB, PUVA, or other systemic/biologic
patient’s tolerability. Acitretin is a relatively agents.166,167
JUNE 2020
Combination treatment Safety

Combined therapy with acitretin and photo- The most important safety concern with acitretin
therapy is more efficacious than monotherapy alone. therapy is teratogenicity when used in women
The combination helps to limit long-term adverse of childbearing potential. This medication is
effects and decreases the cumulative doses of contraindicated in pregnancy. Multiple malforma-
phototherapy, frequency, and duration of photo- tions are associated with the use of acitretin during
therapy.168 Combination therapy is more convenient pregnancy, particularly if used between weeks 3 and
and more cost-effective for patients. Broadband 6 of gestation. These include abnormalities on
UVB (BB-UVB) plus acitretin has been compared skeletal and craniofacial bones, the central nervous
with acitretin monotherapy169-172 and was found to system, and auditory, ocular, and cardiovascular
improve treatment safety, because lower doses of systems.178 Patients should also not use acitretin
acitretin and lower cumulative amounts UVB could before or during nursing. Although the half-life of
be used. In another study, treatment with acitretin acitretin is 49 hours, it may undergo spontaneous
25 mg daily plus phototherapy was as effective as transformation into etretinate, which has a half-life of
acitretin 35 mg daily monotherapy.171 The median 168 days. Alcohol ingestion promotes conversion of
cumulative BB-UVB dose necessary for 75% acitretin to etretinate, but the actual amount of
improvement was 41% lower in the combination alcohol necessary to do so is unknown.
group than with BB-UVB monotherapy.171 In a study Given this uncertainty, unintentional exposure to
in which combination therapy with acitretin 50 mg alcohol-containing items may pose a risk. As such,
daily and BB-UVB was compared with either agent use of acitretin should be avoided in women
alone, there was a 74% improvement in psoriasis of childbearing potential and is absolutely
severity score in the combination group compared contraindicated in women who plan to become
with 42% with acitretin alone and 35% with BB-UVB pregnant or who do not use sufficient contraception.
alone.170 Women who wish to become pregnant after
The recommended schedule is to begin with discontinuing acitretin should wait at least 3 years
2 weeks of acitretin monotherapy, followed by after completion of treatment. Acitretin apparently
UVB phototherapy. Acitretin 25 mg/d can also be does not have an effect on fertility or teratogenicity
added to a failing UVB regimen to augment when men are taking the drug. This is based on
treatment response. Because oral retinoids can limited data.179
increase susceptibility to UVB-induced erythema, The other adverse effects of acitretin are
an initial UVB dose decrease of 30% to 50% is minimized by appropriate dosing, monitoring, and
recommended for the first week, followed by a patient selection.179 Nearly all patients experience
gradual increase, as tolerated. mucocutaneous adverse effects, including xerosis,
While fewer data exist, NB-UVB has also been dryness of the eye, nasal/oral mucosa, epistaxis,
used with great efficacy in combination with acitretin cheilitis, itching or burning skin, and brittle nails, all
in the treatment of psoriasis. In 40 patients who were of which may range from mild to severe, depending
refractory to monotherapy, when treated with on individual patient characteristics and the dose of
combination therapy, 72.5% experienced more acitretin. Hair loss is more common in women,
than 75% improvement in psoriasis severity.173 especially in doses that exceed 17.5 mg per day.
As with UVB, the addition of acitretin to PUVA is ‘‘Retinoid dermatitis’’ is a less common adverse
more effective than either treatment alone.174-176 effect, which manifests as scaly, erythematous
Patients experiencing inadequate benefit from plaques with superficial fissuring. Pyogenic
PUVA monotherapy may have acitretin added to granulomas, particularly in periungual locations,
their regimen while simultaneously reducing the have also been associated with long-term acitretin
UVA dose. When acitretin is combined with PUVA, therapy.156,180
fewer photochemotherapy sessions are necessary, Hyperlipidemia is present in 25% to 50% of
and the cumulative UVA dosage required to achieve patients and is the most common laboratory
clinical success is reduced. In addition, acitretin, abnormality associated with acitretin use.181 The
when combined with PUVA, decreases the incidence risk of acitretin-induced hypertriglyceridemia is
of cutaneous squamous cell carcinoma compared higher in patients with obesity, diabetes mellitus, or
with PUVA alone.177 In contrast, treatment with excessive alcohol intake, conditions that are also
cyclosporine increases squamous cell carcinoma commonly seen in the psoriatic population.182
incidence in patients who have been treated with Rarely, hypertriglyceridemia can reach levels that
PUVA. A 2-week period of acitretin therapy is will cause pancreatitis, which has been fatal in some
recommended before initiating PUVA. patients.183 For those experiencing sustained
VOLUME 82, NUMBER 6
Table XII. Strength of recommendations for acitretin in psoriasis therapy

4.1 Acitretin can be recommended as monotherapy for plaque psoriasis. B
4.2 Acitretin can be recommended for treatment of erythrodermic, pustular, and palmar- B
plantar psoriasis.
4.3 Acitretin can be recommended as combination therapy with PUVA for psoriasis. B
4.4 Acitretin can be combined with BB-UVB for plaque psoriasis.* B
BB-UVB, Broadband ultraviolet B; PUVA, psoralen plus ultraviolet A.

*From the 2019 American Academy of Dermatology/National Psoriasis Foundation phototherapy psoriasis guideline.192
Table XIII. Level of evidence for acitretin therapy in psoriasis

Recommendation
Recommendation No. Level of evidence Studies
33,150,152,154-157,159,161,162,193
Acitretin monotherapy for psoriasis 4.1 II
154-157,159,161,162
Acitretin in other psoriasis types 4.2 II
d Erythrodermic
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
BB-UVB, Broadband ultraviolet B; PUVA, psoralen plus ultraviolet A.
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.
JUNE 2020
Table XIV. Acitretin supplementary table*

Statement No. Supporting statement
1. Dosing
d 10-50 mg/d given as a single dose
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%.
d Women of childbearing potential cannot consider pregnancy up to 3 years after completion of treatment.
d Severely impaired liver or kidney function
d Chronic abnormally elevated blood lipid values
d Lipid profile, CBC, LFTs, renal function tests
Ongoing monitoring
d LFTs, lipid profile monthly for the first 3 months, then every 3 months
d CBC, renal function tests 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
d Etretinate can be formed with concurrent ingestion of acitretin and ethanol.
d Acitretin might interact with glucose-lowering effect of glibenclamide.
d May interfere with the contraceptive effect of microdosed progestin preparation.
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
CBC, Complete blood count; LFTs, liver function tests.

VOLUME 82, NUMBER 6
Table XV. Tofacitinib supplementary table*

Statement
No. Supporting statement
1. Tofacitinib can be considered for treatment of moderate to severe psoriasis but is not currently FDA approved
for that indication.
2. The recommended dose of tofacitinib for psoriasis is 5 mg by mouth 2 times a day or 10 mg by mouth 2 times a
day, which is more beneficial in efficacy but with a higher risk of adverse effects (off-label dosing).
3. Tofacitinib 10 mg twice a day is associated with a higher risk of adverse effects, such as infection and cytopenia,
compared with tofacitinib 5 mg twice a day.
4. Before initiation of tofacitinib, vaccination with zoster vaccine (Shingrix)y should be considered to reduce the
risk of herpes zoster.
5. Tofacitinib should not be initiated, if the
a. Lymphocyte count is \500 cells/mm3
b. Absolute neutrophil count (ANC) is \1000 cells/mm3
c. Hemoglobin is \9 g/dL
6. Tofacitinib should be discontinued, at least temporarily, if the
a. Lymphocyte count is \500 cells/mm3 (confirmed by repeat testing)
b. ANC is \500 cells/mm3 (confirmed by repeat testing)
For persistent decreases in ANC \1000 cells/mm3, tofacitinib should be held until ANC is [1000 cells/mm3.
c. Hemoglobin decreases by [2 g/dL or is \8.0 g/dL (confirmed by repeat testing). Tofacitinib should be held
until hemoglobin values have normalized.
7. The recommended tofacitinib dose in patients with moderate and severe renal or hepatic impairment is 5 mg
once daily.
8. Tofacitinib is not recommended in patients with severe hepatic impairment.
9. The recommended dose of tofacitinib for patients taking potent inhibitors of cytochrome P450 3A4 (CYP3A4)
(e.g., ketoconazole) or one or more concomitant medications that result in both moderate inhibition of
CYP3A4 and potent inhibition of CYP2C19 (eg, fluconazole) is 5 mg once daily.
10. Tofacitinib can be used with methotrexate. It should not be combined with potent immunosuppressants, such
as azathioprine and cyclosporine, or with biologics used for psoriasis.
11. Tofacitinib should be avoided during an active serious infection.
12. Live vaccines should be avoided in patients on tofacitinib.
13. There is currently not enough evidence to support the combined use of tofacitinib with other systemic agents
or phototherapy.
14. Pregnancy
Tofacitinib can be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
FDA, Food and Drug Administration.

y
Shingrix is the brand name for the zoster vaccine manufactured by GlaxoSmithKline, Research Triangle Park, North Carolina.
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
JUNE 2020
Table XVI. Fumaric acid ester supplementary table*,z,y

Statement
1. Dimethyl fumarate is approved in the United States for treatment of relapsing forms of multiple sclerosis. It can
be recommended for psoriasis.
2. Dosing
d Starting daily dose of 1 pill of lower strength (105 mg of fumaric acid ester mixtures) and then escalate over
8 weeks to 6 pills of regular strength (215 mg of fumaric acid ester mixtures)

d Severe liver disease
d Severe or chronic GI disease
d Severe or chronic kidney disease
d Malignancy or a history of malignancy
d Leukopenia and other hematologic abnormalities
d Pregnancy
d Breast-feeding
d CBC and platelet counts
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 GI (abdominal cramps, nausea, diarrhea, fullness, and flatulence)
d Flushing
d Malaise
d Fatigue
d Lymphopenia, leukopenia, eosinophilia
d Hepatotoxicity and elevated LFT results
d Increased cholesterol, triglycerides
d Increased serum creatinine, potassium, and proteinuria
d Possible renal disease
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.
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
VOLUME 82, NUMBER 6
Table XVII. Hydroxyurea supplementary table*,y,z

Statement
1. Indication
d Not an FDA-approved use for psoriasis
2. Dosing
d Initial dose of 500 mg orally twice daily, increasing to 1.5 g/d as tolerated.
d Marked bone marrow suppression, including leukopenia, thrombocytopenia, or anemia
d CBC
Ongoing monitoring
d Weekly CBC until a stable dose is achieved, then monthly
d Semiannual physical examination focusing on evidence of lymphadenopathy and NMSCs
5. Toxicity
d Bone marrow suppression
d GI symptoms (stomatitis, anorexia, nausea, vomiting, diarrhea, and constipation)
d Dermatologic reactions (rash, ulceration, dermatomyositis-like skin changes, alopecia)
d Dysuria (rare)
d Neurologic disturbances rarely (headache, dizziness, disorientation, hallucinations, and convulsions)
d Temporary impairment of renal tubular function accompanied by elevations in serum uric acid, BUN, and
creatinine
d Fever, chills, malaise, edema, asthenia
d Elevation in hepatic enzymes
d Pulmonary fibrosis
d Fatal and nonfatal pancreatitis and hepatoxicity, and severe peripheral neuropathy have been reported in
HIV-infected patients who received hydroxyurea in combination with antiretroviral agents.

d Concurrent use of hydroxyurea and other myelosuppressive agents or radiation therapy may increase the
likelihood of bone marrow suppression.

d May raise the serum uric acid level; therefore, dose adjustment of uricosuric medication may be necessary.
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.
y
z
II study using a higher dosage of 15 mg tofacitinib Toxicity

twice daily, the PASI 75 score at week 12 was In the OPT Pivotal 1 and 2 studies, adverse event
66.7%.198 rates, including those that led to discontinuation of
Tofacitinib was also compared with etanercept in the medication, were largely comparable across all
a noninferiority trial with 1101 patients with groups, and rates of serious adverse events, such as
psoriasis.199 It showed that tofacitinib 10 mg twice malignancy or infection, were low.197,200 However,
daily was noninferior to etanercept 50 mg twice the incidence of herpes zoster was greater in those
weekly. receiving tofacitinib compared with the placebo
JUNE 2020
Table XVIII. Mycophenolate mofetil supplementary table*,y,z

Statement
1. Indication
d Not FDA approved for psoriasis
2. Dosing
d 1.0-1.5 g orally 2 times/d
3. Contraindication
d Hypersensitivity to mycophenolate mofetil (MMF) and mycophenolic acid
d CBC and platelet counts
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
d Monthly CMP and LFTs
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 Genitourinary (urgency, frequency, dysuria, sterile pyuria)
d Susceptibility to viral, bacterial and mycobacterial infections
d Progressive multifocal leukoencephalopathy
d Hypercholesterolemia, hypophosphatemia, hyperkalemia, hypokalemia
d Fever and myalgias
d Headache, insomnia
d Peripheral edema
d Hypertension
d Patients taking MMF should not be given live attenuated virus vaccines
d Antacids containing aluminum and magnesium
d Calcium and iron
d Cholestyramine
d Antibiotics, including cephalosporins, fluoroquinolones, macrolides, penems, penicillins, sulfonamides,
inhibit enterohepatic recirculation and decrease MMF levels.

d High-dose salicylates
d Phenytoin
d Xanthine bronchodilators
d Probenecid
d Acyclovir, ganciclovir, valganciclovir, and valacyclovir
d Pregnancy and breast-feeding should be avoided during treatment, and patients (including men) must use
adequate contraceptive precautions.
CBC, Complete blood count; CMP, comprehensive metabolic panel; FDA, Food and Drug Administration; LFTs, liver function tests; NMSCs,
nonmelanoma skin cancer.
y
z
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
VOLUME 82, NUMBER 6
Table XIX. Azathioprine supplementary table*,y,z

Statement
1. Indication
d Not FDA-approved for psoriasis
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
d TPMT 5-13.7 U, 0.5 mg/kg
d TPMT 13.7-19.0 U, 1.5 mg/kg
d TPMT [ 19.0 U, 2.5 mg/kg
Without TPMT levels

d Begin at 0.5 mg/kg, and monitor for cytopenia
d If no cytopenia, increase dose by 0.5 mg/kg/d
d After 6-8 weeks, increase by 0.5 mg/kg/d every 4 weeks if necessary
d Usual dose for psoriasis is 75-150 mg/d
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
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 Increased risk of infections
d GI effects (nausea, vomiting, diarrhea)
d Hypersensitivity syndrome
d Pancreatitis
d Hepatitis
d Allopurinoldincreases risks of pancytopenia (if used concurrently, lower the azathioprine dose by 75%)
d Captoprildmay increase risk of anemia and leukopenia
d Warfarindmay need an increased dose of warfarin
d Pancuroniumdmay need an increased dose for adequate paralysis
d Cotrimoxazoledincreased risk of hematologic toxicity
d Rifampicinddecreases azathioprine efficacy; also hepatotoxic
d Clozapinedincreases risk of agranulocytosis
Continued
JUNE 2020
Table XIX. Cont’d

Statement
d Pregnancy and breast-feeding should be avoided during treatment with azathioprine, and patients (including
men) must use adequate contraception.
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.
y
z
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
VOLUME 82, NUMBER 6
Table XX. Leflunomide supplementary table*,y,z

Statement
1. Indication
2. Dosing
d Loading dose of 100 mg/d for 3 days, followed by 20 mg/d thereafter
d Patients with hypersensitivity to leflunomide or its metabolites
d CBC and differential
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
d Severe liver injury
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
d No pharmacokinetic interaction between leflunomide and methotrexate, but coadministration of the 2
drugs can lead to increased risk of hepatotoxicity.

d Rifampin increases leflunomide levels.
7. Pregnancy
d Should be avoided in pregnant patients
Nursing
d Leflunomide should not be used by nursing mothers.
Patients of reproductive potential

d Advise patients to use appropriate contraception during treatment administration and discontinuation.
CBC, Complete blood count; LFTs, liver function tests; FDA, Food and Drug Administration.
y
z
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
JUNE 2020
Table XXI. Tacrolimus supplementary table*,y,z

Statement
1. Indication
2. Dosage
d 0.05-0.15 mg/kg
d Patients with hypersensitivity to tacrolimus or its metabolites
Adverse effect profile similar to cyclosporine

d Most common adverse effects include tremor, headache, nausea, diarrhea, hypertension, and abnormal
renal function test.

d Less common adverse effects include hyperglycemia, hyperkalemia, elevated liver function test, anemia,
leukocytosis, dyspnea, fever, arthralgias, edema, diabetes, insomnia, and paresthesias.

d Complete blood count with differential
d BP
d Renal function test
d LFTs
d TB
Ongoing monitoringdproper frequency is not established

d Blood pressure
d Serum chemistry
d Renal function test
d Liver function test
d Numerous drug interactions due to its metabolization by the cytochrome P450 system
d Tacrolimus and cyclosporine should not be administered together.
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.
y
z
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
VOLUME 82, NUMBER 6
Table XXII. Thioguanine supplementary table*,y,z

Statement
1. Indication
2. Dosing
d Start at 80 mg 2 times/wk; increase by 20 mg every 2-4 weeks
d Maximum dose is 160 mg 3 times/wk
d Pre-existing liver disease
d Immunosuppression
d Anemia, leukopenia, and/or thrombocytopenia
d CBC and platelet counts, CMP, LFTs, hepatitis B and C, TB screen
Ongoing monitoring
d CBC and platelet count every 2-4 weeks; CMP every 3 months
5. Toxicity
d Myelosuppression
d Liver toxicity from hepatic veno-occlusive disease
d Increased ALT and AST
d Hyperuricemia
d Photodermatitis
d Taste changes
d Gastroesophageal reflux, gastric ulcers
d Headache
d Nausea/vomiting
d Aphthous ulcers
d Fatigue
d Nonmelanoma skin cancer
d Verrucae vulgaris, herpes zoster
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.
y
z
of progressive multifocal leukoencephalopathy and then escalate over 8 weeks to 6 pills of

occurring in patients with psoriasis treated with regular strength (215 mg of FAE mixtures), as
FAEs.211 Affected individuals experienced severe tolerated (expect consensus).207,212-214 Dimethyl
antecedent lymphopenia before onset of progressive fumarate has been approved by the FDA for
multifocal leukoencephalopathy. treatment of multiple sclerosis, with a common
Starting at low doses and gradually increasing dosing regimen of 240 mg twice daily.211
them can help minimize GI adverse effects. A Table XVI describes adverse effects, contraindi-
conservative approach is to start with 1 pill of cations, and recommendations regarding the use
lower strength (105 mg of FAE mixtures) daily of FAEs in psoriasis.
JUNE 2020
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
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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
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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.
Workgroup members disclosures Boni E. Elewski,* MD, served as a consultant for

Authors (listed alphabetically) with relevant con- Boehringer Ingelheim, Celgene Corporation, LEO
flicts with respect to this guideline are noted with an Pharma, Lilly ICOS LLC, Menlo Therapeutics, Novan
asterisk*. April W. Armstrong,* MD, MPH, served as (receiving no fees), Novartis Pharmaceuticals Corp,
an investigator for AbbVie, Amgen, Bristol-Myers Pfizer, Inc, Sun Pharmaceutical Industries, Ltd, Valeant
Squibb, Celgene, Dermira, Eli Lilly and Company, Pharmaceuticals International, and Verrica
Janssen-Ortho Inc, LEO Pharma, National Institutes Pharmaceuticals receiving honoraria; as a principal
of Health, Novartis, Regeneron, and UCB, receiving investigator for AbbVie, Amgen, AnaptysBio,
grants and/or research funding; as an investigator for Boehringer Ingelheim, Bristol-Myers Squibb, Celgene
Regeneron and Sanofi receiving no compensation; Corporation, Eli Lilly and Company, Incyte
as an advisory board member for AbbVie, Amgen, Corporation, InflaRX GmbH, Janssen-Ortho Inc, LEO
Janssen-Ortho Inc, Merck & Co, Inc, Novartis, Pfizer, Pharma, Menlo Therapeutics, Merck & Co, Inc, Novartis
Inc, and UCB receiving honoraria; as a consultant for Pharmaceuticals Corp, Pfizer, Inc, Regeneron, Sun
AbbVie, Bristol-Myers Squibb, Celgene, Dermavant, Pharmaceuticals, Ltd, Valeant Pharmaceuticals
Eli Lilly and Company, Genentech, Sanofi Genzyme, International, Vanda Pharmaceuticals, and Vioment
GlaxoSmithKline, Janssen-Ortho Inc, Janssen receiving grants/research funding; as an advisory
Pharmaceuticals, Inc, LEO Pharma, Menlo board member for Foundation for Research &
Therapeutics, Modernizing Medicine, Novartis Education of Dermatology, LEO Pharma, and Verrica
Pharmaceuticals Corp, Ortho Dermatologics, Pfizer, Pharmaceuticals Inc receiving honoraria; and in
Inc, Regeneron, Science 37, Inc, and Valeant another role for Hoffman-La Roche Ltd receiving fees.
receiving honoraria; as a speaker for AbbVie, Eli Craig A. Elmets, MD, served as a consultant for
Lilly and Company, Janssen Pharmaceuticals, Inc, Ferndale Laboratories, Inc, receiving honoraria; as a
Regeneron Pharmaceuticals, Inc, and Sanofi consultant/advisory board member for Vertex
receiving honoraria; and as a data safety member Pharmaceuticals receiving fees and/or honoraria; as
for Boehringer Ingelheim, and Merck & Co, Inc, a principal investigator for the California Association
receiving honoraria. of Winegrape Growers receiving grants and/or
Cody Connor, MD, has no relationships to disclose. research funding; as an investigator for Elorac, Inc,
Kelly M. Cordoro,* MD, served as a consultant for Idera Pharmaceuticals, Inc, Kyowa Hakko USA, and
Valeant receiving honoraria; as a consultant for Solgenix LLC receiving grants/research funding; as a
Pfizer, Inc, receiving fees; as an advisory board data safety monitoring board member for Astellas
member for Anacor Pharmaceuticals, Inc, receiving Pharma US, Inc, and LEO Laboratories Ltd receiving
honoraria; and in another position as a member of fees; as a stockholder for Medgenics, Inc, receiving no
the Scientific Steering Committee for Celgene fees; and as a stockholder for Aevi Genomic Medicine
receiving fees. (receiving stock) and Immunogen (paid to spouse).
Dawn M.R. Davis, MD, served as an investigator Joel M. Gelfand,* MD, MSCE, served as a consul-
for Regeneron receiving no compensation. tant for AbbVie, BMS, Boehringer Ingelheim,
VOLUME 82, NUMBER 6
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,
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,
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
JUNE 2020
disclosure of interests that was updated and diagnosis, treatment/prevention/screening, or prog-

reviewed for potentially relevant conflicts of in- nosis) as follows:
terest throughout guideline development. If a
I. Good-quality patient-oriented evidence (ie, evidence
potential conflict was noted, the work group
measuring outcomes that matter to patients:
member recused himself or herself from the morbidity, mortality, symptom improvement, cost
discussion and drafting of recommendations reduction, and quality of life)
pertinent to the topic area of the disclosed II. Limited-quality patient-oriented evidence
interest. III. Other evidence, including consensus guidelines,
An evidence-based model was used, and evi- opinion, case studies, or disease-oriented evidence
dence was obtained using a search of the PubMed (ie, evidence measuring intermediate, physiologic,
and MEDLINE databases from January 1, 2011, or surrogate end points that may or may not reflect
through December 31, 2017, for clinical questions improvements in patient outcomes)
addressed in the previous version of this guideline
published in 2008-2011. Searches were limited to
publications in the English language. Medical Clinical recommendations were developed on the
Subject Heading terms/search terms used in best available evidence tabled in the guideline.
various combinations in the literature search These are ranked as follows:
included psoriasis (palmoplantar, pustular, guttate, A. Recommendation based on consistent and good-
inverse, genital, plaque, scalp, nail) methotrexate, quality patient-oriented evidence
cyclosporine, acitretin, tofacitinib, fumaric acid B. Recommendation based on inconsistent or limited-
ester, apremilast, hydroxyurea, mycophenolate quality patient-oriented evidence
mofetil, leflunomide, tacrolimus, thioguanine, and C. Recommendation based on consensus, opinion, case
systemic. studies, or disease-oriented evidence
After removal of duplicate data, 134 studies were
retained for final review based on relevancy and the
highest level of available evidence for the outlined In those situations in which evidence-based data
clinical questions. Evidence tables were generated were not available, expert consensus was used to
for these studies and used by the work group in generate our clinical recommendations.
developing recommendations. The Academy’s prior This guideline has been developed in accordance
published guidelines on psoriasis were evaluated, as with the American Academy of Dermatology (AAD)/
were other current published guidelines on AAD Association Administrative Regulations for
psoriasis.194,215 Evidence-based Clinical Practice Guidelines (May
The available evidence was evaluated using a 2014),217 which includes the opportunity for review
unified system called the Strength of and comment by the entire AAD membership and
Recommendation Taxonomy (SORT) developed by final review and comment by the AAD Board of
editors of the United States family medicine and Directors. Additionally, this guideline is developed
primary care journals (ie, American Family in collaboration with the National Psoriasis
Physician, Family Medicine, Journal of Family Foundation, and as part of the review process; the
Practice, and BMJ USA).216 Evidence was graded National Psoriasis Foundation medical board mem-
using a 3-point scale based on the quality of bers provided their feedback. This guideline will be
methodology (eg, randomized control trial, case- considered current for a period of 5 years from the
control, prospective/retrospective cohort, case se- date of publication unless reaffirmed, updated, or
ries, etc) and the overall focus of the study (ie, retired before that time.

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FROM THE ACADEMY

Joint American Academy of

CONFLICT OF INTEREST STATEMENT other methods of care reasonably directed toward

Table I. Clinical questions

FDA, Food and Drug Administration.

Table II. Methotrexate supporting information*

d Alcoholic liver disease or other chronic liver diseases

d Bone marrow hypoplasia, leukopenia, thrombocytopenia, or significant anemia

d Abnormalities in liver function

d Persistent abnormal liver function test findings

d History of liver disease including chronic hepatitis B or C

d Family history of inheritable liver disease

d History of exposure to hepatotoxic drugs or chemicals

d Hepatitis B and C (baseline monitoring)

Marlborough, MA], or QuantiFERON Gold [Qiagen, Germantown, MD])

d Additional monitoring recommended for patients with impaired kidney function

B Blood urea nitrogen and creatinine levels

Medications that may increase the risk of methotrexate toxicity

Naproxen Sulfonamides Colchicine

Table III. Strength of recommendation for methotrexate in psoriasis therapy

GI, Gastrointestinal; TNF, tumor necrosis factor; NB-UVB, narrowband ultraviolet B.

Table IV. Level of evidence of methotrexate therapy in psoriasis

ADA, Adalimumab; IFX, infliximab; NB-UVB, narrowband ultraviolet B.

Table V. Supporting statements for methotrexate associated hepatotoxicity*

*Supplemental information is expert consensus and not part of evidence-based recommendations.

Table VI. Supporting statements for apremilast in psoriasis

*Supplemental information is expert consensus and not part of evidence-based recommendations.

Apremilast is metabolized in the liver by CYCLOSPORINE

Table VII. Strength of recommendation for the apremilast in psoriasis therapy

Table VIII. Level of evidence for apremilast in Efficacy

Table IX. Supporting statements for cyclosporine in psoriasis*

when hypertension or decreased renal function are observed

d Abnormal renal function

d Live vaccinations should be avoided

d Caution with major infections and poorly controlled diabetes

d BUN and creatinine

d Consider latent tuberculosis test

d LFTs, CBC, lipid profile, magnesium, uric acid, and potassium

d Pregnancy test if indicated

and then monthly monitoring if no persistent abnormalities are identified

d Pregnancy testing if indicated

d Nausea, vomiting, and diarrhea

d Increased risk of infections

d May increase risk of cancer

Table IX. Cont’d

d St John’s Wort (decreases cyclosporine concentration)

d Cyclosporine may reduce clearance of digoxin, colchicine, prednisolone, and statins

d Potassium-sparing diuretics (may cause hyperkalemia)

d Thiazide diuretics (increased nephrotoxicity)

d Killed and/or recombinant vaccines

d Nonsteroidal anti-inflammatory drugs

appears not to be teratogenic in patients with transplantation.

be orally absorbed by the nursing infant

therapy to the patient.

Table X. Strength of recommendation for cyclosporine therapy in psoriasis

Table XI. Level of evidence for cyclosporine in psoriasis therapy

Cyclosporine for psoriasis flare 3.3 III Expert consensus

Contraindications slow-acting medication that can take 3 to 6 months

Combination treatment Safety

Table XII. Strength of recommendations for acitretin in psoriasis therapy

BB-UVB, Broadband ultraviolet B; PUVA, psoralen plus ultraviolet A.

Table XIII. Level of evidence for acitretin therapy in psoriasis

BB-UVB, Broadband ultraviolet B; PUVA, psoralen plus ultraviolet A.