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Guideline

DOI: 10.1111/ddg.13516

S3 Guideline for the treatment of


psoriasis vulgaris, update – Short
version part 1 – Systemic treatment

Alexander Nast1, Lasse Amelunxen2, Matthias Augustin3,


Wolf- Henning Boehncke4, Corinna Dressler 1, Matthew Gaskins1,
Peter Härle5, Bernd Hoffstadt6, Joachim Klaus7, Joachim Koza7,
Ulrich Mrowietz8, Hans-Michael Ockenfels9, Sandra Philipp10,
Kristian Reich11, Thomas Rosenbach12, Berthold Rzany13,
Martin Schlaeger 14, Gerhard Schmid-Ott15, Michael Sebastian16,
Ralph von Kiedrowski17, Tobias Weberschock18

(1) Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin,


Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Der-
matology, Venereology und Allergy, Division of Evidence-Based Medicine (dEBM)
(2) Fachklinik Bad Bentheim [Bad Bentheim Specialist Hospital]
(3) Universitätsklinikum Hamburg-Eppendorf, Institut für Versorgungsforschung in
der Dermatologie und bei Pflegeberufen [University Hospital Hamburg-Eppendorf,
Institute for Health Care Research in Dermatology and Nursing]
(4) Service de Dermatologie et Vénéréologie, Hôpitaux Universitaires de Genève
[Dermatology and Venereology Service, Geneva University Hospitals]
(5) Katholisches Klinikum Mainz, Zentrum für Rheumatologische Akutdiagnostik,
Klinik für Rheumatologie, Klinische Immunologie und Physikalische Therapie [Catho-
lic Medical Center Mainz, Center for Rheumatological Diagnostics, Department of
Rheumatology, ClinicaI Immunology and Physical Therapy]
(6) Selbsthilfegemeinschaft Haut e. V. [Skin self-help association]
(7) Deutscher Psoriasis Bund e. V. [German Psoriasis Society]
(8) Psoriasis-Zentrum, Klinik für Dermatologie, Venerologie, Allergologie, Univer-
sitätsklinikum Schleswig-Holstein, Campus Kiel [Psoriasis Center, Department of
Dermatology, Venereology and Allergology, University Hospital Schleswig-Holstein,
Kiel campus]
(9) Haut- und Allergieklinik, Klinikum Hanau [Department of Dermatology and Aller-
gology, Hanau Medical Center]
(10) Charité - Universitätsmedizin Berlin, corporate member of Freie Universität
Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department
of Dermatology, Venereology und Allergy, Psoriasisstudienzentrum [Psoriasis Study
Center]
(11) Dermatologikum Hamburg [Dermatologikum Hamburg]
(12) Niedergelassener Dermatologe, Osnabrück [Office-based Dermatologist, Osna-
brück]
(13) Privatpraxis Rzany & Hund, Berlin [Office-based Dermatologists Rzany & Hund,
Berlin]
(14) Niedergelassener Dermatologe, Oldenburg [Office-based Dermatologist, Osna-
brück]
(15) Berolina Klinik, Löhne [Berolina Medical Center, Löhne]
(16) Niedergelassener Dermatologe, Mahlow [Office-based Dermatologist, Mahlow]

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(17) Niedergelassener Dermatologe, Selters [Office-based Dermatologist, Selters]


(18) Klinik für Dermatologie, Venerologie und Allergologie, Universitätsklinikum
Frankfurt, Frankfurt/Main und Arbeitsgruppe EbM Frankfurt, Institut für Allgemein-
medizin, Goethe-Universität Frankfurt, Frankfurt/Main [Department of Dermatolo-
gy, Venereology and Allergology, Frankfurt University Hospital, Frankfurt/Main and
EbM Frankfurt working group, Institute for General Medicine, Goethe University
Frankfurt, Frankfurt/Main]

Summary
The German guideline for the treatment of psoriasis vulgaris was updated using
GRADE methodology. The guideline is based on a systematic literature review com-
pleted on December 1, 2016, and on a formal consensus and approval process. The
fi rst section of this short version of the guideline covers systemic treatment options
considered relevant by the expert panel and approved in Germany at the time of the
consensus conference (acitretin, adalimumab, apremilast, cyclosporine, etanercept,
fumaric acid esters, infl iximab, methotrexate, secukinumab and ustekinumab). De-
tailed information is provided on the management and monitoring of the included
treatment options.

Introduction Evidence search and assessment

This is a short version of the German evidence- and con- The literature search was performed on September 30, 2016,
sensus-based (S3) guideline for the treatment of psoriasis vul- using Embase Ovid (1980 to September 29, 2016), MED-
garis. The long version is available at www.awmf.org. Please LINE Ovid (1946 to the third week of September 2016),
refer to the long version for the following sections: introduc- MEDLINE(R) In-Process & Other Non-Indexed Citations
tion, aims of the guideline, indicators of quality of care, inst- Ovid (September 29, 2016) databases and the Cochrane Cen-
ructions on using the guideline, detailed description of metho- tral Register of Controlled Trials CENTRAL. Autoalerts
dology, defi nition of the severity of psoriasis vulgaris, quality were screened up to December 1, 2016. The evidence was as-
of life, treatment aims, treatment costs, benefit-risk assess- sessed according to the methods recommended by Cochrane,
ment and basic therapy. The sections on biosimilars, climate including GRADE methodology [1].
therapy, psychosocial therapy, topical therapy, phototherapy,
interfaces between different providers and sectors of care, and
references can also be found in the long version. The guideline Passages requiring consensus
is an update, and some sections of the text have been taken The authors of the guideline have defined certain parti-
from the previous version of the guideline from 2011. cularly relevant sections as requiring consensus. These
passages were agreed on in consensus conferences and are
highlighted using gray boxes.
Methods
At their initial meeting, the authors of the guideline agreed on
the main points that required updating. It was decided to in- Treatment recommendation
clude new sections on “Special patient populations” and “Spe-
cial treatment situations” and not to update the sections on to- At present, there is no distinct stepwise procedure or
pical therapy, phototherapy, climate therapy and psychosocial strict clinical algorithm for the treatment of psoriasis vul-
therapy as major changes were not anticipated in the content garis. The criteria for selecting appropriate therapies are
of the recommendations in these areas. However, the import- complex.
ance of these therapies continues unchanged, and the recom- Key recommendations formulated in the text are aug-
mendations are included in the appendix of the long version. mented by symbols representing the strength of the treatment
Phototherapy (PUVA, UV) should be regarded as a separate recommendation. The following symbols were used to stan-
treatment category and is not considered a “systemic therapy”. dardize the treatment recommendations:

© 2018 The Authors | Journal compilation © Blackwell Verlag GmbH, Berlin | JDDG | 1610-0379/2018/1605
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ää is recommended (strongly recommended) Consensus procedure


ä may be recommended (recommended)
Consensus was reached by a nominal group process in a
ã may be considered (neutral recommenda- consensus conference (moderator: Prof. Dr. Berthold Rzany,
tion) MSc, AWMF guideline consultant).
å cannot be recommended (recommendation A detailed description of the methodology used to de-
against its use) velop the guideline and declarations of interest can be found
in the methods report (www.psoriasis-leitlinie.de).

Figure 1 Overview of evaluated treatment options for chronic psoriasis vulgaris (the order is alphabetical and does not indicate
priority).

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Table 1 Quick reference table for assessing systemic treatment options.

Drug Efficacy 1 Quality of evidence Safety/tolerability Safety/tolerability Feasibility Feasibility


(GRADE) PASI 75 vs. of induction of maintenance (patient)* (doctor)*
Placebo therapy* therapy*
Acitretin** 0/+* No comparison + + + ++
available
Adalimumab +++* ⊕⊕⊕{ ++ ++ +++ ++
Apremilast + ⊕⊕⊕{ ++ ++ +++ +++
Cyclosporine +* ⊕⊕{{ + + +++ ++
Etanercept ++* ⊕⊕⊕⊕ ++ ++ +++ ++
Fumarate +* ⊕⊕{{ + ++ ++ ++
Infliximab ++++ ⊕⊕{{ + ++ +++ +/–
Methotrexate + ⊕⊕{{ + ++ +++ ++
Secukinumab ++++ ⊕⊕⊕⊕ ++ ++ +++ ++
Ustekinumab +++ ⊕⊕⊕{ ++ ++ ++++ +++
1
– up to ++++: assessment of efficacy taking into account PASI 75 results (placebo and head-to-head trials) and expert
opinion.
*Expert opinion taken into account.
**For women of childbearing age, treatment with acitretin is generally not recommended.

Updates/validity Acitretin
This is an update of the S3 guideline for the treatment of pso-
Treatment Consensus Comment
riasis vulgaris published in 2011 [2]. Some text passages have
recommendations strength
been included without change. The current version is valid
until December 31, 2020. Acitretin may be con- ã Consensus Evidence- and
sidered for induction consensus-
therapy of moderate based
Therapeutic options and treatment to severe psoriasis
evaluation vulgaris.
Acitretin cannot be å Strong Clinical
Figure 1 provides an overview of evaluated treatment options recommended in consensus consensus point
for chronic psoriasis vulgaris. women of child-bea-
ring age with psoria-
Systemic therapies sis vulgaris.

The “tabular evaluation” provided in Table 1 is intended


to serve as a rough guide for assessing therapeutic options. Acitretin summary table
Cumulative calculations of individual aspects in the overall as- Approval of acitretin 1992 (psoriasis vulgaris)
sessment are not possible and cannot be used for a conclusive in Germany
evaluation of a given treatment option. Each column should Recommended initial Initial dose: 20–30 mg acitretin per
be viewed separately. The evaluation may vary significantly dose day for 2–4 weeks. After the initial
on a case-by-case basis. Assessments are based on a literature phase, the dose can be increased
review and expert opinion. For further explanations, please to a maximum of 75 mg acitretin
refer to the long version. per day in individual cases.

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Recommended Individual dose depends on outco- Table 2 Important adverse reactions associated with acitretin.
maintenance dose me and tolerability. Maintenance
Very common Hypervitaminosis A (e.g., associated with
dose: 25–50 mg per day
xerosis of the skin and mucous membra-
Onset of clinical Insufficient data [3] nes), cheilitis, elevated transaminases and
effect AP, elevated serum levels of triglycerides
Selection of main – Renal and hepatic damage and cholesterol
contraindications – Severe hyperlipidemia Common Conjunctivitis (caution: contact lenses),
– Women of child-bearing age effluvium, photosensitivity
who plan to have children
Occasional Muscle, joint and bone pain
– Pregnancy
– Breast-feeding Rare Gastrointestinal symptoms, hepatitis,
– Use of contact lenses jaundice, bone changes with long-term
therapy
Selection of – Hypervitaminosis A such as chei-
important ADRs litis, xerosis, epistaxis, alopecia, Very rare Pseudotumor cerebri, night blindness
increased skin fragility, elevation
of triglyceride and cholesterol
levels A selection of important ADRs can be found in Table 2 .

Selection of import- Tetracyclines, phenytoin, systemic


Prevention/management of ADRs
ant drug interactions retinoids or high-dose vitamin A,
methotrexate, alcohol, minipill
If adverse reactions occur, the dosage can be adjusted or divi-
Miscellaneous Contraception required until three ded into two doses per day. See also Table 3.
years after discontinuation in wo-
men of child-bearing age
Main contraindications/limitations of use
Dosage and dosing regimen
Absolute contraindications
– Severe renal or hepatic dysfunction
An initial dose of 25 mg (25 mg once a day) or 30 mg aci-
– In women of child-bearing age: pregnancy, breast-fee-
tretin (10 mg three times a day) over a period of two to four
ding, desire to have children or when reliable contracep-
weeks is used in adults. The dose is then adjusted according
tion cannot be adequately ensured up to three years after
to tolerability and individual response. The daily maintenan-
discontinuation of treatment
ce dose is generally between 25 –50 mg and can be increased
to a maximum of 75 mg (25 mg three times a day).
Important relative contraindications
At the optimal dose, patients will develop slightly dry
lips. This can be useful in determining the optimal dose [4]. – Alcohol abuse [5]
– Overt diabetes mellitus
Summary of the evidence – Wearing contact lenses
– Childhood
See long version. – History of pancreatitis
– Use of drugs to control hyperlipidemia
Adverse drug reactions/safety – Concomitant use of tetracyclines or methotrexate

See Summary of Product Characteristics. Drug interactions


Treatment with an effective dose is often associated with
many undesirable effects, most of which are reversible, with the See Summary of Product Characteristics.
exception of hyperostosis. In all studies, the reported adverse – Tetracyclines (tetracycline, doxycycline and minocycline)
drug reactions were dose-dependent. Cheilitis occurs in nearly and acitretin may lead to increased intracranial pressure
100 % of treated patients. Teratogenicity significantly limits (pseudotumor cerebri). They should not be used concomi-
the options for treating women of child-bearing age. High-do- tantly with acitretin.
se therapy with retinoids can cause mood changes, with symp- – When used concomitantly, acitretin can displace phenyto-
toms such as irritability, aggressiveness and depression. in from plasma protein-binding sites.

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Table 3 Prevention of adverse reactions associated with Depending on the clinical situation, fewer or more mea-
acitretin. sures or laboratory tests may be required. They should
be selected for each patient on an individual
Adverse drug Management
basis.
reactions (ADRs)
Pretreatment measures
Dry skin and mu- Use of moisturizing agents (pos- – Rule out alcohol abuse
cous membranes sibly including the nasal mucosa), – Inform the patient about the teratogenic risk and need
artificial tears, avoid wearing cont- for prolonged contraception until three years after the
act lenses conclusion of treatment (verbal and written informed
Diffuse alopecia Inform the patient about the rever- consent with signature)
sible nature of this adverse drug – Inform the patient that blood must not be donated
reaction during treatment and up to three years thereafter.
– Ask about bone and joint pain
Photosensitivity Avoid exposure to sunlight, use
– For laboratory tests, see Table 4
sunscreen
Measures during treatment
Elevation of serum Alcohol abstinence, low-fat and – Long-term treatment (roughly one to two years): if
lipids and/or liver low-carbohydrate diet, lipid-lowe- there are any symptoms, radiographic imaging of the
function tests ring agents (gemfibrozil or atorva- spine and joints is recommended to rule out potential
statin) ossification.
If levels fluctuate: monitor fre- – For women of child-bearing age: effective contracep-
quency and discontinue treatment tion and avoidance of alcohol consumption during
if necessary treatment.
Muscle and bone If symptoms persist: X-ray imaging, – Reminder that blood must not be donated during and
pain NSAIDs, avoid excessive physical until three years after treatment.
activity – For laboratory tests, see Table 4
Generalized edema Discontinue treatment, schedule – Patients with risk factors for cardiovascular disease, e.g.,
(rare) renal function tests hypertension, should be monitored regularly.
Posttreatment measures
– Remind patients that they must not donate blood
until three years after discontinuation of
– Concomitant use of high doses of vitamin A and other sys- treatment.
temic retinoids is not advisable. – Effective contraception* in women of child– bearing
– When used concomitantly with methotrexate, there is an age until three years after treatment.
increased risk of toxic hepatitis. – For women of child-bearing age: avoid alcohol
– The contraceptive effect of the low-dose progesterone pill consumption until two months after discontinuation of
(minipill) may be reduced by concomitant use of acitretin. treatment.
*Double contraception is recommended, e.g., condom +
Notes on use pill; coil/Nuva ring + pill; Caution: avoid low-dose proges-
terone products (minipill), as their effectiveness is reduced
The capsules should preferably be taken during a fatty meal
by acitretin.
or with whole milk. To ensure that the patient is not preg-
nant, treatment should be started on the second or third day
of the menstrual cycle if this has been preceded by reliable
contraception for at least one month. In some patients, acitre-
tin is converted to etretinate, which is facilitated by alcohol Table 4 provides an overview of laboratory tests for acitre-
consumption. Alcohol is therefore prohibited in women of tin therapy recommended by the expert group.
child-bearing age while they are taking the drug and for two
months after discontinuation of treatment. Given that acitre- Overdose/management of overdose/feasibility/
tin may be converted to etretinate, women of child-bearing costs and special considerations
age must continue to use contraception until three years after
discontinuation of treatment. See long version.

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Table 4 Laboratory tests in patients on acitretin.

Point in time ã Diagnostic tests å Before After After After Then every
treatment 4 weeks 8 weeks 12 weeks 3 months
Complete blood count* X X X X X
Liver function tests** X X X X X
Renal function tests*** X X X X X
Triglycerides, cholesterol, HDL**** X X X X X
Pregnancy test (urine) (monthly for X X monthly
3 years after treatment)
Fasting blood glucose***** X X
Depending on the clinical situation, fewer or more measures or laboratory tests may be required. They should be selected
for each patient on an individual basis.
*Complete blood count (Hb, Hct, leukocytes, platelets).
**AST, ALT, AP, GGT.
***Creatinine, urea.
****Preferably measured twice with patient in fasting state (2 weeks before and on the day of treatment initiation).
*****Given that retinoids can affect glucose tolerance in diabetic patients, more frequent glucose measurements are recom-
mended during the initial phase of treatment.

Adalimumab Onset of clinical effect PASI 75 response in 25 % of


patients after 4.6 weeks [3]
Treatment Consensus Comment
Selection of main cont- Active tuberculosis or other
recommendations strength
raindications serious infection, NYHA
Adalimumab is ää Strong Evidence- and class III/IV heart failure
recommended for consensus consensus-
Selection of important Reactions at the injection
induction therapy based
ADRs site, serious infections,
of moderate-to-
hair loss, autoimmune
severe psoriasis
phenomena
vulgaris, especially
Selection of important Anakinra (IL1-R antagonist),
if other forms of
drug interactions abatacept
therapy have failed,
are not tolerated Miscellaneous TNF-alpha antagonist
or are contraindi- Approval for children aged 4
cated. and older

Adalimumab summary table


Dosage and dosing regimen
Approval of adalimumab 2005 (psoriatic arthritis)
in Germany 2007 (psoriasis vulgaris) Adalimumab is administered by subcutaneous injection. Ac-
2015 (psoriasis vulgaris in cording to the dosing regimen, a loading dose of 80 mg is
children aged 4 and older) given at the beginning of treatment, 40 mg one week later,
and then 40 mg every other week. The dose is not adjusted
Recommended initial dose 80 mg subcutaneously
for obese patients (> 100 kg).
Recommended 40 mg subcutaneously every If the response is insufficient after 16 weeks of treat-
maintenance dose 2 weeks, starting 1 week after ment, the dose can be increased to 40 mg every week. If there
the induction dose; if there is is no improvement on the increased dose after another eight
an inadequate response after weeks, treatment should be discontinued. If an adequate res-
16 weeks, 40 mg can be given ponse is achieved, the dose should be reduced to 40 mg every
subcutaneously every week other week.

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Summary of the evidence Important relative contraindications


– Severe liver disease
See long version.
– Demyelinating diseases
– Malignant tumors (except for basal cell carcinoma) and
Adverse drug reactions/safety lymphoproliferative disorders or a history thereof
– Vaccination with live vaccines
See Summary of Product Characteristics.
– Pregnancy/breast-feeding
In placebo-controlled studies, reactions at the injec-
tion site were the most commonly reported adverse event Drug interactions
(adalimumab: 20 % of patients; placebo: 14 % of patients).
Combined use of adalimumab and anakinra (IL1-R antago-
A burning sensation that can occur during injection was
nist) or abatacept is not recommended.
reduced by altering the excipients, including not using
citrate. Notes on use
Adalimumab therapy is associated with an increased
rate of infections. Rarely reported hematological effects
Depending on the clinical situation, fewer or more mea-
include thrombocytopenia and leukopenia. Rare severe al-
sures or laboratory tests may be required. They should
lergic reactions include rash, urticaria, pruritus, dyspnea,
be selected for each patient on an individual basis.
chest tightness, as well as swelling of the mouth, face, lips
Pretreatment measures
or tongue.
– Rule out acute infection
Treatment with adalimumab may be associated with the
– Tuberculosis must be definitively ruled out. See long
induction of autoantibodies (ANA, anti-dsDNA antibodies)
version, section on “Tuberculosis”
and the onset of a lupus-like syndrome. In such cases, treat-
– Contraception must be ensured, and pregnancy ruled
ment should be discontinued immediately.
out in women of child-bearing age
Malignant tumors can occur very rarely.
– Patients should be informed that any infection may run
Anti-drug antibodies (ADA) may develop during treat-
an atypical and more severe clinical course and that
ment with adalimumab, which may be associated with a loss
they should seek medical attention as early as possible
of effectiveness (secondary treatment failure).
if an infection is suspected.
Adverse events are more common in older patients on ada-
Measures during treatment
limumab. Infections, in particular, take a more severe course.
– Monitoring for infection; if infection is suspected, tre-
atment should be discontinued, at least temporarily.
Main contraindications/limitations of use Posttreatment measures
– None
Absolute contraindications
– NYHA class III–IV heart failure Table 5 provides an overview of the laboratory tests for adali-
– Active tuberculosis or other serious infections mumab therapy recommended by the expert group.

Table 5 Laboratory tests in patients on adalimumab.

Point in time ã Diagnostic Before treatment After 4 weeks After 12 weeks Then every 3
tests å months
CBC with differential X X X X
AST, ALT, GGT X X X X
Hepatitis B serology X
HIV and hepatitis C serology* X
Pregnancy test (urine) X
If infection is suspected, see pretreatment measures
According to the Summary of Product Characteristics, no laboratory tests are currently suggested during treatment with
adalimumab. The guideline authors recommend the tests listed above. Depending on the clinical situation, fewer or more
measures or laboratory tests may be required. They should be selected for each patient on an individual basis.
*As indicated by patient history, clinical signs or other laboratory test results.

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Overdose/management of overdose/feasibility/ If renal function is severely impaired, the recommended


costs and special considerations dose is 30 mg once a day in the morning.

See long version. Summary of the evidence

Apremilast See long version.

Treatment recommendations Consensus Comment Adverse drug reactions/safety


strength
See long version and Summary of Product Characteristics.
Apremilast may be recom- ä Strong Evidence-
Among the adverse drug reactions, diarrhea in particu-
mended for induction consensus and con-
lar is of significant practical relevance. Just under one-fi fth
therapy of moderate to sensus-ba-
of patients develop diarrhea, usually in the fi rst week during
severe psoriasis vulgaris, sed
dose escalation. Clinical symptoms are frequently rather
especially if other forms of
mild, with several thin bowel movements per day. If approp-
therapy have failed, are not
riately informed, the majority of patients do not deviate from
tolerated or are contrain-
the planned dosing regimen. The diarrhea symptoms usually
dicated.
cease spontaneously within the fi rst month of treatment. In
cases associated with more severe diarrhea, use of loperami-
Apremilast summary table
de has been shown to be effective.
Approval of apremilast in 2015 (moderate to severe Some patients (approximately 15 %) experience signifi-
Germany psoriasis vulgaris and pso- cant weight loss (5–10 %) within the fi rst months of apremi-
riatic arthritis) last therapy. However, this phenomenon is not a contraindi-
Recommended initial dose 10 mg per day according cation for continuing treatment with apremilast.
to the dosing regimen be- There have been occasional reports of suicidal ideati-
low this table on and behavior (with or without a history of depression)
Recommended maintenance 60 mg per day (30 mg both in clinical studies and following market introduction
dose twice a day) according to (frequency ≥ 1/1,000 to ≤ 1/100). Cases of completed suicide
the dosing regimen (see in patients treated with apremilast have been reported follo-
long version) wing market introduction.

Onset of clinical effect PASI 75 response in


25 % of patients after Main contraindications/limitations of use
10.9 weeks with 30 mg
twice a day [6]
Absolute contraindications
Selection of main contraindi- – Pregnancy and – Pregnancy and breast-feeding
cations breast-feeding
Selection of important ADRs – Diarrhea
Important relative contraindications
– Nausea
– Suicidal ideation
– For patients with a history of psychiatric symptoms or pa-
Selection of important drug Strong inducers of CYP3A4 tients taking medications likely to cause psychiatric symp-
interactions (rifampicin, phenobarbital, toms, the benefits of apremilast treatment should be care-
carbamazepine, phenytoin fully weighed against the risks.
and St. John’s wort) may – Underweight patients
cause faster metabolism of – Children and adolescents
apremilast
Miscellaneous PDE-4 inhibitor Drug interactions

Patients should not take apremilast if they are taking strong


Dosage and dosing regimen
inducers of CYP3A4 (e.g., rifampicin, phenytoin, carbama-
The dose of apremilast is increased to 60 mg according to the zepine, phenytoin and St. John’s wort) as this leads to a rele-
dosing regimen (see long version). vant decrease in apremilast levels.

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Notes on use Table 6 provides an overview of the laboratory tests for


apremilast therapy recommended by the expert group.
Depending on the clinical situation, fewer or more mea-
Feasibility and costs
sures or laboratory tests may be required. They should be
selected for each patient on an individual basis.
See long version.

Pretreatment measures
– For laboratory tests see Table 6 Cyclosporine
– Rule out pregnancy and initiate contraception in women
of child-bearing age. Treatment recommendations Consensus Comment
– For patients with a history of psychiatric symptoms or strength
patients taking medications likely to cause psychiatric
Cyclosporine may be ä Strong Evidence-
symptoms, the benefits of apremilast treatment should
recommended for consensus and con-
be carefully weighed against the risks.
induction therapy of mo- sensus-
– Measure body weight
derate to severe psoriasis based
Measures during treatment
vulgaris.
– Interruption of treatment if the patient becomes pregnant
A combination of ä Strong Evidence-
– Discontinuation of treatment if there are new-onset psy-
cyclosporine and topical consensus and con-
chiatric symptoms or exacerbation of existing symptoms
preparations to treat sensus-ba-
or suicidal ideation or attempted suicide
moderate to severe sed
– Contraception
psoriasis vulgaris may be
– Weight should be monitored in underweight patients
recommended.
(BMI < 18.5 kg/m2)
– For laboratory tests see Table 6
Posttreatment measures
Cyclosporine summary table
– None
Approval of cyclosporine 1983 (transplantation
Table 6 Laboratory tests in patients on apremilast. in Germany medicine)
1993 (psoriasis vulgaris)
Point in time ã Before Every 3 Recommended initial 2.5–3 (max. 5) mg/kg body
Diagnostic tests å treatment months dose weight
CBC with differential X X Recommended main- Intermittent therapy
ALT, AST, GGT * X X tenance dose (each cycle 8–16 weeks)
with a dose reduction at
Serum creatinine* X X
the end of induction
Pregnancy test (urine) X therapy (e.g., 0.5 mg/kg body
According to the Summary of Product Characteristics, no weight every 14 days) or
laboratory tests are currently suggested during treatment continuous long-term
with apremilast. The guideline authors recommend the therapy with dose reducti-
tests listed above. Depending on the clinical situation, on, e.g., by 50 mg every 4
fewer or more measures or laboratory tests may be re- weeks after week 12 and dose
quired. They should be selected for each patient on an increase by 50 mg in case of
individual basis. recurrence
*Tests recommended due to need for dose adjustment in Onset of clinical effect PASI 75 response in 25 %
the case of renal failure as well as lack of experience in pati- of patients after 6 weeks
ents with impaired hepatic function. (<5 mg/kg body weight) [ 3]

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Selection of main Absolute: Miscellaneous – Calcineurin inhibitors


contraindications – In transplant patients,
– Relevant renal impairment
increased risk of lympho-
– Uncontrolled arterial hyper-
proliferative disorders
tension
– In psoriasis patients, exces-
– Active tuberculosis or other
sive phototherapy can lead
serious infection
to increased risk of squa-
– Relevant malignancy
mous cell carcinoma
(current or past, especially
– Only moderately effective
hematological disorders
for psoriatic arthritis and
and cutaneous malignan-
not approved
cies, except for basal cell
– Has also been successfully
carcinoma)
used in children with chro-
Relative: nic inflammatory diseases

– Relevant hepatic impair-


ment Dosage and dosing regimen
– Pregnancy and breast- A standard dose for treatment initiation is 2.5–3 mg/kg body
feeding weight. If there is an inadequate response to the initial dose
– Concomitant use of sub- of 2.5–3 mg/kg body weight after four to six weeks, the dose
stances that interact with may be increased to a maximum of 5 mg/kg body weight.
cyclosporine For other dosing regimens, please see the long version.
– Simultaneous phototherapy
or previous PUVA therapy Summary of the evidence
with a cumulative dose See long version.
> 1,000 J/cm²
– Concomitant use of other Adverse drug reactions/safety
immunosuppressants, reti- See long version and Summary of Product Characteristics.
noids or previous long-term The included studies, most of which investigated short-
therapy with methotrexate term treatment (induction therapy), reported various adver-
(MTX) se effects on cyclosporine therapy. Whenever various doses
Selection of important – Renal impairment were studied, the rate of adverse effects was usually clearly
ADRs – Increase in blood pressure dose-dependent [7 ].
– Hepatic impairment The most commonly reported adverse effects included:
– Nausea
Kidneys/blood pressure
– Loss of appetite
– Vomiting – Increase in serum creatinine (by 5–30 % on average, and
– Diarrhea by > 30 % in up to 20 % of patients)
– Hypertrichosis – Drop in creatinine clearance (up to 20 % on average)
– Gingival hyperplasia – Increased urea (in up to 50 % of patients)
– Tremor – Decrease in magnesium levels (by 5–15 % on average)
– Fatigue – Increased uric acid (in about 5 % of patients)
– Paresthesia – Arterial hypertension (in about 2–15 % of patients)
Selection of important The possibility of multiple Liver/gastrointestinal tract
drug interactions interactions should be
considered (see long version) – Gastrointestinal symptoms (nausea, diarrhea, flatulence,
and others, in about 10–30 % of patients)

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– Increase in bilirubin (in about 10–80 % of patients) Notes on use


– Increase in transglutaminases (up to 30 % of patients)
– Gingival hyperplasia (up to 15 % of patients) Depending on the clinical situation, fewer or more mea-
sures or laboratory tests may be required. They should be
Other selected for each patient on an individual basis.
– Paresthesia (up to 40 % of patients) Pretreatment measures
– Muscle pain (in about 10–40 % of patients) General measures
– Headache (in10–30 % of patients) – Patient history including past and current comorbidities
– Tremor (in about 2–20 % of patients) (e.g., severe infections, malignancy, kidney and liver di-
– Hypertrichosis (in < 5 % of patients) sease), concomitant medication (see drug interactions)
Specific measures
Main contraindications/limitations of use – If there is a corresponding history or clinical or laboratory
signs, HIV infection and hepatitis C should be ruled out.
Absolute contraindications – Rule out hepatitis B
– Relevant renal impairment – Screening for potentially malignant skin lesions
– Inadequately controlled hypertension – Signs of existing infection
– Active tuberculosis or other serious infection – Measure blood pressure at two different points in time
– Past or current malignancy (possible exception: adequa- Patient education
tely treated basal cell carcinoma, squamous cell carcino- – Patients should be informed that any infection may run
ma in situ) an atypical and more severe clinical course and that they
should seek medical attention as early as possible if an
infection is suspected.
Important relative contraindications – Drug interactions (also inform other treating physicians
about the treatment)
– Ensure reliable contraception and rule out pregnancy in
– Prior potentially carcinogenic therapies (e.g., arsenic,
women of child-bearing age (Caution: decreased efficacy
PUVA > 1,000 J/cm 2)
of progesterone-based contraceptives)
– Infection- or drug-induced psoriasis (e.g., beta-blockers,
– Avoid excessive exposure to sunlight, especially with
lithium, antimalarial drugs) long-term use; use of sunscreen
– Relevant liver disease
Measures during treatment
– Hyperuricemia Interview/examination
– Hyperkalemia
– Status of skin and mucous membranes (e.g., increased
– Concomitant treatment with nephrotoxic drugs (see drug body hair, gingival hyperplasia, rule out skin cancer)
interactions) – Signs of existing infection
– Concomitant phototherapy (SUP, PUVA) – Gastrointestinal symptoms and neurological symptoms
– Concomitant use of other immunosuppressants (except for – Repeat recommendation with respect to UV protection
topical therapy) – Check co-medication
– Concomitant use of retinoids or treatment with retinoids in – Measure blood pressure
the last four weeks before planned initiation of cyclosporine – With uncomplicated low-dose long-term therapy
– Drug or alcohol abuse (2.5–3 mg/kg body weight daily), follow-up intervals may
subsequently be extended to three months.
– Prior long-term methotrexate (MTX) therapy
– Shorter intervals are required, for example, in patients with
– Pregnancy
risk factors, in case of a dose increase, and with use of drugs
– Breast-feeding
that may affect metabolism or cause drug interactions
– Vaccination with live vaccines – Measure creatinine clearance if plasma creatinine levels
– Epilepsy appear abnormal
– Current treatment with castor oil-based preparations – In select patients on intermittent or short-term treat-
ment, less frequent follow-up may suffice (e.g., regular
Drug interactions measurement of blood pressure and creatinine levels)
The availability of cyclosporine depends especially on the ac- – Measurement of cyclosporine levels may occasionally be
tivity of the hepatic enzyme cytochrome P450-3A4 (CYP3A4) advisable, especially if non-compliance or toxicity due to
and on intestinal P-glycoprotein. There is a large number of drug interactions are suspected
drug interactions. Posttreatment measures
Please refer to the long version for details. – None

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Table 7 Laboratory tests in patients on cyclosporine.

Point in time ã Before After After After Then every 3


Diagnostic tests å treatment 4 weeks 8 weeks 12 weeks months
Complete blood count* X X X X X
Liver function tests** X X X X X
Electrolytes*** X X X X X
Serum creatinine X X X X X
Uric acid X X X
Pregnancy test (urine) X
Cholesterol, triglycerides****
Magnesium*****
Depending on the clinical situation, fewer or more measures or laboratory tests may be required. They should be selected
for each patient on an individual basis.
*Erythrocytes, leukocytes, platelets; differential blood count only if clinically indicated.
** Transaminases, GGT, bilirubin.
***Sodium, potassium.
****Only if clinically indicated.
*****Only if indicated (e. g., muscle cramps).

Table 7 provides an overview of the laboratory tests for Recommended initial 25 mg twice, 50 mg once, or
cyclosporine therapy recommended by the expert group. dose 50 mg twice per week
Overdose/management of overdose Recommended main- 25 mg twice per week, 50 mg
See long version. tenance dose once per week
Onset of clinical effect PASI 75 response in 25 % of pa-
Feasibility and costs
tients after 6.6 weeks (50 mg
See long version.
twice) or 9.5 weeks (50 mg
once/25 mg twice) [3]
Etanercept
Selection of main con- NYHA class III–IV heart failure,
Treatment Consensus Comment traindications active tuberculosis or other seri-
recommendations strength ous infection

Etanercept at a dose ä Consensus Evidence- Selection of important Local reaction, infections


of 50 mg (once) may and con- ADRs
be recommended for sensus- Selection of important Anakinra (IL1-R antagonist), aba-
induction therapy of based drug interactions tacept (co-stimulation inhibitor)
moderate to severe pso- Miscellaneous Tumor necrosis factor receptor
riasis vulgaris, especially fusion protein
if other forms of therapy Approval for children aged 6
have failed, are not tole- and older
rated or are contraindi-
cated.
Dosage and dosing regimen
The etanercept dose approved for the treatment of psoria-
Etanercept summary table sis vulgaris in adults is 25 mg twice a week or alternatively
Approval of eta- 2002 (psoriatic arthritis) 50 mg once a week. If the psoriasis is highly active or in over-
nercept in Germany 2004 (psoriasis vulgaris) weight patients, 50 mg twice a week can initially be given for
2008 (psoriasis vulgaris in children) up to twelve weeks, followed by a dose of 25 mg twice a week
or 50 mg once a week.

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Summary of the evidence Drug interactions


Combined use of etanercept and anakinra (IL1-R antagonist)
See long version. or abatacept is not recommended.

Adverse drug reactions/safety Notes on use

Depending on the clinical situation, fewer or more mea-


See Summary of Product Characteristics. sures or laboratory tests may be required. They should be
The most commonly reported adverse drug reactions are selected for each patient on an individual basis.
local injection site reactions. The risk of serious infections is in-
Pretreatment measures
creased on anti-TNFα therapy. The incidence of malignancy in
General measures
patients given etanercept versus a comparison group was similar
to the rates and incidence expected for the study population. – Rule out acute infection
The number of patients on anti-TNFα therapy who developed – Tuberculosis must be definitively ruled out. See long ver-
lymphoma was slightly higher than in the control group. Adver- sion, section on “Tuberculosis”
se hematological effects, demyelinating diseases and autoimmu- Specific measures
ne disorders are class effects of TNF blockers and have occurred – Ensure reliable contraception and rule out pregnancy in
with etanercept as well as with other TNFα inhibitors. women of child-bearing age
Because of the pharmacokinetics of etanercept, no dose – Patients should be informed that any infection may run
adjustment is required in patients with impaired renal and an atypical and more severe clinical course and that they
hepatic function. No elevated etanercept levels were found should seek medical attention as early as possible if an
in patients on etanercept therapy with acute renal or liver infection is suspected.
failure. Etanercept should be used with caution in patients Measures during treatment
with moderate to severe alcoholic hepatitis.
– Monitor for infection; if infection is suspected, treatment
Main contraindications/limitations of use should be interrupted, at least temporarily.
– Discontinue treatment if the patient becomes pregnant
Absolute contraindications Posttreatment measures
– NYHA class III–IV heart failure
– None
– Active tuberculosis or other serious infections

Important relative contraindications Table 8 provides an overview of the laboratory tests for
etanercept therapy recommended by the expert group.
– Demyelinating diseases
– Malignancy (except for basal cell carcinoma) and lympho-
Overdose/management of overdose
proliferative disorders or a history thereof No dose-limiting toxicity was observed in clinical studies of
– Pregnancy and breast-feeding patients with rheumatoid arthritis [8]. There is no known
– Vaccination with live vaccines antidote to etanercept.

Table 8 Laboratory tests in patients on etanercept.

Point in time → Diagnostic tests ↓ Before treatment Week 4 Week 12 Every 3 months
CBC with differential X X X X
AST, ALT, GGT X X X X
Hepatitis B serology X
HIV and hepatitis C serology* X
Pregnancy test (urine) X
If infection is suspected, see pretreatment measures
According to the Summary of Product Characteristics, no laboratory tests are currently suggested during treatment with
etanercept. The guideline authors recommend the tests listed above. Depending on the clinical situation, fewer or more
measures or laboratory tests may be required. They should be selected for each patient on an individual basis.
*As indicated by patient history, clinical signs or other laboratory test results.

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Feasibility and costs ters need between two and four Fumaderm® tablets per day.
The dose is increased until an adequate clinical response is
See long version. obtained. The individual maintenance dose is subsequently
established by gradual dose reduction.
Fumaric acid esters Fumaric acid ester treatment may be discontinued ab-
ruptly without any rebound effects or pustular flare-ups.
Treatment recommendations Consensus Comment Fumaderm® contains a mixture of fumaric acid esters,
strength the main ingredient being dimethyl fumarate.
Treatment with fumaric ↑ Strong Evidence-
acid esters may be recom- consensus and con- Summary of the evidence
mended for induction the- sensus-
rapy of moderate to severe based See long version.
psoriasis vulgaris.
Adverse drug reactions/safety
Fumaric acid esters summary table See long version and Summary of Product Characteristics.
Approval of fumaric 1994 (psoriasis vulgaris, modera- Gastrointestinal complaints (in up to 60 % of patients,
acid esters in Germany te to severe) especially in the fi rst weeks of treatment) and flushing are the
Recommended initial According to recommended do-
most common adverse effects associated with fumaric acid
dose sing regimen
ester therapy. Gastrointestinal tolerability can be improved
by taking the tablets with milk. Acetylsalicylic acid at a dose
Recommended main- Individual dose adjustment
of 500 mg may help at the fi rst signs of flushing.
tenance dose
Leukopenia, lymphopenia and eosinophilia are fre-
Onset of clinical effect Insufficient data [3]
quently observed during treatment with fumaric acid esters.
Selection of main con- – Severe gastrointestinal disea- The dose must be halved if the lymphocyte count falls below
traindications ses such as gastric and duo- 700/μ L. If there is no rebound of the lymphocyte count af-
denal ulcers ter four weeks, fumaric acid ester therapy must be discon-
– Severe liver or kidney disease tinued. A drop in lymphocytes below 500/μ L requires im-
Selection of important – Gastrointestinal symptoms mediate discontinuation of treatment. Patients who develop
ADRs – Flushing lymphopenia should be monitored for signs and symptoms
– Lymphopenia of opportunistic infections, especially neurological deficits
– Eosinophilia and cognitive or psychiatric symptoms, which may indicate
Selection of important Methotrexate, retinoids, psoralens, progressive multifocal leukoencephalopathy (PML). The in-
drug interactions cyclosporine, immunosuppres- crease in eosinophils is always transient and usually occurs
sants, cytostatic agents and drugs between weeks four and ten.
with a known harmful effect on
the kidneys must not be used con- Table 9 Dosing regimen for treatment with fumaric acid
comitantly with fumaric acid esters esters.
Miscellaneous –
Fumaderm® initial Fumaderm®
Week 1 0-0-1
Dosage and dosing regimen
Week 2 1-0-1

The standard clinical procedure consists of slow dose escala- Week 3 1-1-1
tion according to an established dosing regimen (Table 9). Week 4 1-0-0
The gradual dose increase is intended to improve tolerability,
Week 5 1-0-1
especially with regard to gastrointestinal symptoms.
The dose must be adjusted individually depending on the Week 6 1-1-1
response to treatment and occurrence of adverse effects. The Week 7 2-1-1
recommended maximum dose is 1.2 g per day = six Fuma-
Week 8 2-1-2
derm® tablets; however, effective treatment does not always
require this dose. Most patients treated with fumaric acid es- Week 9 2-2-2

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Renal impairment (proteinuria) is occasionally observed Table 10 Laboratory tests in patients on fumaric acid esters.
and is generally thought to resolve following dose reducti-
on or discontinuation of the drug. Secondary osteomalacia Point in time → Before Every 4 Every 8
(Fanconi syndrome) is a very rare complication that requires Diagnostic tests ↓ treat- weeks weeks
cessation of fumaric acid ester therapy. ment from
Dose adjustment is not required in elderly patients or in- month 4
dividuals with impaired liver function as fumarates are not Complete blood count* X X X**
primarily metabolized through the liver.
Liver function tests*** X X X
Prevention/management of ADRs Serum creatinine X X X
If adverse drug reactions occur, the dose should initially be re- Urinalysis**** X X X
duced; persistent reactions require treatment discontinuation. Depending on the clinical situation, fewer or more mea-
sures or laboratory tests may be required. They should be
Main contraindications/limitations of use selected for each patient on an individual basis.
*Erythrocytes, leukocytes, platelets, CBC with differential
Absolute contraindications **The current Summary of Product Characteristics requi-
– Severe hepatic or renal impairment res a CBC with lymphocyte count on a monthly basis; the
– Severe gastrointestinal disease guideline authors consider 8-week intervals to be suffi-
cient and do not believe that patient safety is improved
Important relative contraindications with more frequent monitoring.
***Transaminase, GGT.
– Pregnancy and breast-feeding
****If repeatedly positive for protein or glucose, Fanconi
– Comedication with MTX, retinoids, psoralens, cyclospori-
syndrome should be ruled out.
ne, immunosuppressants, cytostatic agents and drugs with
a known deleterious effect on the kidneys

Drug interactions Infliximab


Fumaric acid esters can impair renal function. Concomitant Treatment Consensus Comment
use of nephrotoxic substances may therefore be associated recommendations strength
with increased toxicity. The Summary of Product Characte-
Infliximab is recommen- ↑↑ Majority Evidence-
ristics warns about an interaction with nephrotoxic drugs.
ded for induction therapy agreement and
Notes on use of moderate to severe consensus-
psoriasis vulgaris, if other based
Depending on the clinical situation, fewer or more mea- forms of therapy have fai-
sures or laboratory tests may be required. They should be led, are not tolerated or
selected for each patient on an individual basis. are contraindicated.
Pretreatment measures
– For laboratory tests see Table 10 Infliximab summary table
Measures during treatment
Approval of infliximab in 2004 (psoriatic arthritis)/
– For laboratory tests see Table 10
Germany 2005 (psoriasis vulgaris)
Posttreatment measures
– None Recommended initial dose 5 mg/kg body weight (infusi-
ons on day zero and in week
Table 10 provides an overview of the laboratory tests for two and week six)
fumaric acid ester therapy recommended by the expert group.
Recommended main- 5 mg/kg body weight (main-
tenance dose tenance therapy: every 8
Feasibility and costs weeks)
Onset of clinical effect PASI 75 response in 25 % of
See long version.
patients after 3.5 weeks [3]

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Selection of main cont- NYHA class III–IV heart ring with emergency equipment readily available is required
raindications failure, active tuberculosis during and for an hour after the infusion. Serum sickness can
or other serious infection, develop three to twelve days thereafter.
known hypersensitivity to Re-initiation of the drug after a prolonged treatment-free
mouse proteins interval may cause arthralgia, myalgia, angioedema and
Selection of important Infusion reactions, severe other acute reactions.
ADRs infections, autoimmune phe- Moderate infusion reactions can be mitigated or even
nomena prevented by prior administration of an antihistamine [9].
Production of infl iximab antibodies can be reduced by use of
Selection of important Anakinra (IL1-R antagonist) or
low-dose MTX (5–10 mg/week) [10, 11].
drug interactions abatacept
Miscellaneous – TNF-alpha antagonist Infections
– Not approved for use in
Infl iximab therapy has been associated with severe infec-
children with psoriasis
tions including sepsis, sometimes even fatal. Patients with
obvious, clinically relevant infections should therefore not
Dosage and dosing regimen be treated with infl iximab. There have also been rare cases
of opportunistic infections, including listeriosis, histoplas-
The dose required for treatment of psoriasis vulgaris depends mosis, cryptococcosis and Pneumocystis carinii pneumo-
on the patient’s body weight. It consists of a single dose of nia. Reactivation and subsequent generalization of preexis-
5 mg/kg body weight at week zero, week two and week six, ting latent tuberculosis has been reported in patients on
and then regularly every eight weeks. infl iximab therapy.
Prolonged intervals between infusions increase the like-
lihood of infl iximab antibodies being formed. Infl iximab is Cardiac effects
administered by intravenous infusion, delivered over a period
of two hours. If there are no infusion reactions, the time can Infl iximab has been associated with exacerbation of preexis-
be shortened to one hour. During the infusion and for one ting heart failure. Infl iximab must therefore not be used in
hour thereafter, the patient must be monitored with emer- patients with NYHA class III–IV heart failure.
gency equipment readily available in case that there is an in-
fusion reaction. Demyelinating diseases

Summary of the evidence As with other TNF- α blockers, isolated cases of demyeli-
nating diseases of the central nervous system have occurred
See long version. in association with infl iximab. Given that multiple sclerosis
may be exacerbated by infl iximab, patients with multiple sc-
Adverse drug reactions / safety lerosis should therefore receive infl iximab therapy only after
carefully weighing risks and benefits.
See Summary of Product Characteristics.
There is a large body of data on the safety of infl iximab Hepatotoxicity
in patients with chronic inflammatory bowel disease and ar-
thritis. While these safety data can generally be extrapolated There have been isolated reports of severe liver damage
to psoriasis vulgaris, prior treatment of psoriasis patients on infl iximab treatment, including fatal liver failure. The-
(UVB, PUVA) may lead to as yet unidentified adverse drug se were associated with hepatitis B infection and occurred
reactions or risks that must be taken into account. within two weeks until more than a year after treatment
initiation. In psoriasis patients, there have only been reports
Infusion reactions of increases in transaminase levels but not of severe liver
damage. Infl iximab should be discontinued if jaundice oc-
Acute infusion reactions are common. These are usually curs or if there is a significant deterioration of liver function
mild and include chills, headache, flushing, nausea, dyspnea tests.
or infi ltration at the infusion site. The likelihood of an in-
Hematological changes
fusion reaction is increased in patients with anti-infl iximab
antibodies. However, anaphylactoid reactions may also occur Leukopenia, neutropenia, thrombocytopenia and pancytope-
irrespective of anti-infl iximab antibodies. Patient monito- nia, some with fatal outcome, have been reported in patients

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with rheumatoid arthritis or Crohn’s disease who were on – Live vaccines


infl iximab. If the blood count is abnormal, patients should be – Autoimmune diseases
clinically monitored, and infl iximab should be discontinued, – Demyelinating diseases
if necessary. – Pregnancy and breast-feeding
The number of cases of lymphoma in patients treated
with anti-TNF- α antibodies was slightly higher than in the Drug interactions
control group. The risk of other malignancies was not increa- Combined use of infl iximab and anakinra (IL1-R antagonist)
sed relative to the risk in the control group. It is not known or abatacept is not recommended.
whether exposure to infl iximab can increase the incidence of
these diseases. Notes on use

Lupus erythematosus-like syndrome Depending on the clinical situation, fewer or more mea-
sures or laboratory tests may be required. They should be
Treatment with infl iximab may be associated with the induc- selected for each patient on an individual basis.
tion of autoantibodies (ANA, anti-dsDNA antibodies) and
Pretreatment measures
the onset of a lupus-like syndrome. In such cases, treatment
should be discontinued immediately. – Rule out acute infection
– Tuberculosis must be definitively ruled out. See long
Prevention/management of ADRs version, section on “Tuberculosis”
When administering the drug, standard emergency equip- – Ensure reliable contraception and rule out pregnancy in
ment should be readily available. women of child-bearing age
If a severe infection occurs, it is important to bear in – Patients should be informed that any infection may run
mind that – given the long time (six months) required for an atypical and more severe clinical course and that
complete elimination – the immunosuppressant effect of in- they should seek medical attention as early as possible
fl iximab can last several weeks after the last dose. Simulta- if an infection is suspected.
neous administration of methotrexate can reduce the forma- Measures during treatment
tion of anti-infl iximab antibodies [10, 11]. – Monitor up to an hour after the infusion
– Monitor for infection; if infection is suspected, treat-
Main contraindications/limitations of use ment should be interrupted, at least temporarily.
Absolute contraindications Posttreatment measures
– NYHA class III–IV heart failure – None
– Known hypersensitivity to mouse proteins
– Active tuberculosis or other serious infections
Table 11 provides an overview of the laboratory tests for
infl iximab therapy recommended by the expert group.
Important relative contraindications Overdose/management of overdose
– Malignancy (except for basal cell carcinoma) and lympho- Single doses of up to 20 mg/kg body weight were tolera-
proliferative disorders, including a history thereof ted without any direct toxic effect. In the case of overdose,

Table 11 Laboratory tests in patients on infliximab.

Point in time → Diagnostic tests ↓ Before treatment Before every further infusion
CBC with differential X X
AST, ALT, GGT X X
Hepatitis B serology X
HIV and hepatitis C serology* X
Pregnancy test (urine) X
If infection is suspected, see pretreatment measures
According to the Summary of Product Characteristics, no laboratory tests are currently suggested during treatment with
infliximab. The guideline authors recommend the tests listed above. Depending on the clinical situation, fewer or more
measures or laboratory tests may be required. They should be selected for each patient on an individual basis.
*As indicated by patient history, clinical signs or other laboratory test results.

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the patient should be monitored closely and should receive Table 12 Important adverse reactions associated with
prompt adequate symptomatic treatment. methotrexate.

Very common
Feasibility and costs
Common Nausea, fatigue, vomiting, ele-
See long version. vated transaminases, hair loss
(reversible)

Methotrexate Occasional Fever, headache, depression,


infection
Treatment Consensus Comment Rare Bone marrow suppression with
recommendations strength leukopenia, thrombocytopenia,
Methotrexate may ↑ Strong con- Evidence- and agranulocytosis, pancytopenia,
be recommended for sensus consensus- liver fibrosis and liver cirrhosis,
induction therapy of based gastrointestinal ulcers, nephro-
moderate to severe toxicity
psoriasis vulgaris. Very rare Interstitial pneumonia, alveolitis

Methotrexate summary table


Approval of methotrexate 1991 (psoriasis vulgaris) Summary of the evidence
in Germany; many diffe- 1992 (psoriasis vulgaris)
rent suppliers; tablets or 2004 (psoriasis vulgaris) See long version.
solution for injection
Adverse drug reactions/safety
Recommended initial dose 15 mg per week
See Table 12 , the long version and the Summary of Product
Recommended maintenan- 5–20 mg per week depen-
Characteristics.
ce dose ding on the effect
Methotrexate may increase the risk of liver fibrosis and
Onset of clinical effect PASI 75 response in 25 % cirrhosis. Risk factors include obesity and diabetes mellitus.
of patients after 3.2 weeks Measurement of serum levels of the amino-terminal propeptide
(≥15 mg) and 9.9 weeks of type III procollagen (PIIINP) before and during methotrexa-
(< 15 mg) [3] te therapy may help detect incipient liver damage. Ultrasound
Selection of main contrain- Hepatic impairment, preg- is likewise suitable for detecting methotrexate-induced hepato-
dications nancy, preexisting tuberculo- pathy. Myelosuppression, acute pneumonitis or alveolitis and
sis or other serious infections pulmonary fibrosis can lead to death. Myelosuppression has
Selection of important Hepatic fibrosis/cirrhosis, been repeatedly reported, especially in patients with renal fai-
ADRs pneumonia/alveolitis, bone lure. Acute pneumonitis and alveolitis are very rare.
marrow depression, kidney
damage, infections Management of adverse drug reactions
Selection of important Multiple drug interactions
drug interactions (see text) Indications for interrupting treatment include elevated tran-
Miscellaneous Dihydrofolate reductase
saminases (more than three times the upper normal limit),
inhibitor
anemia, decrease in white blood cell or platelet counts in
peripheral blood, increased creatinine levels, acute dyspnea,
cough and severe infections.
Dosage and dosing regimen
A drop in white blood cell and platelet levels usually oc-
For the treatment of psoriasis vulgaris, methotrexate is admi- curs seven to ten days after the last dose. Treatment must be
nistered once a week, preferably by parenteral injection. The discontinued if any of the following occur: severe leukopenia,
recommended initial dose is 15 mg, which may be increased diarrhea (dehydration), ulcerative stomatitis, nephrotoxicity
to 20 mg per week if there is insufficient response. The dose or pulmonary toxicity. An increase in MCH (mean corpu-
can be adjusted on an individual basis during long-term the- scular hemoglobin) is a common side effect and indicates
rapy. Administration of folic acid (5 mg) 24 hours after the developing megaloblastic anemia. Folic acid supplementation
methotrexate dose is recommended, although there is con- (5 mg) the day after the methotrexate dose can help prevent
fl icting evidence regarding the benefit of this intervention. mild adverse drug reactions.

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Main contraindications/limitations of use Important relative contraindications

Absolute contraindications – Men who are currently planning to have children


– Women who are currently planning to have children – Renal impairment
– Pregnancy and breast-feeding – Hepatic impairment
– Inadequate contraception – Chronic congestive cardiomyopathy
– Known hypersensitivity to methotrexate (e.g., – Diabetes mellitus
pulmonary toxicity) – History of hepatitis
– Severe liver disease – Poor patient compliance
– Renal failure – Diarrhea
– Active tuberculosis or other serious infection – Gastritis
– Actives peptic ulcer
– Hematological changes (leukopenia, thrombocytopenia,
anemia) Drug interactions

See Table 13, the Summary of Product Characteristics and


Table 13 Drug interactions associated with methotrexate. the long version.
Antibiotics can affect the intestinal flora and hamper
Mechanism Drugs
MTX (re)absorption. Folic acid can diminish the effective-
Reduced renal elimination – Cyclosporine ness of MTX.
of MTX – Salicylates Caution is required when MTX is administered with
– Sulfonamides other potentially hepatotoxic drugs and alcohol and when
– Probenecid vaccination with a live vaccine is carried out.
– Penicillins
– Colchicine
Notes on use
– Cyclooxygenase inhibitors
(COX inhibitors)
Depending on the clinical situation, fewer or more mea-
Increased bone marrow – Ethanol
sures or laboratory tests may be required. They should be
toxicity and gastrointesti- – Cotrimoxazole
selected for each patient on an individual basis.
nal toxicity – Pyrimethamine
– Chloramphenicol Pretreatment measures
– Sulfonamides General measures
– COX inhibitors – Rule out acute infection
– Cytostatic agents – Tuberculosis must be definitively ruled out. See long
Displacement of MTX – COX inhibitors version, section on “Tuberculosis”
from plasma protein bin- – Probenecid Specific measures
ding – Barbiturates – Inform the patient about how to take the drug (only
– Phenytoin one day a week) and about early symptoms of potential
– Retinoids adverse effects
– Sulfonamides – Physical examination, screening for skin lesions
– Sulfonylureas typically associated with cirrhosis
– Tetracyclines – Liver ultrasound if indicated, i.e., if there is a
– Cotrimoxazole positive history or abnormal findings on physical
– Chloramphenicol examination
Intracellular accumulation – Dipyridamole – Chest X-ray (for later comparison if any pulmonary
of MTX changes occur during treatment)
Hepatotoxicity – Retinoids Measures during treatment
– Ethanol – Consistent contraception in women of child-bearing
– Leflunomide age
Abbr.: MTX, methotrexate. – Laboratory monitoring, see Table 14

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Table 14 Laboratory tests in patients on methotrexate.

Point in time → Diagnostic tests ↓ Before treatment After 1 week After 6 weeks Then every 6–12 weeks
Complete blood count 1 X X***** X X

ALT, AST, GGT X X X X

Creatinine X X X X

Liver ultrasound X **
Hepatitis B serology X

HIV and hepatitis C serology*** X


Chest X-ray X
Amino-terminal propeptide of type III X****
procollagen (PIIINP)

Depending on the clinical situation, fewer or more measures or laboratory tests may be required. They should be selected
for each patient on an individual basis.

*Hb, Hct, erythrocytes, leukocytes, differential blood count, platelets.


**Annually, if weekly dose ≥ 15 mg.
***As indicated by patient history, clinical signs or other laboratory test results.
****May be considered before treatment and during follow-up in case of long-term treatment; further follow-up with
FibroScan® if results are abnormal.
*****Abnormally low cell counts require weekly lab monitoring.

– More frequent laboratory monitoring is necessary Secukinumab


when the dose is increased and in patients at increased
Treatment recommendations Consensus Comment
risk of elevated MTX levels (dehydration, renal impair-
strength
ment, new drugs.
Secukinumab is recom- ↑↑ Strong Evidence-
– Chest X-ray: if there are symptoms such as acute fever,
mended for induction consensus and
cough, dyspnea and cyanosis; Caution: MTX alveolitis
therapy of moderate to consensus-
– MTX in combination with folate is recommended to
severe psoriasis vulgaris, based
reduce toxicity. A common regimen consists of folate
5 mg the day after taking MTX. especially if other forms
of therapy have failed,
Posttreatment measures
are not tolerated or are
– Reliable contraception in women for at least three contraindicated.
months after discontinuation of treatment

Table 14 provides an overview of the laboratory tests re- Secukinumab summary table
commended by the expert group for methotrexate therapy. Approval of secukinu- 2015 (moderate to severe psoriasis
mab in Germany vulgaris and psoriatic arthritis)
Overdose/management of overdose Recommended initial 300 mg subcutaneously (2 injec-
dose tions of 150 mg) weekly in the
See long version.
first month, then 300 mg (2 in-
jections of 150 mg) monthly
Feasibility/special considerations/costs
Recommended main- 300 mg subcutaneously monthly
tenance dose (2 injections of 150 mg)
See long version.

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Onset of clinical effect PASI 75 response in 25 % of pati- Drug interactions


ents after 3.5 weeks with 300 mg
– Vaccination with live vaccines should be avoided during
[6]
secukinumab therapy.
Selection of main con- Active tuberculosis or other seri- – There are no known classic drug interactions.
traindications ous infectious disease
Selection of important Candida infections Notes on use
ADRs
Selection of important Not known Depending on the clinical situation, fewer or more mea-
drug interactions sures or laboratory tests may be required. They should be
Miscellaneous IL-17A inhibitor selected for each patient on an individual basis.
Pretreatment measures
Dosage and dosing regimen – Rule out acute infection
– Tuberculosis must be definitively ruled out. See long
Secukinumab is administered by subcutaneous injection. For
version, section on “Tuberculosis”
technical reasons, the required dose (300 mg) is divided into
– Ensure reliable contraception and rule out pregnancy
two doses of 150 mg (contained in two separate syringes),
in women of child-bearing age
which are injected at the same time. The fi rst five doses (each
– Patients should be informed that any infection may run
consisting of 2 injections of 150 mg) are given at weekly in-
an atypical and more severe clinical course and that
tervals, with subsequent treatment given monthly (2 injec-
they should seek medical attention as early as possible
tions of 150 mg).
if an infection is suspected.
Measures during treatment
Summary of the evidence
– Monitor for infection; if infection is suspected, treat-
See long version.
ment should be interrupted, at least temporarily.
– Suspicion of Candida infection requires diagnostic
Adverse drug reactions/safety confirmation.

See long version and Summary of Product Characteristics. Posttreatment measures


Secukinumab can increase the risk of infection. In cli- – None
nical studies, mild upper respiratory tract infections (naso-
pharyngitis, rhinitis) were observed slightly more often than Table 15 provides an overview of the laboratory tests for
in patients treated with placebo. secukinumab therapy recommended by the expert group.
In clinical trials, patients treated with secukinumab
more frequently developed Candida infections than indivi- Feasibility and costs
duals in the placebo group (roughly 3.5 cases per 100 treated
patients per year, at a dose of 300 mg). The majority of such See long version.
infections were cases of oral and vulvovaginal candidiasis.
These were easily managed and did not require interruption Ustekinumab
of secukinumab therapy.
Treatment Consensus Comment
Main contraindications/limitations of use recommendations strength
Ustekinumab is ↑↑ Strong Evidence- and
Absolute contraindications
recommended for consensus consensus-
– Pregnancy and breast-feeding
induction therapy of based
– Active tuberculosis or other serious infections
moderate to severe
psoriasis vulgaris, if
Important relative contraindications
other forms of the-
– Crohn’s disease and ulcerative colitis (rare cases of exa-
rapy have failed, are
cerbation or initial manifestation of chronic infl ammatory
not tolerated or are
bowel disease were reported in clinical studies)
contraindicated.
– Children and adolescents

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Table 15 Laboratory tests in patients on secukinumab.

Point in time → Diagnostic tests ↓ Before treatment Week 4 Week 12 Every 3 months
CBC with differential X X X X
AST, ALT, GGT X X X X
Hepatitis B serology X
HIV and hepatitis C serology* X
Pregnancy test (urine) X
If infection is suspected, see pretreatment measures
According to the Summary of Product Characteristics, no laboratory tests are currently suggested during treatment with
secukinumab. The guideline authors recommend the tests listed above. Depending on the clinical situation, fewer or more
measures or laboratory tests may be required. They should be selected for each patient on an individual basis.
*As indicated by patient history, clinical signs or other laboratory test results.

Ustekinumab summary table Adverse drug reactions/safety


Approval of ustekinu- January 2009 (psoriasis vulgaris)
See long version and Summary of Product Characteristics.
mab in Germany October 2013 (psoriatic arthritis)
In the placebo-controlled induction phases of the PHO-
June 2015 (psoriasis vulgaris in
ENIX-1 and PHOENIX-2 trials, the rate of common and se-
children and adolescents aged
vere adverse drug reactions on ustekinumab was similar to
12 and older)
that in the placebo groups. The most common adverse drug
Recommended initial 45 mg (90 mg if >100 kg body
reactions were:
dose weight) at week 0 and 4
– Infections in general: 21.5 % and 31.4 %, respectively
Recommended main- 45 mg (90 mg if >100 kg body (placebo: 20 % and 26.7 %), including:
tenance dose weight) every 12 weeks – Nasopharyngitis: 6.8 % and 10.2 % (placebo: 7.1 %
Onset of clinical effect PASI 75 response in 25 % of pa- and 8.6 %)
tients after 4.6 weeks (90 mg) – Upper respiratory tract infections: 2.9 % and 7.1 %
and 5.1 weeks (45 mg) [3] (placebo: 3.4 % and 6.3 %)
Selection of main Active tuberculosis or other seri- – Headache: 4.6 % and 5.5 % (placebo: 2.4 % and 4.1 %)
contraindications ous infectious diseases – Arthralgia: 2.4 % and 3.4 % (placebo: 2.7 % and 2.9 %)
Selection of important Infections
ADRs The incidence of severe adverse events was 0.8 % and
2.0 %, respectively; these percentages were also observed in
Selection of important Not known
the placebo group (0.8 % and 2.0 %). Occasional severe ad-
drug interactions
verse drug reactions in the PHOENIX-1 trial included two
Miscellaneous IL12/IL23p40 antagonist
infections (bilateral erysipelas of the legs and herpes zoster);
both were successfully managed with appropriate treatment.
Dosage and dosing regimen In the PHOENIX-2 trial, only one patient treated with uste-
Ustekinumab is available as injection solution in a prefi lled kinumab developed a serious infection; here, too, the diagno-
syringe (45 mg/0.5 mL and 90 mg/1.0 mL). It is administe- sis was erysipelas.
red by subcutaneous injection into the abdomen or thigh. The rate of severe infections remained low (< 1 %) in
According to the Summary of Product Characteristics, an subsequent study phases. Taking both studies together, the-
initial dose of 45 mg at week zero is recommended, follo- re were 15 malignancies throughout the observation peri-
wed by 45 mg at week four and then every twelve weeks. In od, including 11 cases of skin cancer. An integrated analysis
patients with a body weight > 100 kg, the dose per injection of all safety data from phase II and III trials in psoriasis,
is 90 mg. which was presented to the US Food and Drug Administ-
ration (FDA), was based on data from 2,266 patients, of
Summary of the evidence whom 70 % had received at least six months of ustekinumab
See long version. treatment. This analysis showed no association with lym-
phopenia, nor were there any cumulative toxic effects. The

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Guidelines S3 Psoriasis guideline

number of malignancies continued to be low and similar to Main contraindications/limitations of use


the number in patients on placebo, thus corresponding to
the expected incidence (based on epidemiological data) in Absolute contraindications
healthy individuals. The same is true for serious cardiova- – Active tuberculosis or other serious infections
scular events.
The duration of safety-relevant immunological effects Important relative contraindications
cannot be inferred from the drug’s long duration of action – Malignancy (except for basal cell carcinoma) and lympho-
and sustained clinical effect in between injections. Infections proliferative disorders, including a history thereof
did not occur more frequently at the beginning of the injecti- – Vaccination with live vaccines
on interval, when drug levels are comparatively high, than at – Pregnancy and breast-feeding
the end of the interval, when levels are low. For information
on live vaccines, see below. Drug interactions
Based on data from studies of psoriatic arthritis as well
as from treatment and pharmacovigilance registries, there is Given that ustekinumab is a monoclonal antibody, no che-
currently no evidence that the risk of developing cardiovas- mical interactions or interactions via the cytochrome P450
cular events (MACE) is increased in psoriasis patients on us- system are expected.
tekinumab, despite sometimes conflicting initial reports. The
frequency of MACE in long-term studies is similar to that seen Notes on use
in long-term studies of TNF antagonists such as adalimumab.
Depending on the clinical situation, fewer or more
Prevention/management of ADRs
measures or laboratory tests may be required. They
Infections are among the most important adverse effects. should be selected for each patient on an individual
Patients should therefore be informed about relevant early basis.
symptoms. Pretreatment measures
Although there have only been two published cases of tu-
– Rule out acute infection
berculosis in association with ustekinumab therapy [12, 13],
– Tuberculosis must be definitively ruled out. See long
patients should undergo tuberculosis screening as recommen-
version, section on “Tuberculosis”
ded in the section on “Tuberculosis” in the long version of
– Ensure reliable contraception and rule out pregnancy
this guideline. Active tuberculosis is a contraindication for
in women of child-bearing age
using ustekinumab. Latent tuberculosis requires preventive
– Patients should be informed that any infection may run
measures during treatment.
an atypical and more severe clinical course and that
Prior to administration of a live vaccine, ustekinumab the-
they should seek medical attention as early as possible
rapy should be discontinued for at least 15 weeks and should
if an infection is suspected.
be resumed no earlier than two weeks after the vaccination.

Table 16 Laboratory tests in patients on ustekinumab.

Point in time → Diagnostic tests ↓ Before treatment Week 4 Every 3 months


CBC with differential X X Before each injection
AST, ALT, GGT X X Before each injection
Hepatitis B serology X
HIV and hepatitis C serology* X
Pregnancy test (urine) X
If infection is suspected, see pretreatment measures
According to the Summary of Product Characteristics, no laboratory tests are currently suggested during treatment with
ustekinumab. The guideline authors recommend the tests listed above. Depending on the clinical situation, fewer (for ex-
ample every 6 months) or more measures or laboratory tests may be required. They should be selected for each patient on
an individual basis.
*As indicated by patient history, clinical signs or other laboratory test results.

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Guidelines S3 Psoriasis guideline

2 Nast A , Boehncke WH, Mrowietz U et al. S3 - Guidelines on


Measures during treatment
the treatment of psoriasis vulgaris (English version). Update.
– Monitor for infection; if infection is suspected, treat- J Dtsch Dermatol Ges 2012; 10 (Suppl 2): S1 – 95.
ment should be interrupted, at least temporarily. 3 Nast A , Sporbeck B, Rosumeck S et al. Which antipsoriatic
– If the patient becomes pregnant, treatment should be drug has the fastest onset of action? Systematic review on the
interrupted if possible; if treatment is needed, see secti- rapidity of the onset of action. J Invest Dermatol 2013; 133:
on on “Pregnancy” 1963 –70.
4 Gollnick HP, Dummler U. Retinoids. Clin Dermatol 1997; 15:
– Treatment should be carried out by medically trained
799 – 810.
staff
5 Gronhoj Larsen F, Steinkjer B, Jakobsen P et al. Acitretin is con-
Posttreatment measures verted to etretinate only during concomitant alcohol intake.
– None Br J Dermatol 2000; 143: 1164 – 9.
6 Nast A , Spuls PI, van der Kraaij G et al. European S3-Guideline
on the systemic treatment of psoriasis vulgaris – Update Apre-
Table 16 provides an overview of the laboratory tests milast and Secukinumab – EDF in cooperation with EADV and
for ustekinumab therapy recommended by the expert group. IPC. J Eur Acad Dermatol Venereol 2017; 31(12): 1951 – 63.
7 Ellis CN, Fradin MS, Messana JM et al. Cyclosporine for
Overdose/management of overdose plaque-type psoriasis. Results of a multidose, double-blind
trial. N Engl J Med 1991; 324: 277– 84 .
See long version. 8 Wyeth Information for Professionals. Current version.
9 Augustsson J, Eksborg S, Ernestam S et al. Low-dose glucocor-
ticoid therapy decreases risk for treatment-limiting infusion
Feasibility/special considerations/costs reaction to infliximab in patients with rheumatoid arthritis.
Ann Rheum Dis 2007; 66: 1462 – 6.
See long version. 10 Lecluse LL, Piskin G, Mekkes JR et al. Review and expert opin-
ion on prevention and treatment of infliximab-related infusion
reactions. Br J Dermatol 2008; 159: 527–36.
Correspondence to
11 Maini R , St Clair EW, Breedveld F et al. Infliximab (chimeric
anti-tumour necrosis factor alpha monoclonal antibody)
Prof. Alexander Nast MD
versus placebo in rheumatoid arthritis patients receiving con-
Klinik für Dermatologie, Venerologie und Allergologie comitant methotrexate: a randomised phase III trial. ATTRACT
[Department of Dermatology, Venereology and Allergy] Study Group. Lancet 1999; 354: 1932 – 9.
Division of Evidence-Based Medicine (dEBM) 12 Lynch M, Roche L, Horgan M et al. Peritoneal tuberculosis in
Charité – Universitätsmedizin Berlin, Campus Mitte the setting of ustekinumab treatment for psoriasis. JAAD Case
Rep 2017; 3: 230 –2.
Charitéplatz 1 13 Tsai TF, Chiu HY, Song M, Chan D. A case of latent tuberculosis
10117 Berlin reactivation in a patient treated with ustekinumab without
concomitant isoniazid chemoprophylaxis in the PEARL trial.
E-mail: alexander.nast@charite.de
Br J Dermatol 2013; 168: 444 – 6.

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