German S3-guidelines on the treatment of psoriasis vulgaris (short version)

Abstract

Psoriasis vulgaris is a common and often chronic inflammatory skin disease. The incidence of psoriasis in Western industrialized countries ranges from 1.5 to 2%. Patients afflicted with severe psoriasis vulgaris may experience a significant reduction in quality of life. Despite the large variety of treatment options available, patient surveys have revealed insufficient satisfaction with the efficacy of available treatments and a high rate of medication non-compliance (Richards et al. in J Am Acad Dermatol 41(4):581–583, 1999). To optimize the treatment of psoriasis in Germany, the Deutsche Dermatologische Gesellschaft (DDG) and the Berufsverband Deutscher Dermatologen (BVDD) have initiated a project to develop evidence-based guidelines for the management of psoriasis first published in 2006 and now updated in 2011. The Guidelines focus on induction therapy in cases of mild, moderate, and severe plaque-type psoriasis in adults. This short version of the guidelines presents the resulting series of therapeutic recommendations, which were based on a systematic literature search and discussed and approved by a team of dermatology experts. In addition to the therapeutic recommendations provided in this short version, the full version of the guidelines includes information on contraindications, adverse events, drug interactions, practicality, and costs, as well as detailed information on how best to apply the treatments described (for full version please see Nast et al. in JDDG Suppl 2:S1–S104, 2011 or http://www.psoriasis-leitlinie.de).

Introduction

The Deutsche Dermatologische Gesellschaft and the Berufsverband Deutscher Dermatologen have initiated a project to develop evidence-based guidelines for the treatment of plaque psoriasis which were published in 2006 and now updated in 2011 [152, 155]. The full version has again been published in the Journal der Deutschen Dermatologischen Gesellschaft (JDDG 2011 Supplement 2 [152]) and is available at http://www.psoriasis-leitlinie.de. This article summarizes the key messages from the guidelines.

Background

Needs analysis/challenges in patient care

Psoriasis vulgaris is a common and almost always chronic skin disease

The prevalence of psoriasis in Western industrialized nations is 1.5–2% [157]. About 80% of psoriasis patients have the plaque form of disease. In Germany, the disease affects an estimated 1.6 million people. More than 90% have chronic disease [157].

Patients with plaque psoriasis have a substantially impaired quality of life

Studies on the impairment of quality of life in psoriasis patients have shown that, depending on the severity of disease, related disability or psychosocial stigmatization can present a considerable burden for the patient [198]. Patient surveys have found that the impact on quality of life is comparable to that experienced by patients with type 2 diabetes or chronic lung disease [183].

Patient satisfaction with current therapies is low and compliance is poor

Based on the results of patient surveys, only about one-fourth of patients report being very satisfied with the results of therapy; about 50% are moderately satisfied, and about one-fifth are not very satisfied [206]. There is also a high rate of medication non-compliance (up to 40%) [188]. Reasons for non-compliance include poor tolerability, fear, lacking information about potential side effects, low efficacy, and complicated usage [187, 242].

There is uncertainty concerning the use of systemic therapies

Nast et al. reported in a small survey of 39 dermatologists in private practice that, according to their own self-assessment, 76% of doctors surveyed had some uncertainty about prescribing systemic medications. 79% said they believed that this led to inadequate treatment with systemic therapies [153].

There is inadequate use of systemic therapy options in patients with moderate-to-severe psoriasis

Nast et al. reported in a study from 2006 with 54 dermatologists in private practice that in visits with 2,294 patients with moderate-to-severe psoriasis, about 50% of patients were treated with topical therapies alone. 17% received additional UV therapy and only about 30% were taking some form of systemic therapy [156].

The economic costs of disease are high

The costs of psoriasis, including the costs of statutory health care and other forms of insurance (e.g., unemployment coverage) as well as the costs for the patient himself (e.g., for basic therapies), are about 2,866 € per patient per year [19]. In 2002, about 20,000 patients with psoriasis vulgaris were hospitalized, primarily for initial treatment as well as for severe flare-ups. One German statutory health insurer (AOK West) reported that the number of disability cases for psoriasis vulgaris per year was 7.35 for men and 4.94 for women/10,000 insured persons (28 and 27 days) [216].

Goal of the guidelines

The overall goal of the guidelines is to provide dermatologists in private practice and clinicians with an accepted, evidence-based tool that can aid decision-making in the selection and implementation of appropriate and adequate therapies for patients with psoriasis vulgaris. The focus of the guidelines is on induction therapy for mild to severe psoriasis vulgaris in adult men and women.

Improved patient care through implementation of guideline recommendations and optimization of physician knowledge of reported treatment efficacies

The personal experience of physicians and the use of traditional treatment concepts for psoriasis vulgaris should be augmented or even replaced by an evidence-based assessment of the anticipated results of a given therapy option based on medical science.

Assistance with optimal treatment implementation

The detailed description of systemic therapies, phototherapies, and photochemotherapy, including precise descriptions of their use and safety aspects, should help reduce any reservations on the part of doctors and patients with regard to certain therapies and ensure prompt, sufficient, and optimal treatment. The timely provision of information and prompt induction of adequate therapy should help prevent severe disease which frequently involves hospitalization and lost work days.

Improved patient awareness of current therapy options

A further version of the guidelines, designed for use by the patient, is currently being developed. The aim is to give patients an overview of possible therapies in terms of complications and optimal usage.

Enhancing compliance

Adequate patient compliance/adherence are often related to a good ratio between the benefits of therapy and the related effort, costs, and potential side effects. The choice of an effective therapy by the patient and doctor, taking into account the quality of life variables measured in recent studies, should help ensure a high treatment benefit. Providing information on the prevention and management of adverse effects should help limit or even prevent them. This in turn also increases compliance.

Quality of care indicators

Radtke et al. [180] have proposed eight indicators based on the Delphi method for measuring the quality of care of psoriasis patients. These quality indicators may be applied to the total population of psoriasis patients or used as indicators for monitoring changes in quality of care as a result of the guidelines: (1) average PASI in the total population; (2) average DLQI in the total population; (3) proportion of patients out of the total population with severe psoriasis vulgaris as measured by PASI (>20); (4) proportion of patients out of the total population who have severe psoriasis vulgaris as measured by DLQI (>10); (5) proportion of patients out of the total population who have previously received systemic therapy; (6) proportion of patients with severe psoriasis (PASI > 20) who report prior or current systemic therapy; (7) proportion of patients out of the total population who have been hospitalized in the last 5 years due to psoriasis; (8) average number of lost work days due to psoriasis among the total population.

Methods

A detailed description of the methods and procedures used for developing the guidelines may be found in the methods report (http://www.psoriasis-leitlinie.de). These guidelines are an update of the guidelines published in 2006 [154, 155].

Basis of data

A systematic literature search of published articles up to November 2009 was performed to evaluate the efficacy of various individual therapies. In addition to the 6,224 publications yielded by the literature search in the first version of the guidelines, we identified 1,443 new studies. Of these, 155 studies fulfilled the criteria for inclusion in the current guidelines and were included in the evaluations of treatment efficacy. The methodological quality of the chosen studies was determined using a “literature evaluation form” (LEF). Other aspects included in the guidelines were evaluated on the basis of information from the literature (without a systematic assessment) as well as on the basis of the personal experience of the guidelines expert committee. For 2006/2007, the results of the literature search for the EU guidelines were also included.

Evidence assessment

The efficacy of each intervention was systematically assessed using evidence-based criteria.

The methodological quality of each study was assessed using grades of evidence:

A₁ :

Meta-analysis containing at least one randomized grade A₂ study. The results of the various studies included must be consistent.

A₂ :

Randomized, double-blind, high-quality clinical comparative study (e.g., sample size calculation, flow chart, ITT analysis, sufficient sample size).

B:

Randomized clinical study of lesser quality or other comparative study (non-randomized: cohort study or case–control study).

C:

Non-comparative study.

Evidence levels were also determined as part of evaluating the effectiveness of a drug given as monotherapy. This consisted of an evaluation of the overall evidence on the intervention:

• 1. Intervention is supported by grade A₁ studies or mostly consistent results from grade A₂ studies.

• 2. Intervention is supported by grade A₂ studies or grade B studies with mostly consistent results.

• 3. Intervention is supported by grade B studies or grade C studies with mostly consistent results.

• 4. Little or no systematic empirical evidence.

Treatment recommendations

At present there is no clear step-by-step procedure or strict clinical algorithm for the treatment of psoriasis vulgaris. The criteria for selecting an appropriate therapy are complex. Certain aspects related to selecting a suitable treatment must be assessed and weighed individually. The decision for or against a therapy is made on an individual basis. The guidelines provide a scientifically based aid for decision-making and selection of an appropriate treatment. As such they constitute a medical tool for the optimal use of a necessary therapy.

Key recommendations formulated in the text are augmented by symbols representing the strength of the treatment recommendation. The following symbols have been used to help standardize the treatment recommendations:

↑↑	Measure is recommended	(strongly recommended)
↑	Measure may be recommended	(recommended)
→	Measure may be considered	(neutral recommendation)
↓	Measure cannot be recommended	(recommendation against its use)
↓↓	Measure should be avoided	(strongly disadvised)

Due to the focus of the guidelines on induction therapy, the recommendations in the update are limited to this phase. Some recommendations from the previous version are thus no longer included. This is in the interest of standardization and does not indicate any change to the recommendation level of a previously described drug.

The strength of recommendation takes into account various aspects concerning its effectiveness, including evidence level, safety aspects, feasibility, cost-to-benefit ratio, etc. The strength of the recommendations was agreed on in the framework of a consensus conference.

Results

Therapeutic strategies (Fig. 1)

Fig. 1

Overview of therapy options under evaluation for use in chronic plaque psoriasis (the order of therapies is alphabetical and does not represent a ranking)

Evaluation of topical and systemic therapies in tabular form

The following tables are intended to serve as a rough guide for evaluating therapy options. Cumulative calculations of individual aspects in the overall evaluation are not possible and cannot be used for a conclusive evaluation of a given therapy option. Each column should be viewed separately. The evaluation may vary significantly on a case-by-case basis. The varying degrees of severity of psoriasis render a direct comparison between systemic and topical therapies impossible. The evaluations are based on a literature review and expert opinion.

Topical monotherapy

Therapy	Efficacy	Evidence level	Safety/tolerability of induction therapy	Safety/tolerability for maintenance therapy	Feasibility (patient)	Feasibility (doctor)	Cost/benefit
Calcineurin inhibitors	++	2/3	++	Not indicated	++	–a	++
Dithranol	+++	2	++	Not indicated	+b	+b	+++
					–c	–c
Corticosteroids	++++d	1	+++	+	++	+++	+++
Coal tar	±	4	+	Not indicated	–	±	–
Tazarotene	++	2	++	++	±e	±e	++
Vitamin D3 derivatives	+++	1	+++	+++	+++	+++	++

1. 
2. ^aNo strong consensus (>75%) was achieved using the DELPHI method. The recommendation was therefore made based on a majority vote of 54% (guideline expert committee). Alternatively, members voted for “++.” The reason for the discussion was “off-label” prescribing. The opinions on the effort involved diverged significantly
3. ^bInpatient
4. ^cOutpatient
5. ^dAt least class III steroids; also applies to fixed dose drug combinations
6. ^eNo strong consensus (>75%) was achieved using the DELPHI method. The recommendation was therefore made based on a majority vote of 69% (guideline expert committee). Alternatively, members voted for “−.” The reason for the discussion was the poor availability, i.e., available only via international pharmacies. The opinions on the effort involved diverged significantly

Phototherapy and systemic monotherapy

Therapy	Efficacy	Evidence Level	Safety/tolerability of induction therapy	Safety/tolerability of maintenance therapy	Feasibility (patient)	Feasibility (doctor)	Cost/benefitg
Phototherapy
UVB	+++	2	+++	Not indicated	±	+	++
PUVA	+++ to ++++	2	+a	Not indicated	−	±	++
			++b
Adalimumab	+++	1	++	++	+++	++	+
Etanercept	+d	1	++	++	+++	++	±
	+e
	++f
Cyclosporine	++ to +++	1	+	+	+++	++	++
Fumarate	++	2	+	+++	++	+++	+++
Infliximab	+++ to ++++	1	+	++	+++	±	+
Methotrexate	+ to ++	2	+	++	++	++	+++
Retinoidsc (systemic)	+	2	+	+	+	++	±
Ustekinumab	+++	1	++	++	+++	++	+

1. 
2. ^aSystemic PUVA
3. ^bBath/cream PUVA
4. ^cRetinoid therapy is generally not advised for women of childbearing age
5. ^dFor 1 × 25 mg
6. ^eFor 1 × 50 mg
7. ^fFor 2 × 50 mg
8. ^gFor a 12-week regimen of induction therapy

(a) Efficacy The value in the column “efficacy” reflects the percentage of patients who achieved a reduction in PASI score >75%.

Scale	Systemic therapy (%)	Topical therapy (%)
++++	ca. 90	ca. 60
+++	ca. 70	ca. 45
++	ca. 50	ca. 30
+	ca. 30	ca. 15
±	ca. 10	ca. 5
–	not defined	not defined

The evidence level applies to demonstrated efficacy.

(b) Safety/tolerability of induction/maintenance therapy The risk of severe side effects or the likelihood of side effects resulting in discontinuation of therapy.

(c) Feasibility (patient) Evaluated factors include the amount of time involved in using the therapy, its actual usage, and ease of administration.

(d) Feasibility (doctor) Factors that are evaluated include the amount of work involved (documentation, educating the patient, monitoring), requirements for equipment and personnel, time involved for doctor/patient interactions, reimbursement of treatment measures, invoicing problems/risk of recourse claims by insurers.

(e) Cost/benefit This is assessed according to the costs of induction or maintenance therapy.

The assessment of safety/tolerability for induction or maintenance therapy, as well as the feasibility of therapy for the doctor and patient, and costs/benefits are measured on a scale of − (poor) to ++++ (good). Grades are based on information from a literature review and expert opinion. No evidence level is cited since it was not specifically included in the literature search.

Evaluation of topical therapies

Calcineurin inhibitors

Table 1 Summary table

Coal tar

Table 2 Summary table

Corticosteroids

Table 3 Summary table

Dithranol

Table 4 Summary table

Tazarotene

Table 5 Summary table

Vitamin D3 and vitamin D3 analogues

Table 6 Summary table

Phototherapy

Table 7 Summary table

Evaluation of systemic therapies

Adalimumab

Table 8 Summary table

Table 9 Monitoring

Cyclosporine

Table 10 Summary table

Table 11 Monitoring

Etanercept

Table 12 Summary table

Table 13 Monitoring

Fumaric acid esters

Table 14 Summary table

Table 15 Dosing scheme for fumaderm therapy

Table 16 Monitoring

Infliximab

Table 17 Summary table

Table 18 Monitoring

Methotrexate

Table 19 Summary table

Table 20 Monitoring

Retinoids

Table 21 Summary table

* The use of two contraceptive measures is advised: e.g., condom + pill; contraceptive coil/NuvaRing + pill. Important: avoid the use of low-dose progesterone preparations (minipill) during treatment and for 2 years after stopping treatment as their effectiveness is diminished by acitretin

Table 22 Monitoring

Ustekinumab

Table 23 Summary table

Table 24 Monitoring

Other therapies

Climatotherapy

Table 25 Summary table

Psychosocial therapy

Note on use of the guidelines

These guidelines are intended for use by dermatologists in private practice and by clinicians and other specialists involved in the treatment of patients with psoriasis vulgaris. An update of the patient version of the guidelines is currently underway. Finally, the guidelines also provide a guide for health insurers and policy-makers.

The description of selected therapies is intentionally restricted to the most relevant aspects in the opinion of the guidelines’ expert committee. Those aspects that are not specific to a certain intervention, such as assessing drug intolerance or allergies, ruling out contraindications, etc. are not listed separately but are instead assumed to be a part of the physician’s duty of care.

Physicians are advised to carefully read the package insert and manufacturer information and to determine whether dosage recommendations and other information contained in the guidelines, such as contraindications and drug interactions, is complete and current. Correct dosage and administration are solely the responsibility of the administering physician.

The authors and the publisher kindly ask readers to alert them to any apparent inaccuracies.

Like any science, the field of medicine is in constant flux. Our knowledge of present therapies as well as new treatment options is constantly growing. The utmost care was taken to ensure that the information contained in the guidelines was current at the time of their completion. The reader is advised to keep abreast of current information after their publication.

Appendix 1: Measures for excluding tuberculosis (scheme) modified after Diel et al. [51]

(1) Patient history	Immunosuppression
	Other risk factors for TB
	Prior LTBI/TB
	(Occupational) TB contact
	Origin
	BCG vaccine status
	TST/IGRA status
	Chest X-rays for comparison
(2) Clinical examination
(3) Chest X-ray in two planes, CT of thorax if needed	If there are radiological signs of prior but inadequately or untreated TB without signs of activity, regardless of results of IGRA test:
	chemopreventive therapy with isoniazid (INH) for nine months
(4) IGRA test	IGRA negative:
	generally no chemoprevention
	IGRA positive:
	after ruling out the need for therapy: chemopreventive therapy with isoniazid (INH) for nine months
Complementary TST	If previous exposure to someone with infectious pulmonary TB is plausible despite negative IGRA tests and if BCG vaccine is unlikely given the patient’s native country.
	Or for equivocal results on repeated IGRA test.
	Positive TST determines further procedures
Bacteriology if needed

1. LTBI latent tuberculosis infection, TB tuberculosis, TST tuberculin skin test, IGRA Interferon-Gamma Release Assay

The Interferon-Gamma Release Assay (IGRA) is based on detection of INF-γ, which is secreted by T lymphocytes that are sensitized during a current or previous infection with mycobacterium tuberculosis (MTB).

The two commercially available IGRA tests that are sold in Germany use direct measurement of IFN-γ concentration in whole blood (QuantiFERON-TB^® Gold In-Tube, Cellestis, Australia; QFT) or measurement of the number of IFN-γ secreting T lymphocytes from isolated peripheral mononucleated cells (PBMC; T-SPOT.TB^®, Oxford Immunotec, Great Britain) [51].

Usually at least one of the tests is offered by routine diagnostic laboratories, or the samples are sent by the lab to one that does offer them. The QuantiFERON-TB^® Gold In-Tube (QFT) test requires three special tubes coated with antigen which may be obtained from the respective laboratory.

For the T Spot.TB test, 8 ml of fresh, heparinized whole blood are needed from adult patient and at least 2–4 ml from children. Vacutainer Cell Preparation tubes or Standard Lithium Heparin tubes may be used. The sample must then be thoroughly shaken. For both tests, the samples may be transported at room temperature (QuantiFERON-TB^® within 16 h/T Spot.TB test within 8 h).

For information on outpatient billing, see the resolution of the German Association of Physicians/Health Insurers (Arbeitsgemeinschaft Ärzte/Ersatzkassen), 255th session (written resolution) from 24 September 2010 on the addition of fee number 32670 in section 32.3.7 of chapter 32 of the German Physician Fee Schedule (E-GO) (Resolution No. 930) effective as of 1 January 2011, Dtsch Arztebl 2010; 107(42): A-2069/B-1801/C-1773. For inpatient billing, see OPS Code 1930.0.