Swiss S1 Guidelines on the Systemic Treatment of Psoriasis Vulgaris

On behalf of the Swiss Society of Dermatology and Venereology SGDV/SSDV, the Swiss Dermatology Network for Targeted Therapies has prepared an evidence-based guideline for the treatment of plaque-type psoriasis. This work is partially based on previously published Swiss recommendations [1,2], the updated German S3 guidelines [3] and the European S3 guideline for psoriasis [4]. The goal of the Swiss S1 guidelines is to develop an informal expert consensus to provide a strategy management of systemic therapies by Swiss dermatologists and to focus on induction therapy in cases of moderate-to-severe plaque-type psoriasis in adults, as well as to include useful Swiss-specific aspects and regulatory issues. The varieties of a patient's disease aspects with their medical history, therapy preferences, comorbidities including psoriatic arthritis, childbearing potential, risk of infection, adherence, long-term safety and much more are major points in the decision between patients and their treating physicians to choose the right medication to treat psoriasis and have to be evaluated in the individual patient's consultation.

In Western industrialized nations, psoriasis has a prevalence of 1.5-2%. About 80% of those afflicted suffer from the plaque form, and more than 90% are chronic [5]. Depending on the severity of disease and related disability as well as psychosocial stigmatization, the quality of life can be considerably impaired [6], comparable to patients with type 2 diabetes, cancer and chronic lung disease [7]. Nevertheless, in the past, adherence to therapies was observed to be relatively low. Before the advent of biological therapies, only 25% of patients were very satisfied with the results of their therapy for psoriasis [8], resulting in a high rate of nonadherence of up to 40% [9,10]. In addition, patients reported lack of information about potential side effects of drugs, complicated usage, poor tolerability, fear, costs, and low efficacy [11,12]. Dermatologists have high expertise in managing topical drugs, but 76% are somewhat uncertain about prescribing systemic medications [13]. Thus, about 50% of moderate-to-severe psoriasis patients are treated with topicals alone [14]. However, the choice of an adequate therapy could help to prevent disease and exacerbation of comorbidity which could increase quality of life, avoid hospitalization and avoid reduction of working days, which is also recognized by the World Health Organization [15,16].

Moderate-to-severe psoriasis is defined as Psoriasis Area and Severity Index (PASI) >10 or body surface area (BSA) >10% and/or Dermatology Life Quality Index (DLQI) >10 [17]. The Swiss guideline expert panel unanimously supports this definition and urges insurances and policy makers to accept DLQI >10 as official threshold.

This becomes important in severe involvement of special locations, particularly in areas such as the scalp, genitals, palms and/or soles, nail involvement, presence of single recalcitrant plaques or pruritus leading to scratching. Severe involvement of visible areas but not high BSA is not reflected by representative values of the PASI. Localized tools like palmoplantar PASI (online suppl. calculator; see www.karger.com/doi/10.1159/000445681 for all online suppl. material) [18] and Nail Psoriasis Severity Index [19] have been suggested but are not generally used for severity assessment in special localizations. Especially nail, palmoplantar and inguinal involvement has a severe impact on quality of life. Here the DLQI should be considered for the evaluation of the psoriasis severity.

The PASI is a standard tool to define disease severity in psoriasis as well as the BSA, DLQI, Physician's Global Assessment or Investigator's Global Assessment [20,21,22,23]. An adapted PASI calculation, the Precise PASI, utilizes the same source data as the PASI but does not neglect the percentages of surface involvement, achieving a much higher resolution in the lower BSA ranges (<5%) [24].

The current systemic treatment options in Switzerland for moderate-to-severe psoriasis include small molecules and biologicals. The former group encompasses small molecules such as methotrexate (MTX), cyclosporine A (CsA), apremilast (APR), fumaric acid esters (FAEs) and acitretin. The latter group includes the tumor necrosis fac-tor (TNF)-α antagonists adalimumab (ADA), etanercept (ETA), and infliximab (IFX), the p40 interleukin (IL)-12/23 antagonist ustekinumab (UST) and the IL-17A antagonist secukinumab (SEC). FAEs are not formally registered for the treatment of psoriasis in Switzerland.

Before any of the above treatments are prescribed, external skin care and topical drugs should be used to the fullest extent, namely emollients, topical drugs such as corticosteroids, vitamin D derivates and tacrolimus/pimecrolimus, as well as phototherapy such as narrow-band UVB, UVA or topical/systemic PUVA. These are often additionally used in moderate-to-severe psoriasis as a first-line treatment. Only when insufficient efficacy of these treatments is confirmed, systemic agents should be used. In Switzerland biologicals can be used exclusively in patients who were unsuccessfully treated with at least one conventional systemic therapy and/or phototherapy (limitation for biologicals by insurance/governmental regulations). In addition, IFX is reimbursed only after failure of a previous TNF-α inhibitor and a treatment duration of 1 year but can be extended by permission of the insurance in case of positive treatment success.

Acitretin is a retinoid (vitamin A derivate) that can be used for moderate-to-severe psoriasis vulgaris, as well as local or generalized pustular or erythrodermic psoriasis. In contrast to other systemic therapies, it is not considered cytotoxic or immunosuppressive. This is considered an advantage for patients with malignant tumors. Also, it has an antiproliferative effect that is partially preventive for epithelial tumors of the skin [5,25,26].

Induction therapy for plaque psoriasis is started with 10-20 mg/day (0.3-0.5 mg/day/kg body weight) for 4 weeks, and then slowly increased until patients notice a slight scaliness on the lips which is an indicator for sufficient bioavailability. The general maintenance dose is recommended between 25 and 50 mg/day (0.5-0.8 mg/kg body weight) depending on efficacy and tolerability. Doses up to 20 mg daily do not usually lead to a satisfactory response but have no or only mild side effects [26]. Capsules should be ingested with whole milk or a fatty meal. Combination therapies have been described with UV phototherapy (narrow-band UVB, broad-band UVB, UVA and PUVA) as well as MTX, cyclosporine, TNF inhibitors and UST [27].

Because of the high teratogenicity, double contraception is mandatory for women during and up to 2 years after discontinuation (e.g. condom + pill; intrauterine device/Nuva-Ring + pill; please note: no low-dosed progesterone preparations/minipills). Monthly pregnancy tests are recommended in women of childbearing age; see table 2 for the prevention of adverse events [5]. The patient should be asked about spine/joint complaints at follow-up visits; if yes without a hint for psoriatic arthritis (PsA), further imaging should be performed due to the possibility of diffuse idiopathic skeletal hyperostosis which occurs in less than 1% of patients. Depression is not listed as an official side effect in patients treated with acitretin but is described very rarely.

Headache, nausea and/or vomiting, fatigue, irritability, and pruritus are symptoms of acute overdose. In this case, discontinue retinoids, monitor vital parameters/liver and renal function/electrolytes and consult specialists to manage extracutaneous side effects (tables 1, 2).

• Severe renal or hepatic dysfunction

• Hepatitis

• Women of childbearing age: pregnancy, breast-feeding, desire to have children or insufficient guarantee of effective contraceptive measures up to 2 years after discontinuation of therapy

• Excessive alcohol consumption

• Incompatible comedication

• Unwillingness to cease blood donation during and until 1 year after treatment

• Hypersensitivity to acitretin

• Alcohol abuse

• Diabetes mellitus

• Contact lenses

• Childhood

• History of pancreatitis

• Hyperlipidemia (particularly hypertriglyceridemia) and drug-controlled hyperlipidemia

• Atherosclerosis

Severe, therapy-refractory cases of psoriasis [as limitation, reimbursement criteria of the Federal Office of Public Health (FOPH, in German Bundesamt für Gesundheit, BAG) are considered].

Apremilast (APR, Otezla®) is a small molecule inhibiting intracellular phosphodiesterase-4. It is indicated in patients with moderate-to-severe plaque psoriasis who failed light therapy, MTX, cyclosporine, acitretin or PUVA and is also indicated in psoriatic arthritis patients who failed disease-modifying antirheumatic drugs (table 3).

The recommended dosage is 30 mg p.o. twice daily for maintenance; see table 4 for induction scheme.

In case of infection during treatment, stop temporarily.

• Rare hereditary problems of galactose intolerance, lapp lactase deficiency or glucose-galactose malabsorption

• Pregnancy/breast-feeding

• Hypersensitivity to apremilast

• Live vaccines

• In patients with severe renal impairment (creatinine clearance of less than 30 ml/min estimated by the Cockcroft-Gault equation), the dose should be reduced to 30 mg once daily

• Caution in case of depression

• Underweight at the start of treatment should be monitored regularly; in case of unexplained and clinically significant weight loss, evaluate the patient and consider discontinuation of APR.

With lack of data or recommendations, the following medical states should be considered very carefully: active and latent tuberculosis, acute or severe infections, history of or active chronic hepatitis B and C, HIV, live vaccines, malignancies (apart from successfully treated nonmelanoma skin cancer and cervical dysplasia) and lymphoproliferative disorders. Diarrhea is rather transient over the first weeks of treatment.

Treatment of adults with severe plaque-type psoriasis who did not experience therapeutic success with UVB and PUVA or one of the following systemic therapies: cyclosporine, MTX, acitretin. The treatment has to be stopped in case of no therapeutic success after 24 weeks. Not in combination with biologicals. For psoriasis it can only be prescribed by dermatologists or dermatological university hospitals/outpatient clinics.

CsA is indicated for moderate-to-severe psoriasis (as well as rescue therapy for erythrodermic and pustular psoriasis), especially in induction therapy [29]. A combination with topical steroids and vitamin D analogs may be recommended and reduce the dosage of CsA. Due to side effects such as nephrotoxicity, increased cancer risk and arterial hypertension, therapy is limited to 1 year [5].

CsA capsules contain 12.7% of alcohol which has to be taken into account in patients with liver diseases, alcohol abuse, epilepsy, brain injuries, pregnancy, breast-feeding women and children. CsA itself shows no teratogenicity but may be associated with preeclampsia, premature birth and low birth weight.

There are a lot of possible interactions with other drugs, especially statins, with an increased risk of myopathies. Side effects are possibly dose dependent and disappear with dose reduction (table 5).

The combination of CsA and excessive phototherapy leads to an increased risk of squamous cell carcinoma [5].

• If serum creatinine is increased (5-30%, in up to 20% increase in creatinine by more than 30%):

- ≤30% of baseline value should prompt a revision of the patient's fluid intake

- 30-50% of baseline value (even if in the normal range), a dose reduction of 25% is recommended

- ≥50% of baseline value should lead to a dose reduction of 50%

- If after 30 days an increase of ≥30% persists, stop CsA; calculate creatinine clearance (reduced in up to 20% of patients)

• Arterial hypertension (2-5%) requires an antihypertensive therapy if blood pressure is ≥160/90 mm Hg in two consecutive measurements. However, calcium antagonists could raise CsA levels, and angiotensin-converting enzyme inhibitors/angiotensin-2 receptor antagonists could induce hyperpotassemia. If despite an antihypertensive therapy the blood pressure is still increased, a CsA dose reduction of 25% is necessary, with subsequent stop in case of insufficient response

• Hypomagnesemia (about 5-15%): substitute 200 mg/day, possibly more

• Hyperpotassemia (>5.0 mmol/l): potassium-deficient nutrition, ensure sufficient fluid intake (2-3 l/day), reduce CsA by 25%, acute management of severe hyperpotassemia (≥6.0 mmol/l)

• Elevation of bilirubin (10-80%) or transaminases (up to 30%) by twice the upper limit of normal should lead to a dose reduction by 25% and laboratory control after 30 days; if still elevated, consider CsA cessation

• Elevation of blood lipids (fasting cholesterol and triglycerides) should be answered with a low-cholesterol- and low-fat diet, dose reduction, or stop of CsA, respectively. Statins or fibrates are not recommended due to the risk of restriction of renal function and myalgia to rhabdomyolysis

• Gingival hyperplasia (in up to 15%): optimal dental hygiene, dose reduction, if persistent, stop CsA. More frequent in case of concomitant nifedipine treatment

There are several interactions that need to be checked before initiation of treatment. CsA can reduce the efficacy of progesterone-containing contraceptives. Sufficient contraception has to be ensured.

• Increase in the cyclosporine level (CYP3A inhibition) due to: grapefruit juice, allopurinol, calcium antagonists, amiodarone, antibiotics (macrolides, clarithromycin, josamycin, ponsinomycin, pristinamycin, doxycycline, gentamicin, tobramycin, ticarcillin, quinolones), ketoconazole, oral contraceptives, methylprednisolone (high dosages), ranitidine, cimetidine

• Decrease in the cyclosporine level (CYP3A induction) due to: carbamazepine, phenytoin, barbiturates, metamizole, St. John's wort

• Possible reinforcement of nephrotoxic adverse drug reactions by: aminoglycosides, amphotericin B, ciprofloxacin, acyclovir, nonsteroidal antiphlogistics

• Specific interactions:

- Potassium-saving substances: increased risk of hyperpotassemia

- Reduced clearance of: digoxin, colchicine, prednisolone, HMG-CoA reductase inhibitors (e.g. lovastatin), diclofenac

• Impaired renal function

• Insufficiently controlled arterial hypertension

• Severe infectious disease

• History of malignancy (possible exceptions: treated basal cell carcinoma, history of squamous carcinoma in situ)

• Current malignancy

• Simultaneous PUVA therapy

• Previous potential carcinogenic therapies (e.g. arsenic, PUVA >1,000 J/cm²)

• Psoriasis triggered by severe infection or drugs (β- blockers, lithium, antimalarial drugs)

• Significant hepatic diseases

• Hyperuricemia

• Hyperkaliemia

• Simultaneous therapy with nephrotoxic drugs (see drug interactions)

• Simultaneous phototherapy (selective UV therapy, except PUVA, see above)

• Simultaneous use of other systemic immunosuppressive agents

• Simultaneous use of systemic retinoids or therapy with retinoids in the last 4 weeks prior to planned onset of therapy with cyclosporine

• Drug or alcohol-related diseases

• Long-term previous treatment with MTX

• Pregnancy/breast-feeding

• Vaccination with live vaccines

• Epilepsy

• Current treatment with castor oil preparations

In case of CsA overdosing, CsA should be stopped, drug levels for CsA should be measured; vital parameters, liver and kidney function as well as electrolytes should be measured.

None for psoriasis. It is however common practice to prescribe CsA for psoriasis without prior confirmation of coverage.

FAEs in psoriasis have been known since 1959, but FAEs have so far been registered only in Germany in 1995. Due to tolerability (table 6), FAEs are slowly introduced via Fumaderm initial® (contains 30 mg dimethylfumarate) and Fumaderm® (contains 120 mg dimethylfumarate); see table 7 for a recommended dosage scheme.

Up to 60% of patients suffer from transient gastrointestinal side effects in the first few weeks. In severe cases it is necessary to reduce the dosage and to discontinue treatment. The intake of FAEs with milk products can improve its gastrointestinal tolerability, as can a regular and stable time point during the day for drug intake. After increasing the dose up to Fumaderm® 2-2-2 tablets and/or a dose with a satisfactory psoriasis response, the maintenance dosage can be reduced based on individual treatment requirements.

FAEs have relatively few drug interactions (less than 5%) and can be used also in comorbid patients on a case-by-case basis [30,31,32]. Prior to prescription, the reimbursement must be confirmed for every single patient by the respective health insurance [3].

• Severe general disease

• Chronic gastrointestinal diseases

• Severe liver and kidney diseases

• Chronic diseases accompanied by disturbances in leukocyte counts and functions

• Malignancies

• Pregnant or lactating women

• Hypersensitivity to FAEs

FAEs are off label in Switzerland and need to be imported by an international pharmacy. It is obligatory to seek reimbursement of the health insurance provider prior to prescribing FAEs.

MTX is indicated for moderate-to-severe psoriasis and can also be efficacious in pustular or erythrodermic forms. MTX is also indicated in psoriatic arthritis. There is still no clear consensus about the use of folic acid during MTX treatment. It could be shown that folic acid reduces the incidence of abnormal liver function tests and withdrawal from treatment as well as a trend towards a reduction in gastrointestinal side effects and stomatitis. 5 mg folic acid at least 24 h after MTX is commonly used, or it can also be taken 24 h before MTX in case of persisting gastrointestinal side effects [34,35] (table 8). Contraception (women and men) is warranted during treatment and should be continued for 3 months after treatment discontinuation. More frequent laboratory tests are required in patients with an increased risk of elevated MTX levels (dehydration, diminished renal function) or when increasing the dosage.

It is recommended to perform a chest X-ray before MTX initiation as a baseline image to compare against in case of signs of pneumonitis (table 9). In up to 8% of the patients an MTX-induced pneumonitis occurs [36]. The determination of procollagen III N-terminal peptide is controversial but recommended in the European and German S3 psoriasis guidelines and others [4,37,38,39].

• Severe infections

• Severe liver disease

• Renal failure

• Conception (men and women)/breast-feeding

• Alcohol abuse

• Bone marrow dysfunction/hematological changes

• Immunodeficiency

• Acute peptic ulcer

• Significantly reduced lung function

• Hypersensitivity to MTX

• Kidney or liver disorders

• Ulcerative colitis

• History of hepatitis

• Lack of compliance

• Active desire to have a child for women of childbearing age and men

• Gastritis

• Diabetes mellitus

• Previous malignancies

• Congestive heart failure

Acute toxicity includes myelosuppression, mucosal (especially oral) ulceration and rarely cutaneous necrosis (especially if the dosage of MTX is increased too rapidly) [34]. Calcium leucovorin serves as antidote to MTX-induced hematological toxicity, but its efficacy decreases with the delay after administration of MTX. In case of overdose, calcium leucovorin should be administered at 20 mg (or 10 mg/m²) i.v. or i.m. and repeated every 6 h intravenously, intramuscularly or orally (if given orally the dose of leucovorin should be increased by 15 mg). MTX levels should be measured every 12-24 h until the serum MTX concentration is below 10^-8 mol/l. If MTX levels are not available, continue giving leucovorin until the blood count has normalized and mucosal lesions have healed. To increase drug survival by inhibition of the development of antidrug antibodies or enhancing efficacy, concomitant MTX is often added to TNF inhibitor treatment, especially in patients receiving IFX [40,41].

None for psoriasis. It is however common practice to prescribe MTX for psoriasis without prior confirmation of coverage.

ADA (Humira®) is a recombinant human IgG1 monoclonal antibody binding soluble and membrane-bound TNF-α [42] and is indicated for moderate-to-severe psoriasis patients who failed a prior treatment with at least one conventional systemic drug or phototherapy. ADA is also indicated in psoriatic arthritis. The recommended dosage is 80 mg s.c. on day 0 for induction, followed by 40 mg s.c. every other week beginning 1 week after induction for maintenance of treatment.

In case of infection during treatment, stop temporarily. In case of pregnancy, stop until the end of pregnancy and restart not earlier than 5 months after the last ADA injection, which counts also for breast-feeding. ADA should be discontinued 4-8 weeks prior to and may be restarted 2-3 weeks after a live attenuated vaccination [34]. Patients should be informed about the potential risk for serious and atypical infections and in case of symptoms should seek medical advice. The material of the ADA syringe or pen is to be latex free (table 10).

• Concomitant immunosuppressive therapy

• Active chronic hepatitis B

• Active tuberculosis

• Congestive heart failure (NYHA grade III/IV)

• Pregnancy/breast-feeding

• Hypersensitivity to ADA

• History of recurrent infections

• Underlying conditions predisposing to infections

• Psoriasis patients with concomitant systemic lupus erythematosus or multiple sclerosis

• Live attenuated vaccines

• Localized infections

• Latent tuberculosis

• Patients living in geographical areas where tuberculosis and histoplasmosis are widespread

• Hepatitis C

• >200 PUVA treatments (especially if followed by cyclosporine use)

• Malignancies (apart from successfully treated nonmelanoma skin cancer and cervical dysplasia) and lymphoproliferative disorders

Treatment of adults with severe plaque-type psoriasis who did not experience therapeutic success with UVB and PUVA or one of the following systemic therapies: cyclosporine, MTX, acitretin. The treatment has to be stopped in case of no therapeutic success after 12 weeks. For psoriasis it can only be prescribed by dermatologists or dermatological university hospitals/outpatient clinics.

ETA (Enbrel®) is a soluble TNF receptor Fc fusion protein which binds soluble and membrane-bound TNF-α as well as lymphotoxin-β [42] and is indicated for moderate-to-severe psoriasis patients who failed a prior treatment with at least one conventional systemic drug or phototherapy. ETA is also indicated in psoriatic arthritis. The recommended initial dosage is 1 × 50 mg or 2 × 50 mg weekly over 12 weeks followed by a maintenance dosage of 1 × 50 mg weekly. 2 × 50 mg for the induction phase has a faster onset compared to 1 × 50 mg [43].

In case of infection during treatment, stop temporarily, and in case of pregnancy, stop until the end of pregnancy and breast-feeding. ETA can be discontinued without any relevant loss of efficacy at re-initiation as no neutralizing antibodies against ETA are produced [44]. ETA should be discontinued 4-8 weeks prior to and may be restarted 2-3 weeks after a live attenuated vaccination. Patients should be informed about the potential risk for serious and atypical infections and in case of symptoms should seek medical advice. The removable cap of the SureClick® autoinjector and the prefilled syringe contain latex which may cause an allergic reaction in latex-sensitive individuals (table 11).

• Active (chronic) infections (including tuberculosis and active chronic hepatitis B)

• Congestive heart failure (NYHA grade III or IV)

• Hypersensitivity to ETA

• Pregnancy/breast-feeding

• >200 PUVA treatments (especially if followed by cyclosporine use)

• HIV or AIDS

• Hepatitis C and B

• Congestive heart failure (NYHA grade I or II)

• Demyelinating disease (also family history)

• Malignancies (apart from successfully treated nonmelanoma skin cancer and cervical dysplasia) or lymphoproliferative disorders

• Live attenuated vaccines

Treatment of adults with severe plaque-type psoriasis who did not experience therapeutic success with UVB and PUVA or one of the following systemic therapies: cyclosporine, MTX, acitretin. The treatment has to be stopped in case of no therapeutic success after 12 weeks. For psoriasis it can only be prescribed by dermatologists or dermatological university hospitals/outpatient clinics. Cost coverage has to be granted by the patient's health insurance.

IFX (Remicade®) is a chimeric (mouse/human) monoclonal antibody binding soluble and membrane bound TNF-α [42] and is indicated for moderate-to-severe psoriasis patients who failed a prior treatment with at least one conventional systemic drug or phototherapy and at least one TNF-α antagonist treatment. IFX is also indicated in psoriatic arthritis. IFX is the only available intravenous biological for psoriasis and is available as powder in 100-mg vials which should be stored at 2-8°C and reconstituted in 10 ml sterile water. The total dosage should be diluted with 250 ml of 0.9% saline solution, infused over a period of 2 h and monitored 1 h after treatment. The recommended dosage is 5 mg/kg body weight at weeks 0, 2 and 6 for induction followed by infusions every 8 weeks.

In rheumatological conditions, IFX is often combined with MTX to improve long-term efficacy. It could additionally be shown that the treatment survival rates of all three TNF-α antagonists are better in combination with MTX [40,45]. In case of overdose, the patient should be followed closely for adverse events, particularly infections (table 12).

Infusion reactions occur in about 20% of patients with an increased risk in patients who developed antibodies against IFX. Most reactions are mild to moderate (flush, pruritus, chills, headache, urticaria), and about 1% are severe (anaphylactic reactions, serum-sickness-like delayed-type hypersensitivity reactions like myalgia, arthralgia and/or exanthema occurring between 1 and 14 days after infusion). In case of mild-to-moderate reactions, treatment can be continued with the following measures: the infusion rate should be decreased or temporarily stopped, and pretreatment with oral antihistamines, paracetamol and/or corticosteroids 1 day before and directly before the next infusion should be performed [30,46,47].

Up to 8% of patients develop elevated liver enzymes (aspartate/alanine transaminases >150 U/l and more than twice from baseline). With close monitoring, treatment can be continued in most cases (possible if values <3 times the upper limit of normal; with caution if values are 3-5 times the upper limit of normal; stop if values are >5 times the upper limit of normal).

More than 50% of patients develop anti-nuclear antibodies and about 17% anti-dsDNA antibodies. In case of a lupus-like syndrome (45% cutaneous, 55% systemic) where also other autoantibodies occur, treatment should be discontinued as soon as the diagnosis is made, which leads to a resolution in 94% of cases after 3 weeks to 6 months [48,49].

In severe disease with pulmonary, renal, neurological disease, an additional initiation of corticosteroids and/or immunosuppression might be necessary. Rechallenging with another TNF inhibitor might be a potential option [50,51,52,53].

In case of infection during treatment, interrupt IFX temporarily. In case of pregnancy, IFX should normally be stopped until the end of pregnancy. In women of childbearing age, reliable contraception is required until 6 months after the last infusion. IFX should be discontinued 4-8 weeks prior to and may be restarted 2-3 weeks after a live attenuated vaccination. Patients should be informed about the potential risk for serious and atypical infections and in case of symptoms should seek medical advice.

• Active tuberculosis

• Significant active infection

• Active chronic hepatitis B

• Heart failure (NYHA grade III/IV)

• Hypersensitivity to IFX, murine proteins or any component of the formulation

• Pregnancy or breast-feeding

• Demyelinating diseases

• Live attenuated vaccines

• >200 PUVA treatments (especially if followed by cyclosporine use)

• Malignancies (apart from successfully treated nonmelanoma skin cancer and cervical dysplasia) or lymphoproliferative disorders

• Hepatobiliary disorders

• Hepatitis C

Treatment of adults with severe plaque-type psoriasis where UVB and PUVA or one of the systemic therapies (cyclosporine, MTX, acitretin) and a TNF-α blocker (e.g. ETA) showed no therapeutic success. The treatment has to be stopped in case of lacking therapeutic success after 14 weeks. The maximum duration of treatment is 1 year. In case of psoriasis it can only be prescribed by dermatologists or dermatological university hospitals/outpatient clinics. Cost coverage has to be granted by the patient's health insurance.

SEC (Cosentyx®) is a fully human monoclonal IgG1 antibody that binds and antagonizes the cytokine IL-17A. It can be prescribed to patients with moderate-to-severe psoriasis who failed UVB and PUVA or one of the following systemic therapies: CsA, MTX, acitretin.

The recommended dosage is 300 mg s.c. at week 0, 1, 2 and 3 for induction, followed by 300 mg s.c. every 4 weeks for maintenance of treatment starting in week 4 [54].

In case of infection during treatment, interrupt temporarily, and in case of pregnancy, stop until the end of pregnancy and breast-feeding. Patients should be informed about the potential risk for serious and atypical infections and in case of symptoms should seek medical advice [55].

The removable cap of the Cosentyx SensoReady® pen and the Cosentyx prefilled syringe contain natural rubber latex, which may cause an allergic reaction in latex-sensitive individuals (table 13).

• Active tuberculosis or acute, severe infections

• Live attenuated vaccines

• Active chronic hepatitis B

• Pregnancy/breast-feeding

• Hypersensitivity to secukinumab

• Crohn's disease (monitor closely)

• Malignancies (apart from successfully treated nonmelanoma skin cancer and cervical dysplasia) and lymphoproliferative disorders

With lack of data or recommendations, the following medical states should be considered very carefully: latent tuberculosis, hepatitis C and HIV.

Treatment of adults with severe plaque-type psoriasis who did not experience therapeutic success with UVB and PUVA or one of the following systemic therapies: cyclosporine, MTX, acitretin. The treatment has to be stopped in case of no therapeutic success after 12 weeks. For psoriasis it can only be prescribed by dermatologists or dermatological university hospitals/outpatient clinics. Cost coverage has to be granted by the patient's health insurance.

UST (Stelara®) is a recombinant, fully human IgG1κ antibody with high specificity and affinity to the p40 subunit of IL-12 and IL-23. It can be prescribed to patients with moderate-to-severe psoriasis who failed a prior treatment with at least one conventional systemic drug or phototherapy. UST is also registered for psoriatic arthritis.

The recommended dosage is 45/90 mg s.c. at weeks 0 and 4 for induction, followed by 45/90 mg s.c. every 12 weeks for maintenance of treatment (i.e. 45 mg in patients <100 kg body weight, 90 mg in patients ≥100 mg body weight). As the price of the 45- and 90-mg doses is the same now in Switzerland, dose adjustment of patients receiving 45 mg with insufficient response to 90 mg every 12 weeks may be beneficial [56].

In case of infection during treatment, stop temporarily, and in case of pregnancy, stop until the end of pregnancy. UST should be discontinued 15 weeks prior to live attenuated vaccination or pregnancy. It may be restarted 2 weeks after live attenuated vaccination. Patients should be informed about the potential risk for serious and atypical infections and in case of symptoms should seek medical advice.

The removable cap of the prefilled syringe contains latex which may cause an allergic reaction in latex-sensitive individuals (table 14).

• Hypersensitivity to the active substance or to any of the excipients

• Clinically important active infection including untreated latent tuberculosis

• Malignancies (apart from successfully treated nonmelanoma skin cancer and cervical dysplasia) and lymphoproliferative disorders

• Pregnancy

• Live vaccines

Treatment of adults with severe plaque-type psoriasis who did not experience therapeutic success with UVB and PUVA or one of the following systemic therapies: cyclosporine, MTX, acitretin. The treatment has to be stopped in case of lacking therapeutic success after 3 injections. For psoriasis it can only be prescribed by dermatologists or dermatological university hospitals/outpatient clinics. Cost coverage has to be granted by the patient's health insurance.

Before the decision for a systemic therapy of any kind is made, the expectations of both patient and physician should be considered, as this is crucial for the choice of treatment and adherence. This conversation should cover e.g. efficacy, side-effects, preference of oral versus injectable drugs, monitoring, comorbidities and costs. Tables 1 and 2 show the widely variable PASI75 and PASI90 responses after 10-24 weeks [20,24,57,58]. Where head-to-head studies are lacking, direct comparison between drugs is not advisable.

In case where moderately efficacious drugs yield significant additional advantages such as oral intake, few side effects and/or potentially cheap long-term therapy, the achievement of PASI75 or PASI90 within 3 months might play a secondary role. For newer, expensive drugs such as all the biologicals and novel small molecules, a high efficacy should be expected and taken into account when evaluating the treatment response. A recent European consensus [59] goal (modified by adding the PrecisePASI) is useful and is utilized regularly in the tertiary centers in Switzerland. The aim of effective treatment (fig. 1) is a PASI reduction from baseline to time of evaluation (ΔPASI) as well as a reduction of the DLQI. If after an induction phase of up to 16 weeks (depending on medication) these end points are met, the medication can be continued. If the PASI value is not improved by at least 50%, or if the DLQI is still more than 5 points and the PASI response is between 50 and 75%, the treatment regimen is not satisfactory and needs to be modified. If the DLQI is below 5 points, the treatment regimen could be continued even if the PASI response is between 50 and 75% [17]. In the future, those thresholds might even be increased (online suppl. fig. 1) to PASI90 and Precise PASI90 and DLQI <5 as main goals of treatment [24,57,60]. As quality of life is an important goal in the treatment, and adherence should also be considered in defining a severe psoriasis in patients not having reached PASI of 10, we recommend that patients fill out the DLQI (Appendix 1) prior to consultation [61,62,63]. Different language versions of the DLQI (for English, German, French and Italian see the online suppl. material) can be found online: http://sites.cardiff.ac.uk/dermatology/quality-of-life/dermatology-quality-of-life-index-dlqi/dlqi-different-language-versions/.

For 52 weeks every 3 months and thereafter every 6 months, the same evaluation should be performed and the treatment strategy reevaluated. A potential future goal of reaching PASI90 within 52 weeks after starting therapy seems achievable with newer therapies. However, all options should be considered and discussed with the patient, including keeping alternative drug options available in case a switch should be required later on.

Optimizations of small molecule therapies include the combination of the best effective dose and the lowest rate of possible side effects (see each systemic medication) suggested by the progressive psoriasis initiative as an evidence-based consensus on treatment optimization and transitioning [64].

Transitioning from small molecules (MTX, CsA, acitretin) therapy to biological therapy can in most cases be performed without a washout period or even overlapping if no safety issues arise. APR was not discussed in this work. Combining conventional systemic therapy with biological therapy is currently considered off-label treatment. Nevertheless, this strategy is often used to improve efficacy, optimize the risk-benefit profile, reduce the risk of immunogenicity (with MTX) [41] and improve long-term disease management. Monitoring should be the same as for monotherapy with intervals defined by the agent with more stringent monitoring criteria. If synergistic toxicity is suspected, more frequent monitoring intervals may be required and additional monitoring parameters added. Switching between biologicals due to failure is recommended without a washout period at the time of the next scheduled dose. In case of switching from UST to another biological, the new drug can be used as early as 2-4 weeks after the last dose of UST.

Long-term disease control is achieved with a continuous therapy adjusted to the pathogenesis, comfortable drug intake, long-term safety with minimal pharmaceutical interactions and minimal monitoring. Temporary interruption of systemic therapy can be considered with careful follow-up (please note: in CsA therapy, careful dose reduction is indicated due to the risk of rebound of disease). Recurrence can be expected within 2-6 months. Before interrupting or stopping a certain therapy, all relevant factors should be considered, name ly comorbidities including the presence of psoriatic arthritis, individual risk factors, long-term safety, prior course of disease, especially the pattern of flares and rebounds, availability of other treatment options in case of rebound (and/or lower response after treatment reinitiation) and patients' preference. Recurrence of limited disease may be controlled with topical therapy, systemic therapy should be reintroduced if the Physician's Global Assessment appears to be >2 and/or PASI ≥5 and/or DLQI ≥5 or in case of rapid recurrence.

Dose reduction during successful biological monotherapy can be considered, but there is a risk of loss of efficacy due to immunogenicity by neutralizing antidrug antibody formation [44], especially in case of infliximab and adalimumab. Dosing intervals have been lengthened with ADA and ETA, but this is not recommended for IFX and UST. Dose reduction is possible for IFX down to a minimum of 3 mg/kg body weight, for UST in patients who are treated with 90 mg s.c. every 12 weeks and for ETA in patients who are treated with 50 mg s.c. every week or 25 mg s.c. biweekly. Strategies for nonresponders are to increase the dosage for ADA (40 mg every other week to 40 mg every week), for ETA (50 mg every week to 50 mg biweekly), for UST (45 mg every 12 weeks to 90 mg every 12 weeks [56], with the possibility to further decrease the intervals to every 8 weeks [65]) and for IFX (interval reduction from every 8 weeks to every 6 weeks and in special cases an increase in dose >5 mg/kg body weight). These strategies can increase costs of treatment enormously, therefore secondary loss of response due to immunogenicity has to be ruled out [66]. Combination of small molecules with biologicals is discussed above.

In recent years comorbidities of psoriasis like psoriatic arthritis, cardiovascular disease and risk factors including obesity, arterial hypertension, dyslipidemia and type 2 diabetes mellitus, nonalcoholic fatty liver disease, inflammatory bowel disease, lymphoma and skin cancer, anxiety and depression, tobacco and alcohol consumption have attracted particular interest.

To prevent progression and treat psoriasis-associated comorbidities as early as possible, an integrated management is required that also takes the side effects of systemic treatments for psoriasis such as arterial hypertension or hyperlipidemia into account. Additionally, medication which can worsen psoriasis like β-blockers, angiotensin-converting enzyme inhibitors, antimalarials, lithium, interferons, and less commonly contraceptives or nonsteroidal antirheumatic drugs should be ruled out, especially in newly arising forms of psoriasis. Lastly, uncontrolled interruption of systemic corticosteroid treatment should be considered as a risk factor for flares of psoriasis. Six-monthly screening intervals for comorbidities have been suggested in patients with systemic treatment and every 12 months in patients receiving topical treatment (noninterfering with the recommended control intervals during different treatments) [67] (table 15).

Psoriatic arthritis is a common comorbidity in psoriasis patients (up to 41%) and supposed to be underdiagnosed [68]. We recommend the use of a fast and simple screening tool for psoriatic arthritis, e.g. the PEST assessment (Psoriasis Epidemiology Screening Tool) which the patients can fill out prior to consultation (Appendix 2; see also online suppl. material for different language versions) or at least to routinely ask for joint and back pain [69,70].

Guidelines are intended for use by clinicians, dermatologists in private practice and other specialists involved in the treatment of patients with psoriasis vulgaris and also provide a guide for health insurers and policy-makers.

The description of selected therapies (tables 16, 17) is intentionally restricted to the most relevant aspects in the opinion of the guidelines' expert committee. Certain aspects which are not listed separately but might be of interest are 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, are complete and current. Correct dosage and administration are solely the responsibility of the administering physician.

Science and medical research are under constant development, and our knowledge is constantly growing. In case of any inaccuracies we kindly ask the readers of this guideline to inform us. We took great care to ensure that this guideline represents current knowledge [3].

We thank Prof. Philip S. Helliwell, Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Chapel Allerton Hospital, Leeds, UK, for getting formal permission for using the PEST assessment and Prof. Andrew Finlay, Department of Dermatology, Cardiff University School of Medicine, Cardiff, UK, for getting formal permission for using the DLQI score in our guideline.

The planned translation in the national languages of the guideline will be supported by educational grants of AbbVie, Janssen, and Pfizer to the Department of Dermatology, University of Zurich. The pharmaceutical industry had no influence on the content of the guideline.

Nikhil Yawalkar has served as an investigator, speaker, and/or advisor for AbbVie, Amgen, Celgene, Eli Lilly, Galderma, Janssen, Leo Pharma, MSD, Pfizer, Novartis, and does not hold any shares or other financial interest in any related pharmaceutical company. Mark Anliker served as an investigator, speaker, and/or advisor for AbbVie, Janssen, Merck, Celgene, Novartis, and does not hold any shares or other financial interest in any related pharmaceutical company. Wolf-Henning Boehncke has served as advisor and/or speaker for Abbvie, Almirall, Amgen, Celgene, Janssen, Leo, Lilly, MSD, Novartis, and Pfizer. Luca Borradori has no conflict of interest related to the subject. Curdin Conrad has served as consultant, paid speaker, and/or principal investigator in clinical trials for AbbVie, Actelion, Amgen, Celgene, Eli Lilly, Galderma, Janssen-Cilag, Leo Pharma, MSD, Novartis, and Pfizer. Michel Gilliet has no conflict of interest related to the subject. Peter Häusermann has no conflict of interest related to the subject. Peter Itin has no conflict of interest. Emmanuel Laffitte served as an investigator, speaker, and/or advisor for AbbVie, Abbott, Janssen, MSD, Pfizer, Celgene, Novartis, Leo, Amgen, Eli Lilly, and does not hold any shares or other financial interest in any related pharmaceutical company. Carlo Mainetti served as an advisor and/or speaker for AbbVie, Abbott, MSD, Celgene, Novartis, Leo Pharma, Amgen, and Eli Lilly. Lars E. French has served as consulting, advisory, and/or principal investigator for AbbVie, Amgen, Celgene, Actelion, Janssen-Cilag, and Novartis. Alexander Navarini has served as an investigator, speaker, and/or advisor for AbbVie, Janssen, MSD, Pfizer, Celgene, Novartis, Amgen, Actelion, and does not hold any shares or other financial interest in any related pharmaceutical company. Antonios Kolios has served as an investigator, speaker, and/or advisor for AbbVie, Abbott, Janssen, Eli Lilly, MSD, Pfizer, Celgene, Novartis, Actelion, Leo, Amgen, Alk-Abello, and does not hold any shares or other financial interest in any related pharmaceutical company.