Diagnostic and therapeutic guidelines for plaque psoriasis - Brazilian Society of Dermatology*

Psoriasis is a chronic inflammatory disease that affects 1.3% of the Brazilian population. The most common clinical manifestations are erythematous, scaling lesions that affect both genders and can occur on any anatomical site, preferentially involving the knees, elbows, scalp and genitals. Besides the impact on the quality of life, the systemic nature of the disease makes psoriasis an independent risk factor for cardiovascular disease, especially in young patients with severe disease. By an initiative of the Brazilian Society of Dermatology, dermatologists with renowned clinical experience in the management of psoriasis were invited to form a work group that, in a partnership with the Brazilian Medical Association, dedicated themselves to create the Plaque Psoriasis Diagnostic and Treatment Guidelines. The relevant issues for the diagnosis (evaluation of severity and comorbidities) and treatment of plaque psoriasis were defined. The issues generated a search strategy in the Medline-PubMed database up to July 2018. Subsequently, the answers to the questions of the recommendations were devised, and each reference selected presented the respective level of recommendation and strength of scientific evidence. The final recommendations for making up the final text were worded by the coordinators.

# Introduction
In

## Objective
To establish the recommendations for the diagnosis (assessment of severity and comorbidities) and the treatment of plaque psoriasis.

## Tools of severity assessment
With the aim of evaluating the role of the assessment tools applied to psoriasis patients, a Medline-PubMed database search was conducted, resulting in 984 studies, of which 14 were selected to answer to the clinical question. [bib_ref] Interobserver reliability of the Nail Psoriasis Severity Index, Aktan [/bib_ref] [bib_ref] What are the best outcome measures for assessing quality of life in..., Bronsard [/bib_ref] [bib_ref] The Simplified Psoriasis Index (SPI): A Practical Tool for Assessing Psoriasis, Chularojanamontri [/bib_ref] [bib_ref] Assessing clinical response and defining minimal disease activity in plaque psoriasis with..., Gottlieb [/bib_ref] [bib_ref] Infliximab induction therapy for patients with severe plaque-type psoriasis: a randomized, doubleblind,..., Gottlieb [/bib_ref] [bib_ref] Evaluating psoriasis with Psoriasis Area and Severity Index, Psoriasis Global Assessment, and..., Langley [/bib_ref] [bib_ref] Skin pain and skin discomfort is associated with quality of life in..., Ljosaa [/bib_ref] [bib_ref] Is the Nail Psoriasis Severity Index reliable in the assessment of nail..., Lubrano [/bib_ref] [bib_ref] Healthrelated quality of life in patients with psoriasis and atopic dermatitis measured..., Lundberg [/bib_ref] [bib_ref] Psoriasis Area Severity Index (PASI) and the Dermatology Life Quality Index (DLQI):..., Mattei [/bib_ref] [bib_ref] Infliximab induction and maintenance therapy for moderate-to-severe psoriasis: a phase III, multicentre,..., Reich [/bib_ref] [bib_ref] Nail Psoriasis Severity Index: a useful tool for evaluation of nail psoriasis, Rich [/bib_ref] [bib_ref] Physician Global Assessment (PGA) and Psoriasis Area and Severity Index (PASI): why..., Robinson [/bib_ref] [bib_ref] Product of the Physician Global Assessment and body surface area: a simple..., Walsh [/bib_ref] What is the role of the assessment tools PASI, BSA, DLQI and PGA for the assessment of severity and therapeutic response of plaque psoriasis?

## Pasi
In the PASI (Psoriasis Area Severity Index) score, the evaluator should observe the erythema, thickness, scaling, and the percentage of the area affected of four regions (head/neck, trunk, lower and upper limbs) and calculate the score, which varies from 0 to 72 (B). [bib_ref] Product of the Physician Global Assessment and body surface area: a simple..., Walsh [/bib_ref] In the evaluation of severity in plaque psoriasis patients, the PASI tool demonstrated adequate content validity and internal consistency and moderate intraobserver variation. Despite some limitations, PASI can be recommended for the scientific evaluation of the severity of plaque psoriasis (B). [bib_ref] What are the best outcome measures for assessing plaque psoriasis severity? A..., Puzenat [/bib_ref] 

## . 2 p g a this tool [physician s global assesment (pga)] only
evaluates the features of the lesion, measuring the degree of erythema, scaling and thickness of psoriasis lesions of the whole body, grading in a six-point scale, ranging from 0 (no lesion) to 6 (severe); however, it does not provide information on the extension of the disease (B). [bib_ref] Product of the Physician Global Assessment and body surface area: a simple..., Walsh [/bib_ref] It demonstrated adequate content validity, moderate interobserver variation and low intraobserver variation (B). [bib_ref] What are the best outcome measures for assessing plaque psoriasis severity? A..., Puzenat [/bib_ref] 1.3 BSA BSA (Body Surface Area) was defined as the percentage of body area, where 1% corresponds to approximately the palm of the hand of the patient being assessed (B). [bib_ref] Product of the Physician Global Assessment and body surface area: a simple..., Walsh [/bib_ref] It demonstrated little intraobserver variation, however, an unacceptable interobserver variation for the evaluation of the severity of disease. It is not adequate to define psoriasis severity because it does not assess the intensity of the lesion (B). 16

## Dlqi
The Dermatology Life Quality Index (DLQI) measures the impact of the skin disease in the quality of life of the patient in the last seven days. It consists of 10 items, six dimensions and one overall summary score. Each question has four alternative answers: "not at all", "a little", "a lot" or "very much", with scores of 0, 1, 2 and 3, respectively. The overall summary score aggregates the score of each item and ranges between 0 (the best score) and 30
(the worst score). (B). [bib_ref] Healthrelated quality of life in patients with psoriasis and atopic dermatitis measured..., Lundberg [/bib_ref] In plaque psoriasis patients, the DLQI tool demonstrated adequate content validity, construct validity, internal consistency, replicability, acceptability and sensitivity in appropriately detecting changes in the disease (B). [bib_ref] The Simplified Psoriasis Index (SPI): A Practical Tool for Assessing Psoriasis, Chularojanamontri [/bib_ref] Due to its briefness and simplicity, it is useful for the clinical practice (B). 3

## Napsi
NAPSI (Nail Psoriasis Severity Index) is used to evaluate the severity of psoriasis in the nail bed and nail matrix. The nail plate is divided into quadrants using an imaginary longitudinal and horizontal lines. The involvement of the nail matrix and nail bed is assessed, and the score ranges from 0 to 8 per nail. The tool is replicable and the analysis is simplified (B). [bib_ref] Nail Psoriasis Severity Index: a useful tool for evaluation of nail psoriasis, Rich [/bib_ref] Although it has a few limitations (B), the scoring agreement among observers was considered between good to moderate with NAPSI (B). [bib_ref] Interobserver reliability of the Nail Psoriasis Severity Index, Aktan [/bib_ref] [bib_ref] Is the Nail Psoriasis Severity Index reliable in the assessment of nail..., Lubrano [/bib_ref] FIgure 4: Prevalence of Asthma/COPD in moderate to severe plaque psoriasis patients FIgure 5: Prevalence of chronic liver disease in moderate to severe plaque psoriasis patients

## Systemic hypertension
The prevalence of systemic hypertension (SHT) in psoriasis patients in the random effects model is of.9% (CI 95%: 21.5-33; .

## Diabetes mellitus
The prevalence of diabetes mellitus (DM) in psoriasis patients in the random effects model is of 11.7% (CI 95%: 8.9-15.2; .

## Coronary insufficiency
The prevalence of ischemic cardiomyopathy or coronary insufficiency in psoriasis patients in the random effects model is of [bib_ref] What are the best outcome measures for assessing quality of life in..., Bronsard [/bib_ref].4% (CI 95%: 2.3-5%; [fig_ref] 6. 11: Is there a difference in the efficacy of the treatment with immunobiologics... [/fig_ref].

## Inflammatory bowel disease
The prevalence of inflammatory bowel disease in psoriasis patients in the random effects model is of 0.9% (CI 95%: 0.6-1.3; .

## Migraine
The prevalence of migraine in psoriasis patients in the random effects model is of 15.5% (CI 95%: 0.3-84.8; .

## Other comorbidities
Other prevalent comorbidities in psoriasis patients were alexithymia; other dermatological conditions such as seborrheic dermatitis, acne, rosacea; pulmonary hypertension; and celiac disease In a study that evaluated clobetasol propionate lotion, cream or its vehicle, the use of lotion and cream showed significant and similar improvement (p<0.001). There was a reduction of lesions in 55% of patients using clobetasol propionate in both groups of active treatment (NNT=2) on the fourth week. Three patients of each treatment group with the active ingredient reported telangiectases, and four patients in the group using clobetasol cream reported mild to moderate skin atrophy (A). [bib_ref] Clobetasol propionate lotion in the treatment of moderate to severe plaque-type psoriasis, Decroix [/bib_ref] The use of 0.05% clobetasol propionate foam for two weeks was more effective than placebo (vehicle with no active ingredient), with improvement ranging from 47% to 22% (placebo) of patients reaching PGA score 0 or 1 (p<0.0001, NNT=3). The most common adverse event was burning sensation on the area of application (5% of the patients in the intervention group and 7% of the comparison group). There were no severe side effects, (A). [bib_ref] The efficacy and tolerability of clobetasol propionate foam 0.05% in the treatment..., Gottlieb [/bib_ref] [bib_ref] A randomized, double-blind, placebo-controlled study of clobetasol propionate 0.05% foam in the..., Lebwohl [/bib_ref] The use of betamethasone valerate (BMV) on one side of the body and placebo on the other side, twice daily for 12 weeks lead to at least 50% improvement against 24% in the placebo group . Adverse events were limited, being burning sensation and pruritus the most common (A). [bib_ref] Betamethasone valerate foam for treatment of nonscalp psoriasis, Stein [/bib_ref] The safety and efficacy of 0.005% fluticasone propionate ointment for four weeks was evaluated, in comparison with its vehicle. There was significantly more improvement in the intervention group (p<0.0001) measured by PGA 0/1 between 29.4% (NNT=4) and 36% (NNT=3). The adverse events were mild to moderate, the most common being burning sensation and pruritus on the area of application, which occurred in 6% of patients, both in the intervention and the comparison group (A). [bib_ref] Efficacy and safety of fluticasone propionate 0.005% ointment in the treatment of..., Olsen [/bib_ref] Dyslipidemia Prevalence FIgure 9: Prevalence of systemic hypertension in moderate to severe plaque psoriasis patients In the comparison between 0.05% betamethasone propionate ointment, its ointment vehicle and 0.05% diflorasone diacetate ointment, the group using betamethasone showed a faster improvement, seen already on the first week of treatment, with significant difference in relation to the group using diflorasone or to the control group (p=0.01). The improvement seen was maintained on the third
week. The adverse events were minimal (A). 105

## Recommendations:
In plaque psoriasis, the use of the topical corticosteroids clobetasol propionate, betamethasone valerate and fluticasone propionate, proved to be significantly effective in improving signs and symptoms of erythema, scaling, thickness of the plaque and pruritus, besides the significant improvement in the evaluation of the physician or the patient regarding clearance of the lesions. The most frequent adverse events were burning sensation and stinging on the area of application, both with the active ingredient and the placebo, with no significant difference among the comparison groups.

## What is the efficacy and risk of tar derivatives (coal tar and liquor carbonis detergens -lcd) for the treatment of psoriasis?
The use of 2% dithranol ointment, for one minute, once daily, associated to UVB phototherapy, resulted in significant clearance measured by the physician and the patient after eight weeks, except for pruritus (p=0.004). The adverse event reported during the study was skin irritation on the area of application (A). 42

## Recommendations:
Of the tar derivatives, only dithranol (associated to phototherapy) showed significant efficacy in the improvement of erythema, scaling and thickness of psoriasis plaques, not being effective for the improvement of pruritus. The adverse event observed with dithranol was local skin irritation.
There are no evidences that allow for the recommendation of coal tar and Liquor Carbonis Detergens for the treatment of Plaque Psoriasis.

## Prevalence

## Systemic hypertension
Diagnostic and therapeutic guidelines for plaque psoriasis -Brazilian Society of Dermatology FIgure 10: Prevalence of diabetes mellitus in moderate to severe plaque psoriasis patients

## What is the efficacy and risk of topical calcineurin inhibitors for the treatment of psoriasis?
The use of 6% salicylic acid gel associated to 0.1% tacrolimus ointment twice daily, on one side of the body, compared to 6% salicylic acid gel associated to placebo on the other side, lead to an improvement in the pruritus, erythema and scaling on weeks 1, 2 and 8 (p<0.05), as well as a significant improvement in the global assessment of the disease in week 8, except for the evaluation of erythema (A). [bib_ref] Better medication adherence results in greater improvement in severity of psoriasis, Carroll [/bib_ref] In a study that evaluated twice-daily 0.005% calcipotriol ointment or once-daily 0.3% tacrolimus ointment or placebo, there was no significant reduction in PASI with the use of topical tacrolimus in relation to placebo (p=0.77) (A). 116

## Recommendations:
Regarding the topical use of calcineurin inhibitors, tacrolimus does not show significant improvement in PASI reduction. However, in an evaluation eight weeks after starting the application, it proved to be effective for the improvement of pruritus, erythema and scaling of psoriatic plaques. When using the global assessment index from 0 to 5 points, there is no significant improvement in the erythema with the use of tacrolimus. There is no response evaluation after eight weeks of follow-up.

## What is the efficacy and the risk of vitamin d analogues for the treatment of psoriasis?
Calcipotriol ointment at 0.05% significantly improved lesions compared to the control group (p<0.001) (A), however, the active ingredient in a cream, in the same concentration did not show improvement when compared to placebo (p=0.12). [bib_ref] Comparison of the antipsoriatic effect and tolerability of calcipotriol-containing products in the..., Queille-Roussel [/bib_ref] In the physician's global assessment there is also a statistically significant difference between treatments, favoring twice-daily 0.005% calcipotriol, since the first week (p<0.001), which was maintained after the eighth week of treatment (A). [bib_ref] Calcipotriene ointment 0.005% for psoriasis: a safety and efficacy study. Calcipotriene Study..., Highton [/bib_ref] Prevalence Diabetes FIgure 11: Prevalence of coronary insufficiency in moderate to severe plaque psoriasis patients When compared to placebo, the use of 3 g/g calcitriol showed difference between 11.9% (p=0.05, NNT=9) and 21% (p<0.01, NNT=5)
in the physician's global assessment. The adverse events reported were mild, and included discomfort, pruritus or erythema (A). [bib_ref] Calcitriol 3 microg/g ointment in the management of mild to moderate plaque..., Lebwohl [/bib_ref] The efficacy evaluation of 15 g/g calcitriol according to the PASI score, showed there was a significant difference of response of 81% favoring topical treatment with calcitriol after two months of follow-up (NNT=2). Nonetheless, in the control group, 83.3% did not show any changes in the lesions and 1.2% had worsening (A). [bib_ref] Efficacy and safety of topical calcitriol (1,25-dihydroxyvitamin d3) for the treatment of..., Perez [/bib_ref] Regarding PGA, when 15g/g calcitriol was evaluated on one side of the body and its vehicle on the other side, there was a significant difference between the treatments on both sides of the body from the first week (p=0.0004), which was maintained after the sixth week (p=0.002), favoring calcitriol use (NNT=3) (A). 106

## Recommendations:
Vitamin D analogues, 50 g/g calcipotriol ointment, 0.005% calcipotriol foam and 6g/g calcitriol, were shown to be effective for the topical treatment of plaque psoriasis in a period of 4 to 16 weeks for the analysis of clinical features like erythema, scaling and plaque thickness, and for PASI and the investigator's or patient's global assessment. This class of drugs proved to be safe, since most side effects are mild and related to reactions on the areas of application such as erythema, pruritus and burning sensation.
3.5 What is the advantage of using the combination betamethasone + calcipotriol and the advantage in relation to topical corticosteroids for the treatment of psoriasis?
The comparison between 50g/g calcipotriol associated to 0.5mg/g betamethasone, or 50g/g calcipotriol alone, or 0.5mg/g betamethasone alone, when the SUM score is used (it evaluates erythema, thickness and scaling in the lesion), demonstrates that the mean percentage of score reduction in four weeks is of 61% for the combination of drugs, 32% for calcipotriol alone and 41% for betamethasone alone; on the sixth week, this reduction was of 58%, 45%
and 56%, respectively (A). [bib_ref] Treatment of plaque psoriasis with the two-compound product calcipotriol/betamethasone dipropionate versus both..., Van Der Velden [/bib_ref] When the difference in PASI change (in percentage) between the combination of drugs compared to betamethasone alone was evaluated, the result was 10.3% (CI95% 5.8% to 14.7%, p<0.001, NNT=10). (A). [bib_ref] Early onset of action and efficacy of a combination of calcipotriene and..., Papp [/bib_ref] If the mean PASI difference is evaluated in points during the treatment, the result was -13.1 for the intervention group (CI95% -16.9 to -9.3, p<0.001) in one study (A) and -14.2 for the intervention group (CI95% -17.6 to -10.8, p<0.001) in another (A) in up to eight weeks. [bib_ref] A new calcipotriol/betamethasone formulation with rapid onset of action was superior to..., Douglas [/bib_ref] [bib_ref] A New Calcipotriol/Betamethasone Dipropionate Formulation (Daivobet<sup>TM</ sup>) Is an Effective Once-Daily Treatment..., Kaufmann [/bib_ref] Side effects were mild and comparable between the groups analyzed (A). [bib_ref] A new calcipotriol/betamethasone formulation with rapid onset of action was superior to..., Douglas [/bib_ref] [bib_ref] A New Calcipotriol/Betamethasone Dipropionate Formulation (Daivobet<sup>TM</ sup>) Is an Effective Once-Daily Treatment..., Kaufmann [/bib_ref] Recommendations:
In plaque psoriasis lesions, the use of calcipotriol associated to topical betamethasone shows statistically significant improvement in comparison to the use of the topical corticosteroid alone, in a period of assessment of 4 to 8 weeks, regarding the evaluation with the PASI score.
3.6. What is the advantage of the use of the combination of betamethasone + calcipotriol and the advantage in relation to calcipotriol alone for the treatment of psoriasis? When 50g/g calcipotriol ointment, 50g/g calcipotriol cream, 50g/g calcipotriol associated to 0.5mg/g betamethasone dipropionate ointment, the same association in gel and 25g/g calcipotriol associated to 10mg/g hydrocortisone for up to 21 days were evaluated, there was a statistically significant difference bet-Prevalence Migraine ween the use of calcipotriol associated to betamethasone compared to the use of calcipotriol alone, considering erythema, scaling and thickness of psoriatic lesions (A). [bib_ref] Comparison of the antipsoriatic effect and tolerability of calcipotriol-containing products in the..., Queille-Roussel [/bib_ref] When evaluated with the SUM score, there is a statistically significant difference in the three variables analyzed on the fourth and sixth weeks (p<0.001) favoring the use of the combination of drugs. The mean percentage of reduction on the fourth week was of 61% for the use of the combination of drugs, 32% for calcipotriol alone and 41% for betamethasone alone; on the sixth week, this reduction was of 58%, 45% and 56% respectively (A). [bib_ref] Treatment of plaque psoriasis with the two-compound product calcipotriol/betamethasone dipropionate versus both..., Van Der Velden [/bib_ref] In the evaluation of the mean reduction in PASI, this was of 6.99 for the intervention group and 5.04 for the comparison group (A). [bib_ref] Efficacy, safety and quality of life of calcipotriol/betamethasone dipropionate (Dovobet) versus calcipotriol..., Saraceno [/bib_ref] The evaluation of the PASI reduction in eight weeks showed 73.3% reduction of the mean PASI percentage for the compound twice daily, 68.2% for the combination for four weeks, followed by calcipotriol alone for four more weeks and 64.1% for calcipotriol alone (A). [bib_ref] Efficacy of once-daily treatment regimens with calcipotriol/betamethasone dipropionate ointment and calcipotriol ointment..., Kragballe [/bib_ref] 

## Recommendations:
The use of calcipotriol associated to topical betamethasone demonstrates a statistically significant improvement in relation to the use of topical calcipotriol alone for plaque psoriasis lesions in the period of 2 to 8 weeks of evaluation.

## Phototherapy
With the aim of establishing the recommendations on the efficacy and safety of phototherapy for plaque psoriasis, a search was carried out in the Medline-PubMed database, resulting in 436 studies, with 09 selected to answer the clinical questions.

## What is the efficacy and risk of phototherapy for the treatment of psoriasis?
In the evaluation of the treatment of plaque psoriasis with the concurrent use of narrowband ultraviolet B (NB-UVB) phototherapy and fumaric acid esters and the use of fumaric acid esters alone, it was observed that the NB-UVB combined treatment led to a higher median reduction in the PASI score in six weeks of treatment, when compared to the use of fumaric acid alone (p=0.016), therefore, with a higher positive impact in the quality of life (p=0.031) and
less side effects (A). [bib_ref] Fumaric acid esters in combination with a 6-week course of narrowband ultraviolet..., Tzaneva [/bib_ref] In a study that compared NB-UVB phototherapy, the asso- (p=0.018, NNT=3)) (A). [bib_ref] A randomized study comparing the combination of nbUVB and etanercept to etanercept..., Lynde [/bib_ref] [bib_ref] Treatment with 311-nm ultraviolet B accelerates and improves the clearance of psoriatic..., Wolf [/bib_ref] The association of phototherapy to adalimumab also significantly accelerated and improved resolution of lesions, assessed by the PASI adapted for half of the body, with a 33% reduction of the PASI in the sixth week (NNT=3) (B). [bib_ref] 311 nm ultraviolet B-accelerated response of psoriatic lesions in adalimumab-treated patients, Wolf [/bib_ref] Adding calcipotriol to the NB-UVB phototherapy regime lead to a significant improvement (p<0.001) in week 12 when compared to NB-UVB alone or twice-daily calcipotriol only (A). [bib_ref] Comparison of clinical effects of psoriasis treatment regimens among calcipotriol alone, narrowband..., Takahashi [/bib_ref] Only one study did not show difference between the application of the topical active ingredient alone and the same application associated to phototherapy (A). [bib_ref] A non-inferiority randomized controlled clinical trial comparing Unani formulation & psoralen plus..., Khanna [/bib_ref] In patients with palmoplantar plaque psoriasis, the use of PUVA (psoralen + ultraviolet A) phototherapy yielded better lesion resolution when evaluated according to complete or partial improvement of lesions (>50% improvement or <50% improvement).
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## Recommendations:
Phototherapy with PUVA or UVB, associated or not to other treatments such as etanercept, adalimumab, methotrexate, fumaric acid esters and calcipotriol ointment, accelerates the process of improvement of psoriasis, in evaluations with 6 and 16 weeks of follow-up, with significant reduction in PASI compared to these treatments alone.

## What are the advantages and disadvantages of nb-u-

## Vb in relation to puva?
A study proved NB-UVB to be superior to PUVA for plaque psoriasis, with 75% of achieving complete resolution in the NB-UVB versus 54% in the PUVA group. There was no significant difference between the groups regarding time for remission, neither in the number of adverse events (A). [bib_ref] A randomized controlled trial of narrowband ultraviolet B vs bath-psoralen plus ultraviolet..., Dawe [/bib_ref] When comparing NB-UVB with the use of UVA associated to trisoralen, there was a median PASI reduction in 32% favoring UVB phototherapy (p<0.001, NNT=3) (A).A study showed that, in patients with skin phototype I to IV, PUVA was significantly more effective than NB-UVB regarding response to resolution (84% vs. 65%, p=0.02, NNT=6), but with more side effects and longer treatment time for clearance of lesions (A). [bib_ref] TL-01) phototherapy vs oral 8-methoxypsoralen psoralen-UV-A for the treatment of chronic plaque..., Markham [/bib_ref] Another similar study showed that clearance of psoriasis lesions was achieved in a significantly higher proportion of patients treated with PUVA (84%) compared to those treated with NB-UVB (63%) (CI95%, 1.18 to 7.84, p=0.018, NNT=5), but at the expense of more side effects (A). [bib_ref] A randomized comparison of narrow-band TL-01 phototherapy and PUVA photochemotherapy for psoriasis, Gordon [/bib_ref] When PASI median was evaluated, treatment with PUVA showed a significantly higher reduction in PASI median than in the NB-UVB group (26.72%, CI 95%, p=0.005, NNT=4) (A). [bib_ref] Bath psoralen+ultraviolet A photochemotherapy vs. narrow band-ultraviolet B in psoriasis: a comparison..., Salem [/bib_ref] The index of resolution with NB-UVB was of 80% in patients pre--treated with topical retinoids, compared to a 90% index in patients pre-treated with topical retinoids that were submitted to NB-UVB, and an index of 100% in patients using PUVA ant topical retinoids Diagnostic and therapeutic guidelines for plaque psoriasis -Brazilian Society of Dermatology concomitantly (A). [bib_ref] Bath psoralen+ultraviolet A photochemotherapy vs. narrow band-ultraviolet B in psoriasis: a comparison..., Salem [/bib_ref] The association of etretinate and PUVA lead to 100% of complete improvement in a study, while the association of the medication with NB-UVB improved 80% of patients. [bib_ref] A comparison of the efficacy and relapse rates of narrowband UVB (TL-01)..., Green [/bib_ref] When the combined treatment of phototherapy and acitretin was analyzed, psoriasis clearance was seen in 56.6% of patients treated with NB-UVB and in 63.3% of patients treated with PUVA (A). [bib_ref] A randomized comparison of acitretinnarrow-band TL-01 phototherapy and acitretin-psoralen plus ultraviolet A..., Ozdemir [/bib_ref] In other studies, no difference in improvement as measured by PASI was observed between the use of NB-UVB and PUVA in the treatment of plaque psoriasis, (A), but there seems to be a higher frequency of side effects in patients using PUVA (A). [bib_ref] Narrowband ultraviolet B versus psoralen plus ultraviolet A therapy for severe plaque..., Chauhan [/bib_ref] Evaluating a 0 to 4 index similar to PGA for the treatment of palmoplantar psoriasis, a higher percentage in the reduction of the index with PUVA (85.45%) was observed, rather than with NB-UVB (61.08%-p=0.0001) (A). 134

## Recommendations:
In the efficacy comparison between NB-UVB and PUVA, most studies demonstrate a higher efficacy of PUVA in relation to NB-UVB in the evaluation of up to 3 months of treatment, although there is evidence that NB-UVB can occasionally be superior. The mean number of necessary treatments for clearance of the lesions was also significantly lower in patients undergoing PUVA, compared to patients undergoing UVB. The most frequent adverse events in all treatments were mucocutaneous xerosis, erythema, pruritus and nausea, most of the times mild, not interfering with the treatments.

## Classic systemic treatment
With the aim of establishing recommendations on the classic treatment for plaque psoriasis (acitretin, methotrexate and cyclosporine), a search was carried out using the Medline-PubMed database and the best scientific evidences were selected to answer the clinical questions.

## What is the efficacy and risk of methotrexate in the systemic treatment of psoriasis?
Patients diagnosed with plaque psoriasis (n=120) were treated with methotrexate 17.5mg SC once weekly or placebo injections in the first 16 weeks of the study (phase 1). In the second phase of the study (weeks [bib_ref] What are the best outcome measures for assessing plaque psoriasis severity? A..., Puzenat [/bib_ref]. There was a statistically significant improve-ment in the complete resolution of lesions (PASI 100) in the patients treated with adalimumab (16.7%) in relation to patients treated with methotrexate (7.3%) or in patients treated with placebo (1.9%). Regarding adverse events, there was no statistically significant difference between the groups for infections, moderate to severe adverse events and adverse events related to the drugs. More adverse events lead to discontinuation of the study in the methotrexate group, mainly due to the events related to liver dysfunction. (A). [bib_ref] Benefitrisk analysis of adalimumab versus methotrexate and placebo in the treatment of..., Reich [/bib_ref] Recommendations:
In the treatment of moderate to severe psoriasis with methotrexate, there is significant PASI reduction in relation to baseline at 2, 4 and 6 months of evaluation when compared to placebo, with a number necessary to treat varying from 3 to 6 patients. The most frequent adverse events are nausea, vomiting and abnormalities in transaminases.

## What is the efficacy and risk of acitretin in the systemic treatment of psoriasis?
A randomized, double-blind study evaluated the efficacy and safety of oral acitretin in the treatment of moderate to severe plaque psoriasis, in three treatment groups with different doses:
25mg, 35mg or 50mg/day. Clinical improvement was observed in all groups with PASI 75 response at week 12. The mean PASI dropped 76% in the 35mg group after 12 weeks of treatment, this difference was statistically significant compared to the 25mg and 50mg groups (p<0.05). In the evaluation at 12 weeks of treatment, PASI 75 response was achieved in 47%, 69% and 53% patients in the 25, 35
and 50mg/day acitretin groups, respectively. Most adverse events were mucocutaneous, mild to moderate and dose-dependent (A). [bib_ref] Efficacy and safety of acitretin in three fixed doses of 25, 35..., Dogra [/bib_ref] In another study, patients with moderate to severe plaque psoriasis were randomized to the following doses of acitretin: eight patients using 10mg to 25mg per day, or 16 patients using 50mg to 75mg per day. Patients treated with acitretin doses of 50 to 75mg per day showed a significant therapeutical response (p<0.05) in the evaluation at eight weeks. More adverse events occurred in patients receiving the dose of 25mg per day or more of acitretin, but usually mild and with no need to discontinue the treatment(A). 139

## Recommendations:
In patients with moderate to severe plaque psoriasis, the use of doses of acitretin of 35 to 75mg per day showed significant improvement, evaluated by the PASI response. The most frequently observed adverse events are cheilitis, scaling of palmoplantar regions and alopecia, however, the need to discontinue the treatment was rare.

## What is the efficacy and risk of cyclosporine in the sys

## Recommendations:
The use of cyclosporine in moderate to severe plaque pso-

## Treatment with immunobiologics
With the aim of establishing the recommendations on the treatment of psoriasis with immunobiologics, questions regarding indication, efficacy and safety of these medications were structured.
A search was carried out in Medline-PubMed database and the best scientific evidences were selected to answer the clinical questions.
This search encompassed all immunobiologics approved in Brazil for the treatment of plaque psoriasis: adalimumab, etanercept, in-fliximab, ustekinumab, secukinumab, ixekizumab and guselkumab.

## In which conditions is the treatment with immunobiologics indicated?
The indications for the use of immunobiologics in patients older than 18 years of age, with moderate to severe plaque psoriasis, with PASI score above 10 to 12 or involvement of more than 10% of body surface area are:
- Patients that did not respond to the treatment or have contraindications or intolerance to the adequate dose and course of at least one of the systemic drugs or phototherapy (A). [bib_ref] Infliximab induction therapy for patients with severe plaque-type psoriasis: a randomized, doubleblind,..., Gottlieb [/bib_ref] 

## Recommendations:
The indications for the use of immunobiologic drugs in patients older than 18 years of age, with moderate to severe plaque psoriasis, with PASI score above 10 or body surface area involvement higher than 10% are: the lack of response to systemic treatment or phototherapy, contraindications or intolerance to the adequate dose and course of at least one of the systemic treatments.

## What is the efficacy and risk of etanercept for the treatment of psoriasis?

## Recommendations:
The treatment with etanercept for moderate to severe plaque psoriasis, for the period of 12 weeks, was effective and safe with the evaluation of the PASI 75 response (

## What is the efficacy and risk of infliximab for the treatment of psoriasis?

## Recommendations:
The induction treatment with infliximab in moderate to severe plaque psoriasis for the period of 10 weeks, was effective with the evaluation of the PASI 75 response (65.8-79.6%) and improvement in quality of life with the DLQI score (8.9 to 9.9%), besides being safe, com few mild to moderate side effects reported, mainly infusion reactions, with the doses of 3mg/kg, 5mg/kg or 10mg/kg, on weeks 0, 2 and 6 ( weeks, that did not require discontinuation of treatment. In the study that evaluated the efficacy and safety of infliximab and methotrexate for the treatment of psoriasis, severe adverse events were reported more frequently in the group using infliximab, encompassing severe infections (tuberculosis, opportunistic infections such as P. carinii pneumonia, listeriosis, atypical mycobacte-

## Recommendations:
Immunobiologics are more effective in the treatment of moderate to severe plaque psoriasis when compared to the classic treatment. Except for infliximab, immunobiologics are safer and better tolerated when compared to the classic drugs. Studies with infliximab showed higher risk of severe infections and infusion reactions. [bib_ref] Adalimumab therapy for psoriasis in real-world practice: efficacy, safety and results in..., Van Lumig [/bib_ref] The evaluation of 282 patients using adalimumab which had not used TNF-alpha blocker previously, was compared to 448 patients on adalimumab, with previous use of TNF-alpha blockers.
In the evaluation at 16 weeks, there was a 22.7% difference for PASI 75 favoring patients who had not been previously treated with TN-F-alpha blockers, compared to the group of patients that had been previously treated with two or more TNF-alpha blockers (NNT=5, p=0.016). the adverse events were similar in both groups, with the presence of infections being the most common (A). [bib_ref] Efficacy and safety of adalimumab in patients with psoriasis previously treated with..., Ortonne [/bib_ref] Another study had

## Recommendations:
In the efficacy evaluations at treatment weeks 12 and 16, adalimumab showed better response rates for the patients who were not previously treated with other immunobiologic drugs or tumor necrosis factor blockers; however, in the evaluations at 24 and 48 weeks this benefit was not observed.
In the efficacy evaluations at treatment weeks 12 and 24, etanercept 50mg demonstrated better response rates in patients that did not receive previous treatment with immunobiologics.
Regarding ixekizumab, there was no difference between those previously treated with other immunobiologics and those not.

## -combined treatment
With the aim of establishing the recommendations on the combined treatment of plaque psoriasis with different drugs (immunobiologics, phototherapy and drugs from the classic re-

## Recommendations:
Although the treatment combination (methotrexate + cyclosporine and methotrexate + acitretin) show superior efficacy data when compared to efficacy data as monotherapy, the lack of studies proving the safety of these associations limit the recommendations for their use in the management of patients with moderate to severe plaque psoriasis.

## What are the advantages and disadvantages of

## Recommendations:
The combination of phototherapy (UVB and PUVA) with classic systemic treatments showed higher efficacy than the respective treatments separately, according to evaluation of both PGA 0 or 1 response and PASI 75 response.

## What are the advantages and disadvantages of the combined treatment with phototherapy and immunobiologics when compared to those treatments separately?
In the first phase of the study (8 weeks

## Recommendations:
In the comparison of etanercept as monotherapy or associated to NB-UVB phototherapy, there was no difference for PASI 75 or In another study, with 24 weeks duration, patients with partial response to methotrexate (at least three months of treatment)
were included and allocated into two groups: the first group (n=28)

## Recommendations:
In the evaluation of the use of etanercept as monotherapy compared to the immunobiologic associated to methotrexate or acitretin, there was improvement to PASI 75 on week 24 in patients treated with the association. Adverse events were reported in 74.9% of the patients receiving combined therapy and in 59.8% of the patients receiving monotherapy with immunobiologic or the classic treatment. It was also observed in one study that the use of low and medium potency did not show significant increase of the risk of fetal growth restriction, on the other hand, those of high and very high potency showed increase of the risk (RR 2.08; 95% CI 1.40-3.10;

## Treatment of pregnant and breastfeeding women
p<0.001, NNH=168). There was no association between maternal exposure to topical corticosteroids of all potencies and increased risk of fetal death, premature labor or fetal malformations (B). [bib_ref] Safety of topical corticosteroids in pregnancy: a population-based cohort study, Chi [/bib_ref] 

## Calcineurin inhibitors (tacrolimus)
Authors found an association with prematurity and low birth weight. When used topically, calcineurin inhibitors are weakly absorbed systemically (242) (D). Their use is allowed in small areas when there is no other alternative, due to the lack of studies on safety during pregnancy (B). [bib_ref] Psoriasis in pregnancy: a review (II), Ruiz [/bib_ref] 

## Vitamin d analogues (calcipotriol)
Calcipotriol or calcipotriene, vitamin D analogue, when applied in small areas and doses < 10,000 IU/day has a small risk of systemic absorption (D). [bib_ref] Review of treatment options for psoriasis in pregnant or lactating women: from..., Bae [/bib_ref] There are no studies conducted on pregnant women (B). [bib_ref] Transmission of a vitamin-D metabolite in breast milk, Goldberg [/bib_ref] In animal studies, calcipotriol resulted in a higher incidence of skeletal abnormalities, including incomplete ossification of the pubic bones and anterior phalanges (D). [bib_ref] Treating Psoriasis During Pregnancy: Safety and Efficacy of Treatments, Bangsgaard [/bib_ref] [bib_ref] Safety of dermatologic medications in pregnancy and lactation: Part I. Pregnancy, Murase [/bib_ref] When there are no alternatives, the topical use of calcipotriol on small surfaces is allowed, but it should be avoided under occlusive dressings, avoiding systemic absorption and reducing the risk of toxicity (D). 247

## Topical retinoids (adapalene, tretinoin and tazarotene)
Some topical retinoids, such as adapalene and tretinoin, are categorized into pregnancy category C according to the FDA's classification, due to the risk of teratogenesis. On the other hand, tazarotene is currently labeled as pregnancy category X, and is totally contraindicated in pregnant women due to the risk of teratogenesis. The use of dithranol and coal tar is not recommended during pregnancy (D). 247

## Methotrexate
Methotrexate was shown to be teratogenic and abortive during pregnancy. There are evidences that methotrexate is found on the liver for up to four months after exposure and a prospective review of nine cases of methotrexate exposure prior to pregnancy showed that in four cases, where the exposure took place within six months of the pregnancy, spontaneous abortions occurred (D). [bib_ref] Treating Psoriasis During Pregnancy: Safety and Efficacy of Treatments, Bangsgaard [/bib_ref] [bib_ref] Safety of dermatologic medications in pregnancy and lactation: Part I. Pregnancy, Murase [/bib_ref] [bib_ref] Safety of conventional systemic therapies for psoriasis on reproductive potential and outcomes, Yiu [/bib_ref] There are reports of spontaneous abortions after its use on the first trimester of pregnancy (B). [bib_ref] Outcome of first-trimester exposure to low-dose methotrexate in eight patients with rheumatic..., Kozlowski [/bib_ref] Multiple malformations (craniofacial, skeletal, cardiopulmonary and gastrointestinal) were detected on the 18 th week of gestation in a patient who received the drug on the first week of gestation (C). [bib_ref] Clinical teratology counseling and consultation case report: low dose methotrexate exposure in..., Feldkamp [/bib_ref] it is paramount that its serum levels be monitored more frequently and, when necessary, dose adjustments be made (B). [bib_ref] Ciclosporin use during pregnancy, Paziana [/bib_ref] High levels of cyclosporine in the placenta and/or umbilical cord blood were found in many studies, with 6% of the maternal concentration of cyclosporine reaching the fetus albeit no detection of the drug in the maternal or fetal brain (B). [bib_ref] Ciclosporin use during pregnancy, Paziana [/bib_ref] A meta-analysis with 15 studies including 410 pregnant women who underwent a transplant and were exposed to cyclosporine during gestation was conducted to determine if exposure to cyclosporine during pregnancy is associated to an increased risk of congenital malformations, premature labor or low birth rate. The results suggest that the use of cyclosporine during pregnancy is not teratogenic, but can be associated to premature labor and low birth weight in children (2,500g) (B), 212 (D). [bib_ref] Treating Psoriasis During Pregnancy: Safety and Efficacy of Treatments, Bangsgaard [/bib_ref] Many studies indicate that a short course of cyclosporine (3 to 4 months), with a low dose (less than 5 mg/kg/day), results in an 80-90% improvement in psoriasis, demonstrating the efficacy of cyclosporine use during pregnancy to control severe psoriasis. No incidence of maternal complications was reported, although prematurity and/or low birth weight are common (B). [bib_ref] Ciclosporin use during pregnancy, Paziana [/bib_ref] 

## Phototherapy
Phototherapy, narrowband ultraviolet B (NB-UVB) and
broadband ultraviolet V (BB-UVB) are considered safe options during pregnancy (D). [bib_ref] Ciclosporin use during pregnancy, Paziana [/bib_ref] The use of narrowband UVB seems to reduce the serum levels of folate, and can increase the risks of neural tube defects in the fetus/ therefore, the concurrent use of folic acid 5 mg/day is recommended (B). [bib_ref] Effect of narrowband ultraviolet B phototherapy on serum folic acid levels in..., El-Saie [/bib_ref] In a prospective study that followed 159 pregnant women, psoralen + UVA (PUVA) did not show an increase in the incidence of fetal malformations or fetal deaths (B). [bib_ref] Psoralen photochemotherapy (PUVA) and pregnancy, Gunnarskog [/bib_ref] [bib_ref] Outcomes of pregnancies among women and partners of men with a history..., Stern [/bib_ref] Since psoralen is a known mutagen and teratogen, avoidance of treatment with PUVA during pregnancy is recommended (D). [bib_ref] Safety of dermatologic medications in pregnancy and lactation: Part I. Pregnancy, Murase [/bib_ref] 

## Immunobiologics
There are reports that the use of infliximab during pregnancy did not cause abnormalities in fetal development (C). [bib_ref] Is infliximab safe to use while breastfeeding?, Stengel [/bib_ref] Adalimumab and infliximab are complete IgG1 antibodies, so its transplacental transport is expected. An international, multicentric, prospective cohort study

## Recommendations:
There are evidences that the use of low and medium potency topical corticosteroids are safe for the treatment of the pregnant woman with psoriasis. There seems to be an association of very high potency topical corticosteroids with low birth weight, and it should be avoided.
Since tazarotene has teratogenic potential, it is contraindicated during pregnancy.
Tacrolimus used topically is very little absorbed, however, due to the lack of safety studies in pregnant women, it is indicated to be used on small areas when there is no other therapeutic alternative.
There are no studies with calcipotriol conducted in pregnant women, and it should be avoided in this population.
The use of topical salicylates should be avoided in pregnant women due to the risk of systemic absorption of the salicylate and subsequent fetal risk.
Ultraviolet B phototherapy is the systemic therapy with best evidence of safety during pregnancy. PUVA phototherapy should be avoided during pregnancy due to the teratogenic potential of psoralen.
Despite being classified as category C by the FDA (US -Food and Drug Administration Agency), cyclosporine has good evidences of safety for use during pregnancy.
Acitretin is absolutely contraindicated in pregnant women because of its teratogenic potential, and effective contraception must be ensured during its use and for at least two years after ceasing the drug.
Methotrexate is contraindicated during pregnancy because it is teratogenic and abortive.
There are reports that the use of infliximab, etanercept and adalimumab do not alter fetal development, being safe to the fetus when used during pregnancy. Nonetheless, there are no sufficient data for recommending these medications for the treatment of psoriasis in the pregnant woman, and effective contraception is recommended during their use in women of childbearing age.
There are very limited data on the safety of the treatment with ustekinumab, secukinumab, ixekizumab and guselkumab during pregnancy, with not enough data yet to recommend their use in pregnant women; effective contraception is recommended during their use in women of childbearing age.

## Treatment of plaque psoriasis in breastfeeding women

## Topical corticosteroids
The first line of treatment for breastfeeding mothers is limited to emollients and low to medium potency topical corticosteroids (D). [bib_ref] Treatment of psoriasis and psoriatic arthritis during pregnancy and breastfeeding, Kurizky [/bib_ref] Topical corticosteroids have been proven safe during breastfeeding (C). [bib_ref] Glucocorticosteroid-resistant pemphigoid gestationis: successful treatment with adjuvant immunoadsorption, Westermann [/bib_ref] There is one report of hypertensive crisis in an infant after maternal use of high potency topical corticosteroid (C). [bib_ref] Factitious hypertension with mineralocorticoid excess in an infant, Stefano [/bib_ref] 

## Calcipotriol
Regarding calcipotriol, a vitamin D analogue, it presents a low risk of systemic absorption when used in small doses < 10,000 IU/day, however, there are no reports of its use during breastfeeding (D). [bib_ref] Transmission of a vitamin-D metabolite in breast milk, Goldberg [/bib_ref] 

## Tar derivatives
Coal tar can be transferred to the infant during breastfeeding through skin-to-skin or skin-to-mouth contact (C). [bib_ref] Uptake of pyrene in a breast-fed child of a mother treated with..., Scheepers [/bib_ref] [bib_ref] The Use and Safety of TNF Inhibitors during Pregnancy in Women with..., Johansen [/bib_ref] Etanercept is only found in small concentrations in breast milk and is undetectable in the blood of breastfeeding infants (C). [bib_ref] Etanercept concentrations in maternal serum, umbilical cord serum, breast milk and child..., Berthelsen [/bib_ref] [bib_ref] Etanercept during pregnancy and lactation in a patient with rheumatoid arthritis: drug..., Murashima [/bib_ref] In all case reports of mothers using etanercept, the breastfeeding infants achieved all development milestones. The authors described the concentration in breast milk of 5 ng/ml and etanercept was not detected in the infants' blood. Because it is a large protein, oral absorption of etanercept is believed to be minimal or absent (D). [bib_ref] Treatment of psoriasis and psoriatic arthritis during pregnancy and breastfeeding, Kurizky [/bib_ref] Adalimumab and infliximab had similar results to etanercept and seem to be safe for use during breastfeeding according to some reports (C). [bib_ref] Etanercept concentrations in maternal serum, umbilical cord serum, breast milk and child..., Berthelsen [/bib_ref] [bib_ref] Infliximab and adalimumab use during breastfeeding, Fritzsche [/bib_ref] [bib_ref] Absence of infliximab in infants and breast milk from nursing mothers receiving..., Kane [/bib_ref] [bib_ref] Is infliximab safe to use while breastfeeding?, Stengel [/bib_ref] Ixekizumab is excreted in low levels in breast milk from cynomolgus monkeys, but it is unknown if it is excreted in human breast milk or if it is systemically absorbed after ingestion. It is a large protein molecule (molecular weight of 146,000 kDa), therefore, absorption is unlikely after the first weeks after delivery. The same is described for secukinumab (molecular weight 151,000 kDa) (D). [bib_ref] Psoriasis in those planning a family, pregnant or breast-feeding. The Australasian Psoriasis..., Rademaker [/bib_ref] Data on monoclonal antibodies anti-IL-12/23 are very immature to make any recommendations. Since ustekinumab has a molecular weight of 149,000 kDa, the amount in breast milk is likely to be very low and the absorption is unlikely due to its destruction in the infant's gastrointestinal tract (D). [bib_ref] Psoriasis in those planning a family, pregnant or breast-feeding. The Australasian Psoriasis..., Rademaker [/bib_ref] The effects of the use of ustekinumab during breastfeeding were studied in cynomolgus monkeys, in which low levels of ustekinumab (1/1000 of the level found in maternal serum) were found in breast milk. There are no reports of breastfeeding in humans; however, due to the fact that other immunoglobulins and proteins are present in colostrum, it is suggested that ustekinumab is excreted in breast milk (B). 214

## Recommendations:
Topical corticosteroids have been proven safe during breastfeeding.
There are no reports on the use of calcipotriol during breastfeeding.
Ultraviolet B phototherapy is the safest modality of systemic treatment to be indicated during breastfeeding. PUVA phototherapy should be avoided. The lack of data on ustekinumab, ixekizumab, secukinumab and guselkumab does not allow to recommend their use during breastfeeding.

## Medications associated to the development or aggrava-

## Tion of psoriasis
With the aim of establishing the recommendations on systemic medications associated to the development or aggravation of psoriasis, a search was carried out using Medline-PubMed database, and the best scientific evidences were selected to answer the clinical questions. This search encompassed drugs that have been historically associated to the development and/or aggravation of psoriasis: angiotensin converting enzyme I inhibitors, angiotensin II receptor antagonists, lithium, beta-blockers, anti-inflammatories, antimalarials and interferon.

## 9.
Which systemic medications are associated to the development or aggravation of psoriasis?

## Tnf-alpha blockers
Patients with chronic inflammatory conditions being treated with TNF-alpha blockers can progress with psoriasis as a paradoxical effect, also known as reactive psoriasis, most frequently reported in patients with inflammatory bowel disease (C). [bib_ref] Anti-TNF antibody-induced psoriasiform skin lesions in patients with inflammatory bowel disease are..., Tillack [/bib_ref] [bib_ref] Induction of psoriasis with anti-TNF agents in patients with inflammatory bowel disease:..., Guerra [/bib_ref] [bib_ref] Pattern and Severity of Psoriasiform Eruptions in Patients with Inflammatory Bowel Diseases,..., Darrigade [/bib_ref] [bib_ref] Anti-TNF antibody-induced psoriasiform skin lesions in patients with inflammatory bowel disease: an..., Jeyarajah [/bib_ref] Many studies evidenced this relationship, with incidence ranging from 1.6% to 2.5% (253-256) (C). Smoking (C) [bib_ref] Anti-TNF antibody-induced psoriasiform skin lesions in patients with inflammatory bowel disease are..., Tillack [/bib_ref] and female gender (C) [bib_ref] Pattern and Severity of Psoriasiform Eruptions in Patients with Inflammatory Bowel Diseases,..., Darrigade [/bib_ref] were considered significant among the factors possibly related with the development of psoriasis as a paradoxical effect.

## Interferon alpha
During treatment with interferon alpha for the Hepatitis C, 36
cases of patients who developed psoriasis lesions (aggravation in 22
cases and triggering in 14 cases) were reported in 32 publications (C). 257

## Angiotensin ii receptor antagonists
The use of losartan for the treatment of hypertension in a 49-year-old man lead to the subsequent appearance of psoriasiform lesions (confirmed by biopsy) one week after the medication was commenced. The skin lesions gradually resolved after discontinuation of losartan (C). 258

## Nonsteroidal anti-inflammatories
Isolated cases of patients with inflammatory arthopathies are reported with the development of psoriasis for using nimesuli-de 259 (C) and rofecoxib (C) [bib_ref] Psoriasis associated with rofecoxib, Clark [/bib_ref] , with subsequent remission of psoriasis after withdrawal of the anti-inflammatory.
The association between many pain killers widely used, including aspirin, nonsteroidal anti-inflammatories (NSAIDs) and acetaminophen (paracetamol) and the risk for psoriasis and pso- Twenty-three psoriasis patients using betablockers first developed psoriasis after commencing the drug in seven cases, and this number was statistically significant when compared to the control group (psoriasis patients with no previous use of betablocker) -p<0.001. four of these patients had a generalized presentation (severe) of psoriasis and in three the symptoms remitted after discontinuation (B). 263

## Lithium
The use of lithium in 36,702 patients (and the same number of controls) with first-time diagnosis of psoriasis registered between 1994 and 2005, when compared to non-use prior to development of psoriasis, resulted in an Odds Ratio (OR) of 1.68 (CI95% 1.18-2.39, p<0.01), demonstrating that the use of lithium was associated to a small risk of an increased incidence of psoriasis (B). [bib_ref] Lithium, antipsychotics, and risk of psoriasis, Brauchli [/bib_ref] Patients with psychiatric disorders that received lithium for the first time developed psoriasis in 6% of cases (of the 51 patients receiving lithium, three developed lesions); compared to the control group, p value was not significant (B). [bib_ref] A control study of the cutaneous side effects of chronic lithium therapy, Chan [/bib_ref] 

## Angiotensin i converting enzyme inhibitors
There are reports that the angiotensin II converting enzyme inhibitors (ACEI) captopril and lisinopril exacerbated or triggered psoriasiform lesions (C). [bib_ref] Angiotensin-converting enzyme inhibitors as possible exacerbating drugs in psoriasis, Gilleaudeau [/bib_ref] In a cohort where [bib_ref] What are the best outcome measures for assessing plaque psoriasis severity? A..., Puzenat [/bib_ref] 

## Recommendations:
TNF alpha blockers can paradoxically cause psoriasiform lesions in patients with chronic inflammatory conditions, being more frequent in inflammatory bowel disease, occurring in 1.6-2.5% of patients.
Results of the largest studies regarding betablockers and lithium are still controversial because they are drugs with considerable evidences, however insufficient, to cause or aggravate psoriasis.
Therapy with interferon alpha, nonsteroidal anti-inflammatories, angiotensin receptor antagonists and ACE inhibitors seem to trigger or exacerbate preexisting psoriasiform lesions, although with weak evidences of causal relationship. q
[fig] FIgure 8: Prevalence of dyslipidemia in moderate to severe plaque psoriasis patients 3.1. What is the efficacy and the risk of topical corticosteroids for the treatment of psoriasis? Twice-daily application of 0.05% clobetasol propionate spray or placebo for four weeks, in placebo-controlled studies, showed improvement of psoriasis lesions after four weeks [Number Needed to Treat (NNT=2)], with significant response in the intervention group already on the first week of treatment (p<0.001). Local burning sensation was observed in similar rates to the placebo group. No serious adverse event was reported 89 (A) 101 (A). [/fig]
[fig] 6. 8: What is the efficacy and risk of secukinumab for the treatment of psoriasis? Recommendations: the studies conducted in the evaluation of the efficacy and safety of secukinumab for moderate to severe plaque psoriasis showed improvement evaluated by the PASI 75 response (77.1-81.6% for 300mg and 67.0-71.6% for 150mg) and PGA 0 or 1, and maintenance of quality of life (DLQI) with the use for up to three years, with the best results achieved with the weekly dose of 300 mg in the first four weeks of treatment, followed by 300mg every four weeks ( [/fig]
[fig] 6. 11: Is there a difference in the efficacy of the treatment with immunobiologics in patients with psoriasis that already used one or more immunobiologics in comparison to those patients who never used an immunobiologic?In a publication presenting integrated data of efficacy results of 12 weeks of two phase 3 studies, where patients were treated with ixekizumab 80mg every two weeks (n=736), ixekizumab 80mg every four weeks (n=733) after initial 160mg dose, or etanercept 50mg twice weekly, patients with and without previous use of immunobiologic were included. Of the total of patients evaluated, 497 (19.3%) had been previously exposed to immunobiologics. Inpatients being treated with ixekizumab, PASI 75 response rates were very similar among patients with previous use of immunobiologics (91.5%) and with no previous use of immunobiologics (87.7%). For patients being treated with etanercept, PASI 75 response rates were superior in the group that did not previously use immunobiologics (50.7%) when compared to those that has used immunobiologics previously (34.6%) (B). 188 A study evaluated the efficacy of adalimumab in 30 patients with moderate to severe plaque psoriasis with primary or secondary treatment failure (PASI<50), or intolerance to etanercept. In relation to PASI scores prior to commencement of etanercept, PASI 75 response was obtained in 27% (NNT=4), 36% (NNT=3) of patients on weeks 12 and 24, respectively, of treatment with adalimumab. These response rates are similar to those presented by patients who responded to etanercept. The total rate of adverse events per year with etanercept was of 3.41% compared to 3.18% in patients treated with adalimumab. The most frequent events were infections, mainly respiratory, muscular, joint, gastrointestinal complaints, and dermatological abnormalities. The efficacy of treatment with adalimumab was not influenced by previous failure to etanercept (B). 189 Sixty-nine treated with adalimumab were evaluated, which have already had previous treatment with other immunobiologics and/or TNF-alpha blockers (etanercept, efalizumab, alefacept, infliximab or ustekinumab). The comparison was with 16 patients using adalimumab as the first immunobiologic treatment. In relation to the original baseline (beginning of the study), the difference to PASI 75 in the evaluation at 12 weeks was of 27% favoring the group that used immunobiologics for the first time (NNT=4, p=0.004). There was no significant difference between the comparison groups for PASI 75 response rate in the evaluation at 24 and 48 weeks. Of all patients in the study, 19% presented adverse events, and only 29% of these were possibly or probably related to the drug being investigated (B). [/fig]
[fig] , 236 8.1. 8: AcitretinAcitretin, a synthetic derivative of vitamin A, was shown to be teratogenic in animal studies, supporting it being absolutely contraindicated in pregnant women (D).224 The teratogenic effects associated to retinoids and hypervitaminosis A include craniofacial dysmorphia, hip malformations, meningomyelocele, meningoencephalocele, multiple synostoses and limb abnormalities. There are six known cases of fatal outcome after exposure to acitretin, including two with malformations consistent with the teratogenic effects (D), 251 (B).214 Since acitretin can be re-esterified into etretinate, that has a longer elimination half-life (up to 150 weeks), it is necessary to ensure contraception for at least two years after finishing treatment with acitretin (D), 251 (B).214 8.1.9 CyclosporineThe physiologic adaptations and clinical changes that occur in pregnant women can affect cyclosporine absorption, distribution and clearance. Gastric emptying and motility of the small intestine are reduced during pregnancy, what can lead to a higher absorption time and a lower peak serum level of cyclosporine. Therefore, [/fig]
[table] Table 2: The adverse events presented were mild to moderate, mainly of reactions on the site of injection. The best responses occurred in patients using 50mg twice weekly. PASI 75 response rates in 12 weeks in the different regimens ranged from10-28% with the dose of 25 mg once weekly; 26-39% in the dose of 25mg twice weekly; and 35-54%, in the dose of 50 mg twice weekly.144,149,151,152,155,158,162,167 [/table]
[table] Table 3: What is the efficacy and risk of adalimumab for the treatment of psoriasis?The treatment of moderate to severe plaque psoriasis with adalimumab, during 12 to 16 weeks, was effective with the evaluation of the PASI 75 response and improvement in quality of life with [/table]
[table] Table 8: 159,182 It was superior when compared to etanercept, evidenced by better results in the response rates for PASI 90 and PASI 100 in 12 weeks (54.2% vs. 20.7% and 24.1 vs. 4.3%, respectively). [/table]
[table] table 5: Evaluation of ustekinumab expressed by the benefit estimated in percentage [/table]