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

Marcelo Arnone,1 Maria Denise Fonseca Takahashi,1 André Vicente Esteves de Carvalho,2 Wanderley Marques Bernardo,3 Aline Lopes Bressan,4 Andrea Machado Coelho Ramos,5 Aripuanã Cobério Terena,6 Cacilda da Silva Souza,7 Daniel Holthausen Nunes,8 Maria Cecília de Carvalho Bortoletto,9 Maria de Fátima Santos Paim de Oliveira,10 Jane Marcy Neffá,11 Luciana Cristina Fieri,12 Luna Azulay-Abulafia,13,14 Paulo Antônio Oldani Felix,15 Renata Ferreira Magalhaes,16 Ricardo Romiti,1 and Tatiana Jerez Jaime17

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1.1 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).15

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). 16

1.2 PGA

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).15 It demonstrated adequate content validity, moderate interobserver variation and low intraobserver variation (B).16

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).15 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

1.4 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).10 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).4 Due to its briefness and simplicity, it is useful for the clinical practice (B).3

1.5 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).13 Although it has a few limitations (B), the scoring agreement among observers was considered between good to moderate with NAPSI (B).2,9

1.6 PGA X BSA (PGA multiplied by BSA)

The instrument PGA X BSA was calculated multiplying the PGA result by BSA. When associated to BSA, a tool that evaluates the body surface area involved, PGA showed moderate to high correlation with changes in PASI (0.53-0.89) to detect disease severity (B).15 Using PGA x BSA to evaluate the clinical response and define minimal disease activity, the author found a significant correlation with percentage changes in PASI (0.915-0.943; P <.001) and medium correlation compared to DLQI (0.303-0.407; P <.008), independent of the category of baseline PASI score (12-19 or higher than 20) (B).5

1.7 PASI versus DLQI

When the mean percentage of PASI improvement was compared to the mean improvement with DLQI, the value of the correlation coefficient observed was of 0.898 (p<0.01), showing a high correlation between the indexes (Spearman correlation coefficient = 0.87, where the coefficient higher than 1 demonstrates total agreement) (A).11

1.8 PASI versus PGA

The two instruments, PASI and PGA, when used to evaluate the PASI 75 therapeutical response (75% or more reduction in the PASI score) e and PGA zero (no lesion) or 1 (almost no lesion), showed high correlation with each other (p<0.01). PGA and PASI are redundant, and the use of either PASI or PGA only is recommended (A).13 There is a high correlation between those two tools (Spearman correlation coefficient = 0.87), with low intra-evaluator variation for PGA (and high variation for PASI. The inter-evaluator variation was higher with PASI when compared to PGA (B).7

Recommendations:

The instrument PASI is recommended for the evaluation of the severity of the disease and the therapeutical response. The reduction in the PASI score has a good correlation with the clinical improvement seen by the physician and with the improvement of the symptoms reported by the patients.

The instrument DLQI showed a high correlation with PASI in patients with moderate to severe psoriasis, being a useful instrument for the clinical practice due to its briefness and simplicity.

The instrument PGA, when associated to BSA, has a high correlation with the instrument PASI, and is recommended for the evaluation of disease severity. Differently to PASI, PGA has the advantage of not depending of the experience of the evaluator (low intra-evaluator variation).

NAPSI is a simple tool that can be used to evaluate nail psoriasis. It has good to moderate scoring agreement between observers.

2.1 Depression

The prevalence of depression in psoriasis patients in the random effects model is of 16% (CI 95%: 13.2-19.3; Figure 1).

2.2 Anxiety

The prevalence of anxiety disorder in psoriasis patients in the random effects model is of 15.4% (CI 95%: 10.6-21.7; Figure 2).

2.3 Suicide attempt

The prevalence of suicide attempt in psoriasis patients in the random effects model is of 2.9% (CI 95%: 1.4-5.9; Figure 3).

2.4 Asthma or COPD

The prevalence of asthma or chronic obstructive pulmonary disease (COPD) in psoriasis patients in the random effects model is of 2.7% (CI 95%: 1.3-5.5; Figure 4).

2.5 Chronic liver disease

The prevalence of chronic liver disease in psoriasis patients in the random effects model is of 0.8% (CI 95%: 0.1-4.9; Figure 5).

2.6 Nonalcoholic fatty liver disease

The prevalence of nonalcoholic fatty liver disease in psoriasis patients in the random effects model is of 15.3% (CI 95%: 5.8-34.5; Figure 6).

2.7 Obesity

The prevalence of obesity in psoriasis patients in the random effects model is of 25.6 (CI 95%: 22.7-28.7; Figure 7).

2.8 Dyslipidemia

The prevalence of dyslipidemia in psoriasis patients in the random effects model is of 20.4% (CI 95%:13.6-29.3; Figure 8).

2.9 Systemic hypertension

The prevalence of systemic hypertension (SHT) in psoriasis patients in the random effects model is of 26.9% (CI 95%: 21.5-33; Figure 9).

2.10 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; Figure 10).

2.11 Coronary insufficiency

The prevalence of ischemic cardiomyopathy or coronary insufficiency in psoriasis patients in the random effects model is of 3.4% (CI 95%: 2.3-5%; Figure 11).

2.12 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; Figure 12).

2.13 Migraine

The prevalence of migraine in psoriasis patients in the random effects model is of 15.5% (CI 95%: 0.3-84.8; Figure 13).

2.14 Other comorbidities

Other prevalent comorbidities in psoriasis patients were alexithymia; other dermatological conditions such as seborrheic dermatitis, acne, rosacea; pulmonary hypertension; and celiac disease (Table 1).

Recommendations:

Psychiatric comorbidities, such as depression and anxiety, and the diseases associated to metabolic syndrome, such as obesity, nonalcoholic fatty liver disease, diabetes, systemic hypertension and dyslipidemia stand out among the possible comorbidities associated to psoriasis.

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.

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.

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.

Recommendations:

Vitamin D analogues, 50 µg/g calcipotriol ointment, 0.005% calcipotriol foam and 6µg/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.

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.

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.

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.

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.

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.

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.

Recommendations:

The use of cyclosporine in moderate to severe plaque psoriasis demonstrates significant improvement evaluated by the PASI response, with the best responses obtained with the dose of 5mg/ kg/day. The most important severe adverse events were reported in long treatments (21 months), encompassing malignancies and systemic hypertension. For those patients who showed an adequate therapeutic response in up to 16 weeks, maintenance treatment with administration of cyclosporine on weekends proved to safely and effectively prolong maintenance of the therapeutic response.

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.

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 (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

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 (Table 3).6,12,146,148

Recommendations:

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 the DLQI score (49-81%), in the following therapeutic regimen: 40 mg every two weeks (PASI 75 57.9-79.6%, PASI 90 43%, PASI 100 16.7-19% and PGA 80.5%); 80 mg in week 0 followed by 40 mg every two weeks (PASI 75 62.8%); and 80 mg every two weeks (PASI 75 81%); besides being safe, with the report of few mild to moderate adverse events (Table 4).136,137,143,145,150,170

Recommendations:

the studies conducted in the evaluation of the efficacy and safety of ustekinumab for moderate to severe plaque psoriasis showed improvement evaluated by the PASI 75 response (52.9-76.5% for 45mg and 61.2-78.6% for 90mg) and in the quality of life with the DLQI score (46.4-58.1%), besides mild to moderate adverse events, upon analysis of a period of 12 weeks (Table 5).157,166,169,174-177 When compared to etanercept, ustekinumab in the 45 and 90mg doses was superior when PASI 75 and PGA 0/1 were evaluated in 12 weeks of follow-up. After this period, although studies have performed a crossover, the treatment with ustekinumab for up to five years was safe and effective after dose adjustment.

Recommendations:

the studies on the evaluation of efficacy and safety of guselkumab for moderate to severe plaque psoriasis showed improvement in 16 weeks, evaluated by the PASI 90 response (50mg of 70.8% and 100mg of 69.8-73.3%) and PGA (0/1) (Table 6).178,179 Mild to moderate adverse events occurred in the analysis during a period of 36 weeks. When compared to adalimumab, guselkumab (100mg) was superior to adalimumab (80 and 40mg) in the PGA and PASI 90 response.

Recommendations:

the studies performed for the evaluation of the efficacy and safety of ixekizumab for the treatment of moderate to severe plaque psoriasis showed improvement evidenced by the PASI 75 (90-93.4%), PASI 90 (79.7%), PASI 100 (56.3%) and PGA (57-81.9%) responses (Table 7).180,181 When compared to etanercept, the results of ixekizumab used in doses every two or four weeks were significantly better for the outcomes PASI 75, PASI 90, PASI 100 and PGA 0/1. Mild to moderate adverse events were observed in the analysis of a period of 96 weeks, that did not require discontinuation of treatment.

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 (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).

Recommendations:

In the evaluation of immunobiologic drugs regarding PASI 75 score, similar benefits were found with: etanercept, infliximab, adalimumab, ustekinumab, guselkumab, ixekizumab, secukinumab. Guselkumab was superior to adalimumab in IGA 0/1 and PASI 90.

There was a significant improvement for PASI 75 and in the evaluation with PGA score for the use of ustekinumab in relation to etanercept. Results of ixekizumab used in doses every two or four weeks were significantly better for the outcomes PASI 75, 90, 100 and IGA 0/1 when compared to etanercept. There was a significant improvement for PASI 75, 90 and 100, as well as for PGA 0/1 for the use of secukinumab in relation to etanercept.

Even though not all drugs have studies assessing the PGA score, the best results were with: ustekinumab, guselkumab, secukinumab and ixekizumab.

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.

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.

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.

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.

Recommendations:

In the comparison of etanercept as monotherapy or associated to NB-UVB phototherapy, there was no difference for PASI 75 or PASI 90 in the evaluation at 24 weeks. However, in the evaluation at 12 and 16 weeks after starting the treatment, there are controversies regarding the benefit of the combined treatment for PASI 90.

With ustekinumab, the association with UVB phototherapy speed up the process of improvement of the lesions on week 6, with a difference of PASI 75 in 67% for the half of the body receiving the combined therapy (NNT=2), in relation to the half of the body that was treated with the immunobiologic alone.

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.

8.1.1 Topical Corticosteroids

The safety of topical glucocorticoids varies according to the strength of the agent and the specific vehicle used. Current evidence suggests that mild/moderate topical corticosteroids are preferred during pregnancy. The risk of high potency applied in large areas of the body surface approach those seen with systemic steroids due to the increased potential of systemic absorption (D).247

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; 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).216

8.1.2 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).241

8.1.3 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).210 There are no studies conducted on pregnant women (B).223

In animal studies, calcipotriol resulted in a higher incidence of skeletal abnormalities, including incomplete ossification of the pubic bones and anterior phalanges (D).211,234

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

8.1.4 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. Its risk is enhanced by the fact that it is applied on large areas of the body surface in cases of moderate to severe psoriasis, therefore increasing its systemic absorption. Topical tazarotene should be avoided in pregnant women (D).227

8.1.5 Salicylates

There are many concerns regarding the use of topical salicylates during pregnancy. When combined to other drugs, particularly topical corticosteroids, salicylic acid increases percutaneous absorption of other agents. There is also a concern with the systemic absorption of the salicylic acid itself applied topically, in concentrations ranging from 9% to 25%. Some cases of acute systemic toxicity by salicylates after topical use have been reported, usually with the prolonged use on extensive body surfaces and/or the use of occlusive dressings (D).227

8.1.6 Tar Derivatives

A retrospective study evaluated 23 pregnant women who used coal tar during pregnancy and no increase in the risk of mal-formations was observed, when compared to population data (B).220

Even though there are animal studies demonstrating that the maternal exposure to high doses resulted in perinatal mortality and increased risk of palate fissures and pulmonary abnormalities in the offspring, literature on human exposure did not reveal any effect (D).234

The use of dithranol and coal tar is not recommended during pregnancy (D).247

8.1.7 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).211,234,251 There are reports of spontaneous abortions after its use on the first trimester of pregnancy (B).231

Multiple malformations (craniofacial, skeletal, cardiopulmonary and gastrointestinal) were detected on the 18th week of gestation in a patient who received the drug on the first week of gestation (C).219,236

8.1.8 Acitretin

Acitretin, 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 Cyclosporine

The 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, it is paramount that its serum levels be monitored more frequently and, when necessary, dose adjustments be made (B).238 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).238

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). 211

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). 238

8.1.10 Phototherapy

Phototherapy, narrowband ultraviolet B (NB-UVB) and broadband ultraviolet V (BB-UVB) are considered safe options during pregnancy (D).238

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).218

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).225,246 Since psoralen is a known mutagen and teratogen, avoidance of treatment with PUVA during pregnancy is recommended (D).234

8.1.11 Immunobiologics

There are reports that the use of infliximab during pregnancy did not cause abnormalities in fetal development (C).245

Adalimumab and infliximab are complete IgG1 antibodies, so its transplacental transport is expected. An international, multicentric, prospective cohort study of 80 pregnant women with inflammatory bowel disease (IBD) that received adalimumab or infliximab, found an inverse correlation between the time since the last exposure to the drug during pregnancy and the concentration in the blood from the cord (B).228

A case report found a ratio of concentration of etanercept between maternal blood and blood from the umbilical cord of 14:1 during delivery, in a woman with ankylosing spondylitis receiving 25 mg subcutaneously once a week during the second and third trimester, evidencing the low transplacental transport (B).228 Anti-TNF-alpha transplacental transport seems not to occur before the second trimester and, although it increases during the third trimester, etanercept shows considerably less transport than other anti-TNFs (B).215

Two ustekinumab studies on fetal development conducted in monkeys did not reveal any evidence of maternal toxicity, embryotoxicity or teratogenicity. There are very limited data on treatment safety, with only two case reports in the literature, all with healthy infants. A report grouped 4-year data of clinical trials with 31 pregnant women, with no incidences of fetal malformations or death. The FDA attributed pregnancy category B to ustekinumab, similar to anti-TNF-alpha; however, due to lack of evidences proving its safety during pregnancy, its use is not recommended (D).211

Animal studies with secukinumab, a monoclonal antibody against IL-17A, do not show harmful effects regarding the pregnancy, embryonic/fetal development, labor or post-natal development, including that of the immune system (B).249

In a global safety database, the results of pregnancies where there was maternal or paternal exposure to secukinumab were analyzed, and overall rates of spontaneous abortion were 30/292 (10.3%), according to the rates observed for the general population. Most of the spontaneous abortions happened within 10 weeks of gestation and there were no stillbirths (> 20 weeks’ gestation). Of the 38 cases of exposure in patients with psoriatic arthritis spontaneous abortions occurred in 7.9% and in 6.7% of 15 patients with adverse events. Most patients discontinued the treatment in the first trimester, knowing that secukinumab is transferred through the placenta in the third trimester. There are no human data about the effect of secukinumab in the immune system of newborns after in utero exposure (B).249

Ixekizumab, a humanized monoclonal antibody (IgG4) that binds to IL-17A, has very limited usage data in pregnant women. In the development toxicity studies, ixekizumab crossed the placenta and was present in the blood up to six months of age, but animal studies still do not indicate directly or indirectly harmful effects regarding pregnancy, embryos, or fetal development, labor or post-natal development (D).239

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.

8.2.1 Topical Corticosteroids

The first line of treatment for breastfeeding mothers is limited to emollients and low to medium potency topical corticosteroids (D).232

Topical corticosteroids have been proven safe during breastfeeding (C).250 There is one report of hypertensive crisis in an infant after maternal use of high potency topical corticosteroid (C).244

8.2.2 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).223

8.2.3 Tar Derivatives

Coal tar can be transferred to the infant during breastfeeding through skin-to-skin or skin-to-mouth contact (C).243 Cases of detection of tar derivatives in breast milk have been reported (D).232

8.2.4 Phototherapy

Ultraviolet B (UVB) phototherapy is compatible with breastfeeding. Regarding PUVA, topical psoralen has little systemic absorption, however, it is unknown if it is absorbed into breast milk. PUVA phototherapy is contraindicated during breastfeeding (B).210

8.2.5 Acitretin

Acitretin should be avoided during breastfeeding due to its cumulative toxic effect. Breastfeeding infants are not capable of excreting the drug through the kidneys or liver due to the immaturity of these organs; this would increase the serum levels of the drug and it could reach toxic levels.

It was recently described that there are traces of acitretin (30-40 ng/ml) excreted in the breast milk; this corresponds to a ratio of concentration milk/serum of 0.18. the estimated dose for the infant is 1.5% of the maternal dose. Acitretin is almost exclusively found in the fat component of breast milk, thus, there are no reports of neonatal toxicity after exposure to acitretin in breast milk; however, it should be avoided in breastfeeding women. Recommendations are lacking regarding the time frame after finishing treatment during which breastfeeding should be contraindicated (B).214

8.2.6 Methotrexate

Methotrexate has reports of transference into breast milk in small concentrations, and can be deposited in the child’s tissues for many months. Due to the limited number of studies in breastfeeding women and analysis of its long term effects in infants, its use is not recommended (C).229

Two-hourly samples of breast milk from a patient treated with a first dose of 22.5mg of methotrexate for postpartum choriocarcinoma showed it was excreted in small concentrations in the breast milk. The maximum level of methotrexate measured in the breast milk was around 3% of the maximum maternal serum level, with the higher ratio milk-serum of 0.08 at 10 hours (D).251 The meaning of these measures is uncertain due to limited reports, and its use is contraindicated during breastfeeding (B),210 (D).226

8.2.7 Cyclosporine

There are reports of infants, born from renal transplant recipients using cyclosporine during breastfeeding, who did not develop renal toxicity or other side effects, with undetectable levels of cyclosporine (B),237 even though other reports show cytotoxicity and suggest avoiding the drug during breastfeeding (C).221

Data show that the use of calcineurin inhibitors such as cyclosporine during pregnancy does not increase the risk of congenital defects in breastfeeding infants. Besides, it is known that cyclosporine is excreted in breast milk and the American Association of Pediatrics advises against breastfeeding during the use of the drug. Of the 15 cumulative breastfeeding infants in different reports, only one had detectable cyclosporine. The mother ceased breastfeeding and the child was well and developing adequately in the last follow-up. Although any immunosuppressing exposure to the baby can exceed safety limits, the relatively small amount of the drug transferred and the absence of reported adverse events, together with the documented benefits from breastfeeding, can overcome theoretical risks of this exposure (B).238

8.2.8 Immunobiologics

Data on the use of immunobiologic drugs are still scarce. The absorption of maternal antibodies through breast milk in humans is limited. Small amounts of IgG and other larger immunoglobulins cross mammary acini and, therefore, would hardly reach significant concentrations in the infant’s blood. For this reason, the flow of anti-TNF drugs through breast milk is expected to be minimal (D).232

Adalimumab and infliximab are complete IgG1-type antibodies, and can cross the placental barrier. The mean clearance time for adalimumab in breastfeeding infants is four months, and for infliximab is 7.3 months. The latter was detected until 12 months of age (B).228

Etanercept is only found in small concentrations in breast milk and is undetectable in the blood of breastfeeding infants (C).213,235 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).232 Adalimumab and infliximab had similar results to etanercept and seem to be safe for use during breastfeeding according to some reports (C).213,221,230,245

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).239

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).239

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.

Methotrexate, acitretin, cyclosporine and psoralen (PUVA) are contraindicated during breastfeeding.

Adalimumab, infliximab and etanercept are safe for use during breastfeeding.

The lack of data on ustekinumab, ixekizumab, secukinumab and guselkumab does not allow to recommend their use during breastfeeding.

9.1 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).252-256 Many studies evidenced this relationship, with incidence ranging from 1.6% to 2.5% (253-256) (C). Smoking (C)252,256 and female gender (C) 254,256 were considered significant among the factors possibly related with the development of psoriasis as a paradoxical effect.

9.2 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

9.3 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

9.4 Nonsteroidal Anti-inflammatories

Isolated cases of patients with inflammatory arthopathies are reported with the development of psoriasis for using nimesulide259 (C) and rofecoxib (C)260, 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 psoriatic arthritis (PsA) was evaluated in 95,540 participants during follow-up. During 1,321,280 person-years of follow-up, 646 cases of psoriasis and 165 cases of PsA were documented. Compared to women who did not report their use, regular acetaminophen and NSAIDs users, with longer than 10 years of use, showed multivariate risk rates of 3.60 (CI95%:2.02-6.41] and 2.10 (CI95%:1.11-3.96), respectively, for PsA. There was no clear association between aspirin and psoriasis risk or PsA. In conclusion, the prolonged use of acetaminophen and NSAIDs can be associated to an increased risk of psoriasis and PsA (B).261

9.5 Betablockers

An analysis of 36,702 patients (and the same number of controls) with first-time diagnosis of psoriasis who used cardioselective and non-cardioselective betablocker revealed that according to the number of prescriptions (1-4, 5-19, >20) the incidence of psoriasis was, respectively OR 0.93 (0.70 to 1.13 CI95%), 1.10 (0.97 to 1.24 ) and 1.10 (1.01 to 1.20), not supporting evidences that the use of betablockers increase the incidence of psoriasis (B).262

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

9.6 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).264

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).265

9.7 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).266

In a cohort where 16,342 patients received captopril, 25,686 patients received enalapril maleate and 11,235 patients received lisinopril, six developed psoriasiform lesions (one case of exacerbation and five cases of new onset). The rate of association of psoriasiform lesions was 1.3 for 10,000 in total, 2.1 for each 10,000 women and 0.4 for each 10,000 men (C).267

9.8 Antimalarials

Six days after starting chloroquine phosphate 500mg/week and proguanil 200mg/day for malaria prophylaxis, a 45-year-old patient with psoriasis presented with worsening of the inflammation and pain in preexisting lesions (C).268

Another report revealed exacerbation of plaque psoriasis lesions in a patient using chloroquine sulfate 400mg/week and proguanil 200mg/day as prophylaxis, requiring hospitalization for systemic treatment with methotrexate (C).269

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.

Contributed by

AUTHORS’ CONTRIBUTIONS

Marcelo Arnone

0000-0002-7192-5161

Approval of the final version of the manuscript; Design and planning of the study; Preparation and writing of the manuscript; Data collection, analysis and interpretation; Critical literature review; Critical manuscript review

Maria Denise Fonseca Takahashi

0000-0001-8671-6680

Approval of the final version of the manuscript; Design and planning of the study; Preparation and writing of the manuscript; Data collection, analysis and interpretation; Critical literature review; Critical manuscript review

André Vicente Esteves de Carvalho

0000-0002-0407-538X

Approval of the final version of the manuscript; Preparation and writing of the manuscript; Data collection, analysis and interpretation; Critical literature review; Critical manuscript review

Wanderley Marques Bernardo

0000-0002-8597-5207

Statistical analysis; Approval of the final version of the manuscript; Design and planning of the study; Preparation and writing of the manuscript; Data collection, analysis and interpretation; Critical literature review; Critical manuscript review

Aline Lopes Bressan

0000-0002-3296-5232

Data collection, analysis and interpretation; Critical literature review

Andrea Machado Coelho Ramos

0000-0001-7414-3395

Data collection, analysis and interpretation; Critical literature review

Aripuanã Cobério Terena

0000-0002-2550-1341

Data collection, analysis and interpretation; Critical literature review

Cacilda da Silva Souza

0000-0002-8157-7658

Data collection, analysis and interpretation; Critical literature review

Daniel Holthausen Nunes

0000-0002-1303-5419

Data collection, analysis and interpretation; Critical literature review

Maria Cecília de Carvalho Bortoletto

0000-0002-6156-6097

Data collection, analysis and interpretation; Critical literature review

Maria de Fátima Santos Paim de Oliveira

0000-0002-8594-200X

Data collection, analysis and interpretation; Critical literature review

Jane Marcy Neffá

0000-0002-7888-0154

Data collection, analysis and interpretation; Critical literature review

Luciana Cristina Fieri

0000-0002-7981-9398

Data collection, analysis and interpretation; Critical literature review

Luna Azulay-Abulafia

0000-0002-4698-2009

Data collection, analysis and interpretation; Critical literature review

Paulo Antônio Oldani Felix

0000-0002-1055-0597

Data collection, analysis and interpretation; Critical literature review

Renata Ferreira Magalhaes

0000-0001-9170-932X

Data collection, analysis and interpretation; Critical literature review

Ricardo Romiti

0000-0003-0165-3831

Data collection, analysis and interpretation; Critical literature review

Tatiana Jerez Jaime

0000-0002-7594-620X

Data collection, analysis and interpretation; Critical literature review

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