Psoriasis in moderate grave plaque - immunobiological treatment

Abstract

The Guidelines Project, an initiative of the Brazilian Medical Association, aims to combine information from the medical field in order to standardize producers to assist the reasoning and decision-making of doctors.

The information provided through this project must be assessed and criticized by the physician responsible for the conduct that will be adopted, depending on the conditions and the clinical status of each patient.

INTRODUCTION

Immunobiological agents are recombinant, genetically engineered proteins, which may be monoclonal antibodies, fusion proteins or recombinant human cytokines. Its action is to block, neutralize or antagonize specific targets of the inflammatory process.

METHOD

A systematic review of the literature was carried out, with the descriptors according to PICO, where P corresponds to patients with moderate to severe plaque psoriasis, I as in intervention with etanercept, infliximab, adalimumab, ustekinumab, guselkumab, ixekizumab, secukinumab and O as in outcome, effectiveness and safety. The search to answer the clinical doubts was carried out in the Medline-PubMed database, and for each of them an evidence search strategy was prepared:

3.1. Psoriasis AND (itolizumab OR brodalumab OR secukinumab OR tildrakizumab OR ixekizumab OR guselkumab OR Briakinumabe OR Tofacitinib OR Certolizumab OR etanercept OR TNFR-Fc fusion protein OR Enbrel OR Receptors, Tumor Necrosis Factor OR infliximab OR monoclonal antibody OR monoclonal antibodies OR Remicade OR MAb cA2 OR adalimumab OR Humira OR ustekinumab OR Stelar OR immunobiological therapy) AND random* Psoriasis AND (acitretin OR neotigason) AND random*

• Psoriasis AND (etanercept OR TNFR-Fc fusion protein OR Enbrel) AND random*

• Psoriasis AND (infliximab OR Remicade OR MAb cA2) AND random*

• Psoriasis AND (adalimumab OR Humira) AND random*

• Psoriasis AND (ustekinumab OR Stelara) AND random*

• Psoriasis AND Guselkumab AND random*

• Psoriasis AND Ixekizumab AND random*

• Psoriasis AND Tildrakizumab AND random*

• Psoriasis AND (itolizumab OR brodalumab OR secukinumab OR tildrakizumab OR ixekizumab OR guselkumab OR Briakinumabe OR Tofacitinib OR Certolizumab OR etanercept OR TNFR-Fc fusion protein OR Enbrel OR Receptors, Tumor Necrosis Factor OR infliximab OR monoclonal antibody OR monoclonal antibodies OR Remicade OR MAb cA2 OR adalimumab OR Humira OR ustekinumab OR Stelar OR immunobiological therapy) AND random*

The eligibility criteria are non-randomized studies with weak evidence strength, non-PICO related studies, articles in languages other than Portuguese, English or Spanish. Recovered evidence was selected from the critical evaluation using discriminatory instruments (scores): JADADe GRADE for Randomized Clinical Trials and New Castle Otawa scale for observational studies.

RESULTS

In which conditions treatment with immunobiology is indicated?

Indications for the use of immunobiologicals in patients over 18 years of age with moderate to severe plaque psoriasis with a PASI score above 10 to 12 or a compromised body surface area of more than 10% are:

• Patients with failure to respond to treatment, or contraindications, or intolerance to at least one of the systemic treatments or phototherapy performed in adequate dose and sufficient time^1–36(A).

• Treatment failure is considered to be less than 50% improvement in PASI pre-treatment or improvement of less than 75% relative to PASI pre-treatment associated with a significant impact of the disease on quality of life measured by DLQI (Dermatology Life Quality Index) >= 10.

Some groups of patients with moderate to severe plaque psoriasis have not been studied for immunobiological treatment^1–36(A).

• Patients with associated infections or use of antibiotics in the last week before the beginning of the study;

• Patients with other associated skin conditions, in addition to guttate, erythrodermic, or pustular psoriasis;

• Patients with hematological, renal and/or hepatic dysfunction;

• Patients with a history of cancer of any etiology in the last 5 years;

Treatment with PUVA in the last 4 weeks, or topical corticosteroids, vitamin A or D analogues, dithranol or UVB phototherapy in the last 2 weeks; or use of any immunobiological or anti-TNF antibody at any time prior to the beginning of the study;

Pregnant women or patients with intentions of pregnancy.

RECOMMENDATIONS

Indications for the use of immunobiological drugs in patients over 18 years of age with moderate to severe plaque psoriasis with a PASI score above 10 or a compromised body surface area of more than 10% are the non-responsive to systemic or phototherapeutic treatment, contraindications, or intolerance to at least one of the systemic treatments or phototherapy performed in adequate dose and sufficient time.

What is the effectiveness and what is the risk of ethanercept in the treatment of psoriasis?

Involving 121 patients over 18 years of age, with moderate to severe psoriasis, with involvement of more than 10% of the body surface or more than 30% of the scalp; study allocated 59 patients on etanercept, subcutaneous use, 50mg twice weekly for one week, followed by 50mg once a week for 12 weeks and compared with 62 patients on placebo, subcutaneously, twice weekly for one week, followed by once a week for 12 weeks. The proportion of patients who responded with PASI 50/75/90 at the end of 12 weeks of follow-up were significantly higher in the intervention group, using ethanercept, (78% had PASI 50, NNT=2, p<0.001, 54% had PASI 75, NNT=2, p <0.001; 23% had PASI 90, NNT=5, p<0.001). At the 24-week assessment, the proportion of patients achieving PASI 50/75/90 were similar in the intervention and comparison groups. Adverse effects occurred in the first 12 weeks of follow-up, 54.2% of patients taking etanercept and 54.8% of patients on placebo, with no deaths or serious effects. The most commonly described were application site infection, arthralgia and headache¹(A).

Another study selected 350 patients with clinical diagnosis of plaque psoriasis for more than 6 months, stable in the last 2 months, with a compromise of more than 10% of the body surface area, with an overall evaluation performed by the physicians (PGA) at least moderate (≥ 3) and PASI ≥ 12. They were divided into three different groups, group A being 139 patients treated with briakinumab 200mg, subcutaneously at weeks 0 and 4, followed by 100mg at week 8; group B with 139 patients treated with etanercept 50mg, subcutaneously twice weekly, 3 to 4 days apart, for 12 weeks and 72 patients in group C on placebo³(A).

Of the patients treated with briakinumab, 72.7% achieved PGA 0/1 at week 12 of evaluation, compared to 29.5% of etanercept-treated patients and 4.2% of placebo patients (p <0.001 in both comparisons). Of the patients treated with briakinumab, 80.6% achieved a PASI 75 response at week 12, compared to 39.6% of patients on etanercept and 6.9% of patients on placebo (p <0.001 in both comparisons). Serious adverse events were reported in 2 patients (1.4%) of patients in group A, one patient in group B (0.7%) and two patients (2.8%) in group C³(A).

Patients (n = 142) with moderate to severe plaque psoriasis, involving more than 10% of the body surface area, with a PASI score of at least 10, stable, with failure to respond or contraindications or intolerance to at least one of the systemic or phototherapy treatments performed at adequate dose and sufficient time, were randomized, being 96 patients on etanercept 50mg once a week and 46 patients on placebo once a week. Thus, 36 patients (37.5%) from the etanercept group and 1 patient (2.2%) from the placebo group presented PASI 75 response at the end of 12 weeks (p<0.0001) and PASI 90 response in 13 patients of the intervention group (13.5%) and 1 (2.2%) in the comparison group (p <0.05). The mean percentage of improvement in PASI compared to the start of treatment was 55.4% for the intervention group and 9.4% for the comparison group (p<0.0001). The difference in lesions lightening through the PGA was 34.2% for the group that performed etanercept (38.5% vs. 4.3%, p<0.0001). And the mean difference for improvement in quality of life through the DLQI score was 49.2% for the etanercept group (p<0.0001). The adverse effects reported with significant difference between the groups, with the highest number in the intervention group, were migraine (p=0.04) and influenza-like syndrome (p=0.03). The other signs and symptoms did not present a statistically significant difference⁴(A).

Authors evaluated 583 patients who were allocated to 2 intervention groups: 196 patients for the use of etanercept 50 mg per week and 194 patients for the use of etanercept 50 mg twice a week and 193 patients on placebo. There was a statistically significant difference for the use of etanercept compared to placebo, both for once a week use (46%, p<0.0001, NNT=3) and twice a week (51%, p<0.0001, NNT=2) in the intervention group, and for the DLQI quality of life assessment at the end of 12 weeks⁵(A).

Another study has included patients for the use of etanercept 25 mg per week (n = 160), 50 mg per week (n=162) or 50 mg twice a week (n=164) and compared with placebo use (n=166). There was a significant improvement in quality of life, based on a minimum reduction of 5 points in the DLQI score, in patients who used etanercept at all different doses in relation to placebo, improvement of 22% for etanercept 25mg once a week, in 26% with 50mg once a week, 35% with 50mg twice a week (p <0.0001 in all groups, with NNT=5, NNT=4 and NNT=3, respectively). For the score of 5 to 14 points in the DLQI, there was significant improvement for both the use of etanercept 50mg once or twice a week (p<0.05)⁶(A).

Of the 611 patients selected for the study, 194 received etanercept 50 mg twice a week and another group of 196, etanercept 25 mg twice a week; compared with 193 patients on placebo. There was a statistically significant difference between the use of etanercept versus placebo in the reduction to PASI 75, from 43% to etanercept 50mg twice a week and 29% to etanercept 25mg twice a week (p<0.0001, NNT=3 and NNT=4, respectively). There was also a statistically significant difference (p<0.0001) for PASI 50 (68% for 50mg, NNT=2 and 55% for 25mg, NNT=2) and PASI 90 (20% for 50mg, NNT=2 and 10% for 25mg, NNT=10); and for the physician's global evaluation as to lightening of lesions (53% for 50mg, NNT=2 and 35% for 25mg, NNT=3, p <0.0001). Adverse events reported in the first 12 weeks of evaluation were injection site reaction, respiratory infection, headache, influenza-like syndrome, and all without any difference between the intervention and comparison groups⁷(A).

Another 112 patients with similar characteristics were included in the study, and treatments with PUVA or systemic treatment should not have been performed in the last four weeks prior to the beginning of the study; UVB phototherapy, the use of topical corticosteroids, vitamins A and D analogues or anthralin should not have been used in the last two weeks. In the evaluation for PASI 75 there was a significant improvement regarding the use of etanercept in 28% (95% CI 16% to 40%, p<0.001, NNT=4). The percentage of patients reporting adverse events was similar in the intervention and comparison groups, with the most frequent being the injection site reaction⁸(A).

In another study involving 652 patients with psoriasis, 160 received a low dose of etanercept (25 mg once a week), 162 received an intermediate dose of etanercept (25 mg twice a week), and 164 patients received a high-dose of etanercept (50 mg twice a week), compared with 166 patients on placebo. In the evaluation at the end of week 12, there was a significant improvement in the treatment for all doses of etanercept for PASI 50 (27%, 44% and 60%, respectively, p<0.001), and for PASI 75 (10%, 30% and 45% respectively, p<0.001); for PASI 90 there was a significant improvement for the intermediate doses and high doses of etanercept (11% and 21% respectively, p<0.001). There was also a significant improvement in the total or almost total lightening of the lesions at the end of 12 weeks with all the different doses of etanercept (18%, 29% and 44%, p<0.001). The most frequently reported adverse events were injection site reaction, headache and respiratory infection, with no difference between groups⁹(A).

RECOMMENDATIONS

Treatment with etanercept for moderate to severe plaque psoriasis during the 12-week period after no response to other systemic or phototherapy psoriasis treatment was effective for PASI 75 response evaluation and safe with mild to moderate adverse events, especially at the injection site, for doses of 25 mg once a week, 25 mg twice a week or 50 mg twice a week, with the best responses at higher doses of etanercept, which may vary from 10-28% 26-39.6% and 35-54%, respectively (table 1).

TABLE 1
EVALUATION OF THE ETANERCEPT EXPRESSED BY THE ESTIMATED BENEFIT IN PERCENTAGE.

Author	Dose	Follow-up Time	PASI 50 (%)	PASI 75 (%)	PASI 90 (%)	PGA (%)	DLQI (%)
Bagel J1	100mg/week	12 weeks	78	54	23
Gottlieb AB3	50mg/week.	12 weeks		39.6		29.5
Van de Kerkhof4	50mg/week.	12 weeks		37.5		38.5	49.2
Krueger GG5	50mg/week.	12 weeks		46
Feldman ST6	25mg/week.	12 weeks		22
Feldman ST6	50mg/week.	12 weeks		26
Feldman ST6	100mg/week.	12 weeks		35
Pappa KA7	50mg/week.	12 weeks	55	29	10	35
Pappa KA7	100mg/week.	12 weeks	68	43	20	53
Gottlieb AB8	25mg/week.	12 weeks		28
Leonard GL9	25mg/week.	12 weeks	27	10			18
Leonard GL9	50mg/week.	12 weeks	44	30	11		29
Leonard GL9	100mg/week.	12 weeks	60	45	21		44

What is the efficiency and what is the risk of infliximab in the treatment of psoriasis?

With 835 patients with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy with PASI of at least 12 or involvement of at least 10% of the body surface, with no history of severe infection, lymphoproliferative disease, or active tuberculosis; the study randomized 627 patients on infliximab 3mg/kg or 5mg/kg on weeks 0, 2 and 6. The comparison was made with 208 patients on placebo. At week 10, patients on infliximab 3 and 5 mg/kg showed a significant improvement in DLQI scores compared to placebo (8.9 and 9.9, respectively, p<0.001)¹¹(A).

A group of 301 patients on intravenous infliximab 5 mg/kg at weeks 0, 2, 6 and every 8 weeks up to week 46, and a comparison group with 77 patients on placebo at weeks 0, 2, 6, 14 and 22, were submitted to the study and then cross over was performed for the use of infliximab. There was a significant improvement of PASI in the 10^th week of evaluation in patients using infliximab, 79.6% had a PASI 75 response (NNT=2, p<0.001) and 55.8% had a PASI 90 response (NNT=2, p<0.001). Regarding the DLQI score, there was also a significant improvement for the use of infliximab of 9.9, p<0.001)¹³(A).

Patients (n=249) over 18 years of age with a diagnosis of plaque psoriasis over the past 6 months, previous treatment with PUVA or other systemic treatment for psoriasis were randomized, with 99 patients using intravenous infliximab 3mg/kg and 99 patients on infliximab 5 mg/kg treated at weeks 0, 2 and 6. The comparison consisted of 51 patients on placebo. The induction treatment with infliximab resulted in significant improvement in PASI evaluated by obtaining a PASI 50 response (62.2% for the use of 3 mg/kg and 75.4% for the use of 5mg/kg, NNT = 2 for both groups, p<0.001), obtaining of PASI 75 response (65.8% for the use of 3mg/kg and 82% for the use of 5mg/kg, NNT=2 for both groups, p <0.001) and PASI 90 response (45.5% for the use of 3mg/kg and 55.6% for the use of 5mg/kg, NNT=3 and NNT=2 respectively, p <0.001). There were also significant lightening in the physician's overall evaluation in both the group that used 3mg/kg (61.9% NNT=2, p<0.001) and for the group that used 5mg/kg (80.1% NNT=2, p<0.001). As for the safety of the use of infliximab, over 70% of patients in the intervention groups and more than 60% of the comparison group patients experienced adverse events, mostly mild to moderate, and the most frequent were the infusion reactions¹⁴(A).

One study involved 33 patients aged 21-69 years with moderate to severe plaque psoriasis involving more than 5% of body surface area. The intervention was performed with 11 patients using infliximab 5mg/kg, 11 patients using infliximab 10mg/kg, at weeks 0, 2 and 6, and comparing with 11 patients on placebo. There was a significant improvement, evaluated by obtaining the PASI 75 response with the use of infliximab at week 10 (63.6% for the use of 5mg/kg and 54.5% for the use of 10mg/kg, both with NNT=2, p<0.05). The mean percentage of PASI improvement was significant (p<0.0003) for the use of infliximab at the two different doses from the second week of treatment. The reported adverse events were all mild to moderate¹⁶(A).

RECOMMENDATIONS

The induction treatment with infliximab in moderate to severe plaque psoriasis during the 10-week period was effective by evaluating the PASI75 response (65.8-79.6%) and improvement of the quality of life by the DLQI score (8.9 to 9.9%), besides being safe, with few mild to moderate adverse events, mainly infusion reactions, at doses of 3mg/kg, 5mg/kg or 10mg/kg, at weeks 0, 2 and 6 (table 2).

TABLE 2
EVALUATION OF INFLIXIMAB EXPRESSED BY THE ESTIMATED BENEFIT IN PERCENTAGE

Author	Dose	Follow-up time	PASI 50 (%)	PASI 75 (%)	PASI 90 (%)	PGA (%)	DLQI (%)
Feldman SR11	3mg/kg	10 weeks					8.9
Feldman SR11	5mg/kg	10 weeks					9.9
Reich K13	5mg/kg	10 weeks		79.6	55.8		9.9
Gottlieb AB14	3mg/kg	10 weeks	62.2	65.8	45.5	61.9
Gottlieb AB14	5mg/kg	10 weeks	75.4	82	55.6	80.1
Chaudhari U16	5mg/kg	10 weeks		63.6
Chaudhari U16	10mg/kg	10 weeks		54.5

What is the efficiency and what is the risk of adalimumab in the treatment of psoriasis?

In period A of a double blind, placebo-controlled study of 12 weeks, patients were randomized 4:1 to receive adalimumab 40 mg every two weeks (followed by a single dose of 80 mg) or placebo every two weeks. In the 12 following weeks, period B, open trial, all patients received adalimumab 40 mg every two weeks starting at week 13, followed by a single blinded dose at week 12 of adalimumab 80 mg or placebo (for patients receiving placebo or adalimumab at period A, respectively). In Period A, efficacy was analyzed for all randomized patients and safety for all patients who received ≥1 dose of the study drug. For the 425 patients in this study (87 placebo, 338 adalimumab), a higher percentage with adalimumab achieved a 75% reduction of baseline PASI score (PASI 75 response) at week 12: placebo 11.5% (10/87); adalimumab 77.8% (263/338; NNT=2, P<0.001). The obtaining of PGA response 0 or 1 (total or almost total lightening), was achieved at week 12 by 14.9% placebo (13/87) and 80.5% adalimumab (272/338, NNT=2, P<0.001). For patients receiving adalimumab at any time during the study, treatment-emergent adverse events (AEs) were reported by 63.4%; the most common was infection of the upper respiratory tract (16.1%). Severe AEs were reported by 3.5% of the population receiving adalimumab and severe infectious AEs by 1.2%, which include pulmonary infection, pneumonia and tuberculosis – 2 (0.5%) patients each. There was 1 death (chronic heart failure)¹⁷(A).

Authors involved patients over 18 years of age with moderate to severe psoriasis with 10% or more of body surface involvement and PASI score above 10. All patients had plaque psoriasis for at least 1 year and lesion stability for at least 2 months. The period without other treatments was 2 weeks for topical treatment and phototherapy, and 12 weeks for biological treatment. Patients were randomized to 3 groups: 108 patients for adalimumab (ADA), subcutaneously, 80mg at week 0, followed by adalimumab 40mg every 2 weeks, from week 1 to 15, and 110 patients for oral methotrexate (MTX) 7.5 to 25mg per week for 16 weeks. The comparison consisted of 53 patients for the use of placebo. After 16 weeks of follow-up, 79.6% of adalimumab-treated patients achieved a PASI 75 response, compared with 35.5% for the methotrexate-treated group and 18.9% for the placebo-treated group, which means 60.7% improvement for ADA (NNT=2, p<0.001) and 16.6% for MTX (NNT=6, p<0.05). There was a statistically significant improvement in complete improvement of the lesions (PASI 100) in patients treated with ADA (16.7%) compared to patients treated with methotrexate (7.3%) or in patients treated with placebo (1.9%). Regarding adverse events, 73.8% of patients in the ADA group, 81.8% in the MTX group, and 79.2% in the placebo group had at least one adverse effect. However, there was no statistically significant difference between the groups for infectious conditions, moderate to severe adverse events, and drug-related adverse events. Adverse events leading to interruption of the study were higher in the methotrexate group, mainly due to events related to hepatic dysfunction. There were no reports of tuberculosis or deaths during the study^18–20(A).

Patients with similar characteristics but with a PASI score above 12 (N=1212) received phototherapy with UVB or topical treatment for more than 2 weeks and for more than 4 weeks for prior treatment with PUVA or non-biological systemic treatment, 6 weeks for the use of efalizumab and 12 weeks for any other biological treatment. The intervention was performed with 814 patients on adalimumab 80mg at week 0, followed by adalimumab 40mg every 2 weeks from week 1 to 15. The comparison was made with 398 patients taking placebo from week 0 to week 15. There was a significant improvement, evaluated by the obtaining of the PSI 75 response, with a 64% difference for the use of adalimumab (p<0.001, NNT= 2). There were also significant differences for the PASI 90 and PASI 100 responses at the 16^th week of 43% (NNT=3) and 19% (NNT=6) respectively (p<0.001 for both comparisons). Regarding quality of life, there was also a significant improvement in the DLQI score for the intervention group from the fourth week of treatment. Adverse events were significantly higher in ADA patients, especially upper respiratory tract infections (p=0.01)^21–23(A).

Recruited from 42 locations in Japan, 169 patients over 20 years of age with moderate to severe plaque psoriasis, diagnosed for more than 6 months, stable for more than 2 months. Body surface involvement was greater than 10% or PASI greater than 12 for all patients. Group 1 with 38 patients on adalimumab 40 mg every 2 weeks; group 2 with 43 patients taking adalimumab 80mg every 2 weeks at week 0, followed by adalimumab 40mg every 2 weeks from week 2; group 3 with 42 patients taking adalimumab 80mg every 2 weeks. Group 4 was the control with 46 patients on placebo. There was a significant difference for the use of ADA in all the different doses for PASI 75 response (57.9% for group 1, 62.8% for group 2 and 81% for group 3, and 4.3% for placebo group, NNT=2 for all groups), in addition to significant improvement for lightening assessed by PGA. Injection site reactions and liver changes were the most commonly reported adverse events in the intervention group²⁴(A).

The authors assigned 808 patients on adalimumab 80mg at week 0 followed by 40mg at week 1 at week 15, and 397 patients on placebo. At week 16, patients receiving adalimumab showed improvement and a significant increase in the PCS score (physical components summary), without improvement over the MCS score (mental components summary)²⁵(A).

Authors divided 148 patients, being: group 1 with 46 patients taking adalimumab 80mg at week 0, followed by 40mg weekly from week 1, group 2 with 50 patients on adalimumab 80mg at weeks 0 and 1, followed by 40mg per week from week 2; with 52 patients receiving placebo from week 0. At week 12, there was a significant difference of 49% for group 1 compared to placebo (NNT=2, p<0.001) and 76% for group 2 (NNT=2, p<0.001) in the improvement assessed by the PASI 75 response. All adverse events were moderate to severe and had a similar frequency in all groups²⁶(A).

RECOMMENDATIONS

Adalimumab treatment in moderate to severe plaque psoriasis over the period of 12 to 16 weeks was effective by evaluating the PASI 75 response and improving quality of life through the DLQI score (49-81%) in the following therapeutic regimens: 40 mg every 2 weeks (PASI75 57.9-79.6%, PASI90 43%, PASI100 16.7-19% and PGA 80.5%); 80 mg at week 0 followed by 40 mg every 2 weeks (PASI75 62.8%); and 80 mg every 2 weeks (PASI75 81%), in addition to being safe, with few mild to moderate adverse events (Table 3)

TABLE 3
EVALUATION OF ADALIMUMAB EXPRESSED BY THE ESTIMATED BENEFIT BY PERCENTAGE.

Author	Dose	Follow-up time	PASI 75 (%)	PASI 90 (%)	PASI 100 (%)	PGA (%)
Cai L17	40mg + 80mg	12 weeks	77.8			80.5
Reich K18–20	80mg + 40mg	16 weeks	79.6		16.7
Revicki D21–23	80mg + 40mg	16 weeks	64	43	19
Asashina A24	40mg every 2 weeks	16 weeks	57.9
Asashina A24	80mg every 2 weeks + 40mg from week 2	16 weeks	62.8
Asashina A24	80mg every 2 weeks	16 weeks	81
Gordon KB26	80mg + 40mg from week 1	12 weeks	49
Gordon KB26	80mg + 40mg from week 2	12 weeks	76

What is the effectiveness and what is the risk of ustekinumab in the treatment of psoriasis?

A multi-center randomized, double blind, placebo-controlled study evaluating the efficacy and safety of ustekinumab 45 mg and 90 mg at 5-year follow-up. The study included four distinct periods: (i) placebo control (weeks 0-12); (ii) placebo crossover and active treatment (weeks 12-28); (iii) random setting of the dose range (weeks 28-52) and (iv) long-term extension (weeks 52-264), during which dose and/or dose interval adjustments were made by the investigator. Baseline randomization was stratified by research site, weight (≤90 kg or >90 kg) and if the patient did not have an inadequate response, intolerance or contraindication to less or more than three conventional systemic therapies. The second randomization, at week 28, was stratified by research site and baseline weight (≤ 90 kg or >90 kg). In the general population, 70% (849 of 1212) of ustekinumab-treated patients completed treatment by week 244, with better responses at doses of 45 and 90 mg. Improvement in the Severity Index (PASI 75 response) of 76.5% and 78.6%, and PASI 90, 50% and 55.5%, respectively. By week 264, safety rates did not increase and event rates were generally comparable between dose groups and between patients with and without dose adjustments. Treatment with ustekinumab for up to 5 years was safe and effective. The improved response was generally demonstrated after dose adjustments²⁷(A).

Studies have involved 766 patients over 18 years of age, diagnosed with plaque psoriasis for more than 6 months, candidates for phototherapy or systemic therapy, with initial PASI greater than 12, or compromise of more than 10% of body surface area. Group 1 with 255 patients on ustekinumab (UST) 45mg at weeks 0, 4 and 12, group 2 with 256 patients on UST 90mg at weeks 0, 4 and 12 and group 3 with 255 patients on placebo at weeks 0 and 4, and that from week 12 onwards they were randomized to receive 45 or 90mg of UST (crossover study). There was a significant improvement in the use of UST over placebo for the response of PASI 75 above and for PGA scores 0 or 1 at the 12^th week of evaluation. Regarding the DLQI score, there was a significant increase in patients who reached a score of 0 or 1 compared to placebo (47.2% for the use of 45mg, NNT=2 and 46.4% for the use of 90mg of UST, NNT=2, p<0.001) in the 12^th week, in addition to significant clinical improvement (increase of at least 5 points) in the SF-36 physical score (7.5% for 45mg NNT=14, 18.1% for 90mg NNT=6, p<0.001) and in the SF-36 mental score (10.7% for 45mg, NNT=10, 16.5% for 90mg, NNT=6, p<0.001)^28–31(A).

Other studies (N=1230) also randomized patients to: group 1 with 409 patients using UST 45mg at weeks 0, 4 and 12, group 2 with 411 patients using UST 90mg at weeks 0, 4 and 12 and group 3 with 410 patients on placebo at weeks 0 and 4, and who were randomized to receive 45 or 90 mg of UST from week 12 (crossover study). In the evaluation of the PASI, there was a significant improvement evaluated by obtaining the PASI 50, PASI 75, PASI 90 and PASI 100 responses for the use of UST 45mg (73%, NNT=2, 63%, NNT=2, 41.6% NNT=3 and 18.1%, NNT=6, respectively), and for the use of UST 90 mg (78.6%, NNT=2, 72%, NNT=2, 50.2%, NNT=2, 18.2% NNT=6). There was also a significant improvement in the use of UST compared to placebo in the visual analogue productivity scale at week 12 of evaluation (improvement of 72.6% for use of 45mg and of 71.4% for use of 90 mg of UST, p<0.001). As for the DLQI score, there was also a significant improvement in the use of UST compared to placebo (-9.13 vs. −0.53, respectively, p<0.001), with a difference of 48.9% for the use of UST 45mg (NNT=2, p<0.001) and 54.6% (NNT=2, p<0.001)^32–35(A).

Among 158 patients over 20 years of age, with moderate to severe plaque psoriasis diagnosed in the last 6 months, with at least 10% of body surface involvement or PASI of 12 or more, and eligible for phototherapy or systemic therapy, were randomized into 3 groups. Group 1 with 64 patients on UST 45mg, group 2 with 62 patients on UST 90mg per week and group 3 with 32 patients on placebo at weeks 0 and 4, followed by crossover at week 12. There was significant improvement assessed through the obtaining of PASI 50, PASI 75, PASI 90 responses for patients that used UST both at 45mg (69.9%, NNT=2, 52.9%, NNT=2, 29.6%, NNT=4, respectively, p<0.0001> and 90mg (71%, NNT=2, 61.2%, NNT=2, 40.3%, NNT=3, respectively, p <0.0001). Patients treated with 45mg and 90mg of UST also showed a significant improvement in mean DLQI scores (7.7 and 7.1, respectively, p <0.001), with improvement of 58.1% to 45mg (NNT=2, p<0.0001) and 54.1% to 90mg (NNT=2, p<0.0006)^36,37(A).

In one study, 61 patients received UST 45mg per week, compared to 60 patients on placebo. At week 12, the proportion of patients who achieved PASI 75 response was 62.2% higher in the group that received UST 45mg per week (NNT=2, p<0.001); with the PGA (percentage of patients who achieved PGA 0 or 1), there was a difference of 62.2% for patients using UST (NNT=2, p<0.001); and the mean improvement in quality of life for the DLQI score was −11 (p<0.001) also for the benefit of UST use³⁸(A).

A randomized, non-double-blind study comparing doses of 45 and 90 mg of ustekinumab with etanercept with a primary outcome measured by PASI 75 improvement at week 12 observed responses of 67.5%, 75.8% and 56.8%, respectively (P=0.01 in the comparison between ustekinumab 45mg / ethanercept and P<0.001 in the comparison between 90mg with etanercept). In the PGA 0/1 outcome, the results were 65.1%, 70.6% and 49.0% respectively (P<0.001 for both comparisons)³⁹(A).

RECOMMENDATIONS

Studies evaluating the efficacy and safety of ustekinumab for moderate to severe plaque psoriasis show improvement assessed by the PASI75 response (52.9-76.5% for 45mg and 61.2-78.6% for 90mg) and in quality of life according to the DLQI score (46.4-58.1%), as well as mild to moderate adverse events, in a 12-week period. Ustekinumab at doses of 45 and 90mg was superior to etanercept when evaluating PASI 75 and PGA 0/1 at 12 weeks of follow-up. After this period, although studies have carried out crossover, treatment with ustekinumab for up to five years was safe and effective following dose adjustment. (table 4)

TABLE 4
EVALUATION OF USTEKINUMAB EXPRESSED BY THE ESTIMATED BENEFIT BY PERCENTAGE

Author	Dose	Follow-up Time	PASI 50 (%)	PASI 75 (%)	PASI 90 (%)	PSI 100 (%)	PGA (%)	DLQI (%)
Langley RG27	45mg	244 weeks		76.5	50
Langley RG27	90mg	244 weeks		78.6	55.5
Kimball AB28–31	45mg	12 weeks						47.2
Kimball AB28–31	90mg	12 weeks						46.4
Reich K32–35	45mg	12 weeks	73	63	41.6	18.1	72.6	48.9
Reich K32–35	90mg	12 weeks	78.7	72	50.2	18.2	71.4	54.6
Nakagawa H36,37	45mg	12 weeks	69.9	52.9	29.6			58.1
Nakagawa H36,37	90mg	12 weeks	71	61.2	40.3			54.1
Tsai TF38	45mg	12 weeks		62.2			62.2

What is the efficiency and what is the risk of guselkumab in the treatment of psoriasis?

Phase 3, randomized, double blind, placebo-controlled study. The study included a placebo-controlled period (weeks 0-16), a placebo-crossover and active treatment period (weeks 16-52) and a long-term extension phase. Eligible patients were randomized (1: 1: 1) for guselkumab 50 mg, 100 mg or placebo, injected subcutaneously at weeks 0, 4 and every 8 weeks thereafter. Patients receiving placebo were crossed to receive (1: 1) guselkumab 50 mg or 100 mg at weeks 16 and 20 and every 8 weeks. At week 16, a significantly greater proportion (P<0.001) of patients receiving guselkumab 50 mg (NNT=2) and 100 mg (NNT=2) versus placebo achieved IGA 0/1 (92.3% and 88.9% vs. 7.8%) and PASI90 (70.8% and 69.8% vs. 0%). Patients in the 50 mg and 100 mg groups of guselkumab and in the placebo group had improvement evaluated by the PASI75 response (89.2% and 84.1% vs 6.3%, P<0.001) at week 16; improvement was maintained until week 52. Incidences of treatment-emergent adverse events were comparable between groups up to week 16; the most commonly reported was nasopharyngitis⁴⁰(A).

The patients (n=992) were randomized (guselkumab: n=248; placebo: n=496; adalimumab: n=248) to 100 mg guselkumab at weeks 0, 4, 12 and 20; placebo at weeks 0, 4, 12 followed by guselkumab 100 mg at weeks 16, 20; or adalimumab 80 mg at week 0, 40 mg every 2 weeks, from week 1 to week 24. Guselkumab was superior to adalimumab at week 16 and 24 (P <0.001). From weeks 28 to 48, a better persistence of response was observed in maintenance groups with guselkumab versus abstinence groups (P<0.001). Of the non-responders of adalimumab who switched to guselkumab, 66.1% achieved PASI 90 at week 48. Guselkumab improved the outcomes reported by the patient. Adverse events were comparable between groups⁴¹(A).

In one study the patients were randomized to 100 mg guselkumab (weeks 0 and 4, then every 8 weeks, n = 329); placebo → guselkumab (weeks 0, 4 and 12, then guselkumab at weeks 16 and 20, then every 8 weeks, n = 174); or adalimumab (80 mg weekly, 0.40 mg week 1, then 40 mg every 2 weeks to week 47, n = 334). Guselkumab was superior (P <0.001) to placebo at week 16 evaluated by IGA response 0/1, 85.1% vs 6.9% (NNT = 2) and 73.3% vs 2.9% as assessed by the PASI 90 response (NNT = 2). Guselkumab was also superior to adalimumab in IGA 0/1 (NNT = 6, P <0.001) and PASI 90 (NNT = 5, P <0.001) at week 16 85.1% vs 65.9% and 73.3% vs 49.7%); at week 24, 84.2% vs 61.7% (NNT = 5, P <0.001) and 80.2% vs 53.0% (NNT = 4, P <0.001)) and at week 48, 80.5 % vs 55.4% (NNT = 4, P <0.001) and 76.3% vs 47.9% (NNT = 4, P <0.001). In addition, guselkumab significantly improved outcomes reported by patients up to week 48. Rates of adverse events were comparable among treatments⁴²(A).

RECOMMENDATIONS

Studies evaluating the efficacy and safety of guselkumab for moderate to severe plaque psoriasis show improvement evaluated by the PASI90 response (50mg of 70.8% and 100mg of 69.8-73.3%) and IGA (0/1). Occurrence of mild to moderate adverse events, under analysis for a period of 36 weeks (table 5). Guselkumab (100mg) was superior to adalimumab (80 and 40mg) in IGA and PASI 90 response.

TABLE 5
GUSELKUMAB ASSESSMENT EXPRESSED BY THE ESTIMATED BENEFIT BY THE PERCENTAGE

Author	Dose	Follow-up Time	PASI 50 (%)	PASI 75 (%)	PASI 90 (%)	PGA (%)	DLQI (%)
Ohtsuki M40	50mg	16 weeks		89.2	70.8	92.3
Ohtsuki M40	100mg	16 weeks		84.1	69.8	88.9
Blauvelt A M42	100mg	16 weeks			73.3	85.1

What is the effectiveness and what is the risk of ixekizumab in the treatment of psoriasis?

Randomized patients 2: 2: 2: 1 (n = 1346, UNCOVER-3), groups that received subcutaneous injections of 80 mg of ixekizumab every 2 weeks or every 4 weeks after an initial dose of 160 mg of ixekizumab, 50 mg of etanercept twice weekly or placebo, respectively, over a 12-week induction dosing period (weeks 0 to 12). At week 12, patients entered the long-term follow-up (LTE) period, during which they received ixekizumab 80 mg every 4 weeks. After week 60, patients could increase their dose from 80 mg every 4 weeks to 80 mg every 2 weeks of ixekizumab until the end of study at the discretion of the investigator. The high response rates observed during the previous treatment periods persisted for 108 weeks of treatment. In patients receiving the 80 mg dose of ixekizumab every 2 weeks during induction and every 4 weeks during LTE (N = 385), the response rates observed were 93.4% for PASI 75; 79.7% for PASI 90; 56.3% for PASI 100; 82.6% for sPGA (0.1); and 57.0% for sPGA (0). Response rates were similar for each treatment arm at 108 weeks. At week 156 the observed response rate was 97.2% for PASI 75⁴⁴. The frequency, severity, and distribution of treatment-emergent adverse events (TEAEs) were similar between treatment arms. The most frequently observed TEAEs (> 5%) during the LTE period included nasopharyngitis, upper respiratory tract infections, injection site reactions, arthralgia bronchitis, and headache. Of 1077 (84.5%) TEAEs reported during the LTE period, 910 (85%) were of mild or moderate severity. Of the TEAEs of special interest that occurred during LTE, Candida infections were the most common, occurring at a rate of 3.8%. Overall, the results presented demonstrate that ixekizumab is well tolerated and provides a long-term and persistent clinical response^43,44(A).

In UNCOVER-1, patients were randomized 1: 1: 1 to receive subcutaneous ixekizumab 80 mg every 2 weeks (IXE2S), ixekizumab 80 mg every 4 weeks (IXE4S) (each with a starting dose of 160 mg) or placebo (PBO) for 12 weeks. In UNCOVER-2, patients were randomized 2: 2: 2: 1 to receive IXE2S, IXE4S (each with an initial dose of 160 mg), etanercept 50 mg twice weekly or placebo by 12 weeks. In both trials, the 12-week induction period was followed by a 48-week (12-60) randomized maintenance period, in which those responding to ixekizumab at week 12 (sPGA = 0 or 1) were randomized (1 : 1: 1) to receive subcutaneous placebo, IXE4S. A total of 1226 treated patients reached the sPGA 0, 1 at week 12 and entered the maintenance phase; of these patients, 402 and 416 were randomized to PBO and IXE4S, respectively. Among patients who discontinued treatment, 157 (82.2%) of IXE4S / PBO and 176 (83.4%) of IXE2S / PBO they had an sPGA of ≥3 at week 60; the mean time to relapse was approximately 20 weeks regardless of the induction dose. At week 60, continuously treated patients maintained high levels of PASI and sPGA responses (90.0% PASI 75 IXE2S / IXE4S, 81.9% sPGA 0.1, IXE2S / IXE4S, non-responder imputation). After 24 weeks of retreatment with IXE4S (IXE2S / PBO / IXE4S and IXE4S / PBO / IXE4S), 87% (107 of 123) and 95% (97 of 102) (observed), respectively, of patients recovered PASI 75 and 70.7% (104 of 147), and 82.3% (107 of 130) (observed) recovered aPGA 0, 1. In general, adverse events in continuously treated and portrayed patients were comparable^45,46,47(A).

In a study (UNCOVER-2) that evaluated 347 patients on ixekizumab every 4 weeks, 351 patients on ixekizumab every 2 weeks, 358 patients on etanercept and 168 patients on placebo, an improvement was observed for PASI 75 in the first 12 weeks of 77.5%, 89.7%, 41.6% and 2.4% respectively (P <0.0001 for comparisons between ixekizumab/placebo and ixekizumab/etanercept). Regarding the PASI 90 improvement, the results were 59.7%, 70.7%, 18.7% and 0.6% respectively (P <0.0001 for the comparisons between ixekizumab/placebo and ixekizumab/etanercept). When analyzing PASI 100 improved, it was observed 30.8%, 40.5%, 5.3% and 0.6%, respectively, P <0.0001 for the comparisons between ixekizumab/placebo and p <0.0082 between ixekizumab/etanercept). Similar results were observed in the PGA 0/1 outcome⁴⁷(A).

Study (UNCOVER 3) evaluating 386 patients on ixekizumab every 4 weeks, 385 patients on ixekizumab every 2 weeks, 382 patients on etanercept and 193 patients on placebo, found improvement in PASI 75 in the first 12 weeks of 84.2%, 87.3%, 53.4% and 7.3% respectively (P <0.0001 for the comparisons between ixekizumab/placebo and ixekizumab/etanercept). Regarding PASI 90 improvement, the results were 65.3%, 68.1%, 25.7% and 3.1%, respectively. When analyzing PASI 100 improved, it was observed 35%, 37.7%, 7.3% and 0% respectively (P <0.0001 for all comparisons between ixekizumab/placebo and between ixekizumab/etanercept). Also in this study, similar results were observed in the PGA 0/1 outcome⁴⁷(A).

The 12 patients in this study were randomized 1: 1 to receive 80 mg of ixekizumab every two (IXE2S) or four (IXE4S) weeks during the induction period (0-12 weeks) after an initial dose of 160 mg ixekizumab. All patients received 80 mg ixekizumab (IXE4S) during the maintenance period (12-48 weeks) with the final dose of ixekizumab administered at week 44. The mean time to an improvement of at least 1 point or 2 points in the baseline of the PatGA score was 5.0 and 10.0 days for patients randomized to IXE2S and 6.0 and 13.5 days for patients randomized to IXE4S. All patients achieved at least a 50% or 75% improvement in PASI since the beginning of weeks 2 and 4, respectively. At least half of the patients achieved a 4-point improvement over baseline Itch NRS on Day 14. Improvement in disease was conspicuously evident within one week of treatment in patient photographs⁴⁸(A).

RECOMMENDATIONS

Studies in the evaluation of the efficacy and safety of Ixekizumab and moderate to severe plaque psoriasis show improvement in PASI 75 (90-93.4%), PASI 90 (79.7%), PASI 100 (56.3%), PatGA, Itch NRS and sPGA (57-81.9%). Results of ixekizumab used in doses every two to four weeks were significantly better for PASI75, 90, 100 and IGA 0/1 outcomes compared to etanercept. Occurrence of mild to moderate adverse events in a 96-week period. (table 6)

TABLE 6
EVALUATION OF IXEKIZUMAB EXPRESSED BY THE ESTIMATED BENEFIT BY MEANS OF THE PERCENTAGE.

Author	Dose	Follow-up Time	PASI 50 (%)	PASI 75 (%)	PASI 90 (%)	PASI 100 (%)	PGA (%)
Blauvelt A43,44	80mg every 4 weeks	12 weeks		93.4	79.7	56.3	57.0
Blauvelt A43,44	80mg every 2 weeks	60 weeks		90			81.9

What is the efficacy and what is the risk of secukinumab in the treatment of psoriasis?

Treatment with subcutaneous 300 or 150 mg secukinumab in a FI or RAN regimen. FI was administered once every 4 weeks, and in the RAN regimen, participants received placebo until the onset of relapse, defined as ≥20% loss of maximal PASI improvement versus baseline plus loss of PASI 75 response. When the relapse onset criterion was met, the subject received active secukinumab at the originally randomized dose (every 4 weeks) until the PASI 75 response was restored, at which point the subject started receiving placebo again. A group of 168 subjects received secukinumab 300 mg IF and another group with 172 received secukinumab 300 mg RAN. Secukinumab 300 mg IF maintained high efficacy: at the end of year 3, the PASI 90 response was 63.8% and PASI 100 was 42.6%. The mean absolute PASI remained low (2-4) from week 52 to week 152 with 300 mg FI, with approximately two-thirds of individuals reporting no impact of the skin disease on their lives (Dermatology Quality of Life Index of 0/1). Improvements in overall scores and subscales in all quality of life instruments were well supported. The IF dosage was consistently more effective than the RAN. No new safety signal has been identified for year 3⁴⁹(A).

Patients ≥ 18 years, diagnosis (with ≥6 months) of moderate to severe plaque psoriasis (PASI) ≥12; IGA of 3 or 4; BSA ≥10% were selected for a study that had a 12-week induction period, a 40-week maintenance period, and an 8-week follow-up period. Patients in the ERASURE trial were randomly assigned in a 1: 1: 1 ratio to receive secukinumab at a dose of 300 mg, secukinumab at a dose of 150 mg or placebo; those in the FIXTURE study were randomly assigned 1: 1: 1: 1 to receive secukinumab at the 300 mg or 150 mg dose, etanercept or placebo. Patients randomly assigned to secukinumab in both studies received two subcutaneous injections of 150 mg secukinumab (there is, 300 mg total) or one 150 mg injection plus one placebo injection, with both injections administered once weekly in the beginning and at weeks 1, 2, 3 and 4 and then every 4 weeks until week 48. Patients randomly assigned to etanercept received 50 mg given subcutaneously twice weekly from baseline to week 12 and then once weekly until week 51, according to the standard dosing regimen. In the FIXTURE study, the placebo group received placebo injections corresponding to the secukinumab and etanercept regimens, and the secukinumab and etanercept groups received placebo injections corresponding to the other active drug regimen, in order to maintain a dual simulation design. In the ERASURE study, patients randomly assigned to receive placebo received placebo injections corresponding to the secukinumab regimens. In each study, patients in the placebo group who did not meet the criteria for a 75% or greater reduction in baseline PASI score (PASI 75) at week 12 were again randomized at 1: 1 ratio to receive secukinumab at a dose of 300 mg or 150 mg; those who achieved the PASI 75 response at week 12 continued to receive placebo. The proportion of patients meeting the criteria for PASI 75 at week 12 was higher in the use of secukinumab compared to placebo or etanercept: in the ERASURE study, rates were 81.6% with 300 mg of secukinumab, 71.6% with 150 mg of secukinumab, and 4.5% with placebo; in the FIXTURE study, rates were 77.1% with 300 mg of secukinumab, 67.0% with secukinumab 150 mg, 44.0% with etanercept and 4.9% with placebo (P <0.001)⁵⁰(A).

The proportion of patients with a response of 0 or 1 in the global evaluation of the investigator modified at week 12 was higher with secukinumab than with placebo or etanercept: in the ERASURE study, rates were 65.3% with 300 mg of secukinumab, 51.2% with 150 mg of secukinumab and 2.4% with placebo; in the FIXTURE study, rates were 62.5% with 300 mg of secukinumab, 51.1% with 150 mg of secukinumab, 27.2% with etanercept and 2.8% with placebo (P <0.001). Rates of infection were higher with secukinumab than with placebo in both studies and were similar to those of etanercept⁵⁰(A).

RECOMMENDATIONS

Studies in the evaluation of the efficacy and safety of secukinumab for moderate to severe plaque psoriasis show improvement assessed by the PASI 75 response (77.1-81.6% for 300mg and 67.0-71.6% for 150mg) and IGA 0 or 1, and maintenance of quality of life (DLQI) with use for up to 3 years. Occurrence of mild to moderate adverse events. The best results were obtained with weekly dosing of 300 mg in the first 4 weeks of treatment and then a dose of 300 mg of secukinumab every 4 weeks (table 7).

TABLE 7
EVALUATION OF SECUKINUMAB EXPRESSED BY THE ESTIMATED BENEFIT BY PERCENTAGE.

Author	Dose	Follow-up Time	PASI 75 (%)	PASI 90 (%)	PASI 100 (%)
Bissonnette R49	300mg/ 150mg	3 years		63.8	42.6
Langley RG50	300mg	12 weeks	81.6
Langley RG50	150mg	12 weeks	71.6
Langley RG50	300mg	12 weeks	77.1
Langley RG50	150mg	12 weeks	67.0

The proportion of patients who fulfilled the criteria for PASI 75 at week 12 was higher in the use of secukinumab (300mg – 77.1%, 150mg – 67%) compared to placebo (4.9%) or etanercept (50mg 2x/44%), as well as the proportion of patients with a response of 0 or 1 in the overall evaluation of the investigator modified at week 12 was higher with secukinumab (300mg – 62.5%, 150mg – 51.1%) than placebo (2.8%) or etanercept (27.2%). PASI 90 and PASI 100 responses at week 12 were also significantly higher in the group that used secukinumab 300mg compared to the group that used etanercept (54.2% vs.20.7% and 24.1% vs. 4.3%, respectively).

Is there a safety and effective difference between immunobiological treatments?

Adults between 18 and 75 years of age with moderate to severe stable plaque psoriasis (> 6 months) PASI ≥ 12, sPGA ≥ 3 and BSA ≥10 were included in the study, and each study included an induction phase of 12 weeks and a maintenance phase of 40 weeks. Patients were randomly assigned in a ratio of 2: 2: 1: 1 to receive brodalumab at the dose of 210 mg or at the dose of 140 mg (subcutaneous injection on day 1 and weeks 1, 2, 4, 6, 8 and 10), ustekinumab or placebo. At week 12, patients who were originally randomized to receive brodalumab underwent repeated randomization at a ratio of 2: 2: 2: 1 to one of four maintenance regimens: brodalumab at 210 mg every two weeks, 140 mg every two weeks, 140 mg every 4 weeks or 140 mg every 8 weeks, stratified according to body weight (≤100 kg or >100 kg), induction and response regimen and week 12 (sPGA score, 0 or ≥ 1) response. Patients who were originally randomly assigned to receive placebo were transferred to brodalumab at the dose of 210 mg every two weeks. Patients who were originally randomized to receive ustekinumab continued to receive ustekinumab every 12 weeks to week 52, while patients who were still receiving the regimen could receive brodalumab at the 210 mg dose every two weeks in an open-label extension study. Blinding of the original treatment was maintained during the re-randomization process and up to week 52. At week 12, PASI 75 response rates were higher with brodalumab at the 210 mg and 140 mg doses than with placebo (86% and 67%, respectively, vs. 8% [AMAGINE-2] and 85% and 69%, respectively, vs. 6% [AMAGINE-3], NNT = 2, P <0.001); the rates of 0 to 1 sPGA scores were also higher with brodalumab (P <0.001). At week 12, PASI response rates were significantly higher with 210 mg of brodalumab than with ustekinumab (44% vs. 22% [AMAGINE-2] and 37% vs 19% [AMAGINE-3], (NNT = 5 and NNT = 6, P <0.001). The rates of PASI 100 response with 140 mg of brodalumab were 26% in AMAGINE-2 (P = 0.08 for the comparison with ustekinumab) and 27% for AMAGINE-3 (P = 0.007). Mild or moderate infections with candida more frequent with brodalumab than with ustekinumab or placebo. Up to week 52, severe infectious episode rates were 1.0 (AMAGINE-2) and 1.3 (AMAGINE-3) per 100 patient-years of exposure to brodalumabe^51–53(A).

In another study with a similar population, patients were randomized 3: 3: 1: 3 (CZP 400 mg every 2 weeks or CZP 200 mg every 2 weeks (after loading doses of 400 mg at weeks 0, 2 and 4) for 16 weeks, placebo every 2 weeks for 16 weeks, or etanercept 50 mg twice weekly for 12 weeks. Double-blind treatments with CZP and placebo were administered subcutaneously, treatment with etanercept was given subcutaneously. At week 16, patients in the CZP treatment groups who achieved a PASI were randomized (2: 2: 1): from CZP 400 mg every 2 weeks to CZP 200 mg every 2 weeks, and from CZP 200 mg every 2 weeks or placebo, and from CZP 200 mg every 2 weeks to CZP 400 mg every 4 weeks, CZP 200 mg every 2 weeks, or placebo for the maintenance period of 32 weeks. PASI 75 placebo-treated responders continued on placebo during the maintenance period and etanercept-treated PASI 75 responders were randomized (2: 1) to 200 mg CZP every 2 weeks (after 400 mg loading doses at weeks 16, 18 and 20) or placebo. PASI 75 non-responders at week 16 entered an escape arm and received treatment with CZP 400 mg every 2 weeks. At week 12, the PASI 75 response rate was significantly higher for patients treated with CZP versus patients treated with placebo (NNT = 2, P <0.0001). The differences were evident between the drug and placebo groups as early as week 4 and increased up to week 16. At week 12, CZP 400 mg was higher and CZP 200 mg (NNT = 19, P <.0001) and it was not lower than etanercept for the PASI 75 response rate. Similar trends occurred for the PGA 0/1 and PASI 90 response rates for both CZP versus placebo doses⁵⁴(A).

In another study involving the Investigator Global Assessment (IGA) ≥ 3, ≥ 10% of the body surface area, patients were randomized to 100 mg guselkumab (weeks 0 and 4, then every 8 weeks; n = 329); placebo → guselkumab (weeks 0, 4 and 12, then guselkumab at weeks 16 and 20, then every 8 weeks, n = 174); or adalimumab (80 mg weekly, 0.40 mg week 1, then 40 mg every 2 weeks to week 47, n = 334). Guselkumab was superior (P <0.001) to placebo at week 16, 85.1% vs 6.9% at IGA from 0/1 (NNT = 2) and 73.3% vs 2.9% at PASI 90 (NNT = 2). Guselkumab was also superior to adalimumab in IGA 0/1 (NNT = 6, P <0.001) and PASI 90 (NNT = 5, P <0.001) at the 16^th week 85.1% vs 65.9% and 73.3% vs 49.7%); at week 24, 84.2% vs 61.7% (NNT = 5, P <0.001) and 80.2% vs 53.0% (NNT = 4, P <0.001)) and at week 48, 80.5% vs 55.4% (NNT = 4, P <0.001) and 76.3% vs 47.9% (NNT = 4, P <0.001). In addition, guselkumab significantly improved patient outcomes by week 48. Adverse event rates were comparable among treatments⁴²(A).

Nine hundred and three patients over 18 years of age with a diagnosis of moderate to severe plaque psoriasis for more than six months, who are candidates for phototherapy or systemic treatment, with a PASI score of 12 or greater, with a minimum PGA of 3, on a scale of 0 to 5, with involvement of at least 10% of the body surface were included in the study. Patients were allocated to 3 groups: group 1 with 347 patients taking ethanercept 50mg, twice weekly, group 2 with 209 patients on ustekinumab (UST) 45mg at weeks 0 and 4, and group 3 with 347 patients using ustekinumab 90mg at weeks 0 and 4. There was a significant improvement to PASI 75 for the use of UST 45mg in relation to etanercept in 10.7% (95% CI 2.4 to 19, p = 0.001, NNT = 10) and for the use of UST 90mg in relation to etanercept in 17% (95% CI 10 to 24, p <0.001, NNT = 6). For PASI 90 the benefit was 13.3% for UST 45mg in relation to etanercept (95% CI 5.8 to 20.7, p <0.001, NNT = 8) and 21.6% for use of UST 90mg in with etanercept (95% CI 14.6 to 28.5, p <0.001, NNT = 5). In the evaluation of the PGA score regarding lightening of the lesions, the benefit was 16.1% for UST 45mg compared to etanercept (IC95% 7.6 to 24.2, p <0.001, NNT = 7) and 21.6% for the use of UST 90mg in relation to etanercept (95% CI 14.4 to 28.6, p <0.001, NNT = 5). Adverse events were reported in 70% of the patients receiving ethanercept, 66% of patients taking UST 45mg and 69.2% of patients using UST 90mg³⁹(A).

Authors studied the intervention group with 139 patients taking 200mg of briakinumab at weeks 0 and 4 and 100mg at week 8, 139 patients taking 50mg of etanercept, twice a week for 11 weeks, and 72 patients on placebo. In the evaluation by PGA, the benefit was 42.7% for briakinumab compared to etanercept (p <0.001, NNT = 3) and 68.5% for briakinumab compared to placebo (p <0.001, NNT = 2). For PASI above 75 the response at 12 weeks was 41% for briakinumab in relation to etanercept (p <0.001, NNT = 3) and 73.7% in relation to placebo (p <0.001, NNT = 2). Serious adverse events were reported in 1.4% of patients in the briakinumab group, 0.7% in the etanercept group, and 2.8% in the placebo group²(A).

In the lack of “head to head” trials comparing all the different immunobiological drugs in the treatment of moderate to severe plaque psoriasis, to assess and compare the different biological treatments, tables 1, 2, 3 and 4 of each drug separately and table 5 with all drugs, and the benefit estimated value by the necessary number to treat (NNT) to achieve PASI 50, PASI 75 and PASI 90, in addition to the analysis of lightening by the PGA and the DLQI score, despite of the possibility of comparing the NNTs of the different studies.

RECOMMENDATIONS

In the evaluation of immunobiological drugs in relation to the PASI 75 score, similar benefits were found in: 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 PGA score assessment for the use of ustekinumab in relation to etanercept.

Results of ixekizumab used in doses every two to four weeks were significantly better for PASI75, 90 100 and IGA 0/1 outcomes compared to etanercept.

There was a significant improvement for PASI 75, 90 and 100, as well as for PGA0/1 for use of secukinumab in relation to etanercept

Although not all drugs have studies regarding the PGA score the best results were with: Ustekinumab, Guselkumab, Secukinumab and Ixekizumab.

REFERENCES

• ¹
  Bagel J, Lynde C, Tyring S, Kricorian G, Shi Y, Klekotka P. Moderate to severe plaque psoriasis with scalp involvement: a randomized, double-blind, placebo-controlled study of etanercept. J Am Acad Dermatol. 2012 Jul;67(1):86-92. PubMed PMID: 22014541.
• ²
  Strober BE, Crowley JJ, Yamauchi PS, Olds M, Williams DA. Efficacy and safety results from a phase III, randomized controlled trial comparing the safety and efficacy of briakinumab with etanercept and placebo in patients with moderate to severe chronic plaque psoriasis. Br J Dermatol. 2011 Sep;165(3):661-8. PubMed PMID: 21574984.
• ³
  Gottlieb AB, Leonardi C, Kerdel F, Mehlis S, Olds M, Williams DA. Efficacy and safety of briakinumab vs. etanercept and placebo in patients with moderate to severe chronic plaque psoriasis. Br J Dermatol. 2011 Sep;165(3):652-60. PubMed PMID: 21574983.
• ⁴
  van de Kerkhof PC, Segaert S, Lahfa M, Luger TA, Karolyi Z, Kaszuba A, Leigheb G, Camacho FM, Forsea D, Zang C, Boussuge MP, Paolozzi L, Wajdula J. Once weekly administration of etanercept 50 mg is efficacious and well tolerated in patients with moderate-to-severe plaque psoriasis: a randomized controlled trial with open-label extension. Br J Dermatol. 2008 Nov;159(5):1177-85. PubMed PMID: 18673365.
• ⁵
  Krueger GG, Langley RG, Finlay AY, Griffiths CE, Woolley JM, Lalla D, Jahreis A. Patient-reported outcomes of psoriasis improvement with etanercept therapy: results of a randomized phase III trial. Br J Dermatol. 2005 Dec;153(6):1192-9.
• ⁶
  Feldman SR, Kimball AB, Krueger GG, Woolley JM, Lalla D, Jahreis A. Etanercept improves the health-related quality of life of patients with psoriasis: results of a phase III randomized clinical trial. J Am Acad Dermatol. 2005.
• ⁷
  Papp KA, Tyring S, Lahfa M, Prinz J, Griffiths CE, Nakanishi AM, Zitnik R, van de Kerkhof PC, Melvin L; Etanercept Psoriasis Study Group. A global phase III randomized controlled trial of etanercept in psoriasis: safety, efficacy, and effect of dose reduction. Br J Dermatol. 2005 Jun;152(6):1304-12. PubMed PMID: 15948997.
• ⁸
  Gottlieb AB, Matheson RT, Lowe N, Krueger GG, Kang S, Goffe BS, Gaspari AA, Ling M, Weinstein GD, Nayak A, Gordon KB, Zitnik R. A randomized trial of etanercept as monotherapy for psoriasis. Arch Dermatol. 2003 Dec;139(12):1627-32; discussion 1632. PubMed PMID: 14676082.
• ⁹
  Leonardi CL, Powers JL, Matheson RT, Goffe BS, Zitnik R, Wang A, Gottlieb AB; Etanercept Psoriasis Study Group. Etanercept as monotherapy in patients with psoriasis. N Engl J Med. 2003 Nov 20;349(21):2014-22. PubMed PMID: 14627786.
• ¹⁰
  Feldman SR, Gottlieb AB, Bala M, Wu Y, Eisenberg D, Guzzo C, Li S, Dooley LT, Menter A. Infliximab improves health-related quality of life in the presence of comorbidities among patients with moderate-to-severe psoriasis. Br J Dermatol. 2008;159(3):704-10. PubMed PMID: 18627375.
• ¹¹
  Feldman SR, Gordon KB, Bala M, Evans R, Li S, Dooley LT, Guzzo C, Patel K, Menter A, Gottlieb AB. Infliximab treatment results in significant improvement in the quality of life of patients with severe psoriasis: a double-blind placebo-controlled trial. Br J Dermatol. 2005 May;152(5):954-60. PubMed PMID: 15888152.
• ¹²
  Reich K, Nestle FO, Papp K, Ortonne JP, Wu Y, Bala M, Evans R, Guzzo C, Li S, Dooley LT, Griffiths CE. Improvement in quality of life with infliximab induction and maintenance therapy in patients with moderate-to-severe psoriasis: a randomized controlled trial. Br J Dermatol. 2006 Jun;154(6):1161-8. PubMed PMID: 16704649.
• ¹³
  Reich K, Nestle FO, Papp K, Ortonne JP, Evans R, Guzzo C, Li S, Dooley LT, Griffiths CE; EXPRESS study investigators. Infliximab induction and maintenance therapy for moderate-to-severe psoriasis: a phase III, multicentre, double-blind trial. Lancet. 2005 Oct 15-21;366(9494):1367-74. PubMed PMID: 16226614.
• ¹⁴
  Gottlieb AB, Evans R, Li S, Dooley LT, Guzzo CA, Baker D, Bala M, Marano CW, Menter A. Infliximab induction therapy for patients with severe plaque-type psoriasis: a randomized, double-blind, placebo-controlled trial. J Am Acad Dermatol. 2004 Oct;51(4):534-42. PubMed PMID: 15389187.
• ¹⁵
  Gottlieb AB, Chaudhari U, Mulcahy LD, Li S, Dooley LT, Baker DG. Infliximab monotherapy provides rapid and sustained benefit for plaque-type psoriasis. J Am Acad Dermatol. 2003 Jun;48(6):829-35. PubMed PMID: 12789171.
• ¹⁶
  Chaudhari U, Romano P, Mulcahy LD, Dooley LT, Baker DG, Gottlieb AB. Efficacy and safety of infliximab monotherapy for plaque-type psoriasis: a randomized trial. Lancet. 2001 Jun 9;357(9271):1842-7. PubMed PMID: 11410193.
• ¹⁷
  Cai L, Gu J, Zheng J, Zheng M, Wang G, Xi LY, Hao F, Liu XM, Sun QN, Wang Y, Lai W, Fang H, Tu YT, Sun Q, Chen J, Gao XH, Gu Y, Teixeira HD, Zhang JZ, Okun MM. Efficacy and safety of adalimumab in Chinese patients with moderate-to-severe plaque psoriasis: results from a phase 3, randomized, placebo-controlled, double-blind study. J Eur Acad Dermatol Venereol. 2017 Jan;31(1):89-95. doi: 10.1111/jdv.13746. PubMed PMID 27504914
  » https://doi.org/10.1111/jdv.13746
• ¹⁸
  Reich K, Signorovitch J, Ramakrishnan K, Yu AP, Wu EQ, Gupta SR, Bao Y, Mulani PM. Benefit-risk analysis of adalimumab versus methotrexate and placebo in the treatment of moderate to severe psoriasis: comparison of adverse event-free response days in the CHAMPION trial. J Am Acad Dermatol. 2010 Dec;63(6):1011-8. PubMed PMID: 20933301.
• ¹⁹
  Saurat JH, Stingl G, Dubertret L, Papp K, Langley RG, Ortonne JP, Unnebrink K, Kaul M, Camez A; CHAMPION Study Investigators. Efficacy and safety results from the randomized controlled comparative study of adalimumab vs. methotrexate vs. placebo in patients with psoriasis (CHAMPION). Br J Dermatol. 2008 Mar;158(3):558-66. Epub 2007 Nov 28. PubMed PMID: 18047523.
• ²⁰
  Revicki D, Willian MK, Saurat JH, Papp KA, Ortonne JP, Sexton C, Camez A. Impact of adalimumab treatment on health-related quality of life and other patient-reported outcomes: results from a 16-week randomized controlled trial in patients with moderate to severe plaque psoriasis. Br J Dermatol. 2008 Mar;158(3):549-57. Epub 2007 Nov 28. PubMed PMID: 18047521.
• ²¹
  Menter A, Gordon KB, Leonardi CL, Gu Y, Goldblum OM. Efficacy and safety of adalimumab across subgroups of patients with moderate to severe psoriasis. J Am Acad Dermatol. 2010 Sep;63(3):448-56. doi: 10.1016/j.jaad.2009.09.040. Epub 2010 Jun 3. PubMed PMID: 20605254.
  » https://doi.org/10.1016/j.jaad.2009.09.040
• ²²
  Menter A, Tyring SK, Gordon K, Kimball AB, Leonardi CL, Langley RG, Strober BE, Kaul M, Gu Y, Okun M, Papp K. Adalimumab therapy for moderate to severe psoriasis: A randomized, controlled phase III trial. J Am Acad Dermatol. 2008 Jan;58(1):106-15. Epub 2007 Oct 23. PubMed PMID: 17936411.
• ²³
  Revicki DA, Willian MK, Menter A, Gordon KB, Kimball AB, Leonardi CL, Langley RG, Kimel M, Okun M. Impact of adalimumab treatment on patient-reported outcomes: results from a Phase III clinical trial in patients with moderate to severe plaque psoriasis. J Dermatolog Treat. 2007;18(6):341-50. PubMed PMID: 18058494.
• ²⁴
  Asahina A, Nakagawa H, Etoh T, Ohtsuki M; Adalimumab M04-688 Study Group. Adalimumab in Japanese patients with moderate to severe chronic plaque psoriasis: efficacy and safety results from a Phase II/III randomized controlled study. J Dermatol. 2010 Apr;37(4):299-310. PubMed PMID: 20507398.
• ²⁵
  Revicki DA, Menter A, Feldman S, Kimel M, Harnam N, Willian MK. Adalimumab improves health-related quality of life in patients with moderate to severe plaque psoriasis compared with the United States general population norms: results from a randomized, controlled Phase III study. Health Qual Life Outcomes. 2008 Oct 2;6:75. PubMed PMID: 18831744.
• ²⁶
  Gordon KB, Langley RG, Leonardi C, Toth D, Menter MA, Kang S, Heffernan M, Miller B, Hamlin R, Lim L, Zhong J, Hoffman R, Okun MM. Clinical response to adalimumab treatment in patients with moderate to severe psoriasis: double-blind, randomized controlled trial and open-label extension study. J Am Acad Dermatol. 2006 Oct;55(4):598-606. Epub 2006 Aug 10. PubMed PMID: 17010738.
• ²⁷
  Langley RG, Lebwohl M, Krueger GG, Szapary PO4, Wasfi Y, Chan D, Hsu M, You Y, Poulin Y, Korman N, Prinz JC, Reich K; PHOENIX 2 Investigators. Long-term efficacy and safety of ustekinumab, with and without dosing adjustment, in patients with moderate-to-severe psoriasis: results from the PHOENIX 2 study through 5 years of follow-up. Br J Dermatol. 2015;172(5):1371-83. doi: 10.1111/bjd.13469. PubMed PMID: 25307931
  » https://doi.org/10.1111/bjd.13469
• ²⁸
  Kimball AB, Papp KA, Wasfi Y, Chan D, Bissonnette R, Sofen H, Yeilding N, Li S, Szapary P, Gordon KB; PHOENIX 1 Investigators. Long-term efficacy of ustekinumab in patients with moderate-to-severe psoriasis treated for up to 5 years in the PHOENIX 1 study. J Eur Acad Dermatol Venereol. 2013 Dec;27(12):1535-45. PubMed PMID: 23279003.
• ²⁹
  Kimball AB, Gordon KB, Fakharzadeh S, Yeilding N, Szapary PO, Schenkel B, Guzzo C, Li S, Papp KA. Long-term efficacy of ustekinumab in patients with moderate-to-severe psoriasis: results from the PHOENIX 1 trial through up to 3 years. Br J Dermatol. 2012 Apr;166(4):861-72. PubMed PMID: 22356258.
• ³⁰
  Lebwohl M, Papp K, Han C, Schenkel B, Yeilding N, Wang Y, Krueger GG. Ustekinumab improves health-related quality of life in patients with moderate-to-severe psoriasis: results from the PHOENIX 1 trial. Br J Dermatol. 2010 Jan;162(1):137-46. PubMed PMID: 19903183.
• ³¹
  Leonardi CL, Kimball AB, Papp KA, Yeilding N, Guzzo C, Wang Y, Li S, Dooley LT, Gordon KB; PHOENIX 1 study investigators. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 1). Lancet. 2008 May 17;371(9625):1665-74. PubMed PMID: 18486739.
• ³²
  Reich K, Schenkel B, Zhao N, Szapary P, Augustin M, Bourcier M, Guenther L, Langley RG. Ustekinumab decreases work limitations, improves work productivity, and reduces work days missed in patients with moderate-to-severe psoriasis: results from PHOENIX 2. J Dermatolog Treat. 2011 Dec;22(6):337-47. PubMed PMID: 21034290.
• ³³
  Guenther L, Han C, Szapary P, Schenkel B, Poulin Y, Bourcier M, Ortonne JP, Sofen HL. Impact of ustekinumab on health-related quality of life and sexual difficulties associated with psoriasis: results from two phase III clinical trials. J Eur Acad Dermatol Venereol. 2011 Jul;25(7):851-7. PubMed PMID: 21521375.
• ³⁴
  Langley RG, Feldman SR, Han C, Schenkel B, Szapary P, Hsu MC, Ortonne JP, Gordon KB, Kimball AB. Ustekinumab significantly improves symptoms of anxiety, depression, and skin-related quality of life in patients with moderate-to-severe psoriasis: Results from a randomized, double-blind, placebo-controlled phase III trial. J Am Acad Dermatol. 2010 Sep;63(3):457-65. PubMed PMID: 20462664.
• ³⁵
  Papp KA, Langley RG, Lebwohl M, Krueger GG, Szapary P, Yeilding N, Guzzo C, Hsu MC, Wang Y, Li S, Dooley LT, Reich K; PHOENIX 2 study investigators. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 52-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 2). Lancet. 2008 May 17;371(9625):1675-84. PubMed PMID: 18486740.
• ³⁶
  Nakagawa H, Schenkel B, Kato M, Kato T, Igarashi A; Japanese Ustekinumab Study Group. Impact of ustekinumab on health-related quality of life in Japanese patients with moderate-to-severe plaque psoriasis: results from a randomized, double-blind, placebo-controlled phase 2 / 3 trial. J Dermatol. 2012 Sep;39(9):761-9. PubMed PMID: 22409383.
• ³⁷
  Igarashi A, Kato T, Kato M, Song M, Nakagawa H; Japanese Ustekinumab Study Group. Efficacy and safety of ustekinumab in Japanese patients with moderate-to-severe plaque-type psoriasis: long-term results from a phase 2/3 clinical trial. J Dermatol. 2012 Mar;39(3):242-52. PubMed PMID: 21955098.
• ³⁸
  Tsai TF, Ho JC, Song M, Szapary P, Guzzo C, Shen YK, Li S, Kim KJ, Kim TY, Choi JH, Youn JI; PEARL Investigators. Efficacy and safety of ustekinumab for the treatment of moderate-to-severe psoriasis: a phase III, randomized, placebo-controlled trial in Taiwanese and Korean patients (PEARL). J Dermatol Sci. 2011 Sep;63(3):154-63. PubMed PMID: 21741220.
• ³⁹
  Griffiths CE, Strober BE, van de Kerkhof P, Ho V, Fidelus-Gort R, Yeilding N, Guzzo C, Xia Y, Zhou B, Li S, Dooley LT, Goldstein NH, Menter A; ACCEPT Study Group. Comparison of ustekinumab and etanercept for moderate-to-severe psoriasis. N Engl J Med. 2010 Jan 14;362(2):118-28. PubMed PMID: 20071701.
• ⁴⁰
  Ohtsuki M, Kubo H, Morishima H, Goto R, Zheng R, Nakagawa H. Guselkumab, an anti-interleukin-23 monoclonal antibody, for the treatment of moderate to severe plaque-type psoriasis in Japanese patients: Efficacy and safety results from a phase 3, randomized, double-blind, placebo-controlled study. J Dermatol. 2018 Jun 15. doi: 10.1111/1346-8138.14504. PubMed PMID: 29905383
  » https://doi.org/10.1111/1346-8138.14504
• ⁴¹
  Reich K, Armstrong AW, Foley P, Song M, Wasfi Y, Randazzo B, Li S, Shen YK, Gordon KB. Efficacy and safety of guselkumab, an anti-interleukin-23 monoclonal antibody, compared with adalimumab for the treatment of patients with moderate to severe psoriasis with randomized withdrawal and retreatment: Results from the phase III, double-blind, placebo- and active comparator-controlled VOYAGE 2 trial. J Am Acad Dermatol. 2017 Mar;76(3):418-431. doi: 10.1016/j.jaad.2016.11.042. PubMed PMID: 28057361
  » https://doi.org/10.1016/j.jaad.2016.11.042
• ⁴²
  Blauvelt A, Papp KA, Griffiths CE, Randazzo B, Wasfi Y, Shen YK, Li S, Kimball AB. Efficacy and safety of guselkumab, an anti-interleukin-23 monoclonal antibody, compared with adalimumab for the continuous treatment of patients with moderate to severe psoriasis: Results from the phase III, double-blinded, placebo- and active comparator-controlled VOYAGE 1 trial. J Am Acad Dermatol. 2017 Mar;76(3):405-417. doi: 10.1016/j.jaad.2016.11.041. PubMed PMID: 28057360
  » https://doi.org/10.1016/j.jaad.2016.11.041
• ⁴³
  Blauvelt A, Gooderham M, Iversen L, Ball S, Zhang L, Agada NO, Reich K. Efficacy and safety of ixequizumab for the treatment of moderate-to-severe plaque psoriasis: Results through 108 weeks of a randomized, controlled phase 3 clinical trial (UNCOVER-3). J Am Acad Dermatol. 2017 Nov;77(5):855-862. doi: 10.1016/j.jaad.2017.06.153. PubMed PMID: 28917383
  » https://doi.org/10.1016/j.jaad.2017.06.153
• ⁴⁴
  Leonardi C, Maari C, Philipp S, Goldblum O, Zhang L, Burkhardt N, Ball S, Mallbris L, Gonzalez P, Fernández-Peñas P, Puig L. Maintenance of Skin Clearance With Ixequizumab Treatment of Psoriasis: Three-Year Results From the UNCOVER-3 Study. J Am Acad Dermatol. 2018 May 24. pii: S0190-9622(18)30828-4. doi: 10.1016/j.jaad.2018.05.032. PubMed PMID: 29803904
  » https://doi.org/10.1016/j.jaad.2018.05.032
• ⁴⁵
  Blauvelt A, Papp KA, Sofen H, Augustin M, Yosipovitch G, Katoh N, Mrowietz U, Ohtsuki M, Poulin Y, Shrom D, Burge R, See K, Mallbris L, Gordon KB. Continuous dosing versus interrupted therapy with ixequizumab: an integrated analysis of two phase 3 trials in psoriasis. J Eur Acad Dermatol Venereol. 2017 Jun;31(6):1004-1013. doi: 10.1111/jdv.14163. PubMed PMID: 28190255
  » https://doi.org/10.1111/jdv.14163
• ⁴⁶
  Papp KA, Leonardi CL, Blauvelt A, Reich K, Korman NJ, Ohtsuki M, Paul C, Ball S, Cameron GS, Erickson J, Zhang L, Mallbris L, Griffiths CEM. xekizumab treatment for psoriasis: integrated efficacy analysis of three double-blinded, controlled studies (UNCOVER-1, UNCOVER-2, UNCOVER-3). Br J Dermatol. 2018 Mar;178(3):674-681. doi: 10.1111/bjd.16050. PubMed PMID: 28991370
  » https://doi.org/10.1111/bjd.16050
• ⁴⁷
  Griffiths et al. Comparison of ixekizumab with etanercept or placebo in moderate-to-severe psoriasis (UNCOVER-2 and UNCOVER-3): results from two phase 3 randomised trials. Lancet. 2015 Aug 8;386(9993):541-51. doi: 10.1016/S0140-6736(15)60125-8. Epub 2015 Jun 10.
  » https://doi.org/10.1016/S0140-6736(15)60125-8
• ⁴⁸
  Khattri S, Goldblum, Solotkin K, Amir Y, Min MS, Ridenour T, Yang FE, Lebwohl M. Early Onset of Clinical Improvement with Ixequizumab in a Randomized, Open-label Study of Patients with Moderate-to-severe Plaque Psoriasis. J Clin Aesthet Dermatol. 2018 May;11(5):33-37. PubMed PMID: 29785237
• ⁴⁹
  Bissonnette R, Luger T, Thaçi D, Toth D, Messina I, You R, Guana A, Fox T, Papavassilis C, Gilloteau I, Mrowietz U. Secukinumab sustains good efficacy and favourable safety in moderate-to-severe psoriasis after up to 3 years of treatment: results from a double-blind extension study. Br J Dermatol. 2017 Oct;177(4):1033-1042. doi: 10.1111/bjd.15706. PubMed PMID: 28580579.
  » https://doi.org/10.1111/bjd.15706
• ⁵⁰
  Langley RG, Elewski BE, Lebwohl M, Reich K, Griffiths CE, Papp K, Puig L, Nakagawa H, Spelman L, Sigurgeirsson B, Rivas E, Tsai TF, Wasel N, Tyring S, Salko T, Hampele I, Notter M, Karpov A, Helou S, Papavassilis C; ERASURE Study Group; FIXTURE Study Group. Secukinumab in plaque psoriasis--results of two phase 3 trials. N Engl J Med. 2014 Jul 24;371(4):326-38. doi: 10.1056/NEJMoa1314258.
  » https://doi.org/10.1056/NEJMoa1314258
• ⁵¹
  Lebwohl M, Strober B, Menter A, Gordon K, Weglowska J, Puig L, Papp K, Spelman L, Toth D, Kerdel F, Armstrong AW, Stingl G, Kimball AB, Bachelez H, Wu JJ, Crowley J, Langley RG, Blicharski T, Paul C, Lacour JP, Tyring S, Kircik L, Chimenti S, Callis Duffin K, Bagel J, Koo J, Aras G, Li J, Song W, Milmont CE, Shi Y, Erondu N, Klekotka P, Kotzin B, Nirula A. Phase 3 Studies Comparing Brodalumab with Ustekinumab in Psoriasis. N Engl J Med. 2015 Oct;373(14):1318-28. doi: 10.1056/NEJMoa1503824. PubMed PMID: 26422722
  » https://doi.org/10.1056/NEJMoa1503824
• ⁵²
  Gottlieb AB, Gordon K, Hsu S, Elewski B, Eichenfield LF, Kircik L, Rastogi S, Pillai R, Israel R. Improvement in itch and other psoriasis symptoms with brodalumab in phase 3 randomized controlled trials. J Eur Acad Dermatol Venereol. 2018 Mar 6. doi: 10.1111/jdv.14913. PubMed PMID: 29512200
  » https://doi.org/10.1111/jdv.14913
• ⁵³
  Blauvelt A, Papp KA, Lebwohl MG, Green LJ, Hsu S, Bhatt V, Rastogi S, Pillai R, Israel R. Rapid onset of action in patients with moderate-to-severe psoriasis treated with brodalumab: A pooled analysis of data from two phase 3 randomized clinical trials (AMAGINE-2 and AMAGINE-3). J Am Acad Dermatol. 2017 Aug;77(2):372-374. doi: 10.1016/j.jaad.2017.03.026. PubMed PMID: 28711089
  » https://doi.org/10.1016/j.jaad.2017.03.026
• ⁵⁴
  Lebwohl M, Blauvelt A, Paul C, Sofen H, Węgłowska J, Piguet V, Burge D, Rolleri R, Drew J, Peterson L, Augustin M. Certolizumab pegol for the treatment of chronic plaque psoriasis: Results through 48 weeks of a phase 3, multicenter, randomized, double-blind, etanercept and placebo-controlled study (CIMPACT). J Am Acad Dermatol. 2018 Aug;79(2):266-276.e5. doi: 10.1016/j.jaad.2018.04.013. PubMed PMID: 29660425
  » https://doi.org/10.1016/j.jaad.2018.04.013
• ⁵⁵
  Papp KA, Reich K, Paul C, Blauvelt A, Baran W, Bolduc C, Toth D, Langley RG, Cather J, Gottlieb AB, Thaçi D, Krueger JG, Russell CB, Milmont CE, Li J Klekotka PA, Kricorian G, Nirula A. A prospective phase III, randomized, double-blind, placebo-controlled study of brodalumab in patients with moderate-to-severe plaque psoriasis. Br J Dermatol. 2016 Aug;175(2):273-86. doi: 10.1111/bjd.14493. PubMed PMID: 26914406
  » https://doi.org/10.1111/bjd.14493
• ⁵⁶
  Krupashankar DS, Dogra S, Kura M, Saraswat A, Budamakuntla L, Sumathy TK, Shah R, Gopal MG, Narayana Rao T, Srinivas CR, Bhat R, Shetty N, Manmohan G, Sai Krishna K, Padmaja D, Pratap DV, Garg V, Gupta S, Pandey N, Khopkar U, Montero E, Ramakrishnan MS, Nair P, Ganapathi PC. Efficacy and safety of itolizumab, a novel anti-CD6 monoclonal antibody, in patients with moderate to severe chronic plaque psoriasis: results of a double-blind, randomized, placebo-controlled, phase-III study. J Am Acad Dermatol. 2014 Sep;71(3):484-92. doi: 10.1016/j.jaad.2014.01.897. PubMed PMID: 24703722
  » https://doi.org/10.1016/j.jaad.2014.01.897
• ⁵⁷
  Dogra S, D S K, Budamakuntla L, Srinivas CR, Khopkar U, Gupta S, Shetty N, Pratap DV, Gopal MG, Rao TN, Garg V, Sumathy TK, Saraswat A, Bhat R, Kura M, Pandey N, Shah R, Sai Krishna K, Padmaja D, Manmohan G, M S R, Barve A, Montero E. Long-term efficacy and safety of itolizumab in patients with moderate-to-severe chronic plaque psoriasis: A double-blind, randomized-withdrawal, placebo-controlled study. J Am Acad Dermatol. 2015 Aug;73(2):331-3.e1. doi: 10.1016/j.jaad.2015.03.040. PubMed PMID: 26183983
  » https://doi.org/10.1016/j.jaad.2015.03.040
• ⁵⁸
  Blauvelt A, Reich K, Papp KA, Kimball AB, Gooderham M, Tyring SK, Sinclair R, Thaçi D, Li Q, Cichanowitz N, Green S, La Rosa C. Safety of tildrakizumab for moderate-to-severe plaque psoriasis: pooled analysis of three randomized controlled trials. Br J Dermatol. 2018 May 9. doi: 10.1111/bjd.16724. PubMed PMID: 29742274
  » https://doi.org/10.1111/bjd.16724
• ⁵⁹
  Reich K, Papp KA, Blauvelt A, Tyring SK, Sinclair R, Thaçi D, Nograles K, Mehta A, Cichanowitz N, Li Q, Liu K, La Rosa C, Green S, Kimball AB. Tildrakizumab versus placebo or etanercept for chronic plaque psoriasis (reSURFACE 1 and reSURFACE 2): results from two randomised controlled, phase 3 trials. PubMed PMID: 28596043
• ⁶⁰
  Gottlieb AB, Blauvelt A, Thaçi D, Leonardi CL, Poulin Y, Drew J, Peterson L, Arendt C, Burge D, Reich K. Certolizumab pegol for the treatment of chronic plaque psoriasis: Results through 48 weeks from 2 phase 3, multicenter, randomized, double-blinded, placebo-controlled studies (CIMPASI-1 and CIMPASI-2). J Am Acad Dermatol. 2018 Aug;79(2):302-314.e6. doi: 10.1016/j.jaad.2018.04.012. PubMed PMID: 29660421
  » https://doi.org/10.1016/j.jaad.2018.04.012
• ⁶¹
  Valenzuela F, Paul C, Mallbris L, Tan H, Papacharalambous J, Valdez H, Mamolo C. Tofacitinib versus etanercept or placebo in patients with moderate to severe chronic plaque psoriasis: patient-reported outcomes from a Phase 3 study. J Eur Acad Dermatol Venereol. 2016 Oct;30(10):1753-1759. doi: 10.1111/jdv.13702. Pubmed PMID: 27271195.
  » https://doi.org/10.1111/jdv.13702
• ⁶²
  Feldman SR, Thaçi D, Gooderham M, Augustin M, de la Cruz C, Mallbris L, Buonanno M, Tatulych S, Kaur M, Lan S, Valdez H, Mamolo C. Tofacitinib improves pruritus and health-related quality of life up to 52 weeks: Results from 2 randomized phase III trials in patients with moderate to severe plaque psoriasis. J Am Acad Dermatol. 2016 Dec;75(6):1162-1170.e3. doi: 10.1016/j.jaad.2016.07.040. Pubmed PMID: 27692733
  » https://doi.org/10.1016/j.jaad.2016.07.040
• ⁶³
  Papp KA, Menter MA, Abe M, Elewski B, Feldman SR, Gottlieb AB, Langley R, Luger T Thaci D, Buonanno M, Gupta P, Proulx J, Lan S, Wolk R; OPT Pivotal 1 and OPT Pivotal 2 investigators. Tofacitinib, an oral Janus kinase inhibitor, for the treatment of chronic plaque psoriasis: results from two randomized, placebo-controlled, phase III trials. Br J Dermatol. 2015 Oct;173(4):949-61. doi: 10.1111/bjd.14018. Pubmed PMID: 26149717
  » https://doi.org/10.1111/bjd.14018
• ⁶⁴
  Papp KA, Krueger JG, Feldman SR, Langley RG, Thaci D, Torii H, Tyring S, Wolk R, Gardner A, Mebus C, Tan H, Luo Y, Gupta P, Mallbris L, Tatulych S. Tofacitinib, an oral Janus kinase inhibitor, for the treatment of chronic plaque psoriasis: Long-term efficacy and safety results from 2 randomized phase-III studies and 1 open-label long-term extension study. J Am Acad Dermatol. 2016 May;74(5):841-50. doi: 10.1016/j.jaad.2016.01.013. Pubmed PMID 26899199
  » https://doi.org/10.1016/j.jaad.2016.01.013
• ⁶⁵
  Papp KA, Sundaram M, Bao Y, Williams DA, Gu Y, Signorovitch JE, Wang Y, Valdes JM, Mulani PM. Effects of briakinumab treatment for moderate to severe psoriasis on health-related quality of life and work productivity and activity impairment: results from a randomized phase III study. J Eur Acad Dermatol Venereol. 2014 Jun;28(6):790-8. doi: 10.1111/jdv.12177 Pubmed PMID: 23679896
  » https://doi.org/10.1111/jdv.12177
• ⁶⁶
  Reich K, Langley RG, Papp KA, Ortonne JP, Unnebrink K, Kaul M, Valdes JM. A 52-week trial comparing briakinumab with methotrexate in patients with psoriasis. N Engl J Med. 2011 Oct 27;365(17):1586-96. doi: 10.1056/NEJMoa1010858. Pubmed PMID: 22029980
  » https://doi.org/10.1056/NEJMoa1010858
• ⁶⁷
  Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 1996; 17:1-12
• ⁶⁸
  Guyatt G, Gutterman D, Baumann MH, Addrizzo-Harris D, Hylek EM, Phillips B et al. Grading strength of recommendations and quality of evidence in clinical guidelines: report from an american college of chest physicians task force. Chest 2006;129(1):174-81. PMID: 16424429
• ⁶⁹
  Wells G, Shea B, O’Connell D, Robertson J, Peterson J, Welch V, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. Disponível em: http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp
  » http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp
• ⁷⁰
  Levels of Evidence and Grades of Recommendations - Oxford Centre for Evidence Based Medicine. Disponível em http://www.cebm.net/blog/2009/06/11/oxford-centre-evidence-basedmedicine-levels-evidence-march-2009/
  » http://www.cebm.net/blog/2009/06/11/oxford-centre-evidence-basedmedicine-levels-evidence-march-2009/

Publication Dates

• Publication in this collection
  02 May 2019
• Date of issue
  2019

History

• Accepted
  01 July 2018