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Medwave 2018 Mar-Abr;18(2):e7173 doi: 10.5867/medwave.2018.02.7173

�Es efectivo el ustekinumab para la artritis psori�sica que no responde a tratamiento inicial?

Is ustekinumab effective for psoriatic arthritis with insufficient response to initial treatment?

Soledad Venegas-Iribarren, Romina Andino-Navarrete

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Abstract

INTRODUCTION
Psoriatic arthritis is an inflammatory arthritis without a clear etiology. Biological therapy is key for its treatment, especially in more complex patients. There are several alternatives for biological treatment, but due to its high cost, it is important to evaluate their real effectiveness.

METHODS
To answer this question we used Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others. We extracted data from the systematic reviews, reanalyzed data of primary studies, conducted a meta-analysis and generated a summary of findings table using the GRADE approach.

RESULTS AND CONCLUSIONS
We identified 12 systematic reviews including three randomized trials overall. We concluded ustekinumab leads to clinical improvement in psoriatic arthritis, and probably is not associated to severe adverse effects.

Problem

Psoriatic arthritis is an inflammatory arthritis without a clear etiology. It is associated with psoriasis, and most are seronegative for rheumatoid factor. Currently, there are several treatment alternatives for this condition, many of them extrapolated from drugs proven in rheumatoid arthritis. The efficacy of new medications in psoriatic arthritis has been studied in greater depth recently, especially for patients resistant to initial treatment, either with non-steroidal anti-inflammatories, disease modifying drugs (e.g. methotrexate) or biological medication (e.g. TNF inhibitors). Among these new alternatives is ustekinumab, an IL-12 and IL-23 inhibitor.

Methods

To answer the question, we used Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others, to identify systematic reviews and their included primary studies. We extracted data from the identified reviews and reanalyzed data from primary studies included in those reviews. With this information, we generated a structured summary denominated FRISBEE (Friendly Summary of Body of Evidence using Epistemonikos) using a pre-established format, which includes key messages, a summary of the body of evidence (presented as an evidence matrix in Epistemonikos), meta-analysis of the total of studies when it is possible, a summary of findings table following the GRADE approach and a table of other considerations for decision-making.

Key messages

Ustekinumab leads to clinical improvement in psoriatic arthritis.
Ustekinumab is probably not associated to serious adverse events.

About the body of evidence for this question

What is the evidence. See evidence matrix in Epistemonikos later	We found twelve systematic reviews [1],[2],[3],[4],[5],[6],[7],[8],[9],[10],[11],[12], that include three primary studies, reported in six references [13],[14],[15],[16],[17],[18]. All of them are randomized controlled trials. This table and the summary in general are based on the latter.
What types of patients were included*	All of these trials included adult patients with clinical psoriatic arthritis diagnosis and active disease (three or more tender joints, plus C-reactive protein of 3 mg/L [13],[14] or 15 mg/L [15]) and inadequate response or poor tolerance to the use of non-steroidal anti-inflammatories or disease modifying drugs in addition to plaque psoriasis with active lesion or previous history of disease. One trial [13] excluded patients with previous anti-TNF use. On the other hand, the other two trials [14],[15] did include patients with inadequate response or poor tolerance to the use of biological therapies.
What types of interventions were included*	Two trials [13],[14] included subcutaneous ustekinumab 45 mg or 90 mg at baseline, then at week four, then every twelve weeks. One trial [15] did not report the dose or administration scheme. All trials compared against placebo.
What types of outcomes were measured	The outcomes were pooled by the different systematic reviews as follows: ACR 20 (American College of Rheumatology) ACR 50 ACR 70 HAQ-DI (Health assessment questionnaire disability index) PASI 75 (Psoriasis area severity index) Das-28 (Disease activity score) Dactylitis Enthesitis

* The information about primary studies is extracted from the systematic reviews identified, unless otherwise specified.

Summary of Findings

The information on the effects of ustekinumab is based on three randomized trials that included 1073 patients overall [13],[14],[15]. Two trials reported ACR 20 , HAQ-DI, PASI-75 and DAS-28 [13],[14]. Three trials reported serious adverse events [13],[14],[15].

The summary of findings is the following:

Ustekinumab improves ACR 20 in psoriatic arthritis. The certainty of the evidence is high.
Ustekinumab improves PASI 75 in psoriatic arthritis. The certainty of the evidence is high.
Ustekinumab probably leads to little or no difference in serious adverse events in psoriatic arthritis. The certainty of the evidence is moderate.
Ustekinumab improves DAS-28 in psoriatic arthritis. The certainty of the evidence is high.
Ustekinumab leads to an improvement of doubtful clinical relevance in HAQ-DI in psoriatic arthritis. The certainty of the evidence is high.

Following the link to access the interactive version of this table (Interactive Summary of Findings – iSoF)

Other considerations for decision-making

To whom this evidence does and does not apply

This evidence applies to adults with a clinical diagnosis of psoriatic arthritis, active disease and with inadequate response to non-steroidal anti-inflammatories, disease modifying drugs or anti-TNF biological medication.

About the outcomes included in this summary

The outcomes included in this summary are those considered critical for decision-making by the authors of this summary. The selection coincides with most systematic reviews.
ACR 20 and DAS 28 were selected because they are clinical scales that correlate with disease severity or improvement.
PASI 75 was selected because it is a clinical scale that correlates with plaque psoriasis severity or improvement as a secondary outcome, since this would not be the primary purpose of the treatment.
We considered serious adverse events, since non-severe effects should not affect decision-making, given they are more common in other therapeutic alternatives in these cases (e.g. anti-TNF).
Finally, HAQ-DI was considered as it is a quality of life scale. This is an important outcome to be measured in the treatment of chronic diseases.

Balance between benefits and risks, and certainty of the evidence

There is probably little to no difference in severe adverse events against placebo, and there are positive effects in most outcomes evaluated. So, the balance between benefits and risks is very favorable.

Resource considerations

The cost of this drug varies according to the country, but in general is high in comparison with alternatives (e.g. anti-TNF).
It is reasonable to conduct a formal economic analysis in the scenarios where this intervention is intended to be used, to obtain more adequate information.

What would patients and their doctors think about this intervention

Faced with the evidence presented in this summary, most patients and clinicians should be inclined to use this intervention. However, substantial variability can be expected, driven by the cost and the lack of direct evidence comparing ustekinumab with other available alternatives for patients with insufficient response to first-line treatment.

Differences between this summary and other sources

The conclusions of this summary are consistent with those of the systematic reviews identified.
The main clinical guidelines, such as those of the American academy of dermatology [19] and the British association of dermatologists [20] do not mention ustekinumab as part of the alternatives. However, it is important to mention this is a new therapy that was probably not available at the time of publication of these guidelines. The Spanish academy of dermatology and venereology [21] mentions ustekinumab as part of first line treatment along with anti-TNF in patients with moderate to severe psoriasis. Finally, the European league against rheumatism (EULAR) [22] recommends ustekinumab only as second line therapy in patients with psoriatic arthritis.

Could this evidence change in the future?

The probability of future research changing the conclusions of this summary is low, given the certainty of the existing evidence.
We did not identify ongoing trials according to the International Clinical Trials Registry Platform of the World Health Organization.

How we conducted this summary

Using automated and collaborative means, we compiled all the relevant evidence for the question of interest and we present it as a matrix of evidence.

Follow the link to access the interactive version: Ustekinumab for psoriatic arthritis

Notes

The upper portion of the matrix of evidence will display a warning of “new evidence” if new systematic reviews are published after the publication of this summary. Even though the project considers the periodical update of these summaries, users are invited to comment in Medwave or to contact the authors through email if they find new evidence and the summary should be updated earlier.

After creating an account in Epistemonikos, users will be able to save the matrixes and to receive automated notifications any time new evidence potentially relevant for the question appears.

This article is part of the Epistemonikos Evidence Synthesis project. It is elaborated with a pre-established methodology, following rigorous methodological standards and internal peer review process. Each of these articles corresponds to a summary, denominated FRISBEE (Friendly Summary of Body of Evidence using Epistemonikos), whose main objective is to synthesize the body of evidence for a specific question, with a friendly format to clinical professionals. Its main resources are based on the evidence matrix of Epistemonikos and analysis of results using GRADE methodology. Further details of the methods for developing this FRISBEE are described here (http://dx.doi.org/10.5867/medwave.2014.06.5997)

Epistemonikos foundation is a non-for-profit organization aiming to bring information closer to health decision-makers with technology. Its main development is Epistemonikos database (www.epistemonikos.org).

Potential conflicts of interest

The authors do not have relevant interests to declare.

Licencia Creative Commons

Esta obra de Medwave est� bajo una licencia Creative Commons Atribuci�n-NoComercial 3.0 Unported. Esta licencia permite el uso, distribuci�n y reproducci�n del art�culo en cualquier medio, siempre y cuando se otorgue el cr�dito correspondiente al autor del art�culo y al medio en que se publica, en este caso, Medwave.

Edici�n Julio 2022

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