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Abstract
Introduction The Janus kinase and Signal Transducer and Activator of Transcription protein (JAK/STAT) pathway is known to be involved in inflammatory and neoplastic skin diseases, like psoriasis, atopic dermatitis, alopecia areata, vitiligo and melanoma. Improved knowledge of the components of this pathway has allowed the development of drugs, which act by inhibiting the pathway, blocking specific components. This offers new therapeutic opportunities. Although evidence on the use of JAK/STAT blockades in dermatological diseases is growing, none have been approved for use in treating skin diseases. The aim of this study is to develop an a priori protocol to broadly review the available evidence on the use of drugs targeting the JAK/STAT pathway in the treatment of dermatological diseases.
Methods and analysis For the conduction of the scoping review protocol, we will employ an established scoping review methodology described in the Joanna Briggs Institute manual. This methodology outlines a five-stage approach: (1) identify the research question; (2) identify relevant studies; (3) select studies; (4) chart the data and (5) collate, summarise and report the results, with an optional consultation exercise. Finally, we will use the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews to present the results.
Ethics and dissemination Since this is a review of the literature, ethics approval is not indicated. We will disseminate the findings from this study in publications in peer-reviewed journals as well as presentations at relevant national and international conferences.
- protocol
- scoping review
- JAK/STAT pathway
- immune-mediated inflammatory skin diseases
- PRISMA
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Strengths and limitations of this study
Strengths of this study include the importance of unrevealing uncertainty about evidence of using drugs targeting Janus kinase and Signal Transducer and Activator of Transcription proteins pathway when prescribed as off-label for dermatological diseases in the clinical setting.
We will use an established scoping review methodology, a systematic search developed by two health sciences librarians and systematic screening and data abstraction carried out in duplicate.
A limitation of this review is the potential to miss relevant articles, especially in the grey literature. To mitigate this, we will screen meeting abstracts to identify any missed articles describing case reports not published in journals and scan reference lists of included articles and similar reviews.
Introduction
Improving knowledge of the molecular biology of the cell, and its adaptation to the disease pathogenesis, have allowed the design of new drugs directed against key targets in signalling pathway regulation. In this sense, the Janus kinases (JAKs) and Signal Transducer and Activator of Transcription (STATs) proteins (JAK/STAT) pathway is one of a handful of pleiotropic routes used to transduce multiple extracellular signals involved in cell proliferation, differentiation, migration and apoptosis.1 Alterations in the regulation of this process have been associated with pathological events fundamentally related to immunomodulatory and neoplastic (mainly haematological) disorders. In addition, they have been related to the pathophysiology of several dermatological diseases. Therefore, drugs that act on the JAK/STAT pathway represent an opportunity for the treatment of these disorders.2
The JAK family is comprised by four types of cytoplasmic tyrosine kinases: JAK1, JAK2, JAK3 and Tyk2.3 STAT, of which there are seven different subtypes (STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b and STAT6), is the other fundamental component of the cascade.4 After being phosphorylated by JAK, STAT translocates to the nucleus to induce the transcription of specific genes. Different types of ligands, from cytokines, such as interleukins (ILs), to hormones, such as erythropoietin, activate this pathway to produce changes in the cell, and eventually in tissue physiology. Some of these molecules have been shown to be important, directly or indirectly, in the development of dermatological diseases. Examples of these are IL-2 and its family, IL-23, interferon alpha5 and IL-17.6 The overall pathway has shown its implication in the pathophysiology of diseases such as psoriasis, atopic dermatitis, lupus erythematous, melanoma or pyoderma gangrenosum.7
This knowledge has led to the development of drugs that act on the JAK component of the pathway, by selectively inhibiting one (filgotinib, JAK1; pacritinib, JAK2; decernotinib, JAK3) or more than one (tofacitinib, JAK1 and JAK3; ruxolitinib, baricitinib, JAK1 and JAK2) JAK protein.8 Ruxolitinib and tofacinib were the first drugs of this class to be approved by the FDA—in 2011 for myelofibrosis and in 2012 for rheumatoid arthritis, respectively.9 10
So far, no JAK/STAT inhibitors have been approved a license for the treatment of dermatological diseases. However, evidence exists resulting from the off-label use of these drugs, specifically tofacitinib and ruxolitinib, in different skin diseases. Knowing the efficacy and safety profile of each drug used in different dermatological diseases is essential to establish their risk–benefit balance.
Improving knowledge requires ordering evidence, establishing gaps in the evidence and formulating questions that can be answered using systematic synthesis and analysis techniques. The aim of this is to develop guidelines that give support to physicians in making effective decisions in clinical practice. For this purpose, secondary scientific studies can develop methodologies that adapt to the specific needs of the formulated problem. The application of JAK inhibitors for the treatment of dermatological disorders is still in its early stages, and we consider it necessary to broadly review the knowledge available to date. Otherwise, the conduction of studies aimed at answering specific questions can lead to synthesis efforts that cannot be quantified.11
A scope review is a form of scientific synthesis that addresses an exploratory research question, with the aim of mapping key concepts and gaps in research related to a defined area or field.12 The aim of this protocol is to define the methodology that will be used to broadly synthesise the available evidence on the use of inhibitors of the JAK/STAT pathway in dermatological diseases.
Methods
Protocol design
The aim of the study is to broadly address the published evidence on drugs targeting JAK proteins in the treatment dermatological diseases, for three purposes: (a) to structure the existing knowledge in this field; (b) to establish areas where there may be gaps in the evidence; (c) to formulate new questions that can be answered following the methodology of systematic reviews. With this intention, we will use the methodology recently described to conduct scoping reviews.13 This methodology outlines a five-stage approach (table 1): (1) identify the research question; (2) identify relevant studies; (3) select studies; (4) chart the data and (5) collate summarise and report the results, with an optional consultation exercise. Finally, we will use the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Extension for Scoping Reviews to present the results.14 This protocol is reported following the recommendations of the PRISMA for protocols statement. A checklist for this review protocol has been provided in a Supplementary file 1.
Supplementary file 1
Stages of the scoping reviews
Inclusion criteria
We will use participants, concept, context (PCC) mnemotechnic rule to define the inclusion criteria as follows:
Participants
All studies that include evidence on the use of JAK protein inhibitors in humans will be included. No restrictions regarding age, ethnicity, study design or any other characteristics will be made.
Concept
We will review the existing literature on drugs targeting JAK proteins in the treatment of dermatological diseases: indications, epidemiology, genetics, efficacy and safety.
Context
We will not limit the context to a particular setting or country.
Research question
What are the indications, epidemiology, genetics, efficacy and safety of drugs targeting proteins of STAT/JAK pathway for the treatment of dermatological diseases?
Identifying relevant literature
A systematic search developed by two health sciences librarians will perform using a three-step literature search. The first step will include an initial limited search of the MEDLINE and EMBASE databases (table 2). Then, we will carry out analyses of: the text contained in the titles, abstracts of retrieved papers and the index terms used to describe the articles. In second step, we will search the same databases using the identified keywords and index terms. Additionally, CINAHL, Scopus and Web of Science to the search engines will be searched in this second step. Third, the reference list of all identified reports and articles will be searched for additional studies. We will contact authors of primary studies or reviews for further information, if relevant. We have established a time frame of 4 weeks after sending authors a mail requesting information about their study or publication. We will include all studies published in English until October 2018. The process of searching, extracting key words and filtering and excluding studies, will be carried out independently and by duplicate by at least two researchers and in case of disagreement will be decided by agreement with a third reviewer.
Draft of first step of search strategy to be used for at least two electronic databases.
Identifying relevant studies
We will apply the inclusion criteria, described previously, for the selection of studies. The process will be carried out by at least two researchers and in case of disagreement will be decided by agreement with a third reviewer.
Charting the data
We will develop a draft charting to record the information that will be relevant to the review.
Questions focusing on:
Mapping studies: author(s), year of publication, origin/country of origin (where the study was published or conducted), authors affiliation, type of study, a priori design, registration, conflict of interest, funding;
Epidemiological and genetics aspects: study population and sample size, genetic studies;
Evaluation of the efficacy and safety of drugs for each disease: intervention type, comparator and details of these, duration of the intervention, dosage, outcomes and details of these and adverse events.
The data collection will be done by at least two reviewers using a piloting customised Google AppSheet form (https://www.appsheet.com/) and in case of disagreement will be decided by agreement with a third reviewer. We anticipate that we can start retrieving data in April 2019 and finalising by September 2019.
Collating, summarising and reporting results
The elements of the PCC inclusion criteria will guide the presentation of the data. First, we will present the results of the search in the PRISMA flow chart. Second, we will organise the extracted data for topics defined as follows: indications, mechanism of action, efficacy safety and cost. For each category, a clear explanation will be provided. The results of the scoping review will be presented as a map, in both diagrammatic and tabular form, and in a descriptive format. A narrative summary will accompany the tabulated and/or charted results and will describe how the results relate to the review objective and question(s).
Differences between the protocol and the overview
Changes in the methodology that need to be carried out throughout the study will be detailed in the results section.
Ethics and dissemination
This study will analyse only anonymised public data of previously conducted studies, and will not involve any new human or animal studies performed by the authors. We will prepare the publication in accordance with PRISMA guideline and its adaptation for scoping reviews. We will publish our findings in peer-reviewed journals and also may present them at conferences.
Patient and public involvement
Patients and or public were not involved in the development of this protocol. The study group developed this study protocol without patient involvement.
Conclusion
Here, we have presented a protocol for systematically conducting a scoping review to broadly analyse the available evidence on the indications for and the mechanisms of action, efficacy and safety of JAK/STAT pathway-targeting drugs in the use of dermatological therapy. Evidence-based medicine is intended to optimise decision making by emphasising the use of evidence derived from well-designed and well-conducted research. Currently, most reviews of treatments blocking the JAK/STAT pathway are narrative reviews, which lack the necessary methodological detail to promote reproducibility and reduce the risk of bias.15 16 Secondary research methodologies are constantly being developed and must be adapted to the type of research question being asked and the urgency with which the question must be answered.17
Although we will try to analyse the quality of evidence per variable and disease using Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, probably most of the studies have produced documents communicating partial results following an observational design, which is associated with low or very low quality of evidence. However, we believe that the scoping review methodology is the one of the best suited protocols to answer the question posed in this study. The results will provide unique insights into the available evidence on the use of JAK/STAT pathway-targeting drugs in the treatment of dermatological diseases, facilitating the detection of knowledge gaps and the identification of new questions to address via additional systematic reviews.
Acknowledgments
The authors are also grateful to the reviewers for their helpful comments and suggestions. We would also like to thank Editage (www.editage.com) for performing English-language editing of this review.
References
Footnotes
FG-G and JR contributed equally.
Contributors FG-G and JR conceived the study. FG-G, PJG-A, JH, AMM,JG-M, MA-L, IV-G, AVG-N, BI-T, and JR contributed to the protocol design and plan. FG-G,PJG-A, and JH developed the literature search strategy. All the authors workedcollaboratively to draft and revise the manuscript, and read and approved thefinal version. All the authors made substantive intellectual contributions tothe development of this protocol. JR is the guarantor of the review.
Funding This work was supported, in part, by project ICI1400136 (which provided funding for JR), integrated into the National Plan of R+D+I 2008-2011, co-financed by the ISCIII-Subdirección General de Evaluación and European Regional Development Fund (ERDF), by project PIN-0316-2017- Consejería de Salud-Junta de Andalucía (JR). No funding was obtained from any pharmaceutical company. The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the funders.
Competing interests None declared.
Ethics approval This protocol relates to a search for previously conducted studies, and does not involve any new human or animal subjects performed by the authors.
Provenance and peer review Not commissioned; externally peer reviewed.