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 Table of Contents  
PROTOCOL
Year : 2021  |  Volume : 16  |  Issue : 1  |  Page : 79-82

Disease-modifying antirheumatic drugs for the management of takayasu arteritis – Protocol for a systematic review


1 Department of Clinical Immunology and Rheumatology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
2 Department of Telemedicine, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
3 Department of Internal Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh, India

Date of Submission10-Feb-2021
Date of Acceptance13-Feb-2021
Date of Web Publication23-Mar-2021

Correspondence Address:
Dr. Durga Prasanna Misra
Department of Clinical Immunology and Rheumatology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow - 226 014, Uttar Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/injr.injr_34_21

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  Abstract 

Takayasu arteritis (TAK) is a rare systemic large-vessel vasculitis. The evidence base to guide the medical management of TAK is sparse. This systematic review aims to synthesize the published literature on the use of disease-modifying antirheumatic drugs (DMARDs) in TAK. Scopus (which includes data from MEDLINE), Web of Science, PubMed central, the Cochrane Central Register of Controlled Trials (CENTRAL), and the World Health Organization International clinical trials registry platform shall be searched for relevant studies, both observational and interventional, on the use of DMARDs in TAK. Outcomes assessed shall be remission based on clinical, composite measures, inflammatory markers, angiographic assessment, and relapses. Screening of references and data extraction on predesigned pro formas shall be done in duplicate. Quality assessment of studies shall be done at the study level, using the Cochrane Risk of Bias 2 tool for interventional studies and the Newcastle–Ottawa scale for interventional studies. Publication bias shall be assessed wherever appropriate. Proportions of outcomes with DMARDs shall be pooled for uncontrolled observational studies. For controlled observational studies and interventional studies, pooled risk of outcomes versus comparator treatment or placebo shall be presented. Preplanned subgroup analyses are based on whether participants are adults or children with TAK. Certainty of evidence for DMARDs across studies shall be assessed by the GRADE profiler tool. The findings of the present systematic review shall help to understand better the current landscape of evidence for the use of DMARDs in TAK. This might help to guide future recommendations for the management of TAK. Future clinical trials on TAK might also be designed to avoid lacunae identified in the existing evidence for DMARD use on TAK.

Keywords: Disease-modifying antirheumatic drug, systematic review, Takayasu arteritis


How to cite this article:
Rathore U, Patro P, Agarwal V, Sharma A, Misra DP. Disease-modifying antirheumatic drugs for the management of takayasu arteritis – Protocol for a systematic review. Indian J Rheumatol 2021;16:79-82

How to cite this URL:
Rathore U, Patro P, Agarwal V, Sharma A, Misra DP. Disease-modifying antirheumatic drugs for the management of takayasu arteritis – Protocol for a systematic review. Indian J Rheumatol [serial online] 2021 [cited 2021 Apr 16];16:79-82. Available from: https://www.indianjrheumatol.com/text.asp?2021/16/1/79/310976




  Introduction Top


Takayasu arteritis (TAK) is a granulomatous large-vessel vasculitis. It is more common in India and other southeast Asian countries compared to elsewhere. Despite recent advances in therapeutics with disease-modifying antirheumatic drugs (DMARDs) with the advent of targeted therapies such as biologic therapies and targeted synthetic DMARDs, the evidence base for the management of TAK remains sparse. There are few randomized controlled trials to guide the management of TAK. Most of the evidence for pharmacotherapy derives from observational studies.[1],[2],[3]

The assessment of disease activity in TAK remains challenging. Inflammatory markers such as the erythrocyte sedimentation rate and C-reactive protein are imprecise markers of disease activity. Composite measures such as the National Institutes of Health (NIH) criteria for disease activity and clinical scoring systems such as the Indian Takayasu Clinical Activity Score 2010 (ITAS-2010) are widely used, although they have not been validated across populations. Imaging of TAK using computerized tomographic angiography, magnetic resonance angiography, and positron-emission tomography computerized tomography (PET-CT) has increasingly been used to denote active disease, based on vessel wall thickening or uptake. Retardation or improvement of angiographic changes on serial follow-up has been thought to denote inactive disease. Various studies assessing response to therapy have used different outcome measures. In addition to those discussed above, proportions of relapses have also been used as outcome measures.[2],[3]

The present protocol has been designed in line with the preferred reporting items for systematic reviews and meta-analyses protocols (PRISMA-P).[4] This systematic review aims to synthesize the published literature on the role of DMARDs in the management of TAK. The review aims to evaluate whether DMARDs influence clinical outcomes, inflammatory markers, angiographic progression, PET-CT, and outcomes assessed by composite measures in patients with TAK, both in clinical trials and in observational studies. While some systematic reviews have assessed this problem in the published literature, the scope of the literature search underlying such systematic reviews has been limited, often excluding major bibliographic databases such as Scopus or the Web of Science,[5] whereas other systematic reviews have lacked the inclusion of more recent literature in this regard.[6],[7] Through this systematic review, recommendations can be framed to guide further medical management of TAK as well as inform future clinical trials to systematically evaluate commonly used therapies in TAK. The present review shall be conducted in line with recommendations of the Cochrane collaboration for conducting systematic reviews.[8] It shall be reported in line with the preferred reporting items for systematic reviews and meta-analyses (PRISMA) statement[9] and its recent amendments to incorporate searches across multiple databases PRISMA-search.[10] The present protocol was not registered in the prospective register of systematic reviews (PROSPERO) due to the current priority given to systematic reviews on coronavirus disease 19 at the same site and consequent anticipated delays for registration of other systematic review protocols.


  Date and Version of the Current Protocol Top


February 8, 2021. Version 1.


  Literature Searches Top


The databases Scopus (which includes all the data from MEDLINE also), Web of Science, and PubMed Central shall be searched for studies describing DMARDs in TAK. There shall be no restrictions of language or date, searches shall be conducted by combining drugs previously reviewed in TAK or Giant Cell arteritis or thought to have a role based on pathogenesis (methotrexate, hydroxychloroquine, azathioprine, mycophenolate mofetil, cyclophosphamide, leflunomide, dapsone, cyclosporine, tacrolimus, abatacept, tocilizumab, infliximab, etanercept, adalimumab, golimumab, certolizumab, rituximab, ustekinumab, secukinumab, briakinumab, tofacitinib or other Janus kinase inhibitors, resveratrol, and curcumin)[2],[3] with a search term for disease (TAK or Takayasu's arteritis) using the linker AND.

Handsearching of conference abstracts of major international rheumatology conferences (American College of Rheumatology [ACR], Asia-Pacific League of Nations for Rheumatology [Asia Pacific League of Associations for Rheumatology], European Alliance of Associations for Rheumatology over the past 3 years [2018–2020]) shall be done to identify relevant studies that might not yet have been published as full papers. Furthermore, the Cochrane database of controlled clinical trials (CENTRAL) and the World Health Organization International Clinical Trials Registry Platform shall be handsearched to identify relevant studies of DMARDs in TAK that might yet have been unpublished as full papers or conference abstracts, yet whose results are available on the said databases.[11] Any conference abstracts identified through hand-searching conference databases or through searches on Scopus or Web of Science shall be further manually searched to identify full papers which might have been published but were not identified by our database searches.

Inclusion and Exclusion Criteria

Inclusion criteria

Participants

Patients with TAK, either by clinician diagnosis or by using the ACR 1990 classification criteria or any other criteria will be included in the study.[12]

Since TAK is a rare disease, studies including at least five patients shall be included.

Interventions

Drugs previously reviewed in TAK or thought to have a role based on pathogenesis (methotrexate, hydroxychloroquine, azathioprine, mycophenolate mofetil, cyclophosphamide, leflunomide, dapsone, cyclosporine, tacrolimus, abatacept, tocilizumab, infliximab, etanercept, adalimumab, golimumab, certolizumab, rituximab, ustekinumab, secukinumab, briakinumab, tofacitinib or other Janus kinase inhibitors, resveratrol, and curcumin).

Comparators

Studies including comparators as well as those without comparators shall be included.

Comparators might be any of the active interventions listed (other than the one in the intervention group) or placebo.

Outcome measures

Measures of treatment efficacy or effectiveness as presented in the study shall be recorded:

  1. Remission based on clinical outcomes
  2. Remission based on normalization of inflammatory markers
  3. Angiographic stabilization or retardation
  4. Improvement in composite outcomes (NIH criteria or ITAS2010)
  5. Improvement in PET-CT
  6. Improvement of quality of life.
  7. Disease relapses.


All the outcomes are considered as main outcomes since the outcome measures used in studies of patients with TAK are heterogeneous.

Types of studies:

  1. Both observational studies and interventional studies
  2. Studies describing outcomes for patients with a particular therapy with a clearly defined time period. Should an observational study describe outcomes for patients with multiple therapies, only those outcomes which are described for at least five patients in the particular study shall be analyzed
  3. Studies describing outcome with any DMARD (alone or with corticosteroids, at any dose).


Exclusion criteria

  1. Original article other than the observational study of treatment outcomes or interventional study
  2. Review article
  3. Case report, editorial, comment, or letter not describing original data
  4. Studies not related to TAK
  5. Full text not accessible with inadequate information available from the abstract alone, or abstract whose full text has already been published elsewhere
  6. Studies using corticosteroid alone or endovascular/surgical intervention alone, without concomitant DMARD therapy.


Screening and data extraction

All search results shall be screened independently by two investigators (DPM and PP). Any discrepancies shall be resolved by mutual discussion. The search result shall be downloaded onto Endnote X9.3, which shall be used to remove duplicates. Title and abstracts of papers shall be screened to identify studies for the assessment of full text while noting reasons for exclusion. Full text of screened studies shall be assessed to identify relevant studies to the systematic review, detailing reasons for exclusion of any studies. Studies identified across different databases shall be collated, further delineating studies eligible for quantitative synthesis of data across multiple studies if feasible. The search results shall be described using the PRISMA flowchart.

Data shall be extracted into predesigned pro formas for interventional studies [Supplementary Table 1], uncontrolled observational studies [Supplementary Table 2], and observational studies with a control group [Supplementary Table 3] independently by two investigators (DPM and UR). Any discrepancies shall be resolved by mutual discussion.



Quality assessment of studies

Assessment of study quality shall be done at the study level. Interventional studies shall be assessed using the Cochrane Risk of Bias 2 tool[13] to evaluate the risk of bias related to randomization, effect of allocation/adherence to intervention, missing data, outcome measurement, and selective reporting. Observational studies shall be assessed using the Newcastle–Ottawa scale for cohort studies or case–control studies to evaluate selection, comparability, and outcome assessment of individual studies.[14],[15]

Publication bias shall be assessed using funnel plots and the egger test if there are more than ten studies assessing the effect of a particular intervention with a placebo or for a pair or interventions.[16]

Certainty of evidence

Certainty of evidence for a particular outcome shall be assessed using the GRADE profiler software. The type of studies underlying the evidence, risk of bias or study quality, indirectness of evidence, imprecision of estimates, and inconsistency of evidence across multiple studies shall be evaluated to rate the evidence as very low, low, moderate, or high certainty.[17]

Analysis plan

Tables shall summarize the characteristics of individual studies with respect to the study participants, intervention(s), comparator(s) if available, background glucocorticoid dose, measures used to assess disease activity, and outcomes studied.

Observational studies without a control group shall be summarized as proportions (with 95% confidence intervals [CIs]) of outcomes for a particular drug pooled across studies. Observational studies with a control group or interventional studies shall be summarized as risk ratio of outcome for a pair of intervention compared to control, with accompanying 95% CI.

A secondary analysis shall also assess the safety profile of the drug in terms of all adverse events, serious adverse events, or deaths. This shall be presented as proportions for uncontrolled studies, and risk ratios for controlled studies.

Pooling of data shall utilize confidence intervals derived using the score test and Freeman-Tukey double arcsine transformation using the random-effects model since studies are likely to be heterogeneous with respect to patient populations and multiple interventions. Risk ratios shall be pooled using the genetic inverse variance method. Forest plots shall be generated for pooled data. Heterogeneity of estimates shall be assessed using I2 statistics. An I[2] >50% shall indicate significant heterogeneity. Studies not amenable to meta-analysis shall be reported in a descriptive manner.

Subgroup analyses

Subgroup analyses are preplanned based on whether participants are patients with adult or childhood-onset TAK. This is because studies have identified systematic differences between childhood-onset and adult-onset TAK.[18],[19] Any other post hoc subgroup analyses shall be denoted clearly as such.

Plan for dissemination

The findings of the systematic review shall be submitted for publication in a peer-reviewed journal.

Protocol modifications

Any modifications to the present protocol shall be denoted as such in the manuscript presenting the findings of the systematic review.

Involvement of stakeholders

There is no plan presently to include patient representatives. Their role might be considered while designing future guidelines for the management of TAK based on this systematic review.

[Supplementary Table 4] presents the checklist for adherence to the PRISMA-P reporting guidelines for the protocol of a systematic review.




  Discussion Top


This systematic review shall help to evaluate the current status of DMARDs in the medical management of TAK. The findings of this review shall inform the framing of specific guidelines for the management of TAK, particularly in an Indian context where accessibility to biological therapies is sparse. The findings of this review shall also facilitate a critical analysis of the quality of existing studies to enhance the design of future studies in this regard.

The present systematic review does not plan to conduct an individual patient data meta-analysis, which might have been valuable considering the paucity of studies in this regard. The role of endovascular or surgical interventions is beyond the scope of the existing review. These are limitations to the present review.

Financial support and sponsorship

Durga Prasanna Misra acknowledges support from Indian Council of Medical Research (Grant No 5/4/1-2/2019-NCD-II) for his research on Takayasu arteritis.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Ferfar Y, Mirault T, Desbois AC, Comarmond C, Messas E, Savey L, et al. Biotherapies in large vessel vasculitis. Autoimmun Rev 2016;15:544-51.  Back to cited text no. 1
    
2.
Misra DP, Sharma A, Kadhiravan T, Negi VS. A scoping review of the use of non-biologic disease modifying anti-rheumatic drugs in the management of large vessel vasculitis. Autoimmun Rev 2017;16:179-91.  Back to cited text no. 2
    
3.
Misra DP, Wakhlu A, Agarwal V, Danda D. Recent advances in the management of Takayasu arteritis. Int J Rheum Dis 2019;22:60-8.  Back to cited text no. 3
    
4.
Moher D, Shamseer L, Clarke M, Ghersi D, Liberati A, Petticrew M, et al. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Syst Rev 2015;4:1.  Back to cited text no. 4
    
5.
Dua AB, Kalot MA, Husainat NM, Byram K, Springer JM, James KE, et al. Takayasu arteritis: A systematic review and meta-analysis of test accuracy and benefits and harms of common treatments. ACR Open Rheumatol 2021;3:80-90.  Back to cited text no. 5
    
6.
Barra L, Yang G, Pagnoux C, Canadian Vasculitis Network (CanVasc). Non-glucocorticoid drugs for the treatment of Takayasu's arteritis: A systematic review and meta-analysis. Autoimmun Rev 2018;17:683-93.  Back to cited text no. 6
    
7.
Pacheco RL, Latorraca CO, de Souza AW, Pachito DV, Riera R. Clinical interventions for Takayasu arteritis: A systematic review. Int J Clin Pract 2017;71.  Back to cited text no. 7
    
8.
Front Matter. Cochrane Handbook for Systematic Reviews of Interventions; 2019. p. i-xxviii.  Back to cited text no. 8
    
9.
Moher D, Liberati A, Tetzlaff J, Altman DG, Group P. Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement. PLoS Med 2009;6:e1000097.  Back to cited text no. 9
    
10.
Rethlefsen ML, Kirtley S, Waffenschmidt S, Ayala AP, Moher D, Page MJ, et al. PRISMA-S: An extension to the PRISMA Statement for Reporting Literature Searches in Systematic Reviews. Syst Rev 2021;10:39.  Back to cited text no. 10
    
11.
Misra DP, Agarwal V. Systematic reviews: Challenges for their justification, related comprehensive searches, and implications. J Korean Med Sci 2018;33:e92.  Back to cited text no. 11
    
12.
Arend WP, Michel BA, Bloch DA, Hunder GG, Calabrese LH, Edworthy SM, et al. The American College of Rheumatology 1990 criteria for the classification of Takayasu arteritis. Arthritis Rheum 1990;33:1129-34.  Back to cited text no. 12
    
13.
Sterne JAC, Savović J, Page MJ, Elbers RG, Blencowe NS, Boutron I, et al. RoB 2: A revised tool for assessing risk of bias in randomised trials. BMJ 2019;366:l4898.  Back to cited text no. 13
    
14.
Newcastle-Ottawa scale. Available from: http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp. [Last accessed on 14 July 2020].  Back to cited text no. 14
    
15.
Misra DP, Zimba O, Gasparyan AY. Statistical data presentation: A primer for rheumatology researchers. Rheumatol Int 2021;41:43-55.  Back to cited text no. 15
    
16.
Sterne JA, Sutton AJ, Ioannidis JP, Terrin N, Jones DR, Lau J, et al. Recommendations for examining and interpreting funnel plot asymmetry in meta-analyses of randomised controlled trials. BMJ 2011;343:d4002.  Back to cited text no. 16
    
17.
GRADEpro GDT: GRADEpro Guideline Development Tool [Software]. McMaster University, 2020 (developed by Evidence Prime, Inc.). Available from: gradepro.org. [Last accessed on 2021 Feb 08]  Back to cited text no. 17
    
18.
Aeschlimann FA, Barra L, Alsolaimani R, Benseler SM, Hebert D, Khalidi N, et al. Presentation and disease course of childhood-onset versus adult-onset Takayasu arteritis. Arthritis Rheumatol 2019;71:315-23.  Back to cited text no. 18
    
19.
Misra DP, Aggarwal A, Lawrence A, Agarwal V, Misra R. Pediatric-onset Takayasu's arteritis: Clinical features and short-term outcome. Rheumatol Int 2015;35:1701-6.  Back to cited text no. 19
    




 

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