|LETTER TO EDITOR
|Year : 2022 | Volume
| Issue : 2 | Page : 196-198
Is T-helper 17 inhibition the knight in shining armor we were looking for? Comments on the article by shumy et al.
Kunal Chandwar1, Chandani J Shah2, Puja Srivastava3
1 Department of Clinical Immunology and Rheumatology, King George's Medical University, Lucknow, Uttar Pradesh, India
2 Department of Neurology, SMS Hospital, Jaipur, Rajasthan, India
3 Department of Medicine, Sardar Vallabhbhai Patel Institute of Medical Sciences and Research and Smt. NHL Municipal Medical College, Ahmedabad, Gujarat, India
|Date of Submission||04-Mar-2022|
|Date of Acceptance||04-Apr-2022|
|Date of Web Publication||10-May-2022|
Dr. Kunal Chandwar
Department of Clinical Immunology and Rheumatology, King George's Medical University, Lucknow - 226 003, Uttar Pradesh
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Chandwar K, Shah CJ, Srivastava P. Is T-helper 17 inhibition the knight in shining armor we were looking for? Comments on the article by shumy et al. Indian J Rheumatol 2022;17:196-8
|How to cite this URL:|
Chandwar K, Shah CJ, Srivastava P. Is T-helper 17 inhibition the knight in shining armor we were looking for? Comments on the article by shumy et al. Indian J Rheumatol [serial online] 2022 [cited 2022 Jun 26];17:196-8. Available from: https://www.indianjrheumatol.com/text.asp?2022/17/2/196/345012
Shumy et al. through their study on predictors of remission with corticosteroids (CSs) in Bangladeshi patients with Takayasu arteritis (TAK) did show that CS as monotherapy performs dismally with <10% of patients attaining remission by 6 months. Although the number of patients may be small in this study, the trends shown aligns with what many of us see in clinical practice. Misra et al. in their meta-analysis of CSs in TAK showed clinical response in up to 60% of patients (95% confidence interval [CI] 45%-74%), angiographic stabilization in 28% of patients only (95% CI 6%–57%), and relapses in 66% of patients (95% CI 18%–99%). This response is contrary to the better response usually seen in giant cell arteritis (GCA), with a relapse rate of around 47.2% (95% CI 40–54).
What explains the poorer CS response in Takayasu and not in GCA might be explained by a recent study by Singh et al. on a novel T-helper 17 (Th17) lymphocyte population, the Th17.1 subpopulation, which was not only elevated in TAK but also associated with active disease and probably a high p-glycoprotein expression. This might explain the CS resistance in TAK vis-a-vis GCA, as GCA does not have the same amount of CS resistance in its Th17 cell line. In learning how to handle the CS resistance may lie the answer to successfully managing TAK while using CS at the lowest possible dose and shortest possible time. It is also known that there is significant plasticity between Th17 and Th1 cells with interleukin-12 (IL-12), IL-6, and transforming growth factor-beta (TGF-β) playing an important role in maintaining plasticity for Th1 to Th17 and vice versa [Figure 1]. The understanding of plasticity further accentuates the rationale why some patients might not respond to mere Th1 or Th17 blockage and a possible reason why T cell proliferation inhibitors such as tacrolimus show promise in TAK.
|Figure 1: T-helper 17 in Takayasu. Image created using BioRender.com, (a)Vascular dendritic cell interacts with CD-4 helper cells to activate the Th-17 pathway releasing IL-6 (Interleukin 6), IL-23(Interleukin 23), IL-1(Interleukin 1) and TGF- β (Transforming growth factor-beta). (b) IL-6 and TGFβ act through the JAK-STAT(Janus kinase - Signal transducer and activator of transcription) pathway and SMAD pathway respectively leading to the formation of STAT dimers and resulting in the release of IL-21(Interleukin 21). (c) Il-21 acts via the JAK-STAT pathway along with IL1 to activate the ROR-γt transcription factor leading to the formation of IL-23 receptors and IL17A (Interleukin 17A), release (d)IL-23 acts on the IL-23 receptor and activates the STAT dimers and ROR-γt (retinoic acid receptor-related-orphan-receptor-gamma t) for the formation and release of IL-17 A and F, IL-21 and IL-22 (Interleukin 22). (e)These cytokines act on Neutrophils and macrophages to release mediators of inflammation and vascular remodelling including Matrix metalloproteinases (MMPs), Vascular endothelial growth factor (VEGF), Platelet-derived growth factor (PDGF), Reactive oxygen species (ROS) and endothelin (f)There exists plasticity between Th1 and Th17 cells with IL6 and TGF- β favouring Th17 and IL12 favouring Th1The possible treatment targets have been enumerated. 1 IL-6 inhibitors e.g. Tocilizumab. 2 JAK inhibitors e.g. Tofacitinib and baricitinib. 3 TGFβ inhibition (Tadalafil has a role here).4 IL-1 inhibitors e.g. Anakinra. 5 IL-23 inhibitors e.g. Ustekinumab. 6 IL-17 inhibitors e.g. Secukinumab. 7 Dendritic cell, T cells and Myeloid cell inhibitors – GM CSF inhibitors e.g. mavrilimumab. 8 Co-stimulation Inhibitors – CTLA4 inhibitors e.g. Abatacept. 9T Cell proliferation inhibitors – Calcineurin inhibitors e.g. Tacrolimus|
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Understanding the role of Th17 in pathogenesis is important as depicted in [Figure 1] and gives one an idea of which set of drugs might offer promise in the future while reducing CS resistance of Th17.1 by inhibition of P-glycoprotein is important. TNF inhibitors and calcineurin inhibitors, including cyclosporin and tacrolimus, have overcome the steroid resistance mediated by P-glycoprotein on lymphocytes., In the study by Singh et al., the Th17 and Th17.1 cells were reduced by a combination of tadalafil and tacrolimus and their action on the P-glycoprotein and Th17 pathway [Figure 1]. At the same time, the role of granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-6, IL-23, Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway, TGF-β, and IL-17 in the Th17 pathway underlines the importance of their inhibition and its scope in the treatment of TAK.
Effective inhibition of the Th17.1 subpopulation might hold the answer to the effective reduction of CS resistance and hence would go a long way in reducing CS burden and accrual damage cumulative CS doses cause.
While the proof of the pudding may lie in randomized controlled trials of these agents in TAK, the evolving importance of the Th-17 pathway in the pathogenesis of TAK has brightened up the treatment prospects of this difficult to treat disease in coming times.
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Rate and predictors of response to glucocorticoid therapy in patients of Takayasu arteritis at a tertiary level hospital of Bangladesh: A longitudinal study. Indian J Rheumatol 2021;16:375-80. [Full text]
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