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 Table of Contents  
LETTER TO EDITOR
Year : 2016  |  Volume : 11  |  Issue : 4  |  Page : 238-239

Comment on: Emerging evidence base therapies for systemic sclerosis


1 Department of Clinical Immunology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India
2 Department of Clinical Immunology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India

Date of Web Publication8-Nov-2016

Correspondence Address:
Dr. Durga Prasanna Misra
Department of Clinical Immunology, SSB 4th Floor, Jawaharlal Institute of Postgraduate Medical Education and Research, Dhanwantari Nagar, Puducherry - 605 006
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-3698.192679

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How to cite this article:
Misra DP, Agarwal V, Negi VS. Comment on: Emerging evidence base therapies for systemic sclerosis. Indian J Rheumatol 2016;11:238-9

How to cite this URL:
Misra DP, Agarwal V, Negi VS. Comment on: Emerging evidence base therapies for systemic sclerosis. Indian J Rheumatol [serial online] 2016 [cited 2019 Jun 19];11:238-9. Available from: http://www.indianjrheumatol.com/text.asp?2016/11/4/238/192679

Dear Editor,

We read with great interest the review article on emerging therapeutic avenues in systemic sclerosis (SSc).[1] We would like to highlight seminal work in this field pioneered from India [Figure 1] that did not find mention in the paper.
Figure 1: Paradigm shift in the management of systemic sclerosis with phosphodiesterase 5 inhibitors

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Phosphodiesterase-5 (PDE5) inhibitors (PDE5i) are vasodilatory agents that increase levels of cyclic guanosine monophosphate in the endothelial cells of the vessel wall. A single-center double-blind randomized crossover study [2] assessed the role of the add-on PDE5i tadalafil (which has a long half-life of 17.5 h) at a dose of 20 mg every alternate day for 6 weeks in 24 patients with secondary Raynaud's phenomenon (RP) refractory to conventional vasodilators (calcium channel blockers, angiotensin-converting enzyme inhibitors, or angiotensin receptor blockers). Tadalafil reduced frequency and duration of attacks of RP, improved mean Raynaud's condition score (RCS), healed existing digital ulcers (DUs), prevented new DU, improved endothelial function, and was associated with better quality of life compared to placebo. These findings were replicated in a multicentric study of 53 patients with SSc and refractory RP.[3] A meta-analysis of randomized trials on PDE5i in secondary RP [4] (including the above two studies on tadalafil) confirmed the improvement in frequency and duration of RP and improvement in RCS with this group of drugs. Another recent meta-analysis [5] reaffirmed the ability of PDE5i to heal DUs. These findings have resulted in a paradigm shift in the management of SSc, reflected in recent guidelines. The scleroderma clinical trials consortium and the Canadian Scleroderma Research Group [6] now recommend the use of PDE5i as a second-line therapy in patients with SSc for RP as well as for treatment of existing DU and prevention of new DU. The recently published guidelines on the management of SSc by the British Society for Rheumatology [7] also affirm the role of PDE5i in the management of RP and DU associated with SSc. It must be noted that tadalafil is an oral drug that is cheap and easily accessible to patients with SSc from developing countries compared to drugs such as bosentan and iloprost.

The potential benefits of PDE5i extend beyond mere vasodilation. A double-blind randomized placebo-controlled study in patients with interstitial lung disease associated with SSc [8] showed improvement of forced vital capacity (FVC) in 17 patients receiving tadalafil 20 mg alternate day when compared with 13 others receiving placebo (who had a reduction in FVC). Those receiving tadalafil had better scores on patient global assessment.In vitro studies [9] using fibroblasts cultured from skin biopsies of patients with SSc and healthy controls treated with PDE5 inhibitors sildenafil or zaprinast, showed decrease in mRNA and protein levels of profibrotic type 1 collagen, fibronectin, alpha smooth muscle actin 1, and connective tissue growth factor and increase in levels of anti-fibrotic matrix metalloproteinase 2 compared to treatment with transforming growth factor (TGF)-β1 alone. PDE5 inhibition impaired signaling through both canonical and noncanonical pathways induced by TGF-β. Very few therapies have shown such disease-modifying anti-fibrotic potential in SSc and these exciting preliminary findings merit further investigation.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

1.
Raja J, Denton C. Emerging evidence-based therapies for systemic sclerosis. Indian J Rheumatol 2016;11:31-41.  Back to cited text no. 1
    
2.
Shenoy PD, Kumar S, Jha LK, Choudhary SK, Singh U, Misra R, et al. Efficacy of tadalafil in secondary Raynaud's phenomenon resistant to vasodilator therapy: A double-blind randomized cross-over trial. Rheumatology (Oxford) 2010;49:2420-8.  Back to cited text no. 2
    
3.
Agarwal V, Ghosh P, Sharma A, Bhakuni DS, Kumar S, Singh UN, et al. Efficacy of tadalafil in Raynaud's phenomenon secondary to systemic sclerosis: A double blind randomized placebo controlled parallel group multicentric study [abstract]. Arthritis Rheum 2010;62 Suppl 10:2086.  Back to cited text no. 3
    
4.
Roustit M, Blaise S, Allanore Y, Carpentier PH, Caglayan E, Cracowski JL. Phosphodiesterase-5 inhibitors for the treatment of secondary Raynaud's phenomenon: Systematic review and meta-analysis of randomised trials. Ann Rheum Dis 2013;72:1696-9.  Back to cited text no. 4
    
5.
Tingey T, Shu J, Smuczek J, Pope J. Meta-analysis of healing and prevention of digital ulcers in systemic sclerosis. Arthritis Care Res (Hoboken) 2013;65:1460-71.  Back to cited text no. 5
    
6.
Walker KM, Pope J; Participating Members of the Scleroderma Clinical Trials Consortium (SCTC); Canadian Scleroderma Research Group (CSRG). Treatment of systemic sclerosis complications: What to use when first-line treatment fails – A consensus of systemic sclerosis experts. Semin Arthritis Rheum 2012;42:42-55.  Back to cited text no. 6
    
7.
Denton CP, Hughes M, Gak N, Vila J, Buch MH, Chakravarty K, et al. BSR and BHPR guideline for the treatment of systemic sclerosis. Rheumatology (Oxford) 2016;55:1906-10.  Back to cited text no. 7
    
8.
Parida J, Nath A, Neyaz Z, Agarwal V. A double blind randomized control trial of oral tadalafil in interstitial lung disease of scleroderma [abstract]. Arthritis Rheum 2014;66:S739.  Back to cited text no. 8
    
9.
Agarwal V, Rai MK, Agrawal V, Singh H, Chaturvedi S. Phosphodiesterase-5 Inhibitors Attenuate Fibrotic Phenotype and Restore Anti-Fibrotic Resopnses of Cutaneous Fibroblasts in Patients with Scleroderma [abstract]. Arthritis Rheumatol. 2016; 68 (Suppl 10). Availavble from: http://acrabstracts.org/abstract/phosphodiesterase-5-inhibitors-attenuate-fibrotic-phenotype-and-restore-anti-fibrotic-resopnses-of-cutaneous-fibroblasts-in-patients-with-scleroderma/. [Last accessed 2016 Oct 13].  Back to cited text no. 9
    


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