|LETTER TO EDITOR
|Year : 2016 | Volume
| Issue : 4 | Page : 238-239
Comment on: Emerging evidence base therapies for systemic sclerosis
Durga Prasanna Misra1, Vikas Agarwal2, Vir Singh Negi1
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 Publication||8-Nov-2016|
Dr. Durga Prasanna Misra
Department of Clinical Immunology, SSB 4th Floor, Jawaharlal Institute of Postgraduate Medical Education and Research, Dhanwantari Nagar, Puducherry - 605 006
Source of Support: None, Conflict of Interest: None
|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
We read with great interest the review article on emerging therapeutic avenues in systemic sclerosis (SSc). 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|
Click here to view
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  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. A meta-analysis of randomized trials on PDE5i in secondary RP  (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  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  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  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  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  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.
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Conflicts of interest
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