|Year : 2017 | Volume
| Issue : 6 | Page : 227-231
Phosphodiesterase-5 inhibitors: Raynaud's and beyond
Sanat Phatak, Sajal Ajmani, Vikas Agarwal, Durga Prasanna Misra
Department of Clinical Immunology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
|Date of Web Publication||23-Nov-2017|
Durga Prasanna Misra
Department of Clinical Immunology, C block, 2nd Floor, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Rae Bareily Road, Lucknow - 226 014, Uttar Pradesh
Source of Support: None, Conflict of Interest: None
Phosphodiesterases (PDE) are a group of ubiquitously present enzymes involved in regulation of various cellular pathways. PDE5 acts to metabolize cyclic guanosine monophosphate (GMP). The various PDE5 inhibitors available are sildenafil, tadalafil, vardenafil, and mirodenafil. We shall discuss the roles of various PDE5 inhibitors in rheumatic diseases. PDE5 inhibitors prevent degradation of cyclic GMP; hence, they have vasodilatory properties which render them useful in the management of secondary Raynaud's phenomenon. They have also demonstrated efficacy in the healing of digital ulcers in systemic sclerosis and potentially prevent the formation of new digital ulcers. Their vasodilatory property has also been utilized in the management of pulmonary arterial hypertension, wherein their ability to favorably affect hemodynamics of a pressure-overloaded right heart is beneficial. Recent evidences have suggested a potential antifibrotic role of these agents, and studies in idiopathic pulmonary fibrosis and systemic sclerosis-associated interstitial lung disease hold promise for future exploration of these agents for these indications.
Keywords: Fibrosis, phosphodiesterase 5 inhibitors, pulmonary hypertension, Raynaud's phenomenon, sildenafil, tadalafil
|How to cite this article:|
Phatak S, Ajmani S, Agarwal V, Misra DP. Phosphodiesterase-5 inhibitors: Raynaud's and beyond. Indian J Rheumatol 2017;12, Suppl S1:227-31
| Introduction|| |
Phosphodiesterases (PDE) are a group of ubiquitously present enzymes that hydrolyze the nucleotides cyclic adenosine monophosphate (cAMP) or cyclic guanosine monophosphate (cGMP) to their inactive forms AMP and GMP. They regulate the cyclic nucleotide signaling within the cell. The PDE enzymes are classified into 11 families, namely, PDE1–PDE11 in mammals. The classification is based on amino acid sequences, substrate specificities, regulatory properties, pharmacological properties, and tissue distribution. Depending on their relative specificities, PDEs may act on both cAMP and cGMP (PDEs 1, 2, 3, 10, 11) or either of cAMP (PDEs 4, 7, 8) or cGMP (PDEs 5, 6, 9).
Among the PDE inhibitors, the clinically relevant ones are nonselective PDE inhibitors, PDE3, PDE4, and PDE5 inhibitors. Nonselective PDE inhibitor theophylline is used as bronchodilator, and pentoxifylline is used to enhance blood circulation. PDE3 inhibitors (amrinone, milrinone) increase the level of cAMP, leading to phosphorylation of protein kinases, which in turn activates cardiac calcium channels. They are used as inotropes in cardiogenic shock. PDE4 inhibitors (rolipram, roflumilast) increase cAMP in immune cells and central nervous system. They may play a role in the treatment of central nervous disorders such as depression and inflammatory disorders such as chronic obstructive pulmonary disease. PDE5 has been found to be present in corpus cavernosum of the penis and pulmonary blood vessels, where it is responsible for degradation of cGMP.
| Historical Perspective|| |
The first utility of PDE5 inhibitors was described in the 1990s when sildenafil was described as an efficacious treatment for erectile dysfunction, due to its vasodilatory properties resulting in improving blood flow in the corpora cavernosa. Despite being generally safe and well tolerated (side effects of headache, flushing, and dyspepsia were commonly encountered) in healthy adults as well as diabetics  and patients with cardiovascular disease, an important adverse effect was hypotension and cardiovascular collapse when used along with nitrates. There was no synergism noted with other antihypertensive agents. Since then, the use of PDE5 inhibitors has been established in Raynaud's phenomenon (RP) and pulmonary arterial hypertension, and potential uses are emerging as antifibrotic agents in interstitial lung disease [Figure 1].
| Available Phosphodiesterases-5 Inhibitors|| |
Zaprinast is a PDE5 inhibitor used in animal studies. PDE5 inhibitors used in humans are mirodenafil (half-life – t ½ 2 h), sildenafil (t ½ 4–6 h), tadalafil (t ½ 24 h), and vardenafil (t ½ 12 h).
| Phosphodiesterases-5 Inhibitors in Raynaud's Phenomenon|| |
Due to their vasodilatory properties, the potential role of PDE5 inhibitors in Raynaud's was considered. Fries et al. showed efficacy of sildenafil monotherapy at a dose of 50 mg twice daily for treatment of secondary RP compared to placebo in a randomized double-blind crossover study. Most of the patients included in the study had systemic sclerosis (14/18 patients). Use of sildenafil was associated with decreased frequency and severity of RP attacks, improvement of Raynaud's condition score (RCS), and improved capillary microcirculation assessed by Laser Doppler when compared to placebo. Although the study was not designed to look at digital ulcer healing, a tendency toward improvement of digital ulcers was seen. Herrick et al. studied modified-release sildenafil (100 mg once daily for 3 days then 200 mg once daily for 25 days) versus placebo in limited cutaneous systemic sclerosis in a multicenter randomized study and found a significant reduction in the percentage of Raynaud's attacks compared to baseline with modified-release sildenafil compared to placebo. Caglayan et al. compared vardenafil 10 mg twice daily to placebo in patients with RP (most were patients with systemic sclerosis – 38/53) and found a significant decrease in daily frequency of Raynaud's attacks compared to placebo.
In view of the fact that sildenafil and vardenafil were efficacious in treating RP, it was logical to study the role of tadalafil, a longer acting congener with advantage of once every alternate day dosing, for the same indication. Schiopu et al. failed to demonstrate efficacy of tadalafil (20 mg daily) in treating patients with systemic sclerosis-associated RP. A major limitation of the study was that it had been designed with a coprimary endpoint to detect improvement in female sexual endpoint; hence, these patients were healthy enough to be sexually active and therefore might have had less severe systemic sclerosis. Shenoy et al. reported efficacy of tadalafil (20 mg alternate day, as add-on to preexisting vasodilator therapy with calcium channel blockers, angiotensin-converting enzyme blockers, angiotensin receptor blockers, or pentoxifylline) in a single center parallel-group double-blind randomized crossover study compared to placebo in patients with RP secondary to systemic sclerosis or mixed connective tissue disease. Patients receiving tadalafil reported improvement in frequency and duration of RP attacks, RCS, endothelial function as assessed by flow-mediated dilation and quality of life. Importantly, healing of digital ulcers was also noted, and in the group receiving tadalafil, there were no new onset digital ulcers. The latter findings are significant considering that before this study, the only drugs showing efficacy in healing digital ulcers were intravenous prostacyclins, and only bosentan (dual endothelin receptor antagonist) was efficacious in preventing formation of digital ulcers. Use of both these classes of drugs is limited in developing countries due to high costs associated with their use as well as lack of widespread availability. The findings of Shenoy et al. were confirmed in a multicenter study incorporating patients with systemic sclerosis from four centres across India and showed efficacy of tadalafil as an add-on therapy with reduction in frequency and severity of RP attacks, healing of existing digital ulcers, and prevention of new digital ulcers. A recent meta-analysis compiled data from these six studies and confirmed efficacy of PDE5 inhibitors in reducing frequency and duration of RP attacks as well as improving RCS. Another meta-analysis found favorable evidence for healing of digital ulcers in systemic sclerosis with PDE5 inhibitors. These studies have led to changes in treatment policies with incorporation of PDE5 inhibitors in the guidelines of the Canadian Scleroderma Society as second-line therapy for the treatment of RP in systemic sclerosis. The EULAR/EUSTAR updated its recommendations for treatment of systemic sclerosis and included PDE5 inhibitors in the recommendations for RP. In our personal experience, the use of tadalafil has made a significant difference toward the management of RP associated with systemic sclerosis, with significant reductions in the number of admissions for systemic sclerosis-associated Raynaud's and digital ulcers during the winter months.
| Phosphodiesterases-5 Inhibitors in Pulmonary Hypertension|| |
It has been observed that PDE5 expression is upregulated in right ventricular tissue obtained from mice with experimentally induced right ventricular hypertrophy (RVH) as well as in biopsies from human hearts with RVH, but not from normal right ventricles. Hence, it was thought that modulation of PDE5 might be beneficial in patients with pulmonary hypertension and RVH. Furthermore, improvement in left ventricular function by sildenafil in mice with experimentally pressure-overloaded left ventricles  lent further credence to this hypothesis. Furthermore, mice with experimentally induced left ventricular infarction had lesser quantum of myocardial necrosis and apoptosis and better residual left ventricular function when treated with sildenafil compared with placebo. This was mediated by effects on nitric oxide pathway, as well as upregulation of protein kinase G resulting in downstream inhibition of Rho kinase. In mice with pulmonary hypertension induced by monocrotaline, use of sildenafil resulted in reversal of RVH and improvement in right ventricular function. While reversal of PAH was not consistently demonstrable in another model of pulmonary hypertension, i.e., RVH induced by pulmonary artery banding in mice, it was observed that these mice also had improvement in right ventricular function as assessed by tricuspid annular plane systolic excursion. Furthermore, in ex vivo cultured pulmonary artery smooth muscle cells, exposure to sildenafil reduced their proliferation, dependent on inhibition of protein kinase A and protein kinase G, resulting in inhibition of action of platelet-derived growth factor on extracellular signal-related kinase.
These preliminary results in animal models resulted in clinical trials of PDE5 inhibitors in pulmonary hypertension. In a study of 26 patients with primary pulmonary hypertension, used of sildenafil (25–100 mg thrice daily) resulted in significant improvement in exercise tolerance, cardiac index and dyspnea and fatigue assessed using a quality of life questionnaire, compared to placebo. In a larger double-blind randomized placebo-controlled trial of 278 patients with idiopathic as well as secondary pulmonary hypertension, sildenafil used in doses of 20, 40, or 80 mg thrice daily compared to placebo resulted in significant reductions in exercise tolerance assessed using the 6-min walk test, improvements in right heart pressures measured by right heart catheterization, and enhancement of WHO functional class. A recent randomized double-blind study (AMBITION study), including 500 patients with pulmonary hypertension severe enough to be WHO functional class II or III, studied whether use of combination of ambrisentan 10 mg and tadalafil 40 mg daily was better than monotherapy with either of these agents. Combination of ambrisentan and tadalafil was associated with significantly lesser hazard ratio of clinical failure (defined as mortality or hospitalization for worsening pulmonary hypertension, lack of satisfactory clinical response, or disease progression inspite of therapy), better improvement in 6-min walk distance and greater improvement in serum N-terminal pro-brain natriuretic peptide levels, when compared to the pooled data from the monotherapy arm of the study. A secondary analysis revealed that upfront combination of ambrisentan and tadalafil gave a survival advantage. A subgroup analysis of the AMBITION trial was recently published, which confirmed that the beneficial effects remained in the connective tissue disease-associated pulmonary arterial hypertension (PAH) and Scleroderma PAH patient groups, despite having a worse overall prognosis. In 16 patients with pulmonary hypertension secondary to systemic sclerosis, open-label use of sildenafil at a dose of 25 mg thrice daily was associated with significant improvements in pulmonary arterial pressure assessed by echocardiography, WHO class of dyspnea, and 6-min walk distance. Thus, PDE5 inhibitors have today become the first-line therapy for pulmonary hypertension, both idiopathic as well as secondary, including connective tissue disease-associated pulmonary hypertension.
| Phosphodiesterases-5 Inhibitors in Interstitial Lung Disease|| |
Efficacy of PDE5 inhibitors in reducing cardiac remodeling was partly a result of decreased fibrosis observed in cardiac biopsies of mice receiving PDE-5 inhibitors compared to placebo. Moreover, use of mirodenafil was associated with decreased fibrosis of the detrusor muscle and improved bladder compliance in rats with experimentally induced chronic bladder ischemia. Interstitial lung disease is a major cause of morbidity in various connective tissue diseases, with evidence that therapy at the most stabilizes disease in a subset of patients. Hence, PDE5 inhibition is a potentially attractive therapeutic avenue for exploration in these patients.
The use of sildenafil in interstitial lung disease was studied in a randomized, double-blind placebo-controlled trial. The researchers hypothesized that vasodilation due to sildenafil might potentially increase perfusion to areas of lungs which were well ventilated and thus potentially improve exercise tolerance in these patients. The patients selected for the study had advanced idiopathic pulmonary fibrosis with diffusion capacity for carbon monoxide (DLCO) <35% of predicted. A total of 180 patients were randomized to receive either sildenafil 20 mg thrice a day or placebo for 12 weeks. While the study failed to meet its primary end point, namely, proportion of patients achieving at least 20% improvement in 6-min walk distance, a number of secondary endpoints were favorably achieved. Patients receiving sildenafil had a significant improvement in arterial oxygenation, dyspnea as assessed by the Shortness of Breath questionnaire, general health score on the SF36 quality of life questionnaire and DLCO, compared to placebo.
A major limitation of the above study was that it included patients with advanced interstitial lung disease. Such patients inherently would be less likely to improve with therapy. Considering the antifibrotic effects of PDE5 inhibition described earlier, we proposed to study tadalafil 20 mg alternate day in a double-blind randomized placebo-controlled trial in patients with systemic sclerosis-associated interstitial lung disease. A total of 39 patients were randomized to 6 months of tadalafil or placebo. At the end of the study period, 30 patients had completed the trial. Although there was no significant change in forced vital capacity (FVC) from baseline for tadalafil versus placebo, patients receiving tadalafil showed a mean improvement of 1.8% in FVC compared to those receiving placebo, who demonstrated no change from baseline. Patients on tadalafil had significantly better patient global assessment scores, with a trend toward better physician global assessment scores, total lung capacity, and visual analog scale for breathing. This was a small single center study with findings of potential relevance in interstitial lung disease associated with systemic sclerosis. Prior studies have shown marginal benefit with oral  or intravenous cyclophosphamide  therapy in these patients, with stabilization of FVC compared to the placebo groups which showed deterioration of FVC. Hence, there is cause for optimism with the use of tadalafil, which resulted in an increase in FVC compared to placebo. These findings require validation in a multicenter study with larger number of patients.
| Conclusion|| |
PDE5 inhibitors, by virtue of their vasodilatory and antifibrotic effects, are finding a niche in the therapy of various rheumatic conditions. They have demonstrated efficacy in the management of secondary RP and healing of digital ulcers in systemic sclerosis and may have a potential role in preventing new digital ulcer formation. They have emerged as the mainstay for the management of pulmonary hypertension associated with connective tissue diseases. Their potential antifibrotic properties make them attractive targets for study in interstitial lung disease, and they may yet have a role in the management of skin tightening in systemic sclerosis.
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Conflicts of interest
There are no conflicts of interest.
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