Treatment with intravenous iloprost in patients with systemic sclerosis : A short review

Treatment with intravenous iloprost in patients with systemic sclerosis: A short review Elisa Visalli1, Giorgio Amato1, Marcella Di Gangi1, Alessia Benenati1, Nicolò Cino1, Caterina Gagliano2, Raffaele Falsaperla3, Alberto Farina4, Rosario Foti1 1Rheumatology Unit, A.O.U. Policlinico Vittorio Emanuele, Catania, Italy 2General Pediatrics and Pediatric Acute and Emergeny Unit, A.O.U. Policlinico Vittorio Emanuele, Catania, Italy 3Ophthalmology, NEST (Neurovisual Science Technology) and Rare Disease Center (Ra.Di.Ce.), Santa Marta Hospital, Catania, Italy 4Medical Affairs Department, Italfarmaco S.p.A., Milano, Italy


Introduction
Scleroderma (systemic sclerosis or SSc) is a severe, chronic disease characterised by small vessel vasculopathy, autoantibodies production, and fibroblast dysfunction leading to an excessive deposition of collagen in the skin and internal organs 1,2,3 .Severe Raynaud's phenomenon (RP) is the early onset symptom in most SSc patients and may precede other clinical manifestations of the disease by many years 4 .The clinical course of the disease often involves the cardiovascular and respiratory systems; the heart can be directly or indirectly involved with the involvement of other organs, especially kidneys and lungs 5 while for the respiratory system, SSc can affect lung parenchyma and pulmonary blood vessels, leading to interstitial lung disease (ILD) and pulmonary arterial hypertension (PAH).The presence of a cardio-pulmonary involvement generally leads to a poor prognosis for the patient 2 .Patients with significant internal organ involvement remain often asymptomatic until the late stages of SSc; therefore, routine monitoring for the underlying disease and an intensive medical treatment are essential after the first diagnosis.Despite recent advances in the disease management, SSc remains a treatable but not curable disease 2 .
Current European League Against Rheumatism (EULAR) guidelines recommend Iloprost in the treatment of Raynaud's phenomenon and in the healing of ischemic digital ulcers.In particular, intravenous iloprost reduces the frequency and severity of SSc-RP attacks and should be considered for severe SSc-RP and should also be used for the treatment of milder SSc-RP attacks when oral therapy have failed 6 .It should also be considered that treatment with iloprost may offer greater efficacy than calcium antagonists 7,8 .Despite EULAR's recommendations, the correct therapeutic approach is still debated and large differences occur between centres administering such treatment, with implications on clinical practice and health of patients.

Iloprost
Iloprost is a stable prostacyclin presenting vasodilating, anti-platelet, cytoprotective and immuno-modulating properties, with long-lasting effects at the level of cutaneous microcirculation 8,9,10 .The synthetic prostacyclin analogue iloprost closely mimics the whole range of endogenous prostacyclin's physiological effects (figure 1), and is therefore ideally suited for the treatment of micro and macrocirculatory diseases, including disorders in the pulmonary vascular bed, basically determined by an imbalance between prostacyclin with its vasodilatory and anti-platelet effects and thromboxane which acts as a vasoconstrictor and platelet activator.Endogenous prostacyclin assumes a key role in the finely tuned interaction between platelets, leucocytes and endothelium, especially at the level of the microcirculation acting as a vascular repair and protection factor 11,12,13 .
Tissue ischemia beyond the often long standing arterial stenosis or resulting from vasospastic attacks, may be barely adequate to support nutrition in normal circumstances but when intercurrent infection or minor injury is superimposed, the microcirculation breaks down leading to pain, ulceration or gangrene.The low perfusion pressure and decreased microcirculatory blood flow precipitate cellular and biochemical changes, which however can be reversible.The typical changes in severely ischemic areas are an uneven distribution of the nutritive capillary blood flow associated with capillary plugging.The key players are the platelets, white cells and the endothelium.It has been suggested that the low perfusion pressure in the severely ischemic microcirculation causes unbalanced activation of these components.The endothelial damage/disturbance promotes vasoconstriction via release of endotheliumderived constricting factor, endothelin, thromboxane A2, and serotonin, leukocyte adhesion, platelet adhesion and subsequent release of e.g.mitogens, and impairment of the fibrinolytic balance with inappropriate release of tissuetype plasminogen activator and its plasminogen activator inhibitor.Inflammatory factors are involved in these processes to a varying extent (Figure 2).
The overall effect is to cause occlusion of much of the microcirculation by platelet, white cell, fibrin or thrombotic plugs.Disordered vasomotion increases further the maldistribution of blood flow in the microcirculation.Correction of this imbalance is the therapeutic approach for the administration of iloprost.The beneficial effects of iloprost in improving symptoms of ischemia such as Raynaud's phenomenon and digital ulcers in patients with SSc are largely due to modulating the disordered microcirculation.Iloprost restores the disturbed microcirculation by inducing vasodilatation, inhibiting platelet activation, repairing and protecting the endothelium, activating the endogenous fibrinolysis and by correcting cytokine network imbalances (Figure 3).The effects of iloprost are mediated by its binding to specific  prostaglandin I2 (PGI2) receptors and by a subsequent increase in cellular cyclic adenosine monophosphate (cAMP).More recently described, also peroxisome proliferator-activated receptor delta (PPARδ) activation plays a role in controlling the cell fate, i.e. apoptosis 14,15 .

Clinical data on the use of iloprost in SSc
Clinical data from the literature show an improvement in the frequency, duration and intensity of ischemic episodes for up to at least 6 weeks after a short (3 to 5 days) course of intravenous iloprost.Improved healing of active digital ulcers was also reported.Table 1 summarizes the main studies reported in the literature on the use of iloprost in patients with SSc.The long-term studies show the maintenance of efficacy on the vascular symptoms over time.This is an important therapeutic goal since iloprost administration aims to correct vasculopathy and restore the function of microcirculation, which are key factors in the disease.Long-term treatment of vasculopathy may therefore represent a rational therapeutic approach: it has an impact on the quality of patient's life -since RP and DUs are two of the major causes of pain and disability in these patients -and may potentially have a favorable impact on the evolution of the disease.In fact, a low incidence of severe vascular complications, such as pulmonary arterial hypertension, or a stabilization of cardiopulmonary parameters was observed in long-term studies 7,8,25,26 .evaluated in a group of 68 consecutive SSc patients treated with iloprost with a schedule of 5-6 consecutive daily infusions per month (6 h/day, 0.5-2.0ng/kg/min), during a 7 years follow-up 41 .

Recently, at the
Data show a stabilization of the cardiopulmonary disease, in particular in a very long-term follow-up and this results are first supported by NYHA class non-progression and a significant reduction of systolic pulmonary arterial pressure (sPAP), brain natriuretic peptide levels (BNP) and improvement of tricuspid annular plane systolic excursion (TAPSE) values in study population.In particular, a significant sPAP reduction was observed in the subgroup of patients with baseline sPAP ≥36 mmHg and after an average long-term follow-up.The EUSTAR working group recently showed the importance of sPAP considering that baseline values ≥36 mmHg were significantly associated with an increased risk of death up to 3-year follow-up 44 while BNP levels is an important diagnostic marker of early pulmonary artery hypertension and TAPSE is important for assessing disease severity, stability, and prognosis in PAH patients, with a cut-off value > 20 mm indicating a satisfactory patient status 45,46 .It was also observed a stabilization of interstitial lung disease markers, such as Diffusing capacity of the Lung for Carbon Monoxide (DLCO), Forced Vital Capacity (FVC), Alveolar Volume (VA), and DLCO/VA and favourable effect on skin involvement with a significant change of Rodnan skin score value.Finally, the long-term effectiveness of the therapy was confirmed since a significant reduction in the prevalence of digital ulcers was observed.
Concerning the safety profile, data from the literature show a satisfactory tolerability of the drug both in the short and long-term studies, the most common side effects, mainly due to the vasodilating properties of the drug, can be managed with the optimal titration of the individual dose at beginning of treatment.

Conclusions
SSc remains a disease characterized by a poor prognosis due to the occurrence of cardiopulmonary complications and the long-term disease stabilization represents an important therapeutic goal.Intravenous iloprost acts on small vessel vasculopathy, which is one of the key factors of the disease, with proven effectiveness in the treatment

Table 1 .
Rheumatology Unit of Policlinico Vittorio Emanuele, Catania, Italy, the disease progression, specifically in terms of cardiopulmonary function, was Summary of the main clinical studies Raynaud's phenomenon and digital ulcers.Data from observational studies suggest that an intensive and chronic regimen of IV iloprost administration may lead to the stabilization of disease in SSc patients but randomized and controlled trials are needed to confirm these promising results.35.Caravita S, Wu SC, Secchi MB, et al.Long-term effects of intermittent Iloprost infusion on pulmonary arterial pressure in connective tissue disease.Eur J Intern Med.2011; 22: 518-521.36.Casigliani Rabl S, Della Rossa A, Pepe P, et al.Long-term cyclic intravenous iloprost in systemic sclerosis: clinical experience from a single center.Reumatismo.2012; 64(3): 158-165.Trombetta AC, Pizzorni C, Ruaro B, et al.Effects of Longterm Treatment with Bosentan and Iloprost on Nailfold Absolute Capillary Number Fingertip Blood Perfusion and Clinical Status in Systemic Sclerosis.J Rheumatol.2016; 43(11): 2033-2041.41.Colaci M, Lumetti F, Giuggioli D, et al.Treatment of sclerodermarelated digital ulcers with iloprost a cohort study.Rheum Dis.2016; 75(2): 1117 42.Foti R, Visalli E, Amato G, et al.Long-term clinical stabilization of scleroderma patients treated with a chronic and intensive IV iloprost regimen.Rheumatol Int.2017; 37(2): 245-249.43.Cestelli V, Manfredi A, Sebastiani M, et al.Effect of treatment with iloprost with or without bosentan on nailfold videocapillaroscopic alterations in patients with systemic sclerosis.Mod Rheumatol.2017; 27(1): 110-114.44.Hachulla E, Clerson P, Airò P, et al.Value of systolic pulmonary arterial pressure as a prognostic factor of death in the systemic sclerosis EUSTAR population.Rheumatology.2015; 54(7): 1262-1269.45.Allanore Y, Borderie D, Meune C, et al.N-terminal pro-brain natriuretic peptide as a diagnostic marker of early pulmonary artery hypertension in patients with systemic sclerosis and effects of calcium-channel blockers.Arthritis Rheum.2003; 48(12): 3503-3508.46.Galiè N, Hoeper MM, Humbert M, et al.ESC Committee for Practice Guidelines (CPG) Guidelines for the diagnosis and treatment of pulmonary hypertension: the Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT).Eur Heart J. 2009; 30: 2493-2537. of