Abstract
Systemic sclerosis (SSc) is one of the most complex connective tissue diseases. Although the pathogenesis of SSc still remains elusive, it is generally accepted that initial vascular injury due to autoimmunity might result in the constitutive activation of fibroblasts and fibrosis. All of these three processes interact and affect one another resulting in a polymorphous spectrum of clinical and pathologic manifestations of SSc. The disease pleomorphism poses numerous difficulties in defining the ideal outcomes to be used in clinical trials. Despite significant progress over the past decades, the clinical management of patients with SSc remains a challenge. Novel therapies are currently being tested in the treatment of SSc and have the potential for modifying the disease process and improving the clinical outcomes. However, the evaluation of the studies is still difficult, due to either the small size of included patients or the different types and phases of the scleroderma disease under scrutiny.
Introduction
Systemic sclerosis (SSc) is a multifaceted systemic autoimmune disease. Its pathogenesis classically recognizes three different main mechanisms, that is, microvascular damage, autoimmunity-mediated inflammation and fibroblast activation, which may variably interact with each other in the various phases of the disease . The complex interrelationship among the three pathogenetic aspects of SSc results in a wide spectrum of clinical presentations, inducing various degrees of skin involvement, microvasculopathy and more or less severe involvement of different internal organs. The advances in the knowledge of the pathogenetic mechanisms and clinical aspects of the disease have allowed defining a more precise classification of different patient subsets.
On the basis of the extent of skin changes, patients are usually classified as limited cutaneous (lcSSc), and diffuse cutaneous (dcSSc) subsets . This classification is also justified by the fact that the two clinical subsets express distinct autoantibody profiles, and different patterns of skin and organ involvement, disease progression and outcome . Unfortunately, many SSc patients cannot fall within such a rigid classification, and the identification of new additional antibodies and biomarkers enriches the heterogeneity of clinical scleroderma pictures. Besides the variability of clinical presentation and evolution and autoantibody associations, the present knowledge of the disease pathogenetic mechanisms makes it evident that SSc cannot yet be considered a chronic disease with an indolent course. Like other rheumatic diseases, it has flare and remission phases. Keeping in mind these considerations, it appears evident that a comprehensive therapeutic strategy has to consider the particular clinical features of the single patient, as well as the underlying immunomediated inflammatory activity, microvascular abnormalities, and fibrotic changes that are operative in the skin and internal organs. Observational studies have demonstrated that in diffuse scleroderma, most of the pathological processes in the internal organs or systems (gastrointestinal, lung, heart and kidney) occur within the first 3 years since the disease onset . Consequently, the key issue that has to drive the therapeutic approach to SSc is that the prompt detection and treatment of any new pathological process may offer the opportunity to induce remission, by stopping or preventing disease progression, and thus minimize skin and organ damage. Once the fibrotic process has begun, it can independently progress through a self-perpetuating biological pathway. Thus, immunosuppression or anti-inflammatory drug intervention may be effective in the early stages of the disease, but ineffective once the disease has moved into the fibrotic phase. Moreover, in late-stage disease, an evolved fibrosis might remain quite stable and, therefore, not require any intervention . Hence, similar to other rheumatic diseases, an early diagnosis of SSc becomes an important tool to achieve a satisfying result in its management. Recently, different studies stated that Raynaud’s phenomenon (RP), in combination with puffy fingers, characteristic nailfold capillaroscopic changes and SSc-specific autoantibodies, must be taken into account for identifying patients with early SSc who are at risk of developing more severe clinical features .
Advances in the understanding of pathogenesis of the disorder, although not completely elucidated, have allowed identification of the cell types, mediators and pathways as potential targets for therapy. Hence, at the moment, the idea of a targeted therapy is not just a hypothesis but a fact, even in patients with SSc.
Treatment approach
According to the presently known pathogenetic mechanisms of SSc, the treatment approach should consider the three main pathological actors: vasculopathy, autoimmune-mediated inflammation and fibrosis. No single strategy is available for treating all patients with SSc, but a combination of different therapeutic modalities should be tailored in any single patient in relation to disease subtype, time of onset, progression and involved organ or system. The clinician behaviour should be absolutely addressed to correctly approach the dominant clinical aspects with the aim of preventing the disease progression and its possible severe complications.
Immunosuppression
A number of immunotherapies have been used in SSc on the assumption that an activated immune system may drive vascular disease, inflammation and fibrosis, causing progressive damage of internal organs. In the early stages of the disease, inflammatory mediators drive the fibroblast activation, whilst in later stages, once fibrosis has evolved; hence, the disease can progress independently, through paracrine and autocrine self-stimulatory loops, the use of immunosuppressive therapy is believed to be poorly useful in advanced fibrotic stages of the disease.
Different immunosuppressive agents have been used in SSc, showing varying degrees of efficacy.
Methotrexate
Two randomized controlled trials (RCTs) have shown some weak evidence of methotrexate (MTX) superiority over placebo in early dcSSc, namely when skin involvement, evaluated by modified Rodnan skin score (mRss), is considered . On the basis of these studies, and despite their not completely convincing results, MTX has been recommended by the European League Against Rheumatism (EULAR) expert panel as a potentially effective treatment for early skin disease . As many patients with SSc develop muscle or joint involvement, MTX may further be useful in the management of these features.
Cyclophosphamide
The efficacy and safety of cyclophosphamide (CYC) in the treatment of SSc-related interstitial lung disease was shown in two RCTs . Both studies demonstrated that CYC, administered orally or intravenously, improved some lung function tests (forced vital capacity and total lung capacity, but not lung diffusion capacity for carbon monoxide DLCO), dyspnoea score and quality of life. However, follow-up studies showed that the initial benefit decreased over time, suggesting a transient response, and/or the need for prolonged immunosuppression .
With regard to skin involvement, in the scleroderma lung study, a modest but significant improvement in mRss was observed in CYC-treated patients with dcSSc compared to controls . Another prospective open study further confirmed the role of low-dose intravenous CYC in the treatment of early diffuse SSc, as mRss and DLCO significantly improved at both 6 and 12 months .
Mycophenolate mofetil
Mycophenolate mofetil (MMF) is widely used in both treatment of lupus nephritis and the prevention of allograft rejection of solid transplants. The immunosuppressive effects are related to the anti-proliferative effect on B and T lymphocytes, related to the inhibition of the inosine 5’-monophosphate dehydrogenase type II, an enzyme involved in the synthesis of purines, and selectively expressed on activated T and B lymphocytes . Furthermore, MMF has been found to have a relevant effect on TGF-β signalling pathways that are known to be involved in mechanisms of fibroproliferative disorders, including SSc . At present, no RCTs are available for evaluation of MMF in the treatment of SSc. Data from observational studies are worth noting, both for skin and lung involvement . However, the heterogeneity of the observational studies, that is, prospective or retrospective, with variable number of patients included and different durations of treatment, where MMF was used as monotherapy, or in association with other immunosuppressive therapies, makes it difficult to clearly define the role of MMF in the treatment of SSc patients. Many studies reported a significant reduction in the mRss . Nevertheless, in the prospective study by Henrick et al. and in a retrospective analysis by Nihtyanova et al. , the change in mRss in patients with SSc treated with MMF was no different from that observed in patients treated with other immunosuppressive agents.
Most of the studies evaluating MMF in SSc-related interstitial lung disease showed an improvement, or at least stabilisation in terms of lung function and radiological features . A common limitation, however, is represented by the low number of patients included, and by the fact that many patients were previously or concomitantly treated with other immunosuppressive agents. The Scleroderma Lung Study II (SLS II), a randomized, double-blind study evaluating a long-term follow-up of MMF versus CYC in the treatment of SSc-related ILD is currently underway (clinicaltrialsgov/ct2/show/NCT00883129). More consistent results are expected from this study on the real effectiveness of MMF in SSc.
Biologic immunotherapies
Rituximab
B cell-related serological abnormalities such as autoantibody production, hypergammaglobulinaemia as well as B-cell infiltration within skin and lung tissue, have been largely demonstrated in both animal models of scleroderma and in patients with SSc . Furthermore, in a number of small open studies, rituximab (RTX), a chimeric monoclonal antibody, directed against CD20, an antigen expressed on B-lymphocytes, has been reported to be a promising new therapy for both SSc-related skin and lung involvement . Lafyatis et al. did not find such a beneficial effect on skin disease, and lung function of dcSSc patients treated with RTX, when compared to baseline findings, but described a complete depletion of B cell infiltrates in skin biopsies . Two prospective studies showed a significant improvement of skin score after RTX treatment, even in the long-term follow-up . Although limited by the low number of patients, and the lack of control arm, all these studies suggested that RTX may be effective in improving lung function and high-resolution computed tomography features in patients with ILD already present at enrolment time and in preventing the development of lung disease in patients without baseline lung involvement .
The largest study to assess the efficacy of RTX on skin and lung fibrosis included 63 patients with severe dcSSc, compared to 25 matched-control patients. After a single course of RTX, and a follow-up period of 6 months, mRss was significantly improved in the RTX group compared to control group, and the mean mRss was significantly reduced in the RTX-treated patients, with respect to baseline values. In addition, in patients with ILD at baseline, RTX treatment prevented the further decline of FVC significantly when compared with matched controls . All of these studies showed no serious adverse events in RTX-exposed patients, suggesting that RTX might be an effective and safe treatment for skin and lung manifestations of patients with SSc. Controlled prospective studies are certainly required for confirming the role of B-depleting therapy in the treatment of fibrosis in SSc.
Anti-tumour necrosis factor-α agents and other biologic immunotherapies
Biologic compounds targeting inflammatory cytokines and lymphocyte activation mediators have proved to be effective in other systemic rheumatic diseases. On the contrary, contradictory results have been obtained in SSc. Although in vitro and in vivo animal studies showed anti-fibrotic effects of anti-tumour necrosis factor alpha (TNF-α) inhibition , the clinical results, mainly from case series, are still debatable. A systematic review on biologic therapy for SSc, where data from observational studies were carefully analysed, suggested improvement in inflammatory arthritis with anti-TNF-α agents, such as etanercept and infliximab, whereas the effect on fibrosis remains unclear . On the basis of these uncertain data, most of the SSc experts do not recommend a routine use of TNF-α antagonists in SSc .
The autoimmune nature of SSc is further suggested by the role of activated T cells in this disorder. These cells have been demonstrated on SSc cutaneous lesions, and high levels of co-stimulation molecules have been detected in the sera of patients with active SSc . Abatacept, a recombinant CTLA4–Ig fusion protein that is able to selectively down-regulate T cell activation, represents a further attractive targeted immunotherapy for SSc. A recent observational study showed that abatacept is useful for treatment of refractory joint involvement in patients with SSc. No significant change was reported for skin or lung fibrosis.
Tocilizumab is a monoclonal antibody directed against the interleukin (IL)-6 receptor. IL-6 appears to be overexpressed in both skin and serum of patients with SSc . In addition, in vitro studies showed that IL-6 may induce collagen production by normal dermal fibroblasts and promote their differentiation into myofibroblasts . Furthermore, the contribution of IL-6 to dermal fibrosis, but also to lung fibrosis, has been demonstrated in murine models of scleroderma . The observational study by Elhai et al. showed that patients with SSc treated with tocilizumab, as well as patients treated with abatacept, had an improved outcome of SSc-related arthritis, with no effects on fibrosis. It is noticeable that this study was specifically designed to detect the effects of tocilizumab and abatacept on SSc-related joint features, and not on fibrotic changes as it is clearly shown by the inclusion and outcome evaluation criteria. Larger studies with a longer follow-up are ongoing to further determine the safety and effectiveness of these anti-cytokines on SSc.
Anti-fibrotic therapies
The main distinctive features of SSc are fibrotic changes in the skin and internal organs. Active inflammatory and autoimmune processes usually induce myofibroblast activation and the abnormal deposition of extra-cellular matrix in the organs and systems involved. Therefore, it is commonly believed that anti-inflammatory and immunosuppressive agents, when administered in early phases of the disease, have potential effects on the development fibrosis. Nevertheless, later fibrotic disease might not respond to immunosuppressive therapy alone, as once fibrosis has been established, it can progress independently through different self-sustaining pathways . In the last years, the advances in the knowledge of the cellular and molecular mechanisms that lead to fibrotic changes in SSc have opened up new possibilities for developing new pure anti-fibrotic agents.
Anti-TGF-β agents
TGF-β is a multifunctional cytokine that regulates the growth, differentiation and function of various cell types. Specifically, with regard to fibrosis, TGF-β stimulates fibroblasts to produce extracellular matrix proteins. TGF-β has been shown to induce myofibroblast differentiation and to increase expression of collagen type I, III, VI, VII and X . Skin and lung involved in the scleroderma fibrotic process have been characterized by upregulation of TGF-β-associated genes with the consequent overexpression of this cytokine . In addition, inhibition of TGF-β signalling is able to abrogate fibrosis in animal models . All of these data suggest that suppression of TGF-β signal could be an effective anti-fibrotic therapy. However, an initial Phase I/II randomized placebo-controlled study evaluating CAT-192, a recombinant TGF-β-neutralizing antibody, failed to provide any clinical benefit . These negative results could be explained by the incomplete block of all the isoforms of the cytokine by CAT-192. Therefore, the good potentiality of neutralizing TGF-β pro-fibrotic activity has been demonstrated by Rice et al. in a pilot study where fresolimumab, a human IgG4 κ monoclonal antibody, was capable of neutralizing all isoforms of TGF-β, and inducing a rapid inhibition of TGF-β-regulated gene expression in patient skin with a parallel decline in dermal myofibroblast infiltration. These findings seem to support the pivotal role of TGF-β in SSc pathogenesis as patients treated with fresolimumab showed a rapid, significant decrease in mRss, and a closely related consistent and rapid decline of the skin biomarkers of TGF-β activity .
Anti-tyrosine kinases
Platelet-derived growth factor (PDGF) and TGF-β are pivotal mediators in the pathogenesis of scleroderma fibrosis . They are produced by activated fibroblasts as a response to signals mediated by tyrosine kinase receptors. Therefore, the inhibition of tyrosine kinase activity could be an important target for SSc therapy. Imatinib mesylate is a tyrosine kinase inhibitor that binds to c-Abl and PDGF receptors, blocking their tyrosine kinase activity. In different experimental studies, imatinib has been shown to be effective in preventing TGF-β-induced gene expression in extracellular matrix, as well as transformation and proliferation of fibroblasts . These promising pre-clinical studies on the potential efficacy of imatinib use in SSc have not been completely confirmed by clinical trials. The first open-label studies showed statistically significant improvement in skin sclerosis and lung function . By contrast, no benefit for skin or lung was observed in following placebo-controlled trials . Furthermore, in all of these studies, an important rate of adverse events was reported, with fluid retention and gastrointestinal disturbances, requiring dose adjustment or interruption. In two recent studies, instead, it has been demonstrated that low-dose imatinib is safe and well tolerated in the long term, and that imatinib is able to stabilize lung function in SSc patients with ILD refractory to CYC, while it is not effective in skin involvement .
Nilotinib is a second-generation tyrosine kinase inhibitor with antagonistic activity against both c-Abl and PDGFR. When compared to imatinib, it is more potent against c-Abl and less potent against PDGFR . In an open-label pilot trial on patients with early dcSSc, nilotinib was well tolerated and induced a significant mRss improvement. Interestingly, responders to this treatment were characterized by having high expression of genes associated with TGFBR/PDGFRB expression at the time of study inclusion, with a significant decrease in this signalling pathway after treatment .
Cellular therapies
Autologous stem cell transplantation
Over the last decades, haematopoietic stem cell transplantation (HSCT) has emerged as a possible therapeutic option for patients with rapidly progressive SSc. HSCT is used as a form of high-dose immunosuppression, with haemopoietic stem cell rescue employed as a safe way of delivering chemotherapy. In fact, it is hypothesized that its clinical effectiveness apparently depends on its immunoablative effects on the T-cell compartment, followed by the generation of a new tolerant immune repertoire from the re-infused stem cells.
Several small pilot studies were published on the use of HSCT in scleroderma, and they all showed improvement in skin thickness scores, functional ability and stabilization of internal organ function . The results achieved in phase I–II studies formed the basis for three prospective randomized autologous HSCT trials. The results of two of these studies have been published , while the third (scleroderma cyclophosphamide vs. transplantation SCOT) is still ongoing. The ASSIST trial confirmed that HSCT results in a significant improvement in skin score, pulmonary function and quality of life, when compared to intravenous pulse cyclophosphamide.63 Eight out of nine control patients showed constant disease progression, as opposed to none of the patients treated with HSCT. Hence, it was decided to switch seven of the control patients to HSCT, which proved beneficial. The improvement in skin and lung parameters persisted in 11 HSCT patients, after a 2-year follow-up. Remarkably, no deaths were recorded in the trial, which may be explained by the small sample size, the relatively short follow-up or the inclusion of patients with relatively mild disease.
The second randomised trial, Autologous Stem Cell Transplantation International Scleroderma (ASTIS), was more recently published . This study was aimed at comparing HSCT to monthly intravenous cyclophosphamide, as for safety and efficacy. Patients in the HSCT arm showed significant improvement in long-term event-free survival, mRss, lung function (vital capacity), functional ability and quality of life at 2 years. However, a higher treatment-related mortality in the HSCT was reported within the first year and in the smokers included in the study. A drastic lowering of mortality, as a direct consequence of AHSCT, was described by Burt et al. and attributed to a more accurate selection of candidate patients, and, in particular, to a closer attention to pre-transplantation lung and cardiac conditions . Thus, a more accurate cardiac assessment before addressing a patient to AHSCT is certainly needed. Right catheterization with fluid challenge and cardiac magnetic resonance evaluation are the diagnostic tools proposed for that purpose .
Further studies are warranted to determine the position of HSCT among the therapeutic options of SSc and to optimize patient selection.
Mesenchymal stem cells
In the last decade, the knowledge of mesenchymal stem cells (MSCs) has evolved rapidly . Their immunomodulatory properties, their paracrine interactions with specific cell types in damaged tissues, and promising results in some clinical applications have made these cells an attractive option for the treatment of certain diseases, including severe life-threatening autoimmune diseases .
The initial simplistic concept of MSCs trans-differentiating into different healthy functional cells has been replaced by the concept that MSCs, derived from bone marrow and other sites, play a vital role in the injured tissues during tissue repair. Under the stimulation of different inflammatory cytokines at the damaged tissue sites, the MSCs are induced to down-regulate immune responses, by releasing high levels of chemokines, immune inhibitory factors and growth factors. These growth factors in turn orchestrate endothelial cells, fibroblasts as well as local stem cells to promote tissue regeneration and repair by enhancing angiogenesis, thus inhibiting leukocyte transmigration and eliciting intrinsic progenitor cell/stem cell differentiation . The immunosuppressive activity of MSCs was initially observed when MSCs were added to cultures of activated immune cells . However, MSCs are not constitutively inhibitory. They acquire their immunosuppressive functions after being exposed to a right inflammatory environment. By contrast, when this inflammatory background is insufficient, MSCs are induced to produce different chemokines and tropic factors, but are unable to produce enough immune inhibitory mediators . Thus, to use MSCs in the treatment of autoimmune diseases, it is important to identify the optimal subset of patients to be treated, with the right ‘inflammatory background’ for successful MSC therapy. In particular, in the field of scleroderma, patients with long-lasting fibrosis cannot be considered the best choice candidates.
Another important issue is to decide the optimal source of MSCs for this kind of procedure. As in autoimmune patients, in contrast to haematological conditions, the possibility of a good response to alloantigens is preserved, the use of autologous MSCs should be preferred.
Another important question is whether MSCs from patients with autoimmune diseases maintain their ability to exert a beneficial activity. With regard to SSc, different studies suggest that MSCs from bone marrow are defective for some functions, although the immunosuppressive properties seem to be preserved . In addition, the experience of using MSCs in pre-clinical studies has been encouraging , and further optimistic data have been derived from small clinical studies in patients with SSc. The first observation of a patient with SSc treated with an intravenous injection of allogenic MSCs showed a significant decrease in the number of digital ulcers, associated with an improvement of blood flow to the hands and a decrease of mRss. The same authors treated four additional SSc patients with allogeneic MSCs, showing the same trend toward vascular and skin amelioration . Further studies are necessary to clarify the therapeutic potential of MSCs in SSc, as well as in other autoimmune diseases.
Other cellular therapies
Emerging evidence suggests that bone marrow-derived endothelial, haematopoietic stem and progenitor cells contribute to tissue vascularization during both embryonic and postnatal physiological processes. Recent preclinical and pioneering clinical studies have shown that the introduction of bone marrow (BM)-derived endothelial and hematopoietic progenitors can restore tissue vascularization after ischemic events owing to the multiple angiogenetic factors produced by BM–MSC secretome and to their capacity – as pluripotent cells – to differentiate themselves into endothelial cells or into other cell types . Moreover, BM–MSCs have also been employed with different modalities for the treatment of peripheral ischemic lesions in the course of SSc .
Adipose-derived stromal/stem cells (ASCs) are considered to be an attractive alternative as pluripotent cells with characteristics similar to BM–MSCs. Compared with these latter cells, ASCs offer several advantages, including ease of isolation, less donor morbidity, relative abundance and rapidity of expansion. Preliminary attempts with ASC therapy have been made to induce healing of ulcers developed in peripheral vascular diseases of some animal models and human disorders . In a recent study conducted by our group , long lasting and poorly responsive to traditional therapy, SSc-related digital ulcers (DUs) were treated by local implantation of autologous adipose-tissue derived cells (ATDCs). Time to healing after the procedure was the primary end point of the study. A rather fast healing of the digital ulcers was reached in all of the enrolled patients. Furthermore, this grafting procedure was demonstrated to induce a significant increase in local vascularization. Similar results were reported in another open study involving patients with SSc . In this study, autologous ADTC grafting was found to be safe and effective in improving hand disability and fibrosis. In addition, a significant improvement in RP severity was also observed, together with a significant reduction in avascular areas and dystrophic capillaries in the nailfold capillaroscopy examination. Even with the limitations related to the small number of patients included and to the open-label design of these studies, the observed strongly favourable outcome suggests that local grafting with ATDCs could represent a promising option for local treatment of SSc-related microvascular changes and DUs unresponsive to more consolidated therapies.
Vascular disease
Peripheral vasculopathy
The impairment of microvascular system plays a key role in the early pathogenesis of SSc and in some of its later complications . RP is the most common manifestation of SSc, occurring in >95% of patients and is often the earliest manifestation of disease . In SSc, RP results from both functional and structural abnormalities of the digital arteries, arterioles and capillaries . Patients with RP who develop scleroderma exhibit unique changes in vascular structure, characterized by intimal thickening causing progressive vessel lumen occlusion, with ischaemic injury and chronic tissue hypoxia. Skin hypoxia has been documented in SSc patients and is recognized as a potent stimulus for growth factors that mediate tissue fibrosis .
The advanced structural alterations of microvascular habitat can lead to DUs. Their development is a frequent and early complication in SSc. DUs have been reported in 35–60% of SSc patients and 66% of patients experience more than one episode despite RP treatments . DUs cause a deterioration of the patient’s quality of life, which arises from severe pain and disability that accompanies their formation, long-lasting processes of healing and their possible complications that include osteomyelitis, gangrene and amputation.
Multiple pharmacologic agents have been investigated in several trials with regard to the treatment of RP and DUs, but, at present, no specific therapy that may reverse vascular injury or direct normal vascular repair has been identified. Furthermore, it is very difficult to find out a scheme of therapy in the peripheral vasculopathy, as many trials were aimed at evaluating RP and DU outcome was secondary or exploratory, in terms of both healing and prevention.
Calcium channel blockers (CCBs) mediate peripheral vessel dilatation, by acting on smooth muscular cells and also inhibition of platelet activation. A meta-analysis by Thompson et al. demonstrated a moderate reduction in frequency and severity of attacks in patients with SSc treated with CCBs . The EULAR Scleroderma Trial and Research recommendations suggest CCBs, and more specifically oral nifedipine of 10–60 mg a day, as first-line therapy for RP in SSc . When CCBs have failed, they recommend intravenous (IV) iloprost (0.5–2 ng/kg/min for 5 days) that has a long-lasting vasodilatation effect added to inhibition of platelet aggregation . Several single trials have been conducted on RP in SSc, which explored multiple different therapeutic options as ACE inhibitors, alpha-adrenergic blockers, topical nitric oxide (NO), N-acetylcysteine, vitamin E gel, but their place in the therapeutic armamentarium for RP remains to be established .
Several trials have investigated the effects of pharmacologic agents on healing and preventing DUs in SSc, although often these trials were addressed to RP evaluation as primary outcome. Only one study comparing nifedipine to placebo found no statistically significant difference in the prevention of new DUs . EULAR guidelines indicate IV iloprost as effective in DUs healing . However, a following meta-analysis of different studies regarding this issue, where the effect of different prostacyclin analogues was analysed, did not show any statistically significant difference in DU healing or improvement, but only demonstrated a significant effect in preventing new DUs using IV Iloprost .
Endothelin-1 (ET-1) is a peptide having a role in promoting both vascular injury and the fibrotic process in SSc . In placebo-controlled trials, Bosentan, an endothelin receptor antagonist, reduced the number of new DUs in SSc patients, especially if there was a baseline DU at trial entry, but had no effect on ulcer healing . A recent prospective pilot study, lasting 24 weeks and involving 20 patients with SSc, suggested that another endothelin receptor antagonist (ERA), ambrisentan (5 mg once a day), promotes the healing of the existing DUs, but it was not able to prevent the development of new ones .
Sildenafil and other phosphodiesterase type V (PDE V) inhibitors (PDE5is) are attractive candidates for therapy in vasculopathy related to SSc. They trigger the nitric oxide-mediated vasodilatation enhancing the nitric oxide–cGMP pathway, promoting vascular smooth muscle relaxation and consequently improving local blood flow. In addition, PDE5is have shown angiogenic properties and the ability to decrease platelet aggregation. Considering these findings, it is not surprising that the PDE5is have emerged as an effective treatment in RP. Furthermore, three interesting studies were carried out to verify the efficacy of PDE5is on DU improvement and healing. Two studies analysed sildenafil, the first was a cross-over RCT assessing the treatment at 50 mg twice a day versus placebo , the second was an uncontrolled pilot study assessing an increasing dose until the maximum tolerated . Another cross-over RCT analysed tadalafil versus placebo . Although the three trials were individually underpowered to detect a statistically significant benefit, the pooled effect showed a definite benefit of PDE5is on both healing and improvement of DUs. Recently, Hachulla et al. published results from a randomized, placebo-controlled trial conducted to evaluate the efficacy of sildenafil (20 mg thrice daily) on healing of ischaemic DUs in patients with SSc. Although the primary end point evaluating the time to DU healing was not reached, a significantly higher healing rate was observed in patients treated with sildenafil together with a significantly lower incidence of new DUs and a quicker healing of new DUs occurring during the study period . These results strongly suggest that sildenafil could be of interest in patients with SSc suffering from DUs.
There is increasing evidence that statins, developed as lipid-lowering drugs, yield profound benefits beyond their lipid-lowering effects. Statins inhibit cholesterol synthesis, but they also suppress the synthesis of other lipid intermediates, resulting in protection of the endothelium through improvement in endothelial function, mobilization of endothelial precursors, suppression of the inflammatory response and inhibition of fibrosis. These so-called ‘pleiotropic’ effects suggest that statins may be beneficial for treating vasculopathy in SSc. Different studies confirmed the potential benefit of statin therapy on vascular disease of SSc by reducing endothelial activation and inducing vasculogenesis , with significant improvement in the ratings of RP . Abou-Raya et al. published the first randomized, double-blind, placebo-controlled clinical trial evaluating the effect of atorvastatin on vascular manifestations of SSc. They observed significant reductions in the overall number of DUs and in the mean number of new DUs per patient in the statin group. In addition, statin-treated patients experienced significant improvements in disability scores and functional status .
Table 1 provides the most important results about efficacy of the cited drugs in the treatment of DUs.
| Class of drug | Treatment | Study design | Outcomes | Ref. | ||
|---|---|---|---|---|---|---|
| Improvement DU | Healing DU | Prevention DU | ||||
| ERAs | Bosentan (62.5 mg bid for 1 m, then 125 mg bid) | 2 RCTs vs. placebo: RAPIDS1 ( N = 122, 16 w f/up) RAPIDS 2 ( N = 188, 24w f/up) | No efficacy | No efficacy | Significant efficacy | |
| Ambrisentan (5 mg/day) | prospective pilot study ( N = 20, 24w f/up) | NA | Efficacy | No efficacy | ||
| PDE5is | Sildenafil (50 mg bid) | Cross-over RCT vs. placebo ( N = 16, 4w f/up) | Efficacy | Efficacy | Efficacy | |
| Sildenafil (maximum dose tolerated) | Open pilot study ( N = 19, 6 m f/up) | NA | Efficacy | No efficacy | ||
| Tadalafil (20 mg alternate days) | Cross-over RCT vs. placebo ( N = 24, 6w f/up) | NA | Efficacy | Efficacy | ||
| Sildenafil 20 mg tid) | RCT vs. placebo SEDUCE ( N = 83, 12 w f/up) | NA | Efficacy | Efficacy | ||
| Statins | Atorvastatin (40 mg/day) | RCT vs. placebo ( N = 84, 4 m f/up) | NA | No efficay | Significant efficacy | |
Pulmonary hypertension
Pulmonary arterial hypertension (PAH) is a severe, life-threatening vascular manifestation in patients with SSc. A recent meta-analysis calculated a prevalence of PAH in patients with SSc around 9% . Despite increasing recognition and the use of novel therapies, survival in PAH related to SSc remains poor . Hence, all patients with SSc should be screened for PAH. Khanna et al. recently published detailed recommendations for early screening and detection of PAH in SSc .
Current specific therapies for PAH target three different pathways known to be mainly involved in the pathogenesis of PAH . They are endothelin-1, nitric oxide (NO) and prostacyclin pathways. According to the 2015 European Society of Cardiology (ESC)/European Respiratory Society (ERS) guidelines for the diagnosis and treatment of pulmonary hypertension that have been recently revised , the same pharmacologic agents and the same algorithm are recommended for the treatment of idiopathic PAH (IPAH) and connective tissue disease (CTD)-PAH . The most important novelty comes with the recommendation that even low/intermediate-risk patients should be offered upfront combination therapy that in previously published guidelines was reserved to patients classified as at high risk. This statement is directly derived from the concept that early diagnosis and aggressive treatment are imperative steps to improve outcome in patients with PAH.
Focusing on patients with SSc-related PAH, it is important to highlight that survival appears worse to that observed in IPAH . In addition, at present, it is still not clear whether the introduction of PAH-specific therapies has improved the survival in patients with SSc . In reality, several subgroup analyses of patients with SSc-related PAH enrolled in published RCTs suggest a less marked response to PAH therapy. A meta-analysis by Avouac J et al. , evaluating the effects of ERAs and 5PDEis in controlled trials with patients with CTD-related PAH, showed the absence of clinically relevant improvement on exercise capacity in this subgroup of patients after 12–18 weeks of treatment.
Another recent meta-analysis by Kuwana et al. showed similar trends. The mean improvement in exercise tolerance was lower in patients with CTD-related PAH treated with ERAs (bosentan and ambrisentan) in comparison with patients with IPAH receiving the same therapy. Furthermore, no difference in exercise capacity was found between patient groups for PDE-5 inhibitors and PGI2 analogues . These negative results may be partly due to the fact that the reliability of the 6-min walking distance (6MWD), which is the main outcome test used for measuring exercise performance in the majority of RCTs, may be strongly limited by higher age and musculoskeletal problems present in patients with SSc. Another possible independent factor influencing the results of the 6MWD could be the complexity of SSc-related features and namely the possible coexistence of ILD and cardiac involvement.
Additional data on the possible different effectiveness between the various agents utilized in the treatment of SSc-related PAH have been recently provided by a retrospective cohort study based on data from the PHAROS registry (the Pulmonary Hypertension Assessment and Recognition of Outcomes) . Patients with SSc from multiple centres of North America were recorded in this registry. The time to clinical worsening after different initial oral PAH therapy was analysed in 98 patients with similar baseline features. This specific parameter appeared to be significantly worse in patients initially treated with ERA compared to those who were administered PDE5is or the combination of ERA plus PDE5is, even after adjustment for prognostic factors. Further studies are certainly required to clarify the clinical and therapeutic implications of these findings.
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Corrigendum to “Risk of infection with biologic antirheumatic therapies in patients with rheumatoid arthritis” [Best Pract Res Clin Rheumatol 29 (2) (2015) 290–305]
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