1,980
Views
4
CrossRef citations to date
0
Altmetric
Reviews

Immunotherapy of systemic sclerosis

, , &
Pages 2559-2567 | Received 04 May 2018, Accepted 18 Jun 2018, Published online: 16 Jul 2018

ABSTRACT

Systemic sclerosis (SSc) is a chronic systemic disease characterized by microvasculopathy, immune activation, and extensive collagen deposition. Microvasculopathy and immune activation occur very early in the disease process. Evidence from animal models and in vitro studies indicate that T-cells and B-cells activate fibroblasts to produce collagen. Traditional immunosuppressants, cyclophosphamide(CyP), methotrexate(MTX), and more recently mycophenolate mofetil(MMF), may prove more effective if used very early in the disease course. These drugs showed some benefit in skin (MTX, CyP, MMF) and lung function (CyP, MMF). Biologicals, such as intravenous immunoglobulin (IVIg), belimumab(Beli), tocilizumab(TCZ), abatacept(Aba), rituximab(RTX) and fresolimumab(Fresu) appear promising as they exhibited some benefit in skin (IVIg, Beli, TCZ, Aba, RTX, Fresu), hand function (IVIg), and joints (IVIg, TCZ, Aba). Autologous stem cell transplantation showed the best therapeutic efficacy on skin and internal organs, and looks very promising, as modification of transplantation immunosuppression is decreasing the early high mortality.

This article is part of the following collections:
Immunotherapy of Autoimmune Diseases

Introduction

Systemic sclerosis (SSc) is a chronic connective tissue disease (CTD), which affects skin, blood vessels, lungs, heart, kidneys, gastrointestinal (GI) tract and musculoskeletal system. It is characterized by three cardinal features: early microvascular obliterative changes, activation of the immune system and widespread fibrosis of skin and internal organs. Involvement of internal organs results in significant morbidity and mortality. Microvascular changes are exemplified by Raynaud's phenomenon (RP) and microvascular injury seen as nailfold capillaroscopy abnormalities, whereas immune activation is exemplified by SSc-related autoantibodies (auto-Abs).Citation1Citation3

Systemic sclerosis affects all races and may be diagnosed at any age although most cases develop in individuals aged 20–60 years. As data continue to gather from around the world, it is shown that while the incidence of SSc exhibit remarkable variation across different geographic regions (ranging 2–23 cases per million), it appears to rise over the past three decades. Prevalence is also documented to span between 46–655 cases per million among different centers.Citation4,Citation5 Female predominance is evident among cases with limited SSc, while diffuse SSc appear to affect males and females at more comparable rates.Citation2Citation6 SSc is considered to be a chronic, gradually deteriorating disease across several months to years. Some cases can stabilize for prolonged periods of time while others, primarily with diffuse disease, show a fulminate clinical course with detrimental consequences within few months. Mortality as well morbidity among patients with scleroderma is increased. Ten-year cumulative survival rate was found 66% during the 1990s.Citation7 Major morbidity is related to the type and extent of internal organ involvement, such as pulmonary fibrosis and/or pulmonary hypertension that often lead to severe dyspnoea and oxygen dependence.Citation6 GI tract involvement includes both the upper (common) and the lower part (less common); it may also be quite severe leading to malnutrition and death.Citation8 Infections also play significant role for the increased morbidity and mortality of patients with SSc. Propensity to infections is derived from both poor functional status and immunosuppressive treatment. Hand dysfunction due to tight skin, joint contractures and ulceration of the fingertips represent a common disabling factor among patients with SSc, which also leads to significant morbidity due to pain, frequent injuries, gangrene secondary to ischemia and self-amputations.Citation6 In overall diffuse skin disease, male gender, older age at onset, cardiopulmonary involvement, renal crisis and the absence of Raynaud's phenomenon as the initiating clinical symptom represent bad prognostic factors.Citation9,Citation10

Vascular abnormalities and immune abnormalities appear early in the disease course and are likely to drive the pathogenetic cascade of the disease. SSc-related auto-Abs, such as anti-topoisomerase I (anti-Topo; formerly anti-Scl70), anti-centromere (ACA), and anti-RNA polymerase III auto-Abs, appear before, and sometimes years before clinical fibrosis.Citation2 Longitudinal skin biopsies from patients with SSc reveal inflammatory infiltrates early before histological fibrosis, but as the disease progresses inflammatory infiltrates greatly diminish and fibrosis dominates the histological picture.Citation11 Pro-fibrotic cytokines, such as transforming growth factor (TGF)β, are considered pivotal for the disease pathogenesis. Evidence from animal models and in vitro studies indicates that T cells through cell contact, and cytokines activate fibroblast to produce collagen.Citation3,Citation12 Increased levels of T cell cytokines, including the pro-fibrotic IL-4 and IL-13 (Th2 cells), are seen in peripheral blood from SSc patients.Citation13,Citation14 Although aberrations in the expression of individual cytokines may be shared among several different diseases, it is obviously the fine combination of several abnormalities that lead to systemic collagen disposition, a feature unique to SSc among other systemic autoimmune diseases underscoring the complexity of the cellular controls operating in enhancing or suppressing the profibrotic response.Citation15,Citation16 Mononuclear cell infiltrates, consisting mainly of T cells and macrophages, appear very early in the disease process.Citation17 B cells are hyperactivated in SSc, as indicated by the overexpression of the stimulatory CD19 receptor and impairment of the inhibitory CD22 receptor.Citation18 B cells contribute to disease pathogenesis by activating B cells via cell contact, cytokines and autoantibodies.Citation17,Citation18 Some SSc-associated autoantibodies, such as anti-platelet-derived growth factor receptor antibodies, and anti-angiotensin II type 1 receptor (AT1R) antibodies, are agonistic antibodies and can cause collagen production and vasoconstriction, respectively.Citation18Citation20 B cells also can act as antigen-presenting cells to T cells and induce dendritic maturation that promotes profibrotic Th2 response.Citation18 B cells through cell contact activate fibroblasts isolated from SSc patients to produce collagen and profibrotic growth factors IL-6, and TGFβ1.Citation21

It is thus essential to target immune abnormalities early before fibrosis and organ failure develops, where available treatments are largely ineffective. New classification criteria for SSc have been recently developed, that could help diagnose SSc early, and facilitate early recognition of SSc and offer opportunities for early therapeutic intervention.Citation22,Citation23

Immunotherapy includes general immunosuppression and therapies targeting specific molecules involved in T cell and B cell survival and function (targeted therapies). Data on targeted therapies, such as biologics in the treatment of patients with SSc are emerging. However, the new classification criteria of SSc will help to further explore the efficacy of timely intervention with “traditional” treatments. This review summarizes currently available immunotherapeutic agents for SSc.

Immunotherapies

General immunosuppression

  1. Cyclophosphamide. Cyclophosphamide (CyP) is an alkylating and cytotoxic immunosuppressive agent, and, therefore, a general immunosuppressive drug. CyP represents the most widely used and studied therapy for SSc-associated interstitial lung disease (SSc-ILD). CyP can be administered either orally on a daily basis or by intravenous infusions every two to four weeks for several months. Numerous uncontrolled studies and two randomized controlled trials (SLS I and FAST)Citation24,Citation25 showed some efficacy of CyP in SSc-ILD.Citation26 In early diffuse SSc, a prospective trial (ESOS – European Scleroderma Observational Study) included 326 patients from 50 centers (19 countries) and clinicians selected the therapeutic protocol of their choice. The observational period was 24 months. Sixty-five patients received methotrexate, 118 MMF, 87 CyP and 56 no immunosuppressant treatment. CyP was inferior to methotrexate in skin improvement, but it had the best results in Forced Vital Capacity (FVC), especially in those with pulmonary fibrosis in High-Resolution (HR)CT (MTX -2, MMF 3.2, CyP 7.4).Citation27 In an effort to further characterize which patients would benefit from CyP administration, plasmin-α2-plasmin inhibitor complex (PIC) – a potential biomarker of SSc vasculopathy – was measured in the serum of patients with SSc-ILD. Increased levels of PIC were correlated with active lung disease and higher efficacy of CyP.Citation28 CyP is usually given for a maximum of 6 months followed by milder forms of immunosuppression, such as methotrexate or azathioprine. Adverse effects of CyP include nausea and vomiting, bone marrow suppression, increased risk of infections, haemorrhagic cystitis, and bladder cancer.

  2. Methotrexate. Methotrexate (MTX) inhibits dihydrofolate reductase, an enzyme required for DNA synthesis. It also causes extracellular release of adenosine that exerts immunomodulating effects. Two small, randomized, controlled studies of early SSc, and their re-analysis, showed that MTX, used in a relatively low dose (1015mg/w), improved skin score and hand function.Citation29Citation31 Higher doses of MTX (2025mg/w), which are generally a standard, first choice of therapy for rheumatoid arthritis, have been used in a prospective, observational cohort study, which showed statistical significant reduction in mRSS at 12 months compared to placebo.Citation27 Adverse effects of MTX include bone marrow suppression, gastrointestinal upset, hair loss, and liver fibrosis. Lung injury is also a concern, especially in patients with lung fibrosis.Citation32

  3. Azathioprine. Azathioprine (AZA) is a purine analog that inhibits DNA synthesis. AZA has been used as maintenance therapy in SSc-ILD after initial therapy with CyP.Citation25 In a randomized, open-label trial of oral AZA (2.5 mg/Kg/day) versus oral CyP in early diffuse cutaneous SSc, AZA showed no efficacy on skin thickness and pulmonary function,Citation33 whereas a retrospective study reported effectiveness of AZA in stabilizing lung function and improvement of mRSS.Citation34 Adverse effects of AZA include bone marrow suppression, hepatotoxicity and gastrointestinal upset.

  4. Mycophenolate Mofetil. Mycophenolate mofetil (MMF) is an inactive prodrug of mycophenolic acid that inhibits inosine monophosphate dehydrogenase and, therefore, the proliferation of both T cells and B cells. Several retrospective or openlabel prospective studies in SSc and SSc-ILD have shown that MMF improved skin score and stabilized pulmonary function.Citation35Citation37 More importantly, it improved a 5-year survival. Recently a randomized, double-blind, parallel group trial that compared 2 years of oral MMF (target dose 3gr/day) to oral CYP (2 mg/kg/day) for 1 year followed by placebo was conducted.Citation38 Even though this study failed to meet its primary-end point of MMF superiority on lung function over CYP at 24months, an improvement of FVC, comparable to CYP, was clearly observed.Citation38,Citation39 In the same study, MMF treatment (as well as CYP) improved skin score.Citation38,Citation40 MMF is well tolerated and associated with less toxicity than CYP.Citation38 Adverse effects of MMF include bone marrow suppression and increased risk of infections.

  5. Autologous Stem Cell Transplantation. The process of haematopoietic stem cell transplantation (HSCT) eliminates autoreactive T cells and B cells. In autologous HSCT, haematopoietic stem cells (HSCs) are collected from a patient, who then receives strong immunosuppression, including CyP, to destroy immunocytes.

Finally, the patient receives his/her own HSCs to repopulate his/her bone marrow. In SSc patients, HSCT reverses the Th2 cell profile, producing the profibrotic IL-4 and IL-13, into Th1 cell profile, producing the anti-fibrotic interferon [IFN]γ. This turnaround is estimated to last at least 3 years and is associated with substantial skin improvement.Citation41 Because high-dose myeloablative regimen was associated with high frequency of early mortality with no superior efficacy compared to nonmyeloablative HSCT,Citation42 less intense non-myeloablative regimen is recommended. In non-randomized studies, autologous HSCT showed substantial efficacy in up to 90% of patients improving skin score and histological fibrosis and stabilizing the internal organ function up to 7 years after the transplantation.Citation43,Citation44 It may also regenerate capillaries and improve microcirculation, as seen in nailfold capillaroscopy and histochemistry.Citation45,Citation46 In an open-label randomized trial, autologous non-ablative HSCT was superior to monthly pulse CyP, improving skin score and lung function that persisted for up to 2 years.Citation47 Similar results were shown in a more recent multicentre RCT that included 156 patients.Citation48,Citation49 A randomized trial in patients with severe scleroderma compared myeloablative HSCT to CyP, showed long term benefits in the transplantation group. These patients had better event-free and overall survival rates, observed after 2 years, at a cost of increased mortality.Citation50 Adverse effects include early mortality, increased risk of infections, and the development of new (secondary) autoimmune diseases, such as myasthenia gravis. Secondary autoimmune diseases occur in about 3.9% of HSCT cases. Therefore, ASCT should be reserved for carefully selected patients, as patients with rapidly progressing disease.

In current use of general immunosuppressive agents in the treatment of patients with SSc is presented.

Table 1. General Immunosuppressive drugs used in the treatment of systemic sclerosis.

Treatment with immunosuppressants should be introduced early in SSc. Up to few years back, treatment of SSc has been applied to patients fulfilling the 1980 ACR classification criteria for SSc,Citation51 which are based on clinical features that are the sequel of the disease. These criteria included one major criterion (scleroderma proximal to MCP and/or MTP joints) and three minor criteria (sclerodactyly, digital ulcers, bibasilar pulmonary fibrosis). However, by that time, a patient has excess collagen and other extracellular matrix deposition in the skin and internal organs. At this stage of the disease, treatment is largely ineffective. The new EULAR/ACR 201322 criteria help early diagnosis of SSc, before the development of fibrosis in internal organs that allow the introduction of immunosuppressive medications. According to these criteria, a patient with Raynaud, SSc-related autoAbs [antitopoisomerase I (Scl70), anti-centromere autoAb, anti-RNA polymerase III], abnormal nailfold capillaries and puffy hands would have SSc. However, studies report preclinical internal organ involvement in pre-scleroderma patients. In a cohort of patients with very early diagnosis of SSc (VEDOSS) (RP, puffy fingers, ANA plus typical capillaroscopy abnormalities and/or SSc-associated autoantibodies) and a mean duration of disease 7.1 years, pulmonary disease (fibrosis or ground glass opacities on high resolution CT scan or DLCO<80% predicted) and/or lower oesophageal sphincter dysfunction was present in the majority of patients.Citation52 There seems to be a window of opportunity for effective therapy for SSc, and this appears to be confined to pre-scleroderma stage of the disease which in our view is the inflammatory phase of the disease, whilst the later phases, healing predominates with collagen matrix laying. Currently, immunosuppressants are prescribed according to disease manifestations, namely mild immunosuppressants for mild manifestations and strong immunosuppressants for life/organ threatening manifestations. If there was a biomarker with high predictive value for internal organ manifestations in SSc, then even strong immunosuppression might be justified early. However, it is time to consider and prescribe mild immunosuppression in RP patients with typical nailfold capillaroscopy changes and autoAbs in a well-monitored environment.Citation23

Targeted therapies

B1. Biological therapies

  1. Intravenous immunoglobulin. Intravenous immunoglobulin (IVIg) is a human polyspecific IgG (presented as monomeric or multimeric forms) and derives from the plasma of thousands healthy individuals (3,000-80,000).Citation53 IVIg has been increasingly used during the last decades for an growing number of systemic immune-mediated and heterogeneous inflammatory diseases The mechanism of high-dose IVIg remains unclear, but probably works in multiple fronts, such as blocking the binding of serum immunoglobulins, B cell surface immunoglobulins, and T cell antigen receptors to their respective antigens.Citation54 IVIg reduced skin fibrosis and inhibited IL-4 and TGF-β production in tight skin (TSK) mice.Citation55 In two small open-label studies in patients with SSc, IVIg reduced histological skin fibrosis and joint pain and improved hand function.Citation56,Citation57 A recent double-blind multi-center RCT in 63 patients with diffuse cutaneous SSc (dcSSc) concluded that IVIg improved skin score especially after multiple courses.Citation58 Serious adverse reactions are rare and include arterial thrombosis, severe anaphylaxis, aseptic meningitis, and renal tubular crisis. Most adverse effects are mild and are limited to nausea, rhinitis, asthma, chills, low-grade fever, myalgia, and migraine headache. The variables potentially affecting the risk and intensity of adverse events include patient's age, cardiovascular or renal disease, dyslipidemia, diabetes and IgA deficiency with anti-IgA antibodies.Citation59

  2. Belimumab – Belimumab is a human monoclonal antibody currently approved for the treatment of systemic lupus erythematosus (SLE). It inhibits B-cell activating factor (BAFF), also known as B lymphocyte stimulator (BLyS), which is a B cell modulator and maturation factor. High BAFF expression levels in skin biopsies were observed in a tight-skin mouse model and the extent of skin fibrosis, as well as BAFF levels, IL-6 and IL-10 production were decreased after treatment with BAFF antagonist.Citation60 BAFF was increased in the serum of patients with SSc and correlated with the extent of skin fibrosis.Citation61 Addition of BAFF to co-cultures of B cells with SSc fibroblasts increased IL-6, TGFβ1 and collagen production.Citation21

A randomized, double-blind, placebo-controlled, pilot trial assessed the efficacy of belimumab in early dcSSc patients treated with background MMF. There was significant improvement in skin fibrosis that was greater, although not statistically significant, in the group receiving MMF plus belimumab compared to MMF monotherapy.Citation62 Adverse effects of belimumab include increased risk of infections, while caution should be applied in patients with preexisting mood disorder.

  1. Tocilizumab. Tocilizumab is a humanized monoclonal antibody against interleukin-6 receptor, administered intravenously or subcutaneously and is approved for the treatment of rheumatoid arthritis, systemic juvenile idiopathic arthritis and giant cell arteritis. IL-6 is increased in the peripheral blood and lesional skin from patients with SSc, and induces fibroblast collagen production.Citation63 IL-6 also induces Th17 differentiation and promotes B cell differentiation toward Ig-producing plasma cells.Citation64

Case studies reported improvement in skin thickness,Citation65Citation67 however concern regarding gastrointestinal side effects was raised.Citation68 An observational study reported significant improvement in arthritis, with decrease in disease activity score based on 28 joint counts (DAS28) after 5 months of TCZ therapy.Citation69 A phase II study comparing tocilizumab (162 mg/week subcutaneously) vs placebo over 48 weeks followed by an open-label TCZ period to 96 weeks showed a trend towards skin score improvement.Citation70,Citation71 Adverse effects of TCZ include increased risk of infections, elevation of liver enzymes, bone marrow suppression, elevation of lipids, and increased risk of gastrointestinal perforation in patients with diverticulitis.Citation64 TCZ should also be avoided in patients with preexisting or recent onset demyelinating disorder.

  1. Abatacept. Abatacept is a recombinant CTLA4-Ig fusion protein that binds to CD80/CD86 on antigen-presenting cells, blocking CD28 binding to CD80/CD86 and consequently inhibiting T cell activation. In small case series, abatacept has shown good results regarding arthritis.Citation69 Skin thickening, both in patients with SSc and localized scleroderma, has also been improved with abataceptCitation72Citation74 and expression studies in skin biopsies showed modulation of genes implicated in inflammatory pathways.Citation72 Adverse effects of abatacept include increased risk of infections and – potentially serious – exacerbations of chronic obstructive pulmonary disease.

  2. Rituximab. Rituximab (RTX) is a chimeric mouse/human monoclonal antibody, which binds specifically to the transmembrane antigen CD20, located in human pre-B and mature B lymphocytes. Skin biopsies from SSc patients showed increased skin infiltration of B cells in some patients.Citation75 B cells were also found in lung biopsies from patients with SSc-associated interstitial lung disease (ILD).Citation76 In scleroderma mouse models, B-cell depletion significantly improved skin fibrosis.Citation77 Many small studies evaluated the effect of rituximab in SSc. Among 20 relevant references found in the literature, 11 had less than ten patients and/or no comparison group. The remain 9 studies were: 1 open label RCT with two years follow up,Citation78,Citation79 1 open label comparative study,Citation80 1 retrospective nested case-control study,Citation81 1 double-blind RCT with 2 years follow-up,Citation82 1 retrospective study in a single centre combined with literature review of published cases,Citation83 and 3 prospective open label studies.Citation84Citation86 The first study showed improvement in mRSS and lung function tests (FVC and DLCO)Citation78 and further improvement observed after two years of follow up.Citation79 The same results, of skin and lung function improvement, reported in the third study of 51 SSc patients with respiratory involvement.Citation80 Similarly, in the case – control nested study of 46 patients, mRSS were reduced in the RTX group, FVC stabilized and DLCO increased.Citation81 The second open label study assessed the skin score in progressive diffuse SScCitation71 and other two in early disease.Citation84,Citation86 Two of three studies described statistically significant improvements in mRSS from baseline with RTX at all time pointsCitation85,Citation86 and the only trial with no significant changes in mRSS in RTX group was the other open label study.Citation84 The double-blind RCT study by Boonstra M et al. also examined 16 early (<2years disease duration) scleroderma patients.Citation82 Patients treated with Rituximab showed moderately improvement, although not statistically significant, of lung function compared to patients on placebo. Skin score did not differ between groups.Citation82 On the contrary, Thiebaut M et al in their retrospective study of 53 patients (13 from a single centre in France combined with data from 40 additional patients retrieved from published cases) concluded that RTX improves skin, and lung function.Citation83 Currently RTX is considered in cases with worsening ILD following treatment with CyP. Adverse effects of Rituximab include increased risk for infections – including hepatitis B virus re-activation and herpes zoster – bone marrow suppression and potentially serious mucocutaneous reactions.

  3. Anti-TGF monoclonal antibody. Transforming growth factor-β (TGF-β) is a growth factor with important homeostatic function in tissue repair processes, would healing, epithelial integrity and immune responses. Excessive TGF-β activity is associated with fibrosing disorders such as pulmonary fibrosis and SSc.Citation87 Mice with gain-of-function mutations in the TGF-β signaling pathway develop fibrosis in the skin and blood vessel walls in the lung and kidneys characteristic of SSc.Citation88 TGF-β expression in the lesional skin of SSc patients seems high in patients with severe and active disease, in contrast to established skin fibrosis.Citation89 There are also reports of upregulated expression of TGFβ receptors, such as integrins and thrombospondin-1, in skin fibroblasts suggesting that an autocrine TGF-β loop in SSc fibroblasts may be present.Citation90Citation92 TGFβ increases the expression of several pro-fibrotic genes in lung fibroblasts by inducing endothelin-1.Citation93 However, trials of the dual receptor endothelin-1 antagonist have not shown benefit.Citation94 Metelimumab, a human monoclonal neutralizing antibody to TGFβ, failed to improve skin fibrosis in 45 patients with early SSc.Citation95 Fresolimumab, a neutralizing antibody against all three TGFβ isoforms, was studied in an open label study in 15 SSc patients. Significant improvement in skin fibrosis was observed, while sequential skin biopsies showed that fresolimumab was efficient in blocking TGFβ activity. Adverse events included anaemia and bleeding.Citation96

Emerging data on the use of biological drugs in the treatment of patients with SSc are summarized in .

Table 2. Biologic drugs in the treatment of Systemic Sclerosis.

B2.Synthetic targeted therapies

  1. Rapamycin. Rapamycin, is a macrolide that binds to FK-506 binding protein 12 and inhibits the mammalian target of rapamycin and thus inhibits cytokine production, cell proliferation, and collagen production.Citation97,Citation98 In a small single-blind study, 11 dcSSc patients of < 5 years duration were randomized to receive rapamycin (rapa) or MTX for 48 weeks. Rapamycin and MTX improved skin score, but FVC was declined in the rapa group.Citation99 Hypertriglycedemia was the most common adverse effect in the para group, whereas other adverse effects were comparable between the rapa and MTX groups.Citation99

  2. Tyrosine kinase inhibitors. Tyrosine kinases are small molecules involved in numerous intracellular processes, including in the production of PDGF and TGFβ production. Tyrosine kinase inhibitors (TKIs) have been used in malignancies and fibrotic disorders, while they've emerged as the next important breakthrough in the treatment of rheumatoid arthritis.Citation100 In SSc, imatinib, a first generation TKI, exhibited highly variable effects from un-effectivenes to clinical improvement in severe cases, but also considerable toxicity, including fluid retention, alopecia, anaemia, nausea, and diarrhea.Citation101-Citation105 Second generation TKIs, nilotinib, and dasatinib, also have been evaluated in small, open-label studies. Nilotinib in patients with early dcSSc improved skin score at 12 months.Citation106 In a safety and pharmacokinetics study of 9 months duration, dasatinib improved skin score and stabilized lung function in few SSc patients.Citation107 The jury is still out for this class of drugs in SSc because of moderate therapeutic efficacy and serious toxicity.Citation26

Response to treatment

As with most systemic multifaceted diseases, evaluation of treatment response in patients with SSc represents a difficult task. There is an increasing effort to identify biomarkers that are easy to measure in order to be able to assess disease progression and response to treatment in the clinic.Citation108 Currently, only cutaneous induration has been validated for diagnosis, prognosis or response to treatment in patients with SSc. Serum autoantibodies and nailfold capillaroscopic patterns are also used in certain centers as tools to inform treatment decisions. Obviously, regular assessment of cardiopulmonary function (serial measurements of DLCO, FVC and pulmonary artery pressure among others) remain standard practice. However, substantial work has been done towards novel biomarkers. Gene expression patterns in the skin and other organs as well as gene expression changes associated with treatment response has been studied. Moreover it is speculated that potential biomarkers lie within extracellular vesicles (EVs). EVs enclose a vast array of macromolecules that are considered to mirror the physiological or pathological state of the cells of origin. Transcriptomic and proteomic analyses of EVs from SSc patients could provide a valuable source of novel biomarkers for the prognosis of our patients and their response to treatment.Citation108

Concluding remarks

Therapeutic approach of patients with SSc should address all cardinal features of the disease and includes therapies for (a) the vascular manifestations, such as Raynaud's phenomenon, skin ulcers, pulmonary arterial hypertension (PAH) and scleroderma renal crisis, (b) fibrosis of the skin and internal organs as well as (c) immune cell dysregulation. Regarding vascular manifestations several agents have been established in every day practice: Angiotensing converting enzyme (ACE) inhibitors have changed the prognosis for renal crisis while endothelin-1 receptor antagonists, phosphodiesterase (PDE)-5 inhibitors, intravenous, and recently oral prostanoids have been approved for PAH. Fibrosis remains the most challenging part since no fibroblast directed therapy has been able to provide data that could lead to clinical use. On the other hand successful immunotherapy, especially when applied early in the disease course, is expected to prevent disease progression. Currently available immunotherapeutic agents for SSc were summarized here in. Real life data has proven that SSc is one of the most challenging and complex rheumatic diseases. Current treatment strategies are ineffective once fibrosis takes place. The future of SSc treatment we envision in the next few years will most probably include early introduction of medications directed against molecules involved in immune cells-fibroblasts communication.

Disclosure of potential conflicts of interest

No potential conflicts of interest were disclosed.

References

  • Desbois AC, Cacoub P. Systemic sclerosis: An update in 2016. Autoimmun Rev. 2016;15(5):417–26. doi:10.1016/j.autrev.2016.01.007.
  • Koenig M, Joyal F, Fritzler MJ, Roussin A, Abrahamowicz M, Boire G, Goulet JR, Rich E, Grodzicky T, Raymond Y, et al. Autoantibodies and microvascular damage are independent predictive factors for the progression of Raynaud's phenomenon to systemic sclerosis: a twenty-year prospective study of 586 patients, with validation of proposed criteria for early systemic sclerosis. Arthritis Rheum. 2008;58(12):3902–12. doi:10.1002/art.24038.
  • Sakkas LI, Chikanza IC, Platsoucas CD. Mechanisms of Disease: the role of immune cells in the pathogenesis of systemic sclerosis. Nat Clin Pract Rheumatol. 2006;2(12):679–85. doi:10.1038/ncprheum0346.
  • Barnes J, Mayes MD. Epidemiology of systemic sclerosis: incidence, prevalence, survival, risk factors, malignancy, and environmental triggers. Curr Opin Rheumatol. 2012 Mar;24(2):165–70 doi:10.1097/BOR.0b013e32834ff2e8.
  • Nikpour M, Stevens WM, Herrick AL, Proudman SM. Epidemiology of systemic sclerosis. Best Pract Res Clin Rheumatol. 2010 Dec;24(6):857–69. doi:10.1016/j.berh.2010.10.007.
  • Nguyen C, Bérezné A, Baubet T, Mestre-Stanislas C, Rannou F, Papelard A, Morell-Dubois S, Revel M, Guillevin L, Poiraudeau S et al. Groupe Français de Recherche sur la Sclérodermie. Association of gender with clinical expression, quality of life, disability, and depression and anxiety in patients with systemic sclerosis. PLoS One. 2011 Mar9;6(3):e17551. doi:10.1371/journal.pone.0017551.
  • Steen VD, Medsger TA. Changes in causes of death in systemic sclerosis, 1972–2002. Ann Rheum Dis. 2007 Jul;66(7):940–4 doi:10.1136/ard.2006.066068.
  • Sakkas LI, Simopoulou T, Daoussis D, Liossis SN, Potamianos S. Intestinal involvement in systemic sclerosis: A clinical review. Dig Dis Sci. 2018 Apr;63(4):834–44. doi:10.1007/s10620-018-4977-8.
  • Rubio-Rivas M, Corbella X, Pestaña-Fernández M, Tolosa-Vilella C, Guillen-Del Castillo A, Colunga-Argüelles D, Trapiella-Martínez L, Iniesta-Arandia N, Castillo-Palma MJ, Sáez-Comet L et al. First clinical symptom as a prognostic factor in systemic sclerosis: results of a retrospective nationwide cohort study. Clin Rheumatol. 2018 Apr;37(4):999–1009 doi:10.1007/s10067-017-3936-7.
  • Tyndall AJ, Bannert B, Vonk M, Airò P, Cozzi F, Carreira PE, Bancel DF, Allanore Y, Müller-Ladner U, Distler O, et al. Causes and risk factors for death in systemic sclerosis: a study from the EULAR Scleroderma Trials and Research (EUSTAR) database. Ann Rheum Dis. 2010 Oct;69(10):1809–15. doi:10.1136/ard.2009.114264.
  • Kalogerou A, Gelou E, Mountantonakis S, Settas L, Zafiriou E, Sakkas L. Early T cell activation in the skin from patients with systemic sclerosis. Ann Rheum Dis. 2005;64(8):1233–5. doi:10.1136/ard.2004.027094.
  • Sakkas LI, Platsoucas CD. Is systemic sclerosis an antigen-driven T cell disease? Arthritis Rheum. 2004;50(6):1721–33. doi:10.1002/art.20315.
  • Sakkas LI, Tourtelotte C, Myers A, Berney S, Platsoucas CD. Increased levels of alternatively spliced interleukin-4 (IL-4d2) transcripts in peripheral blood mononuclear cells from patients with systemic sclerosis. Clin Diagn LabImmunol 1999;6(5):660–4.
  • Kurasawa K, Hirose K, Sano H, Endo H, Shinkai H, Nawata Y, Takabayashi K, Iwamoto I. Increased interleukin-17 production in patients with systemic sclerosis. Arthritis Rheum. 2000;43(11):2455–63. doi:10.1002/1529-0131(200011)43:11%3c2455::AID-ANR12%3e3.0.CO;2-K.
  • Moudgil KD, Choubey D. Cytokines in autoimmunity: role in induction, regulation, and treatment. J Interferon Cytokine Res. 2011 Oct;31(10):695–703. doi:10.1089/jir.2011.0065.
  • Leask A, Abraham DJ. TGF-beta signaling and the fibrotic response. FASEB J. 2004 May;18(7):816–27. doi:10.1096/fj.03-1273rev.
  • Sakkas LI, Bogdanos DP. Systemic sclerosis: New evidence re-enforces the role of B cells. Autoimmun Rev. 2016;15(2):155–61. doi:10.1016/j.autrev.2015.10.005.
  • Hasegawa M. B lymphocytes: shedding new light on the pathogenesis of systemic sclerosis. J Dermatol. 2010;37(1):3–10. doi:10.1111/j.1346-8138.2009.00763.x.
  • Luchetti MM, Moroncini G, Jose Escamez M, Svegliati Baroni S, Spadoni T, Grieco A, Paolini C, Funaro A, Avvedimento EV, Larcher F, et al. Induction of scleroderma fibrosis in skin-humanized mice by administration of anti-platelet-derived growth factor receptor agonistic autoantibodies. Arthritis Rheumatol. 2016;68(9):2263–73. doi:10.1002/art.39728.
  • Moroncini G, Svegliati Baroni S, Gabrielli A. Agonistic antibodies in systemic sclerosis. Immunol Lett. 2018;195:83–87. doi:10.1016/j.imlet.2017.10.007.
  • François A, Chatelus E, Wachsmann D, Sibilia J, Bahram S, Alsaleh G, Gottenberg JE. B lymphocytes and B-cell activating factor promote collagen and profibrotic markers expression by dermal fibroblasts in systemic sclerosis. Arthritis Res Ther. 2013;15(5):R168. doi:10.1186/ar4352.
  • van den Hoogen F, Khanna D, Fransen J, Johnson SR, Baron M, Tyndall A, MatucciCerinic M, Naden RP, Medsger TA Jr, Carreira PE, et al. 2013 classification criteria for systemic sclerosis: An American College of Rheumatology/European League against Rheumatism collaborative initiative. Arthritis Rheum. 2013;65(11):2737–47. doi:10.1002/art.38098.
  • Sakkas LI, Simopoulou T, Katsiari C, Bogdanos D, Chikanza IC. Early systemic sclerosis-opportunities for treatment. Clin Rheumatol. 2015;34(8):1327–31. doi:10.1007/s10067-015-2902-5.
  • Tashkin DP, Elashoff R, Clements PJ, Goldin J, Roth MD, Furst DE, Arriola E, Silver R, Strange C, Bolster M et al. Scleroderma lung study research group. Cyclophosphamide versus placebo in scleroderma lung disease. N Engl J Med. 2006;354(25):2655–66. doi:10.1056/NEJMoa055120.
  • Hoyles RK, Ellis RW, Wellsbury J, Lees B, Newlands P, Goh NS, Roberts C, Desai S, Herrick AL, McHugh NJ et al. A multicenter, prospective, randomized, double-blind, placebo-controlled trial of corticosteroids and intravenous cyclophosphamide followed by oral azathioprine for the treatment of pulmonary fibrosis in scleroderma. Arthritis Rheum. 2006;54:3962–70. doi:10.1002/art.22204.
  • Mendoza FA, Mansoor M, Jimenez SA. Treatment of rapidly progressive systemic sclerosis: Current and future prospective. Expert Opinion Orphan Drugs 2016;4(1):31–47. doi:10.1517/21678707.2016.1114454.
  • Herrick AL, Pan X, Peytrignet S, Lunt M, Hesselstrand R, Mouthon L, Silman A, Brown E, Czirják L, Distler JHW et al. Treatment outcome in early diffuse cutaneous systemic sclerosis: the European Scleroderma Observational Study (ESOS). Ann Rheum Dis 2017;76:1207–18. doi:10.1136/annrheumdis-2016-210503.
  • Saigusa R, Asano Y, Nakamura K, Yamashita T, Ichimura Y, Takahashi T, Toyama T, Taniguchi T, Yoshizaki A, Miyazaki M, et al. Plasma plasmin-α2-plasmin inhibitor complex levels may predict the effect of cyclophosphamide for systemic sclerosisrelated interstitial lung disease. Mod Rheumatol. 2017;27(4):618–22. doi:10.1080/14397595.2016.1226472.
  • van den Hoogen FH, Boerbooms AM, Swaak AJ, Rasker JJ, van Lier HJ, van de Putte LB. Comparison of methotrexate with placebo in the treatment of systemic sclerosis: a 24 week randomized double-blind trial, followed by a 24 week observational trial. Br J Rheumatol. 1996;35(4):364–72. doi:10.1093/rheumatology/35.4.364.
  • Pope JE, Bellamy N, Seibold JR, Baron M, Ellman M, Carette S, Smith CD, Chalmers IM, Hong P, O'Hanlon D, et al. A randomized controlled trial of methotrexate versus placebo in early diffuse scleroderma. Arthritis Rheum. 2001;44(6):1351–8. doi:10.1002/1529-0131(200106)44:6%3c1351::AID-ART227%3e3.0.CO;2-I.
  • Johnson SR, Feldman BM, Pope JE, Tomlinson GA. Shifting our thinking about uncommon disease trials: the case of methotrexate in scleroderma. J Rheumatol. 2009;36(2):323–9.
  • Lateef O, Shakoor N, Balk RA. Methotrexate pulmonary toxicity. Expert Opin Drug Saf. 2005;4(4):723–30. doi:10.1517/14740338.4.4.723.
  • Nadashkevich O, Davis P, Fritzler M, Kovalenko W. A randomized unblinded trial of cyclophosphamide versus azathioprine in the treatment of systemic sclerosis. Clin Rheumatol. 2006;25(2):205–12. doi:10.1007/s10067-005-1157-y.
  • Poormoghim H, Rezaei N, Sheidaie Z, Almasi AR, Moradi-Lakeh M, Almasi S, Andalib E. Systemic sclerosis: comparison of efficacy of oral cyclophosphamide and azathioprine on skin score and pulmonary involvement-a retrospective study. Rheumatol Int. 2014;34(12):1691–9. doi:10.1007/s00296-014-3026-y.
  • Baqir M, Makol A, Osborn TG, Bartholmai BJ, Ryu JH. Mycophenolate mofetil for scleroderma-related interstitial lung disease: A real world experience. PLoS One. 2017;12(5):e0177107. doi:10.1371/journal.pone.0177107.
  • Koutroumpas A, Ziogas A, Alexiou I, Barouta G, Sakkas LI. Mycophenolate mofetil in systemic sclerosis-associated interstitial lung disease. Clin Rheumatol. 2010;29(10):1167–8. doi:10.1007/s10067-010-1498-z.
  • Shenoy PD, Bavaliya M, Sashidharan S, Nalianda K, Sreenath S. Cyclophosphamide versus mycophenolate mofetil in scleroderma interstitial lung disease (SSc-ILD) as induction therapy: a single-centre, retrospective analysis. Arthritis Res Ther. 2016;18(1):123. doi:10.1186/s13075-016-1015-0.
  • Tashkin DP, Roth MD, Clements PJ, Furst DE, Khanna D, Kleerup EC, Goldin J, Arriola E, Volkmann ER, Kafaja S, et al. Sclerodema Lung Study II Investigators. Mycophenolate mofetil versus oral cyclophosphamide in scleroderma-related interstitial lung disease (SLS II): a randomised controlled, double-blind, parallel group trial. Lancet Respir Med. 2016;4(9):708–19. doi:10.1016/S2213-2600(16)30152-7.
  • Volkmann ER, Tashkin DP, Li N, Roth MD, Khanna D, Hoffmann-Vold AM, Kim G, Goldin J, Clements PJ, Furst DE, et al. Mycophenolate mofetil versus placebo for systemic sclerosis-related interstitial lung disease: An analysis of scleroderma lung studies I and II. Arthritis Rheumatol. 2017;69(7):1451–60. doi:10.1002/art.40114.
  • Namas R, Tashkin DP, Furst DE, Wilhalme H, Tseng CH, Roth MD, Kafaja S, Volkmann E, Clements PJ, Khanna D, Participants in the Scleroderma Lung Study I and members of the Scleroderma Lung Study II Research Group. Efficacy of mycophenolate mofetil and oral cyclophosphamide on skin thickness: Post hoc analyses from two randomized placebo-controlled trials. Arthritis Care Res (Hoboken). 2018;70(3):439–44. doi:10.1002/acr.23282.
  • Tsukamoto H, Nagafuji K, Horiuchi T, Mitoma H, Niiro H, Arinobu Y, Inoue Y, To K, Miyamoto T, Iwasaki H, et al. Analysis of immune reconstitution after autologous CD34+ stem/progenitor cell transplantation for systemic sclerosis: predominant reconstitution of Th1 CD4+ T cells. Rheumatology (Oxford). 2011;50(5):944–52. doi:10.1093/rheumatology/keq414.
  • Tyndall A, Saccardi R. Haematopoietic stem cell transplantation in the treatment of severe autoimmune disease: results from phase I/II studies, prospective randomized trials and future directions. Clin Exp Immunol. 2005;141(1):1–9. doi:10.1111/j.1365-2249.2005.02806.x.
  • Nash RA, McSweeney PA, Crofford LJ, Abidi M, Chen CS, Godwin JD, Gooley TA, Holmberg L, Henstorf G, LeMaistre CF, et al. High-dose immunosuppressive therapy and autologous hematopoietic cell transplantation for severe systemic sclerosis: long-term follow-up of the US multicenter pilot study. Blood. 2007;110(4):1388–96. doi:10.1182/blood-2007-02-072389.
  • Vonk MC, Marjanovic Z, van den Hoogen FH, Zohar S, Schattenberg AV, Fibbe WE, Larghero J, Gluckman E, Preijers FW, van Dijk AP, et al. Long-term follow-up results after autologous haematopoietic stem cell transplantation for severe systemic sclerosis. Ann Rheum Dis. 2008;67(1):98–104 doi:10.1136/ard.2007.071464.
  • Fleming JN, Nash RA, McLeod DO, Fiorentino DF, Shulman HM, Connolly MK, Molitor JA, Henstorf G, Lafyatis R, Pritchard DK, et al. Capillary regeneration in scleroderma: stem cell therapy reverses phenotype? PLoS One. 2008;3(1):e1452. doi:10.1371/journal.pone.0001452.
  • Miniati I, Guiducci S, Conforti ML, Rogai V, Fiori G, Cinelli M, Saccardi R, Guidi S, Bosi A, Tyndall A, et al. Autologous stem cell transplantation improves microcirculation in systemic sclerosis. Ann Rheum Dis. 2009;68(1):94–98. doi:10.1136/ard.2007.082495.
  • Burt RK, Shah SJ, Dill K, Grant T, Gheorghiade M, Schroeder J, Craig R, Hirano I, Marshall K, Ruderman E, et al. Autologous non-myeloablative haemopoietic stem-cell transplantation compared with pulse cyclophosphamide once per month for systemic sclerosis (ASSIST): an open-label, randomised phase 2 trial. Lancet. 2011;378(9790):498–506. doi:10.1016/S0140-6736(11)60982-3.
  • van Laar JM, Farge D, Sont JK, Naraghi K, Marjanovic Z, Larghero J, Schuerwegh AJ, Marijt EW, Vonk MC, Schattenberg AV, et al. EBMT/EULAR Scleroderma Study Group. Autologous hematopoietic stem cell transplantation vs intravenous pulse cyclophosphamide in diffuse cutaneous systemic sclerosis: a randomized clinical trial. JAMA. 2014;311(24):2490–8. doi:10.1001/jama.2014.6368.
  • Host L, Nikpour M, Calderone A, Cannell P, Roddy J. Autologous stem cell transplantation in systemic sclerosis: a systematic review. Clin Exp Rheumatol. 2017; 35 Suppl 106(4):198–207.
  • Sullivan KM, Goldmuntz EA, Furst DE. Autologous stem-cell transplantation for severe scleroderma. N Engl J Med. 2018 Mar 15;378(11):1066–7. doi:10.1056/NEJMc1801275.
  • Preliminary criteria for the classification of systemic sclerosis (scleroderma). Subcommittee for scleroderma criteria of the American Rheumatism Association Diagnostic and Therapeutic Criteria Committee. Arthritis Rheum. 1980 23(5):581–90.
  • Bellando-Randone S, Matucci-Cerinic M. From Raynaud's Phenomenon to Very Early Diagnosis of Systemic Sclerosis- The VEDOSS approach. Curr Rheumatol Rev. 2013;9(4):245–8. doi:10.2174/157339710904140417124819.
  • WHO Expert Committee on Biological Standardization. Fifty-sixth report. WHO Technical Report Series, No. 941, 2007 (352 pages), p: 202 http://apps.who.int/iris/bitstream/handle/10665/43594/WHO_TRS_941.pdf?sequence=1&isAllowed=y
  • Cantarini L, Rigante D, Vitale A, Napodano S, Sakkas LI, Bogdanos DP, Shoenfeld Y. Intravenous immunoglobulins (IVIG) in systemic sclerosis: a challenging yet promising future. Immunol Res. 2015;61(3):326–37. doi:10.1007/s12026-014-8615-z.
  • Blank M, Levy Y, Amital H, Shoenfeld Y, Pines M, Genina O. The role of intravenous immunoglobulin therapy in mediating skin fibrosis in tight skin mice. Arthritis Rheum. 2002;46(6):1689–90. doi:10.1002/art.10363.
  • Levy Y, Amital H, Langevitz P, Nacci F, Righi A, Conforti L, Generini S, Matucci Cerinic M, Shoenfeld Y. Intravenous immunoglobulin modulates cutaneous involvement and reduces skin fibrosis in systemic sclerosis: an open-label study. Arthritis Rheum. 2004;50(3):1005–7. doi:10.1002/art.20195.
  • Nacci F, Righi A, Conforti ML, Miniati I, Fiori G, Martinovic D, Melchiorre D, Sapir T, Blank M, Shoenfeld Y, et al. Intravenous immunoglobulins improve the function and ameliorate joint involvement in systemic sclerosis: a pilot study. Ann Rheum Dis. 2007;66(7):977–9. doi:10.1136/ard.2006.060111.
  • Takehara K, Ihn H, Sato S. A randomized, double-blind, placebo-controlled trial: intravenous immunoglobulin treatment in patients with diffuse cutaneous systemic sclerosis. Clin Exp Rheumatol. 2013;31(2 Suppl 76):151–6.
  • Orbach H, Katz U, Sherer Y, Shoenfeld Y. Intravenous immunoglobulin: adverse effects and safe administration. Clin Rev Allergy Immunol. 2005 Dec;29(3):173–84. doi:10.1385/CRIAI:29:3:173.
  • Matsushita T, Fujimoto M, Hasegawa M, Matsushita Y, Komura K, Ogawa F, Watanabe R, Takehara K, Sato S. BAFF antagonist attenuates the development of skin fibrosis in tight-skin mice. J Invest Dermatol. 2007;127(12):2772–80 doi:10.1038/sj.jid.5700919.
  • Matsushita T, Hasegawa M, Yanaba K, Kodera M, Takehara K, Sato S. Elevated serum BAFF levels in patients with systemic sclerosis: enhanced BAFF signaling in systemic sclerosis B lymphocytes. Arthritis Rheum. 2006;54(1):192–201. doi:10.1002/art.21526.
  • Gordon JK, Martyanov V, Franks JM, Bernstein EJ, Szymonifka J, Magro C, Wildman HF, Wood TA, Whitfield ML, Spiera RF. Belimumab for the treatment of early diffuse systemic sclerosis: Results of a randomized, double-blind, placebo-controlled, pilot trial. Arthritis Rheumatol. 2018;70(2):308–16. doi:10.1002/art.40358.
  • Khan K, Xu S, Nihtyanova S, Derrett-Smith E, Abraham D, Denton CP, Ong VH. Clinical and pathological significance of interleukin 6 overexpression in systemic sclerosis. Ann Rheum Dis. 2012;71(7):1235–42. doi:10.1136/annrheumdis-2011-200955.
  • Sakkas LI. Spotlight on tocilizumab and its potential in the treatment of systemic sclerosis. Drug Des Devel Ther. 2016;10:2723–8. doi:10.2147/DDDT.S99696.
  • Shima Y, Kuwahara Y, Murota H, Kitaba S, Kawai M, Hirano T, Arimitsu J, Narazaki M, Hagihara K, Ogata A, et al. The skin of patients with systemic sclerosis softened during the treatment with anti-IL-6 receptor antibody tocilizumab. Rheumatology (Oxford). 2010;49(12):2408–12. doi:10.1093/rheumatology/keq275.
  • Fernandes das Neves M, Oliveira S, Amaral MC, Delgado Alves J. Treatment of systemic sclerosis with tocilizumab. Rheumatology (Oxford). 2015;54(2):371–2. doi:10.1093/rheumatology/keu435.
  • Shima Y, Hosen N, Hirano T, Arimitsu J, Nishida S, Hagihara K, Narazaki M, Ogata A, Tanaka T, Kishimoto T, et al. Expansion of range of joint motion following treatment of systemic sclerosis with tocilizumab. Mod Rheumatol. 2015;25(1):134–7. doi:10.3109/14397595.2013.874749.
  • Frech TM, Hudson M. Protective role of interleukin-6 in systemic sclerosis gastrointestinal tract involvement: case report and review of the literature. Clin Exp Rheumatol. 2015;33(4) (Suppl 91):S179–81.
  • Elhai M, Meunier M, Matucci-Cerinic M, Maurer B, Riemekasten G, Leturcq T, Pellerito R, Von Mühlen CA, Vacca A, Airo P, et al. EUSTAR (EULAR Scleroderma Trials and Research group). Outcomes of patients with systemic sclerosis-associated polyarthritis and myopathy treated with tocilizumab or abatacept: a EUSTAR observational study. Ann Rheum Dis. 2013;72(7):1217–20. doi:10.1136/annrheumdis-2012-202657.
  • Khanna D, Denton CP, Jahreis A, van Laar JM, Frech TM, Anderson ME, Baron M, Chung L, Fierlbeck G, Lakshminarayanan S, et al. Safety and efficacy of subcutaneous tocilizumab in adults with systemic sclerosis (faSScinate): a phase 2, randomised, controlled trial. Lancet. 2016;387(10038):2630–40. doi:10.1016/S0140-6736(16)00232-4.
  • Khanna D, Denton CP, Lin CJF, van Laar JM, Frech TM, Anderson ME, Baron M, Chung L, Fierlbeck G, Lakshminarayanan S, et al. Safety and efficacy of subcutaneous tocilizumab in systemic sclerosis: results from the open-label period of a phase II randomised controlled trial (faSScinate). Ann Rheum Dis. 2018;77(2):212–20. doi:10.1136/annrheumdis-2017-211682.
  • Chakravarty EF, Martyanov V, Fiorentino D, Wood TA, Haddon DJ, Jarrell JA, Utz PJ, Genovese MC, Whitfield ML, Chung L. Gene expression changes reflect clinical response in a placebo-controlled randomized trial of abatacept in patients with diffuse cutaneous systemic sclerosis. Arthritis Res Ther. 2015;17:159. doi:10.1186/s13075-015-0669-3.
  • de Paoli FV, Nielsen BD, Rasmussen F, Deleuran B, Søndergaard K. Abatacept induces clinical improvement in patients with severe systemic sclerosis. Scand J Rheumatol. 2014;43(4):342–5. doi:10.3109/03009742.2013.812238.
  • Wehner Fage S, Arvesen KB, Olesen AB. Abatacept improves skin-score and reduces lesions in patients with localized scleroderma: A case series. Acta Derm Venereol. 2018;98(4):465–6. doi:10.2340/00015555-2878.
  • Whitfield ML, Finlay DR, Murray JI, Troyanskaya OG, Chi JT, Pergamenschikov A, McCalmont TH, Brown PO, Botstein D, Connolly MKSystemic and cell type-specific gene expression patterns in scleroderma skin. Proc Natl Acad Sci U S A. 2003;100(21):12319–24. doi:10.1073/pnas.1635114100.
  • Lafyatis R, O'Hara C, Feghali-Bostwick CA, Matteson E. B cell infiltration in systemic sclerosis-associated interstitial lung disease. Arthritis Rheum. 2007; 56(9):3167–8 doi:10.1002/art.22847.
  • Hasegawa M, Hamaguchi Y, Yanaba K, Bouaziz JD, Uchida J, Fujimoto M, Matsushita T, Matsushita Y, Horikawa M, Komura K et al. B-lymphocyte depletion reduces skin fibrosis and autoimmunity in the tight-skin mouse model for systemic sclerosis. Am J Pathol. 2006;169(3):954–66. doi:10.2353/ajpath.2006.060205.
  • Daoussis D, Liossis SN, Tsamandas AC, Kalogeropoulou C, Kazantzi A, Sirinian C, Karampetsou M, Yiannopoulos G, Andonopoulos AP. Experience with rituximab in scleroderma: results from a 1-year, proof-of-principle study. Rheumatology (Oxford). 2010;49(2):271–80. doi:10.1093/rheumatology/kep093.
  • Daoussis D, Liossis SN, Tsamandas AC, Kalogeropoulou C, Paliogianni F, Sirinian C, Yiannopoulos G, Andonopoulos AP. Effect of long-term treatment with rituximab on pulmonary function and skin fibrosis in patients with diffuse systemic sclerosis. Clin Exp Rheumatol. 2012;30(2 Suppl 71):S17–22.
  • Daoussis D, Melissaropoulos K, Sakellaropoulos G, Antonopoulos I, Markatseli TE, Simopoulou T, Georgiou P, Andonopoulos AP, Drosos AA, Sakkas L, et al. A multicenter, open-label, comparative study of B-cell depletion therapy with Rituximab for systemic sclerosis-associated interstitial lung disease. Semin Arthritis Rheum. 2017;46(5):625–31. doi:10.1016/j.semarthrit.2016.10.003.
  • Jordan S, Distler JH, Maurer B, Huscher D, van Laar JM, Allanore Y, Distler O, EUSTAR Rituximab study group. Effects and safety of rituximab in systemic sclerosis: an analysis from the European Scleroderma Trial and Research (EUSTAR) group. Ann Rheum Dis. 2015;74(6):1188–94. doi:10.1136/annrheumdis-2013-204522.
  • Boonstra M, Meijs J, Dorjée AL, Marsan NA, Schouffoer A, Ninaber MK, Quint KD, Bonte-Mineur F, Huizinga TWJ, Scherer HU, et al. Rituximab in early systemic sclerosis. RMD Open. 2017;3(2):e000384. eCollection 2017. PubMed PMID: 28879049; PubMed Central PMCID: PMC5574444. doi:10.1136/rmdopen-2016-000384.
  • Thiebaut M, Launay D, Rivière S, Mahévas T, Bellakhal S, Hachulla E, Fain O, Mekinian A. Efficacy and safety of rituximab in systemic sclerosis: French retrospective study and literature review. Autoimmun Rev. 2018;17(6):582–87. doi:10.1016/j.autrev.2017.12.010.
  • Lafyatis R, Kissin E, York M, Farina G, Viger K, Fritzler MJ, Merkel P, Simms RW. B cell depletion with rituximab in patients patients with diffuse systemic cutaneous sclerosis. Arthritis Rheum 2009;60(2):578–83. doi:10.1002/art.24249.
  • Bosello SL, De Luca G, Rucco M, Berardi G, Falcione M, Danza FM, Pirronti T, Ferraccioli G. Long-term efficacy of B cell depletion therapy on lung and skin involvement in diffuse systemic sclerosis. Semin Arthritis Rheum. 2015;44(4):428–36. doi:10.1016/j.semarthrit.2014.09.002.
  • Melsens K, De Keyser F, Decuman S, Brusselle G, De Pauw M, Deschepper E, De Wilde K, Elewaut D, Piette Y, Vandecasteele E, et al. Assessment of sensitivity to change of the European scleroderma study group activity index. Clin Exp Rheumatol. 2016;34(Suppl 100):148–51
  • Gordon KJ, Blobe GC. Role of transforming growth factor-beta superfamily signaling pathways in human disease. Biochim Biophys Acta. 2008;1782(4):197–228. doi:10.1016/j.bbadis.2008.01.006.
  • Sonnylal S, Denton CP, Zheng B, Keene DR, He R, Adams HP, Vanpelt CS, Geng YJ, Deng JM, Behringer RR, et al. Postnatal induction of transforming growth factor beta signaling in fibroblasts of mice recapitulates clinical, histologic, and biochemical features of scleroderma. Arthritis Rheum. 2007;56(1):334–44. doi:10.1002/art.22328.
  • Sargent JL, Milano A, Bhattacharyya S, Varga J, Connolly MK, Chang HY, Whitfield ML. A TGFbeta-responsive gene signature is associated with a subset of diffuse scleroderma with increased disease severity. J Invest Dermatol. 2010;130(3):694705. doi:10.1038/jid.2009.318.
  • Asano Y, Ihn H, Yamane K, Kubo M, Tamaki K. Impaired Smad7-Smurf-mediated negative regulation of TGF-beta signaling in scleroderma fibroblasts. J Clin Invest. 2004;113(2):253–64. doi:10.1172/JCI16269.
  • Asano Y, Ihn H, Yamane K, Jinnin M, Mimura Y, Tamaki K. Increased expression of integrin alpha(v)beta3 contributes to the establishment of autocrine TGF-beta signaling in scleroderma fibroblasts. J Immunol. 2005;175(11):7708–18. doi:10.4049/jimmunol.175.11.7708.
  • Mimura Y, Ihn H, Jinnin M, Asano Y, Yamane K, Tamaki K. Constitutive thrombospondin-1 overexpression contributes to autocrine transforming growth factor-beta signaling in cultured scleroderma fibroblasts. Am J Pathol. 2005;166(5):1451–63. doi:10.1016/S0002-9440(10)62362-0.
  • Shi-wen X, Kennedy L, Renzoni EA, Bou-Gharios G, du Bois RM, Black CM, Denton CP, Abraham DJ, Leask A. Endothelin is a downstream mediator of profibrotic responses to transforming growth factor beta in human lung fibroblasts. Arthritis Rheum. 2007;56(12):4189–94. doi:10.1002/art.23134.
  • Silver RM. Endothelin and scleroderma lung disease. Rheumatology (Oxford). 2008 Oct;47 Suppl 5:v25–26. doi:10.1093/rheumatology/ken283.
  • Denton CP, Merkel PA, Furst DE, Khanna D, Emery P, Hsu VM, Silliman N, Streisand J, Powell J, Akesson A, et al. Cat-192 Study Group; Scleroderma Clinical Trials Consortium. Recombinant human anti-transforming growth factor beta1 antibody therapy in systemic sclerosis: a multicenter, randomized, placebo-controlled phase I/II trial of CAT-192. Arthritis Rheum. 2007;56(1):323–33. doi:10.1002/art.22289.
  • Rice LM, Padilla CM, McLaughlin SR, Mathes A, Ziemek J, Goummih S, Nakerakanti S, York M, Farina G, Whitfield ML, et al. Fresolimumab treatment decreases biomarkers and improves clinical symptoms in systemic sclerosis patients. J Clin Invest. 2015;125(7):2795–807. doi:10.1172/JCI77958.
  • Tamaki Z, Asano Y, Kubo M, Ihn H, Tada Y, Sugaya M, Kadono T, Sato S. Effects of the immunosuppressant rapamycin on the expression of human α2(I) collagen and matrix metalloproteinase 1 genes in scleroderma dermal fibroblasts. J Dermatol Sci. 2014;74(3):251–9. doi:10.1016/j.jdermsci.2014.02.002.
  • Yanaba K. Strategy for treatment of fibrosis in systemic sclerosis: Present and future. J Dermatol. 2016;43(1):46–55. doi:10.1111/1346-8138.13026.
  • Su TI, Khanna D, Furst DE, Danovitch G, Burger C, Maranian P, Clements PJ. Rapamycin versus methotrexate in early diffuse systemic sclerosis: results from a randomized, single-blind pilot study. Arthritis Rheum. 2009;60(12):3821–30. doi:10.1002/art.24986.
  • Gomez-Puerta JA, Mócsai A. Tyrosine kinase inhibitors for the treatment of rheumatoid arthritis. Curr Top Med Chem. 2013;13(6):760–73. doi:10.2174/15680266113139990094.
  • Sfikakis PP, Gorgoulis VG, Katsiari CG, Evangelou K, Kostopoulos C, Black CM. Imatinib for the treatment of refractory, diffuse systemic sclerosis. Rheumatology (Oxford). 2008;47(5):735–7. doi:10.1093/rheumatology/ken104.
  • Khanna D, Saggar R, Mayes MD, Abtin F, Clements PJ, Maranian P, Assassi S, Saggar R, Singh RR, Furst DE. A one-year, phase I/IIa, open-label pilot trial of imatinib mesylate in the treatment of systemic sclerosis-associated active interstitial lung disease. Arthritis Rheum. 2011;63(11):3540–6. doi:10.1002/art.30548.
  • Pope J, McBain D, Petrlich L, Watson S, Vanderhoek L, de Leon F, Seney S, Summers K. Imatinib in active diffuse cutaneous systemic sclerosis: Results of a six-month, randomized, double-blind, placebo-controlled, proof-of-concept pilot study at a single center. Arthritis Rheum. 2011;63(11):3547–51. doi:10.1002/art.30549.
  • Spiera RF, Gordon JK, Mersten JN, Magro CM, Mehta M, Wildman HF, Kloiber S, Kirou KA, Lyman S, Crow MK. Imatinib mesylate (Gleevec) in the treatment of diffuse cutaneous systemic sclerosis: results of a 1-year, phase IIa, single-arm, open-label clinical trial. Ann Rheum Dis. 2011;70(6):1003–9. doi:10.1136/ard.2010.143974.
  • Prey S, Ezzedine K, Doussau A, Grandoulier AS, Barcat D, Chatelus E, Diot E, Durant C, Hachulla E, de Korwin-Krokowski JD et al. Imatinib mesylate in scleroderma-associated diffuse skin fibrosis: a phase II multicentre randomized double-blinded controlled trial. Br J Dermatol. 2012;167(5):1138–44. doi:10.1111/j.1365-2133.2012.11186.x.
  • Gordon JK, Martyanov V, Magro C, Wildman HF, Wood TA, Huang WT, Crow MK, Whitfield ML, Spiera RF. Nilotinib (Tasigna™) in the treatment of early diffuse systemic sclerosis: an open-label, pilot clinical trial. Arthritis Res Ther. 2015;17:213. doi:10.1186/s13075-015-0721-3.
  • Martyanov V, Kim GJ, Hayes W, Du S, Ganguly BJ, Sy O, Lee SK, Bogatkevich GS, Schieven GL, Schiopu E, et al. Novel lung imaging biomarkers and skin gene expression subsetting in dasatinib treatment of systemic sclerosis-associated interstitial lung disease. PLoS One. 2017;12(11):e0187580. doi:10.1371/journal.pone.0187580.
  • Wermuth PJ, Piera-Velazquez S, Rosenbloom J, Jimenez SA. Existing and novel biomarkers for precision medicine in systemic sclerosis. Nat Rev Rheumatol. 2018;14(7):421–32. doi:10.1038/s41584-018-0021-9.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.