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Table of Contents 
REVIEW ARTICLE
Year : 2013  |  Volume : 58  |  Issue : 4  |  Page : 255-268
Systemic sclerosis: Current concepts in pathogenesis and therapeutic aspects of dermatological manifestations


1 Department of Dermatology, Rajiv Gandhi Medical College and CSM Hospital, Kalwa, Thane Municipal Corporation, India
2 L.T.M.M.C and L.T.M. General Hospital, Sion, Mumbai, India
3 Consultant Dermatologist, Thane Skin Centre and Disha Skin and Laser Institute, Thane, Maharashtra, India

Date of Web Publication25-Jun-2013

Correspondence Address:
Vishalakshi Viswanath
102, Eden II, Hiranandani Estate, Patlipada, Thane (W)-400 607, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0019-5154.113930

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   Abstract 

Systemic sclerosis (SSc) is a chronic, multisystem connective tissue disease with protean clinical manifestations. Recent advances in understanding the pathogenic mechanisms have led to development of target-oriented and vasomodulatory drugs which play a pivotal role in treating various dermatological manifestations. An exhaustive literature search was done using Medline, Embase, and Cochrane library to review the recent concepts regarding pathogenesis and evidence-based treatment of salient dermatological manifestations. The concept of shared genetic risk factors for the development of autoimmune diseases is seen in SSc. It is divided into fibroproliferative and inflammatory groups based on genome-wide molecular profiling. Genetic, infectious, and environmental factors play a key role; vascular injury, fibrosis, and immune activation are the chief pathogenic factors. Vitamin D deficiency has been documented in SSc and correlates with the severity of skin involvement. Skin sclerosis, Raynaud's phenomenon (RP) with digital vasculopathies, pigmentation, calcinosis, and leg ulcers affect the patient's quality of life. Immunosuppressives, biologicals, and hematopoietic stem cell transplantation are efficacious in skin sclerosis. Endothelin A receptor antagonists, calcium-channel blockers, angiotensin receptor inhibitors, prostacyclin analogs, and phosphodiesterase type 5 (PDE-5) inhibitors are the mainstay in RP and digital vasculopathies. Pigmentation in SSc has been attributed to melanogenic potential of endothelin-1 (ET-1); the role of ET 1 antagonists and vitamin D analogs needs to be investigated. Sexual dysfunction in both male and female patients has been attributed to vasculopathy and fibrosis, wherein PDE-5 inhibitors are found to be useful. The future concepts of treating SSc may be based on the gene expression signature.


Keywords: Endothelin receptor antagonists, fibrosis, immune activation, immunosuppressives, PDE-5 inhibitors, systemic sclerosis, vascular injury


How to cite this article:
Viswanath V, Phiske MM, Gopalani VV. Systemic sclerosis: Current concepts in pathogenesis and therapeutic aspects of dermatological manifestations. Indian J Dermatol 2013;58:255-68

How to cite this URL:
Viswanath V, Phiske MM, Gopalani VV. Systemic sclerosis: Current concepts in pathogenesis and therapeutic aspects of dermatological manifestations. Indian J Dermatol [serial online] 2013 [cited 2019 Jul 22];58:255-68. Available from: http://www.e-ijd.org/text.asp?2013/58/4/255/113930

What was known? Vascular injury, fibrosis, and immune activation are the primary pathogenic factors responsible for the various clinical manifestations in SSc. SSc is classified into limited and diffuse cutaneous forms based on the extent of skin involvement. Treatment of cutaneous manifestations depends on the stage and subset of the disease.



   Introduction Top


Systemic sclerosis (SSc) is a chronic, multisystem connective tissue disease characterized by microangiopathy leading to inflammation and fibrosis involving skin and internal organs. SSc is divided into diffuse cutaneous (dcSSc) and limited cutaneous (lcSSc) forms based on the extent of skin involvement. This article reviews the current concepts regarding the pathogenesis and treatment of salient dermatological manifestations.

Etiology and pathogenesis

Various genetic, infectious, and environmental factors have been implicated; vascular injury, fibrosis, and immune activation form the key components in pathogenesis as illustrated in [Figure 1].
Figure 1: Summary of etiological factors and pathogenesis of systemic sclerosis

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Genetic factors

SSc occurs more commonly in families with SSc (1.6%) than in the general population. Though positive family history represents the strongest factor identified, indicating an important role for heredity, the likelihood of developing disease is < 1% among offsprings of patients. [1] The presence of SSc in a first-degree relative confers a significantly increased risk of SSc, Raynaud's phenomenon (RP), interstitial lung disease, and other autoimmune diseases. [2] Vasculopathy is the most important heritable component and fibrosis is less polygenic.

Molecular subsets in the gene expression signature of scleroderma skin have been identified using genome-wide expression profiling. The dcSSc subset has been identified with the fibroproliferative gene expression, whereas lcSSc and few cases of diffuse form possess the inflammatory gene expression signature. [3] Particular alleles in the genes for transforming growth factor-β (TGF-β), monocyte chemoattractant protein-1 (MCP-1), interleukin 1-a (IL-1a), tumor necrosis factor-α (TNF-α), connective tissue growth factor (CTGF), fibrillin-1, interferon regulatory factor-5 (IRF-5), signal transducer and activator-4 have been related to disease susceptibility and clinical features. [4] Increased incidence of HLA-B8 is seen in severe cases; [5] mild disease shows raised DR2 and DR5 and anti-centromere antibodies (ACA). HLA-DRB1*11-DQB1*0301 haplotypes have been associated with anti-topo I positivity, whereas HLA-DRB1*01-DQB1*0501 haplotypes are more common in ACA-positive patients. [1]

The concept of shared genetic risk factors for the development of autoimmune diseases is seen in SSc. [6] Recently multiple genes involved in immune regulation including BANK1, C8orf13-BLK, IL-23R, IRF5, STAT4, TBX21, and TNFSF4 have been identified as susceptibility genes for SSc development. [6] PTPN22 has been associated with SSc and also with the development of type I diabetes mellitus, rheumatoid arthritis (RA), and systemic lupus erythematosus (SLE). STAT4 and IRF5 are associated with SSc susceptibility and have been identified as susceptibility genes for the development of SLE and RA. TNFSF4, BANK1, and C8orf13-BLK have joined the list of shared autoimmune genes with risk association with SSc and SLE. BANK1, IRF5, and STAT4 risk alleles displayed a 1.43-fold increased risk of dcSSc. [1] A strong and reproducible association of the STAT4 gene is seen with lcSSc, suggesting that this gene seems to be one of the genetic markers influencing SSc phenotype. [7] The definitive involvement of CTGF variants in the genetic background remains to be established. [1]

Another interesting hypothesis is demonstration of microchimerism in SSc, wherein the transfer of fetal cells to the mother or vice versa during pregnancy may stimulate a unique immune response. [5]

Infections

Numerous infectious agents (bacterial and viral) have been proposed as possible triggering factors, but a direct casual association between infections and SSc is still missing. [8] The various organisms implicated are parvovirus B19, human cytomegalovirus, hepatitis B virus, retroviruses, Helicobacter pylori, and Chlamydia. The four pathogenic hypotheses postulated are molecular mimicry, endothelial cell damage, superantigens, and microchimerism. [9] Homology between viruses and autoantibody targets suggests that in individuals with appropriate genetic and hormonal background, molecular mimicry may have a role in initiating antibody response in SSc. The infectious agents synergize with other factors in the microenvironment and become potential co-factors in initiation of autoimmune response. Endogenous retrovirus (ERV) may lead to autoimmunity directly, by encoding autoantigens, or indirectly, by affecting the expression of genes regulating immune responses and tolerance. Several autoantigens, such as U1nRNP and Scl-70, share cross-reactive epitopes with murine retroviral gag proteins. High Human T-lymphotrophic Virus (HTLV)-related endogenous sequence 1 (HRES-1) peptide binding activity has been found in 23% of SSc sera. Antibodies against p24/p25 gag protein of HIV have been detected.

Environmental factors

SSc is linked with occupational exposure to silica, polyvinyl chloride trichloroethylene, organic solvents, pesticides, hair dyes, and industrial fumes. Drugs implicated include bleomycin, pentazocine, and cocaine. Radiation therapy can give rise to de novo SSc and can cause exacerbation of tissue fibrosis in patients with existing SSc. [10] Physical trauma can precipitate disease in genetically predisposed individuals.

Vitamin D deficiency has been documented in 80% of SSc patients. Levels of vitamin D correlate with severity of skin involvement, [11] higher levels of parathyroid hormone, and higher incidence of acroosteolysis and calcinosis. [12] Thilo et al. found no significant relationship between decreased levels and clinical features of SSc. [13] Low vitamin D levels in SSc patients are universal and independent of geographic origin or vitamin D supplementation. [14] Vitamin D deficiency in SSc is related to several factors. Dermal fibrosis with capillary damage could lead to a reduced drawing of pre-vitamin D3 synthesized from 7-dehydrocholesterol by UVB radiation in the epidermis. Gastrointestinal involvement and malabsorption of dietary vitamin D [15] and skin hyperpigmentation with diminished sunlight exposure could play a role. [16] Adaptive and innate immunity are affected by vitamin D deficiency. [15] Higher doses of vitamin D or novel vitamin D analogs are needed to correct the deficiency, especially in those with high inflammatory activity or severe disease. [17]

Pathogenesis

Vascular injury


The primary event is vascular injury and activation, with evidence of vascular damage being present before fibrosis. There is an altered vasodilator/vasoconstrictor balance which results in impaired blood flow response. Episodes of ischemia-reperfusion lead to oxidative stress that further increases vascular injury. Initial vascular insult is endothelial cell injury triggered by unidentified serum toxic factors or T-cell derived proteolytic enzymes, endothelial cell-directed autoantibodies, vasculotropic viruses, inflammatory cytokines, and environmental stress. Vascular injury leads to endothelial cell activation and dysfunction, leading to increased expression of vascular endothelial cell adhesion molecule-1 and endothelial leukocyte adhesion molecule-1, altered secretion of vasoactive mediators, activation of platelets, and fibrinolytic pathways. Activated platelets release thromboxane A2, platelet-derived growth factor PDGF, and transforming growth factor beta TGF-β which cause vasoconstriction; contribute to fibroblast activation, and myofibroblast transdifferentiation. Activated endothelial cells secrete various vasoactive mediators such as nitric oxide, prostacyclin, and endothelin-1 (ET-1). [4]

ET-1, the most potent vasoconstrictor, promotes leukocyte adhesion, endothelial cells' proliferation, and vascular smooth muscle cell proliferation, and induces fibroblast activation and irreversible vascular obliteration. ET-1 participates in fibrotic cascade by stimulation of fibroblast collagen production and inhibition of matrix metalloproteinase-1 activity. Elevated levels of ET-1 correlate with severity of RP, digital ulcers, pulmonary arterial hypertension PAH, and renal failure in SSc. There are two types of receptors to ET-1: ET-A and ET-B. In SSc, ET-B receptors are down-regulated, displacing the balance toward vasoconstriction and fibrosis. [18] The ability of endothelial cells to synthesize and release prostacyclin is reduced. Production and responsiveness of endothelium to vasodilatory factors is defective. Hypertrophy of intimal and medial layers of small blood vessels, along with adventitial fibrosis results in luminal narrowing. This process along with endothelial cell apoptosis leads to obstructive vasculopathy and vascular rarefaction, causing tissue hypoxia.

Tissue hypoxia normally stimulates neoangiogenesis. In SSc, neoangiogenesis is impaired despite elevated levels of vascular endothelial growth factor (VEGF) and its receptors. The numbers and function of bone marrow-derived CD34+//endothelial progenitor cells are depleted. Ischemia stimulates production of TGF-β/CTGF, followed by fibroblast activation and excessive extracellular matrix (ECM) production. Pericytes become activated and transform to collagen-producing myofibroblasts. Anti-endothelial cell antibodies found in SSc induce endothelial cells' apoptosis. Thus, vascular repair mechanisms are compromised due to paucity, defective mobilization or function of endothelial progenitor cells. [4] Recently, the progressive disappearance of lymphatic vessels has been reported. [19]

Various abnormalities in blood components contribute to tissue anoxia: Red cell deformability is reduced, platelet aggregation to collagen is specifically enhanced, and in vivo markers of platelet activation are increased. Levels of fibrinogen, von Willebrand factor, and other plasma proteins are increased, contributing to increased plasma viscosity, further reducing microvascular blood flow. [5]

Fibrosis

SSc is characterized by fibrosis, a replacement of normal tissue architecture with excess deposition of ECM resulting from inflammation or damage. The fibrosis in SSc is caused by increased production of collagen in subcutaneous tissue. The key cellular moderator of fibrosis is collagen-producing myofibroblasts. Myofibroblasts are activated by paracrine and autocrine signals and through Toll-like receptors [TLRs] on fibroblasts. Fibrosis is driven by multiple mediators such as TGF-β1, PDGF, VEGF, ET-1, IL-13, IL-21, MCP-1, macrophage inflammatory protein, and rennin-angiotensin-aldosterone system. Abnormal balance between matrix metalloproteinases and tissue inhibitor of metalloproteinases results in excess synthesis of ECM and impaired ECM catabolism, leading to collagen accumulation. [4]

The epithelium is a major cover of the skin and mucosal barrier of the oral cavity, gastrointestinal, and respiratory tract; it plays an important role in resurfacing injured tissue. Under ischemic conditions, epithelial cells lose cell-cell attachment and transform into mesenchymal or collagen-producing myofibroblasts. Scleroderma epithelial cells stimulate normal fibroblasts to express CTGF, IL-1a, ET-1, and TGF-β. [20] Production of IL-6 and IL-8 is significantly increased in SSc fibroblasts compared with controls. [21]

TGF-β is one of the central pro-fibrotic cytokines. TGF-β1 triggers signaling through Smad proteins that, in turn, control procollagen I and III gene transcription . Alterations in Smad pathway are responsible for TGF-β hyperresponsiveness in SSc. [22] Angiotensin II, produced locally by activated macrophages and fibroblasts, stimulates TGF-β1 production, fibroblast proliferation, and their differentiation into collagen-producing myofibroblasts. Chemokines contribute to fibrosis by recruiting myofibroblasts, macrophages, and peripheral blood mononuclear cells to sites of tissue injury. [4] Th2 cytokines cooperate with TGF-β to induce fibrosis.

Recent studies have shown that caveolin-1 (membrane protein found clustered within specialized microdomains, termed lipid rafts) participates in the pathogenesis of fibrotic diseases due to its role in the regulation of TGF-β signaling. There is a decrease in caveolin-1 expression in SSc-affected tissues. Restoration of caveolin-1 function employing novel cell permeable peptides coupled to active caveolin-1 may represent a novel treatment for SSc. [23] Abnormal metabolism and responses to serotonin and tryptophan and increase in mast cells may contribute to both fibrosis and vascular abnormalities. [5]

Immune system

Although the immune system is affected, immunologic events occur early in the disease process and are then no longer involved. [24],[25]

Innate and adaptive immunity

An emerging hypothesis implicates an altered balance between Th1 and Th2 cytokines in aberrant response to tissue injury. There is a shift of immune response toward a Th2 pattern which contributes to a more pro-fibrotic environment. T cells polarized to a Th2 pattern secrete abundant IL-4, IL-5, and IL-13, with paucity of Th1 cytokine interferon gamma [IFN-ɤ]. The Th2 cytokines are pro-fibrogenic because they can directly stimulate collagen synthesis and myofibroblast transdifferentiation and induce TGF-β. In contrast, the Th1 cytokine IFN-ɤ blocks these responses and exerts anti-fibrotic effects. SSc patients exhibit reduced levels of IFN-ɤ in blood and defective production of IFN-ɤ by both peripheral blood mononuclear cells and bronchoalveolar lavage cells. [25] Abnormal IL-4 production may be responsible for the prevalent Th2 response.

T lymphocytes

An early event is T-cell activation, (a selective process that appears to be influenced by antigen in SSc patients) with infiltration in skin and internal organs. CD4+ T cells predominate in the skin. Many nonspecific inflammatory cells like macrophages and monocytes, mast cells, eosinophils, basophils, and natural killer cells infiltrate various tissues and show evidence of activation. Soluble mediators made by T cells, B cells, and the non-specific inflammatory cells activate and damage the fibroblasts, endothelial cells, and other vascular cells. [26] The circulating T cells show spontaneous cytokine secretion; there is an increased expression of IL-2 receptor and elevated serum IL-2 levels.

B lymphocytes

Polyclonal activation of B cells leads to hypergammaglobulinemia. [26] Elevated serum levels of B-cell-activating factor and increased expression of CD19 may contribute to B-cell abnormalities. [24] The number of naïve B cells is elevated in circulation, whereas plasma cells are decreased. Memory B cells are chronically activated and display increased CD95, CD86, and CD19. Altered B-cell function and chronic activation causes autoantibody production and fibrosis because activated B cells secrete IL-6, which directly stimulates fibroblast activation and synthesis of collagen.

TLR and non-TLR-based immune responses

TLR activation leads to stimulation of dendritic cells, B-cell maturation, and stimulation of other inflammatory mediators, such as IL-1, IL-6, and TNF-α in macrophages and dendritic cells. Activation of these and other inflammatory mediators, through TLR and non-TLR sensors, upregulates fibrotic mediators such as TGF-β and IL-13. [27] An expanding array of non-TLR innate immune pathways has recently been discovered. Nalp3-mediated inflammasome activation of caspase-1 and conversion of pro-IL-1 to IL-1 play a key role in silica- and bleomycin-mediated pulmonary fibrosis. [27]

Circulating autoantibodies

Various theories have been proposed to explain the generation of autoantibodies. Specific self-antigens like topoisomerase (Scl70) may undergo fragmentation due to proteolytic cleavage by reactive oxygen species, resulting in exposure of normally cryptic epitopes and break in immune tolerance, with recognition of peptide as immunogenic. Specific autoantibodies in SSc may indicate different disease subsets and organ damage. [4] Serum levels of Scl70 may correlate with the extent of skin and lung fibrosis and may fluctuate with the disease. The rates of higher modified Rodnan skin score (mRSS) and organ involvement are significantly higher in patients with anti-topo I compared to those with ACA. In patients with RP and abnormal nail-fold capillaroscopy, the presence of ACA, anti-topo I, and anti-RNAP-III autoantibodies independently predicted progression to definite SSc in 79.5% of patients. The presence of ACA correlated with longstanding RP and SSc, and has been associated with CREST. Absence of ACA and presence of anti-topo I is associated with pulmonary fibrosis, while presence of ACA is associated with less likelihood of pulmonary fibrosis. [4]

Anti-fibrillin-1 antibodies stimulate release of TGF-β, and are predictive of severe skin and systemic involvement. Anti-nucleolar pattern and anti-Th/To antibodies are an index for mild and limited disease. Prevalence of anti-RNAP-III is low, but their presence is associated with severe skin disease and scleroderma renal crisis, and may indicate the link between scleroderma and cancer. [4]

Anti-angiotensin receptor and anti-ET-A receptor autoantibodies correlate with severity and mortality. [4] Functional antibodies to methionine sulfoxide reductase A correlate with cardiac, lung, and renal involvement. Stimulatory antibodies to the PDGF receptor-induces tyrosine phosphorylation, reactive oxygen species accumulation, type I collagen gene expression, and myofibroblast phenotype in normal fibroblasts. [4] Anti-collagen antibodies to collagen types I and IV appear to be inversely related to disease severity. [5] Anti-mitochondrial antibody (AMA) is found in the sera of some patients. [28] Patients with diffuse SSc show reactivity directed to PM/Scl-75 autoantigen. [29]

Hyperpigmentation

The mechanism of diffuse pigmentation in SSc is unknown. Smith et al. concluded that raised plasma beta Melanocyte-stimulating Hormone (βMSH) level is not the cause of pigmentation. [30] ET-1 is produced in keratinocytes, and promotes melanogenesis by multiplication of melanocytes and melanin synthesis. Increased ET-1 productivity in keratinocytes and a correlation between ET-1 productivity in keratinocytes and skin pigmentation is seen in severe cases of SSc. [31] Cytokines such as IL-1a may be overproduced in SSc patients, and therefore promote ET-1 productivity from keratinocytes. [31]

Calcinosis

In SSc, elevated osteonectin mRNA levels are seen in cultured fibroblasts, correlating with increase in type I collagen levels. Circulating concentrations of osteonectin in patients with limited SSc, but not diffuse SSc, are reported to be significantly higher than in controls. A study has identified increased gene and protein expression of osteonectin in cultured dermal fibroblasts. [32] Protein expression of osteonectin and Matrix gla protein (MGP) (a vitamin K-dependent calcium-binding protein) is greater in SSc, and osteonectin expression is significantly higher in endothelial cells and fibroblasts of SSc patients with calcinosis. [32]

Treatment modalities of dermatological manifestations

The cutaneous manifestations depend on stage/subset of the disease. Skin sclerosis is a primary manifestation. [33],[34] RP is the second most common finding seen in more than 95% of patients. [34] Ischemic digital ulcers, a debilitating manifestation, is prevalent in approximately 50% of patients. [34],[35] Pigmentation is more common in Hispanics and African Americans than in Caucasians. [36] The authors have found this to be a presenting feature in many patients of SSc in the Indian subcontinent. Calcinosis cutis, leg ulcers, telangiectasia, and sexual dysfunction are the other concerns posed to the dermatologist. The clinical manifestations have a profound impact on the patient's quality of life. [37]

The therapy of cutaneous manifestations depends on the stage/subset of the disease. SSc has been divided into a fibroproliferative and inflammatory group based on genome-wide molecular profiling. [3] Hence, future concept of treating SSc may evolve into an individualized approach based on gene expression signature. Vascular and inflammatory damage precedes fibrotic component; this is important since therapy that does not target inflammatory component may not be able to target all the manifestations. The salient cutaneous manifestations and treatment modalities have been summarized in [Table 1].
Table 1: Salient dermatological manifestations and their treatment modalities


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Skin fibrosis

Current treatment options for skin fibrosis appear to be limited. Drugs targeting immune system, B cells, interleukins, and inflammatory cytokines which are responsible for skin fibrosis have been used. [Table 2] outlines the various therapies for skin sclerosis.
Table 2: Treatment modalities for skin sclerosis


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A wide array of immunosuppressives has been used based on the concept that immune system contributes to pro-fibrotic environment. Methotrexate (MTX) has been one of the most commonly considered drugs for treatment of early diffuse SSc [38] and helps in inhibition of antigen-induced T-cell activation . [39] Mycophenolate mofetil (MMF) has been used as a second-line drug . The beneficial role of cyclophosphamide is well known in SSc-related interstitial lung disease, but its benefit in improving skin scores is not well documented. Azathioprine can be used as maintenance therapy, whereas use of cyclosporine is limited by marginal therapeutic efficacy and adverse effects. [Table 3] shows the outcome of immunosuppressives on skin sclerosis. [40],[41],[42],[43],[44],[45],[46],[47],[48],[49],[50],[51]
Table 3: Immunosuppressives used in SSc and effect on skin sclerosis[40-51]


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B cells and TNF-α have arisen as possible players in tissue fibrosis; hence, biologicals have been used in SSc. IL-6 produced by B cells may induce matrix synthesis and less collagen degradation. [52] B cells in patients with scleroderma have 20% higher CD19 expression than B cells from healthy subjects. [53] B-cell depletion is a promising therapeutic target in patients with diffuse cutaneous systemic sclerosis. [54] The role of TNF-α in fibrotic conditions is controversial. Anti-TNF-α treatments could be a promising anti-fibrotic strategy for early inflammatory skin fibrosis, while it might be deleterious for later non-inflammatory stages. [55] It was noted that TNF-α inhibitors may improve inflammatory arthritis and disability, but the effect on mRSS is uncertain. [56] Biologicals used in SSc are shown in [Table 4]. [57],[58],[59],[60],[61],[62],[63],[64],[65]
Table 4: Biologicals used in SSc and effect on skin sclerosis[57-65]


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Imatinib mesylate inhibits c-Abl (non-receptor tyrosine kinase) and platelet-derived growth factor receptor. In vitro use has demonstrated its anti-fibrotic property. [66] In a 1-year, phase IIa, single-arm, open-label clinical trial, 30 patients of diffuse cutaneous SSc treated with imatinib showed reduction in mRSS by 22.4%. [67]

d-penicillamine, [68] rapamycin, [69] and halofuginone [70] have been tried with mixed results. d-penicillamine was found effective at a median dose of 750 mg. [71] Rapamycin, a drug that blocks the response of T cells to cytokines including IL-2, was found to be as effective as methotrexate. [69],[72] Topical application of 0.01% of halofuginone reduced skin scores in a pilot study. [73]

Hematopoietic stem cell transplantation (HSCT) following immune ablation allows resetting of immune system and halting of fibrotic processes. Clinical improvement with autologous HSCT was seen in 81% at a median follow-up of 5.3 years. [74] There was a sustained improvement in mRSS at the end of 2-year follow-up period in the HSCT group compared to cyclophosphamide in a recent phase 2 trial. [75] Extracorporeal photopheresis, useful in various T-cell- mediated disorders, has shown significant improvement in skin thickness. [76],[77] Intravenous Immunoglobulin IVIG modulates cytokine production, inhibits IL-4 and TGF-β, and decreases fibrogenesis. [78] A mean reduction in mRSS of 35% was seen with monthly infusions of IVIG at a concentration of 2 g/kg (over a 5-day period for each course ) . [79] IVIG was helpful in refractory joint pain, tenderness, and functioning. [80] In a randomized controlled trial of low-dose Ultraviolet A 1(UVA1), medium-dose UVA1, and narrowband Ultraviolet B (NBUVB) therapy in localized scleroderma, skin scores improved in all three groups; however, medium-dose UVA1 was more effective than NB UVB. [81]

The role of corticosteroids in SSc is controversial. Steroids inhibit collagenase activity, [82] but high-dose steroid is associated with scleroderma renal crisis. [83] Despite this, an analysis of prescriptions and compilation of expert opinion revealed high use of steroids. [84],[85] Efficacy of dexamethasone pulse therapy for skin sclerosis has been proposed by Indian authors in various case series. [86],[87],[88] Dexamethasone pulses may help in lowering skin scores and improving Raynaud's in certain group of patients, but adverse effects may preclude its use in all patients. [89]

RP and digital ulceration

Capillaroscopy can represent an outcome measure for therapeutic interventions in vasculopathies in SSc. [90] [Table 5] outlines the current treatment modalities. [91],[92],[93],[94],[95],[96],[97],[98],[99],[100],[101],[102] Topical glyceryl trinitrate and sustained release patches show subjective efficacy in RP; however, frequent headaches limit its use. [103],[104] Low-molecular-weight dextran shows temporary improvement in digital circulation; [105] however, acute renal failure is a known complication. [106] Pentoxyfylline reduces cutaneous fibrosis, [107],[108] improves microcirculation, and reduces TNF-α. [109] Recently, botulinum toxin has been found useful in RP in overlap syndrome. [110]
Table 5: Drugs used in Raynaud's phenomenon and ischemic digital ulcers[91-102]


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Pigmentary changes

There are no documented studies for treatment of pigmentary changes. Since ET-1 and vasoconstriction have been postulated as factors in pigmentation, [31] ET-1 antagonists and vasodilators may play a beneficial role. Vitamin D deficiency in SSc correlates with the severity of skin involvement . [11],[14] In an open-label study, vitamin D analog (topical calcipotriene 0.005% ointment) has shown significant improvement in induration and dyspigmentation in localized scleroderma. [111] Hence, a possible role of topical vitamin D analogs in the pigmentary changes of SSc needs to be investigated.

Calcinosis

[Table 6] lists the common treatment modalities for calcinosis. [112],[113],[114],[115],[116],[117],[118],[119] Drugs tried anecdotally include low-dose warfarin (1 mg/day), [120] ceftrioxone (2 g/day for 20 days), [121] aluminum hydroxide (1.8-2.4 g/day), [122],[123],[124] and IVIG (2 g/day × 4 days once a month). [125] Surgical excision plus medical management gives good results. [126] Small digital calcified deposits have been effectively treated with carbon dioxide laser. [127],[128] Extracorporeal Shockwave Lithotripsy (ESWL) was found effective against small, ulcerated, and radiopaque calcinosis, with profound analgesic effect. [129]
Table 6: Treatment modalities used in calcinosis[112-119]


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Leg ulcers

Appropriate oral antibiotics and local care are important for treating leg ulcers. Non-digital ulcers refractory to conventional treatments significantly improve by administration of bosentan. [130],[131],[132] Recombinant human erythropoietin showed good improvement for non-healing cutaneous ulcers . [133] A pilot open study reported the usefulness of platelet gel in refractory leg ulcers. [134] Becaplermin (recombinant human platelet-derived growth factor) has been used in conjunction with oral immunosuppressive agents. [135] Granulocyte colony-stimulating factor (G-CSF) has shown significant improvement in non-healing ulcers. [136] Hydrocolloid membrane dressings help in faster healing of leg ulcers and have been used in conjunction with other agents or independently. [137] Low-molecular-weight heparin, darbepoeitin alfa, pentoxifylline, nifedipine, and arterioplasty were used by Shanmugam et al. in SSc with leg ulcers. [138] Surgical correction by revascularization and vein surgeries improve healing of leg ulcers. [139]

Telangiectasia

Telangiectasia can be treated for cosmetic concerns by 585-nm flash lamp pumped pulsed dye lasers. [140] Intense Pulse Light (IPL) is similarly effective, but may cause pigmentation in darker skins. Therapies targeting vascular damage can be tailored based on capillaroscopy or dermatoscopy. Caramaschi found the effectiveness of cyclophosphamide in reversing microvascular damage. [141]

Sexual dysfunction [142]

Male erectile dysfunction, noted in 81% SSc patients, is attributed to vasculopathy and cavernosal fibrosis. In female patients, skin tightening around the vaginal introitus, joint contractures, muscle weakness, changes in skin around the breasts, and joint pain have been found to be associated with lower levels of sexual functioning. Phosphodiesterase type 5 (PDE-5) inhibitors are effective in males, with tadalafil showing better response rates. Use of tadalafil for RP has shown minimal effects on sexual function of the female patients too.


   Conclusion Top


Vascular injury, fibrosis, and immune activation are primarily responsible for the clinical features in SSc. Insights into the various genetic , molecular, and immune mechanisms in the pathogenesis preclude the role of target-oriented therapy for various dermatological manifestations. Pigmentation has been attributed to melanogenic potential of ET-1; therapeutic role of vasodilators, ET 1 antagonists, and vitamin D analogs needs to be investigated. The future concepts of treatment in SSc may be an individualized approach based on genome profiling.


   Acknowledgment Top


We are thankful to Dr. Ashwin Kosambia, Consultant Dermatologist, Mumbai, India, for his contribution toward [Figure 1], the pictorial representation depicting the etiology and pathogenesis in systemic sclerosis.

 
   References Top

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What is new? 1. The concept of shared genetic risk factors for the development of autoimmune diseases is seen in SSc. SSc has been divided into fibroproliferative and inflammatory groups based on the genome.wide molecular profiling, and future treatment may be an individualized approach based on genome profiling. 2. Vitamin D deficiency has been documented in SSc and correlates with the severity of skin involvement. 3. B.cell depletion is a promising therapeutic target in patients with diffuse cutaneous systemic sclerosis. 4. Endothelial receptor antagonist, bosentan, is useful in RP, prevention of new digital ulcers and non.digital ulcers in SSc. 5. Pigmentation has been attributed to melanogenic potential of ET.1; therapeutic role of vasodilators, ET.1 antagonists, and vitamin D analogs needs to be investigated. 6. PDE.5 inhibitors are effective in both male and female SSc patients with sexual dysfunction.


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