Pathophysiology 26 (2019) 103–114

Contents lists available at ScienceDirect

Pathophysiology

jo urnal homepage: www.elsevier.com/locate/pathophys

Review

Scleroderma: An insight into causes, pathogenesis and treatment strategies

a,b a,d a a,c

Deependra Singh , Arun KS Parihar , Satish Patel , Shikha Srivastava ,

a a,b,∗

Prakriti Diwan , Manju R Singh

a

University Institute of , Pt. Ravishankar Shukla University, Raipur, C.G, 492010, India

b

National Centre for Natural Resources, Pt. Ravishankar Shukla University, Raipur, C.G, 492010, India

c

Department of Pharmacy, School of Medical and Allied Sciences, Galgotias University, Greater Noida, U.P, India

d

Drugs Testing Laboratory Avam Anusandhan Kendra, Raipur (C.G), 492001, India

a r a

t i b s

c l e i n f o t r a c t

Article history: is an autoimmune disorder, characterized by morphological changes in skin followed by

Received 23 November 2018

visceral organs. The pathogenesis of scleroderma involves immune imbalance and generation of auto

Received in revised form 2 May 2019

. The major causes of scleroderma include multitude of factors such as immune imbalance,

Accepted 13 May 2019

oxidative stress, genetics and environment factors. A constant effort has been made to treat scleroderma

through different approaches and necessitates life time administration of drugs for maintenance of a good

Keywords:

quality life. It has been reported more in women compared to men. Traditional treatment strategies are

Scleroderma

restricted by limited therapeutic capability due to associated side effects. Advancement in development

Autoimmune disorders

Pathogenesis of novel drug delivery approaches has opened a newer avenue for efficient . Current review

is an effort to reflect scleroderma in provisions of its pathogenesis, causative factors, and therapeutic

Oxidative stress

Antioxidants approaches, with concern to mode of action, pharmacokinetics, marketed products, and side effects of

drugs.

© 2019 Published by Elsevier B.V.

Contents

1. Introduction ...... 104

1.1. Complications of scleroderma ...... 104

1.2. Causes of scleroderma ...... 104

2. Pathogenesis and its causative factors ...... 104

2.1. Importance of and Macrophage: ...... 105

2.2. Progression of scleroderma ...... 105

3. Treatment strategies ...... 106

3.1. Treatment based approach ...... 106

3.1.1. Drug based approach...... 106

3.1.2. Herbs based approach...... 106

3.1.3. Antioxidant therapy ...... 106

3.1.4. Biologics ...... 106

3.2. Novel delivery based approach ...... 111

3.2.1. Recent therapy ...... 111

4. Conclusion and future prospects ...... 112

5. Declaration of interest ...... 112

Acknowledgement ...... 112

References ...... 112

∗

Corresponding author at: University Institute of Pharmacy, Pt. Ravishankar Shukla University, Raipur, C.G., 492010, India.

E-mail address: [email protected] (M.R. Singh).

https://doi.org/10.1016/j.pathophys.2019.05.003

0928-4680/© 2019 Published by Elsevier B.V.

104 D. Singh et al. / Pathophysiology 26 (2019) 103–114

1. Introduction stage of Raynauds phenomena. Limited cutaneous forms include a

distal skin involvement, systemic vascular disorders like delayed

Scleroderma is an autoimmune rheumatic disease character- onset of pulmonary arterial hypertension (PAH) and prevalence

ized by substantial damage of vascular system, tissue fibrosis and of ACA. Mainly antinuclear antibodies (ANA) in between range of

accumulation of in skin. Word ‘scleroderma’ comes from 60–80% are found positively in patients of scleroderma [5]. The

two Greek words in which SCLERO stands for hard and DERMA for disease reduces the efficiency and quality life of patient due to

skin. So it is a disease in which hardening of skin and connective increased level of sleeping disorders, fatigues, depression, and sex-

tissue occurs either locally or all over the body. Scleroderma has ual dysfunction.

been classified into two types on the basis of level of its occurrence

i.e. localized and systemic [1]. Localized scleroderma is limited to

1.2. Causes of scleroderma

skin and muscular levels which are known as morphea and linear

type. If it affects larger area of skin and then it is known as

Immunological imbalance, environmental factors (silica expo-

systemic which further includes limited and diffuse forms [2]. Lim-

sure, chlorinated solvents, trichloroethylene, welding fumes for

ited form includes: Calcinosis (skin ulcer with white deposits and

men, aromatic solvents and ketones), genetic factors and oxidative

mineral crystal deposits); Raynaud’s Phenomena (blue coloration

stress play a major role in the pathogenesis of Scleroderma (Fig. 1).

of fingers); Esophageal motility (severe burn and reflux disor-

Environmental factors and oxidative stress causes immune imbal-

der); sclerodactylia (stiffness and tightening of skin);

ance effecting both B cells and T cells. Immune imbalance causes

(whitening of blood vessels creates flat red mark) [3]. Diffusive

generation of antibodies like anti-centromere, anti-topoisomerase-

form includes: Interstitial Pulmonary fibrosis (damaging heart, dry

I and anti-RNA polymerase III indirectly suggesting role of B cells

cough, shortness of breath, reduced ability to exercise); Pulmonary

which causes vasculopathy and skin fibrosis. Endothelial and fibro-

Hyper Tension (narrowing of the pulmonary , chest pain and

blast cells get exposed to inducing production of

fatigues); symptoms (renal crisis, weakness and fatigue);

reactive oxygen species. This collectively promotes fibroblast cells

Heart symptom (inflammation, arrhythmias and ) [4].

proliferation and fibrosis. Increased risk of pulmonary fibrosis has

Crest syndrome involves c-calcinosis (calcium deposits in skin),

also been observed due to gene associated expression of signal

r- raynauds phenomenon (spasm of blood vessels), e-esophageal

transducer activator of 4 (STAT4) and -

dysfunction (acid reflux and decrease in motility of ),

regulatory factor 5 (IRF5) and c-src tyrosine kinase (CSK) which

s-sclerodactyly (thickening and tightening of skin on fingers and

alters signaling through T-cell receptor and their subunits like

hands), t- (dilation of capillaries) [5]. Scelroderma

CD247. The Fig. 1 depicts the causative factor and pathogenesis of

is also associated with frequent fatigues, depression, sleeping dis-

scleroderma. Oxidative stress too contributes a lot in pathogen-

orders and sexual dysfunction that also lead to disability and a

esis of scleroderma. Oxidative stress provokes respiratory burst

reduced quality of life [6]. Scleroderma is among the auto-immune

in inflammatory cells, promotes production of reactive oxygen

rheumatic diseases with high disease-related mortality and mor-

and nitrites species like superoxides, hydroxyls, peroxynitrites and

bidity with an impaired quality of life. [7]. Women are more

peroxides [14]. All these collectively trigger generation of ROS

frequently affected and especially while pregnant [8]. It is dis-

(Reactive oxygen species) and RNOS (Reactive nitrogen species)

tributed worldwide as 2–10 per million. The prevalence rate of

mediated by endothelial and fibroblast cells. Reactive species

this disease is around 5/100,000 with an incidence of 1/100,000

activates fibroblast proliferation, production of autoantibodies,

[9] Higher rates have been reported in USA, Australia, and Eastern

promotes differentiation to myofibroblast and visceral fibroblast,

Europe and lower rates have been reported in Northern Europe and

and stimulates derived growth factor [15]. These factors

Japan [10].

initiate collagen synthesis, fibrosis and progression of scleroderma

[16].

1.1. Complications of scleroderma

Marked modulation in scleroderma involve overall immune 2. Pathogenesis and its causative factors

activation, vascular damage, impaired angiogenesis and excessive

accumulation of extracellular matrix with deposition of increased The pathogenesis of scleroderma includes active involvement of

content of structurally normal collagen [11] One of the earliest cell mediated and humoral mediated immune response. Major his-

signs of scleroderma is Raynaud’s phenomenon. In this condition tocompatibility complex formed between dendritic cells and T cells

numbness of fingers, toes, ear and nose occurs and color of skin stimulates production of proinflammatory Th2 cells which releases

changes from pale white to blue on restriction of blood oxygen proinflammatory like IL-4 and IL-13. In turn it stimulates

supply and further on supply of blood color changes to red. The B cells and production of vascular epidermal growth factor (VEGF)

condition is worsened during extreme cold condition, stress or [10]. Immune mediated responses have been confirmed by ele-

due to change in temperature.This mainly occurs due to capillaro- vated level of cryoglobulins, rheumatoid factors, gammagloubulins,

−

scopic abnormalities (enlarged capillaries and capillary loss with autoantibodies [17] , over-expression of B cell co-receptors CD19,

or without peri-capillary hemorrhages), involvement of antibod- CD21, CD86 and CD95 in memory B cells [18], increased expression

ies like anti-centromere antibodies (ACA) oranti-Scl70, anti-RNA of anti-endothelial cell receptor antibodies, anti-angiotensin type 1

polymerase III, anti-PmScl (rare antinuclear antibodies and is asso- receptor antibodies and endothelial cell apoptosis [19]. The patho-

ciated with inflammatory and scleroderma) or anti Th/To genesis have been further manifested by increased level of plasma

(antinuclear antibodies and is associated with diffusive sclero- tumor growth factor-␤ (TGF-␤), INF-␥, colony-stimulating factors,

derma including pulmonary fibrosis and scleroderma renal crisis) (IL), , cytokines like IL-1, IL-4, IL-13, Th-2

+

[12–13]. Anticentromereantibodies (approximately 60–80%) are , activated TCD8 lymphocytes, increased level of MCP-1

only found in limited . Diffuse forms associate (monocyte chemoattractant protein1) [20], VCAM-1 (vascular cell

with proximal and distal skin thickening, capillary loss, and visceral adhesion molecule-1) cell, platelet derived growth factor (PDGF-

involvements as pulmonary, renal, myocardial and gastrointesti- R) and the connective tissue growth factor (CTGF) [21–22]. TGF-␤

nal damages. These are often associated with anti-topoisomerase I plays a major role in fibroblast activation and phenotypical modifi-

antibodies (30% in diffusive systemic scleroderma) and the absence cations [23]. Overexpression of dendritic cell CXCL4, TNF␣,

of ACA. (ACA) or anti-Scl70 is also found in patients having initial IL-6 too induces recruitment of -1 which promotes the

D. Singh et al. / Pathophysiology 26 (2019) 103–114 105

Fig. 1. Causative factors and pathogenesis of scleroderma.

Figure 1 contains all the original images and have not been taken from any other sources.

cause of scleroderma. Endothelin-1 activates release of inflamma- matory cells for initiating the fibrotic response. TGF-␤ persuades its

tory mast cells, cytokines, neutrophils, monocytes and free oxygen own production as well as that of other growth factors for cytokine

radicals. Endothelial-1 also promotes generation of tumor burst that result in augmented cytokine secretion and continued

factor-alpha. Thus enhances fibrosis by promoting fibroblast cell autocrine and paracrine signaling. Variations in the comparative

replication, migration and contraction. Collagen and fibronectin proportions and function of regulatory T cells and T-helper 17 cells,

synthesis too are stimulated by reducing collagen degradation by and innate lymphoid cells have been recognized and possibly will

inhibiting MMP-1 production thus effects digital arteries and renal play important roles in pathogenesis [28]. Various gene loci like

arterioles. Collectively these molecular pathogenesis effects many IL12R, STAT4 (Signal Transducer and Activator of Transcription),

organs and leads tovascular damage, pulmonary fibrosis, and pul- CD247, PTPN22 (Protein Tyrosine Phosphatase, Non-Receptor Type

monary hypertension. Thus wide selection of drug is required for 22), and TNFSF4(Tumor necrosis factor superfamily Member 4)

treatment of scleroderma [5,6]. Further detail role of macrophages related with T cell gene function are involved in systemic sclerosis

and T cells has been discussed further below. [28]. A slanted balance among T helper, Th1 and Th2 cytokines man-

ifest fibrosis. Th2 cells produce copious amount of IL-4, IL-5, and

IL-13, but only low levels of the characteristic Th1 cytokines and

2.1. Importance of T cell and Macrophage: ␥

IFN- . Th2 cytokines straightforwardly encourages collagen syn-

thesis, myofibroblast trans-differentiation, and making of TGF-␤, a

Macrophage and T cell are two important cells that are

potent incentive for ECM accumulation, whereas IFN-␥ hunk these

involved in progression of scleroderma. Macrophages activated by

responses and exerts anti-fibrotic effects [29].

lipopolysaccharide (LPS), TNF-␣, IFN-␥ and IL-12 produces high

Allograft inflammatory factor-1 (AIF-1) is a lately notorious

amounts of the pro-inflammatory cytokines as TNF, IL-1, and IL-

protein expressed by macrophages and neutrophils. Some study

6, but little TGF. This is classically activated macrophages that are

demonstrated increased AIF-1 expression in the infiltrating cells

well-organized at presentation, which activates type 1 T

within lesions. It was also seen that AIF-1 encourages T-cell

cells and reduces collagen production by fibroblasts. In contrast,

infiltration and persuade the expression types I and III colla-

macrophages activated by IL-4, TGF and have an

gen and cytokines by normal dermal fibroblasts [30,31]. Some

anti-inflammatory, phagocytic, profibrotic phenotype and activate

study reveals increase level of one pro-inflammatory cytokine MIF

type 2 T cells. These refer as alternatively activated macrophages

(Macrophage migration inhibitory factor). It is released from acti-

produces large amounts of TGF, PDGF, and IL-1 receptor antagonist

vated T cells, macrophages and promotes production of TNF-␣ and

(IL-1ra), but not TNF or IL-1. Alternatively activated macrophages

other cytokines by macrophages and T cells [30].

stimulate collagen production by fibroblasts. Thus, alternatively

activated macrophages appear to be key player in pathologic pro-

cesses that are associated with fibrosis [24–27]. 2.2. Progression of scleroderma

In the initial stages of sclerosis, activated T cells, mono-

cytes and macrophages gathers inside lesioned skin and releases The progression of scleroderma disease includes abnormal mul-

pro-inflammatory and pro-fibrotic intermediates like numerous tiplication of fibroblast cells and endothelial damage across blood

cytokines, chemokines and growth factors mainly TGF-␤. These vessels due to immune imbalance. Disease progresses due to abnor-

activate fibroblasts and endothelial cells to proceeds further inflam- mal growth of connective tissues causing thickness of skin and

106 D. Singh et al. / Pathophysiology 26 (2019) 103–114

its pigmentation followed by constriction of blood vessels. Clini- 1 Todisco M et al 2006 reported that when melatonins were admin-

cally disease progression involves cutaneous, vascular systems and istered to 5 patients along with adrenocorticotropic hormone and

organs. Active changes are observed like thickened skin with pig- E for 3 months no progression of disease was observed

mentation, hair fall and loss. The fibrotic phase further causes [57].

discomfort and restricted motions [5]. Cutaneous system 2 Gaby AR et al 2006 revived that para-aminobenzoic acid, vita-

includes limited cutaneous systemic sclerosis that includes cal- min E, vitamin D, evening primrose oil, estriol, N-acetylcysteine,

cium deposition, numbness of fingers, color changes, oesophageal bromelain, and an avocado/soybean extracts can be used for

dysfunctions, skin tightening, and thickening. Diffusive cutaneous effective treatment of scleroderma [58].

system includes lesion formation over chest, arms, shoulders and 3 Zhou J et al 2018 has examined that by taking bath with decoction

abdomen. Vascular conditions are adverse by narrowing of blood of Taohong Siwu Decoction along with oral prednisone signif-

vessels, cause of numbness and changes in color. Abnormal fibrosis icantly helps in the treatment of preliminary stage of mild to

adversely affects organs includes swelling of hand, , muscles moderate diffuse cutaneous systemic sclerosis (dcSSc) better

pain, chest pain, shorthness of breadth, difficulty in swallowing effect in patients with systemic sclerosis without serious adverse

occurs, heartburns, bloating, and choking occurs pulmonary fibro- effect [59].

sis and . Its difficult to control fibrosis once it has 4 Han L et al 2016 has demonstrated that antiproliferative and pro-

been established. Thus numerous treatment strategies has been apoptotic actions of traditional Chinese as the Wenyang

established to control its growth and relapse nature Huazhuo Tongluo formula decoction has been found effective

against fibroblasts, down-regulation of mRNA, cyclin D1 and sur-

vivin in systemic sclerosis [60].

3. Treatment strategies

5 Wu T et al 2014 has reported that Chinese formula Yiqihuoxue

decoction effectively down regulates extracellular matrix (ECM)

Varied categories of drug have been directed for treatment

gene expressions and collagen production in systemic sclerosis

of scleroderma. Treatment requires targeting inflammation, vas-

dermal fibroblasts. Down regulation of TGF-␤1-induced NIH/3T3

cular damage, excessive collagen production and fibrosis [32].

fibroblasts has been also reported to effectively treat scleroderma

The treatment strategies for scleroderma have been discussed in

[61].

two class i.e. treatment and novel delivery based approach and

recent therepies. Treatment based approach includes drugs, herbs,

3.1.3. Antioxidant therapy

antioxidants and biologics. Novel delivery system based approach

Antioxidants aid in scavenging peroxyradicals, inhibits lipid

generally comprises of vesicular systems, particulate system, self

peroxidation, gene mutation, free radical generation like super-

assembled system, eukaryotic and prokaryotic cell carriers. Recent

oxides, hydroxyls, peroxides, nitrites. Thus antioxidants minimize

therapy includes targeting cells and genes proliferating the cause

the antigen generation and production of autoantibodies. The

of scleroderma.

antioxidants may be supplemented naturally from herbal/dietary

sources or synthetically like vitamin E, polyphenols, flavonoids,

3.1. Treatment based approach carotenes, olives, ascorbic acid, elements like zinc and sele-

nium for proper functioning of enzymes [62]. Higher doses of

Treatment based approach has been reclassified into drug based these antioxidants may alleviates/reduces slight oxidative stress,

approach, herb based approach, antioxidant approach and biologics and are only marginally effective in acute conditions includ-

which have been discussed below. ing ischemia-reperfusion, inflammation and radiation injury [63].

Other specifically derived natural antioxidants as epigallocate-

chin, (-)-epicatechin-3-gallate, epicatechin are found to regulate

3.1.1. Drug based approach

transduction pathway and transcription factors (Nrf2, NF-␬B,

In scleroderma major cause of fibrosis is due to upregula-

AP-1). Their usefulness are proved as antifibrotic, anticancer,

tion of inflammatory cytokines, inflammation and dysregulation

and anti-inflammatory activities as it regulates both TGF-␤ and

in blood flow [32]. The immunosuppressant drugs which are

PDGF-induced 1(I) collagen, fibronectin, -smooth muscle actin

preferred includes , cyclosporine, mycophenolate

(-SMA), and proliferation in activated human and rat hepatic

and [33]. Marrani et al., 2018 investigated

stellate cells, rat pancreatic cells, human keloid fibroblasts, and

the comparative efficacy of Methotrexate or phototherapy (UVA)

SSc dermal fibroblasts [63]. Therapy with Antioxidant enzymes

for treating localized scleroderma and suggested that UVA and

(AOEs) is an alternative and effective means to target oxidative

methotrexate protocols have both a favorable effect in active

stress directly. Basic AOEs include administration of Superoxide

lesions of childhood localized scleroderma. However, methotrex-

dismutase (SOD), catalase, glutathione peroxidase, Paraoxonase

ate resulted significantly superior to UVA, with or without

and Heme-oxygenase-1 [64] and non-enzymatic antioxidants like

Psoralen [34]. Vascular damage could be regulated by calcium

␣

-tocopherol, selenium, carotene and ascorbic acid reduces phos-

channel blocker, angiotensin converting enzyme inhibitor and

phorylation, generation of peroxides in systemic scleroderma and

endothelial-1 receptor inhibitor. Endothelin-1 receptor inhibitors

inhibits collagen proliferation [65]. Paraoxonase is an antioxidant

like /Prostacylins like epoprostenol are highly preferred

extracellular enzyme which posses anti-inflammatory property,

to regulate blood flow. Collagen production could be reduced with

SOD causes conversion of superoxides into peroxides and catalase

help of anti fibrotic agents like dimethyl sulfoxide, colchicines and

decompose superoxide and H2O2 to non toxic molecules. These are

p-aminobenzoic acid. Detailed mechanism of action, pharmacoki-

more potent antioxidants that are not consumed in reaction with

netics, side effects and marketed product of drugs involved in

ROS and inhibit generation of free radicals which aids in destruc-

therapy of scleroderma [35] have been illustrated in (Table 1).

tion of DNA bases and leads to development of antigenic molecules

[66].

3.1.2. Herbs based approach

Alternative to drug approach herbs have been also used by many

3.1.4. Biologics

researchers to treat scleroderma. Few works have been enlisted

Biologics are modified form of recombinant that are

below that promises to restrict the proliferation of scleroderma by

preferred to target interleukins and tumor necrosis factor to treat

use of herbs for example:

autoimmune disorders. Although many are at clinical levels but

D. Singh et al. / Pathophysiology 26 (2019) 103–114 107 ] 38 ] ] ] , ] ] ] ] 35 36 37 37 39 40 41 42 [ References [ [ [ [ [ [ [

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Methotrexate attempts IL-15). activity incorporation affected MPA termination that structure, via inhibition transcription metabolism Mechanism Alkylating Inhibits RNA, DNA monophosphate dehydrogenase mutation. antigenic effects inhibition alkylated repair action inhibit DNA mitosis. analogues also nucleotide reductase, cross-links replication DNA activation purine incorporation ( attachment inhibitor and novo therefore

(AZA)

Immunosuppressant’s

) Methotrexate Drugs Immunosuppressant Cyclophosphamide Other Mycophenolatemofetil Azathioprine Continued (

1

S.No 7 8 Table

110 D. Singh et al. / Pathophysiology 26 (2019) 103–114 ] ] ] ] ] ] ] 52 23 53 54 54 55 56 References [ [ [ [ [ [ [

Co-Hydeltra

Formulation

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1

S.No 9 10 11 Table

D. Singh et al. / Pathophysiology 26 (2019) 103–114 111

Table 2

List of biologics targeting inflammatory interleukins.

S.no Inflammatory interleukins Biologics targeted Remark References

1 IL6 (critical interleukins in (humanized Reported to improve skin texture and [69]

systemic sclerosis) anti-IL6 receptor ) thickness, reduced fibrosis and reduced

patient’s Global Disease Activity scores

2 TNF-␣ (pro-inflammatory , Infliximab, Reduced level of collagen content, TGF-␤, [70]

cytokine) , hydroxyproline and infiltrating myofibroblasts

has been observed

3 IL-1(role in proliferation and Clinical studies reported reduced level of [71]

collagen production of fibroblasts) fibroblast proliferation, IL-6 production and

procollagen synthesis

4 IL13 (profibrotic cytokine that Results are under evaluation in a phase II [72]

interplays with other mediators in idiopathic pulmonary fibrosis

such as TGF-␤)

5 IL-17, IL-17 receptor (actvates and Benefits in other autoimmune disorders has [73]

fibroblast cells and promotes respectively been observed as in psoriatic but no

secretion of pro-inflammatory such data has been observed in scleroderma

cytokines as IL-6 and IL-8, and

increased surface expression of

Intercellular Adhesion Molecule.

6 Tumor growth factor-␤ (central , No significant results were observed in case of [74]

mediator of fibrosis) metelimumab but effect has been found in case

of fresolimumab, posses capacity to inhibit all

isoforms of tumor growth factor.

7 B Cells Improves skin score, reduces hyalinised [75]

collagen score

8 B cell activating factor (found Reduced level of IL6 has been observed [76]

elevated and promote fibrosis)

9 T cells Found effective in treating established fibrosis. [77]

Activated T-cells, B-cells and monocytes

infiltrating the skin were reduced, along with

IL-6 and IL-10 levels, but its treatment is only

limited to inflammatory fibrosis

Table 3

Novel approaches for treatment of Scleroderma.

S.no. Carrier system Drug Remark Reference

1. Liposomes

1.1. Multilamellar liposomes Colchicines Encapsulation in liposomes may reduce the colchicines toxicity. [79]

1.2. Dicationic liposomes interferon ␥ It increases the production of IFN␥ which increases the lymphatic activity. [80]

2. Particulate system

␥ ␥

2.1. IFN- nanoparticles IFN- -coding plasmid Modulate excessive collagen synthesis in scleroderma-affected skin [81]

2.2. Carbon-based nanoparticulate ------Reported to stimulate cytokine gene expression at a higher extent in SSc [82]

keratinocytes versus normal cells

3. Emulsion

3.1. Microemulsion curcumin Treating various skin diseases like scleroderma, psoriasis, and skin cancer [83]

recently tocilizumab has been found to qualify clinical trials and tive means to control the release of drug for inflammatory diseases

two year stability test. Rituximab and has been, recently and local treatment. These systems are mainly made up of phospho-

recommended as a first-line biologic agent for treatment of autoim- lipids and biocompatible polymers for safe homing with controlled

mune disorders like arthritis [67] and skin fibrosis but no such release of drug [66]. Novel carrier systems could be classified into

effect has been observed in fibrotic lesion. Contradictory in case vesicular systems, particulate systems, polymer systems, emul-

of scleroderma TNF inhibitors such as infliximab failed to show sions and cellular carriers [16–17]. The additional benefits can be

marked positive response. Studies have been demonstrated for taken by modifying and exploring cellular carriers, erythrocytes,

tumor growth factor-␤1 antibody and oral type I collagen but no platelets or by utilizing recombinant technoldelivery of gene. Inno-

statistical benefits have been observed [68]. Some of the studies vative systems helps to target the actives at site of action, minimizes

have shown positive effect in animal model but are still struggling drug loss, increased drug bioavailability and targeting at site of

to pass clinical trials. List of many other biologics has been used to action. Inflamed skin allows utmost localization and adsorption

target inflammatory interleukins has been represented in Table 2. of vesicular and particulate system allowing them to release drug

locally and inhibit its toxicity [78]. Numerous novel approaches

opted for therapy of scleroderma has been enlisted with their

3.2. Novel delivery based approach

effects in Table 3.

Novel based are considered to combat disadvan-

tages possessed by conventional therapies. These are advantageous 3.2.1. Recent therapy

in terms of having long lasting action, improved bioavailability, Recent studies suggest that plasmacytoid dendritic cells (pDCs)

enhanced patient compliance, dose minimization, improved load- are one of important cells thatcontributes to cause of scleroderma.

ing of drug at target site, improved safety, reduced toxicity by Normally it secrete interferon to help fight off infections. However,

reducing dose frequency, highly flexible and versatile, potentially as study revealed, in scleroderma patients these cells are chroni-

possess targeting property. Novel delivery system provides effec- cally activated and infiltrates at the site of skin causing fibrosis and

112 D. Singh et al. / Pathophysiology 26 (2019) 103–114

Table 4

List of patents associated with scleroderma.

S.N. Patent no. and Date Title Significant

1. 61/844,983, filed Jul. 11, 2013 Topical treatment of localized Compositions and formulations for topical administration that contain a [91]

scleroderma tyrosin kinase inhibitor, such as imatinib or nilotinib useful in treating

scleroderma.

2. CN106620353A, 2017-05-10 Medicine for treating systemic The invention aims to treat systemic scleroderma by taking mixture of lots of [92]

scleroderma herbs as mixture of mother of pearl, ephedrine, wolfberries, honeysuckle,

calcinied oyster, seaweed, epimedium, hedyotis diffusa, gardenia, hui wheat,

forsythia, codonopsia, calcinied turtle, licorice.

3. WO 2010/102983 A1 on Sep. 16, 2010 Methods for the treatment or The invention involves methods to develop for treatment or prevention of [93]

prevention of systemic fibrosis in patients suffering fromscleroderma, by reducing plasma level of

sclerosis CXCL4.

4. WO 2009/061818 Al, date 14.05.2009 Methods of treating The present invention provides compositions and methods of treating [94]

scleroderma scleroderma and the symptoms associated with scleroderma by inhibitinf type

I interfern gene expression.

inflammation. This study also reveals that depleting pDCs in an ani- inflammation and improvement in lung function were observed

mal model of scleroderma prevented the disease from forming, and in patients by means of human stem cell therapy. Similarly signif-

reversing already existing fibrosis [84]. The inflammasome, a cen- icant improvement in Raynaud’s syndrome and PAH has been also

tral driver of fibrosis is a bulky protein complex that regulates the observed by use of botulinum toxin and Bosentan.

release of various cytokines like IL-1, IL-18, IL-36 and IL-33 hav- Treatment efficacy could also be improved by actively target-

ing important role in the fibrotic response. IL-36 also belongs to ing surface receptors, soluble receptors and signaling pathway

the IL-1 family of cytokines and is a new comer to this field of which could downregulate the activity of inflammatory cytokines

research. Recent studies reported that numerous of them play a playing crucial role in cause of scleroderma. Biologics imatinib

significant role in skin inflammation and fibrosis and their conse- mesylate, a protein tyrosine kinase inihibitor are greatly used to

quent antagonists (IL-1RA and IL-36RA) can repeal this treat fibrosis and vasculopathy in Systemic Scleroderma. Future

[85]. IL-22 expression in infiltrated lymphocytes may encourage the medicine could include active targeting of inflammatory agents as

up-regulation of type I collagen protein in dermal fibroblasts [86]. transforming growth factor -beta, connective tissue growth factor,

Genetic connection for sclerosis lies mainly in the MHC (Major his- platelet-derived growth factor and endothelin-1 which collectively

tocompatibility) region, with loci in HLA-DRB1 (Human leukocyte promotes fibrosis, vasculopathy and pathogenesis of Systemic Scle-

antigens), HLA-DQB1, HLA-DPB1, and HLA-DOA1 being the most roderma.

replicated. The non- HLA genes linked with sclerosis are involved

in a range of functions, with the most robust links including genes 5. Declaration of interest

for B and T cell activation and innate immunity. Genes, IRF5 (Inter-

feron Regulatory Factor 5), STAT4, and CD247 were replicated The authors report no conflicts of interest. The authors alone are

most frequently while SNPs rs35677470 in DNASE1L3 (Deoxyri- responsible for the content and writing of the article.

bonuclease 1 Like 3), rs5029939 in TNFAIP3, and rs7574685 in

STAT4 have the strongest links with sclerosis [87]. Various miR- Acknowledgement

NAs (micro RNA)have been identified in scleroderma patients, like

miR-21, miR-29, miR-130b, miR-21-5p, miR-92a-3p, miR-155-5p,

Authors are thankful to Director, University Institute of Phar-

and miR-16-5p. These are found to be up-regulated in scleroder-

macy, Pt. Ravishankar Shukla University, Raipur (C.G.) India for

mic fibroblasts and dermis involved in the lung proliferation and

providing all necessary facilities for carrying out this work and DST-

angiogenesis [88,89,90,91]. These may shed light in new areas

FIST. Dr. M.R. S is thankful to ICMR for DHR-HRD fellowship. Dr.

for therapeutic development. Few technologies which have been

D.S. is thankful to UGC- Raman fellowship. Ms. S. S. is thankful to

patented have been too enlisted in Table 4.

University Grant Commission and Basic scientific research (UGC-

BSR) F.7-341/2011 for financial assistance relating to this work.

Authors are also thankful to National centre for Natural Resources,

4. Conclusion and future prospects

Pt. Ravishankar Shukla University, Raipur (C.G.).

The cause of scleroderma includes immune modulation and

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