Review

The significance of interleukin-6 and C-reactive in systemic sclerosis: a systematic literature review

C. Muangchan1,2,3, J.E. Pope2

1Research Fellow, Rheumatology; ABSTRACT Introduction 2Schulich School of Medicine & Dentistry, Objectives. Interleukin-6 (IL-6) may Systemic sclerosis (SSc) or scleroder- Western University of Canada (formerly play a role in the pathogenesis of SSc. ma is a systemic autoimmune rheumat- University of Western Ontario), St Joseph C-reactive protein (CRP), an acute ic disease characterised by autoimmun- Health Care, London, ON; 3Division of Rheumatology, Department of phase reactant induced by IL-6, may be ity; fibrosis and dysfunction in vascular Medicine, Faculty of Medicine, Mahidol a prognostic marker in SSc. The goal of regulatory mechanisms highlighted by University, Siriraj Hospital, Bangkok, this systematic review was to address vasculopathy of microcirculation (1). Thailand. the significance and clinical applica- SSc has increased extracellular matrix Chayawee Muangchan, Research Fellow tion of IL-6 and CRP in systemic scle- protein deposition due to increased fi- Janet Elizabeth Pope, MD rosis (SSc). broblast biosynthetic activity (2). SSc is Please address correspondence Methods. A literature search was con- rare and has a female predisposition (3, and reprint requests to: ducted to identify English-language 4). It is classified into diffuse cutane- Dr Janet Pope, original articles within PubMed, Sco- ous SSc (dcSSc) and limited cutaneous St. Joseph’s Health Care, London, SSc (lcSSc) subsets according to extent 268 Grosvenor St., pus, and Medline database from incep- London N6A 4V2, ON, Canada. tion to May 30, 2013 using keywords of cutaneous involvement (5). Patients E-mail: [email protected] “systemic sclerosis or scleroderma and with dcSSc have more skin involve- Received on January 26, 2013; accepted C-reactive protein or interleukin-6”. ment and worse survival rates than lcSSc (6-9). in revised form on May 6, 2013. Results. The search resulted in 156 The pathogenesis of SSc is still obscure Clin Exp Rheumatol 2013; 31 (Suppl. 76): relevant articles. Some single nucleo- as there are no true animal models, but S122-S134. tide polymorphisms and -gene immune activation is present with com- © Copyright Clinical and interactions affect SSc predisposition, plex cytokines and protein interactions. Experimental Rheumatology 2013. manifestation and expression of IL-6. T helper 1 lymphocyte (Th1) cytokines Studies in animal models show IL-6 Key words: scleroderma, systemic e.g. interferon-γ (IFN-γ), tumour ne- and IL-6 trans-signalling are involved sclerosis, interleukin 6, C-reactive crosis factor-α (TNF-α), interleukin-1α in SSc disease development. Derange- protein, systematic review (IL-1α), IL-2 and Th17 cytokines e.g. ments of T and B cells function regulate IL-17, IL-21, IL-23, IL-22 promote in- IL-6 in SSc pathogenesis. Fibroblasts, flammation in SSc, while Th2 cytokines T/B cells, monocytes, macrophages, e.g. IL-4, IL-13, IL-6, IL-10 contribute dendritic cells and endothelial cells tissue fibrosis (10). Interestingly, IL-6 participate in IL-6 expression and in- has a pro-inflammatory function via teract with each other resulting in tis- Th17 differentiation in the presence of sue sclerosis. Up-regulation of serum transforming growth factor-β (TGF-β)/ IL-6 and CRP levels are evident in SSc IL-21 and inhibition of T regulatory patients and associated with disease lymphocyte (Treg) differentiation as activity, severity, disability, worse out- well as fibrogenesis via stimulation of come and reduced survival. Targeted collagen production and inhibition of IL-6 therapy in SSc has occurred in collagenase synthesis (10). small cases series and within a multi- IL-6 also participates in the pathogen- site trial that is under way. esis of a variety of chronic inflammato- Conclusions: Studies show IL-6 and ry disease such as rheumatoid arthritis CRP are important in SSc both in (RA) (11) especially for systemic bone Competing interests: J. Pope received a pathogenesis and clinical manifesta- loss and structural bone damage (12). grant from the Canadian Arthritis Network to study IL-6 in SSc and is a site PI for the tions and may be useful indicators of Treatment with a humanised anti-inter- Genentech Tocilizumab in SSc trials; disease activity, severity, and poor leukin-6 receptor monoclonal antibody C. Muangchan has declared no competing prognosis. IL-6 could be a relevant corrects Th17/Treg cell imbalance (13) interests. treatment target in SSc. and demonstrate efficacy and safety in

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associated with SSc. The TT genotype of TBX21 rs 11650354 SNP variant has a recessive pattern for SSc suscep- tibility, while the A allele of STAT4 rs 11889341 has a dominant pattern. SSc patients carrying the CC genotype of TBX21 rs 11650354 have higher pro- inflammatory cytokines - interleukin-6 (IL-6) and tumour necrosis factor-α (TNF-α) levels; and those with the TT genotype have elevated IL-2, IL-5, IL- 4, and IL-13 levels (21). There are also significant gene-gene interactions for SNPs in cytokine for SSc subset susceptibility such as IL-2 G-330T, IL-6 C-174G, and IFN-γ AUTR5644T SNPs in lcSSc susceptibility and IL-1R (IL- 1 receptor) Cpst1970T, IL-6 Ant565G, and IL-10 C-819T SNPs in dcSSc sus- Fig. 1. Flow diagram of literature search of the systematic review of IL-6 and CRP in SSc. ceptibility (22). For IL-6, SSc patients who have homozygous GG SNPs of RA (14). CRP, an acute phase response the inception through May 30, 2013 us- the -597 region of the IL-6 promoter protein produced prominently under the ing the following key words: (systemic gene (IL-6 pr) have higher disease ac- transcriptional control by IL-6, serves sclerosis OR scleroderma) AND inter- tivity and worse functional scores than as an assessment of disease activity in leukin-6 (IL-6); and (systemic sclerosis the heterozygous GA patients (23). many inflammatory conditions (15). OR scleroderma) AND C-reactive pro- SNPs in Toll-like receptor 2 (TLR2) CRP is correlated with serum levels tein (CRP). Publications were deemed genes (Pro631His) are associated with of IL-6 in RA (16) and is a surrogate relevant to this review if they reported anti-topoisomerase (Scl70) positivity, marker in RA for disease activity and results from in vitro or in vivo studies, dcSSc subset, and the development of increased erosions (17), whereas in animal models, observational cohorts, pulmonary artery hypertension (PAH). SLE, CRP is used more to predict active clinical studies/trials, and both positive This variant influences TLR-2–mediat- infection rather than an exacerbation of and negative studies regarding IL-6 or ed cell responses in monocyte-derived SLE (18). CRP in SSc were reviewed. Publications dendritic cells to produce increased We previously concisely reviewed the were excluded if they were irrelevant, levels of TNF-α and IL-6 (24). The importance of IL-6 in SSc; construct- review articles, letters to the editors, or GGC allelic combination rs2069827- ing a diagram of signalling from vari- did not study systemic sclerosis. Thus rs1800795-rs2069840 of IL-6 gene has ous cell types in SSc (19). We have reports on morphea were not included. an association with overall SSc suscep- also published the importance of CRP tibility (25) but neither selected SNPs in data from the Canadian Scleroderma Results of the IL-6 receptor (IL-6R) gene nor Research Group (CSRG) where el- An overview of the literature search is CRP gene showed an association with evated CRP was especially prevalent found in Figure 1. Ultimately, 156 rele- overall SSc susceptibility (26, 27). in early dcSSc and was associated with vant articles were chosen for the review. SSc disease activity, severity, and poor 2. Scleroderma animal models survival (20). The purpose of this ex- 1. Genetic susceptibility to and interleukin-6 tensive systematic literature review scleroderma in part of interleukin-6 There are no exact animal models of was to address the overall and organ- and C-reactive protein SSc where the spectrum of autoanti- specific significance of IL-6 and CRP Multiple genes are involved in immune bodies, inflammation, fibrosis and vas- in SSc and potential therapeutic targets regulation affecting Th1/Th2 cytokines cular changes are fully manifest. How- that decrease IL-6 in active SSc. production and balance via regulation ever, SSc animal models give insights of T helper cell differentiation and ac- into pathogenesis of SSc and can be Methods tivation. Single nucleotide polymor- divided into 4 inter-related categories We conducted a systematic review of phisms (SNPs) variants in Signal Trans- the literature to determine the signifi- ducer and Activator of Transcription 2.1. Role of IL-6 trans-signalling in cance and clinical application of IL-6 4 (STAT4) and T-box expressed in T fibrogenesis and CRP in SSc. We searched for Eng- cell 21 (TBX21) that regulate Th1 cells Mouse models studying the role of IL-6 lish-language original articles indexed though promotion of Th1 cytokines trans-signalling in fibrogenic responses in PubMed, Scopus, and Medline from and suppression of Th2 cytokines are are summarised in Table I.

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Table I. Role of IL-6 trans-signalling in fibrogenesis.

Animal models Characteristics Interventions Results

Subcutaneous injection with BLM mouse model (28) WT C57BL/6 mice # serum IL-6 levels Anti- mIL-6R mAb $ dermal thickness # expression of IL-6 mRNA in skin, prophylaxis or treatment $ dermal numbers of myofibroblasts, cutaneous lymph nodes and mast cells

IL-6 KO mice $ dermal sclerosis N/A N/A $ dermal numbers of myofibroblasts, and mast cells

Non-treated-BLM mouse model (28) WT C57BL/6 mice-derived fibroblasts Already express α-SMA RmIL-6 stimulation Do not alter α-SMA expression Anti-mIL-6R mAb treatment # IL-6 expression $ α-SMA mRNA expression

IL-6 KO mice-derived fibroblasts $ expressions of α-SMA RmIL-6 stimulation # α-SMA mRNA expression

IL-6 KO mice-derived fibroblasts # α-SMA mRNA expression Anti-mouse IL-6R mAb treatment Inhibition of α-SMA mRNA treated with RmIL-6 expression

Mouse model injected with rh-DNA-topo I and Freund’s complete adjuvant (29) WT C57BL/6 mice # dermal thickness N/A N/A # lung fibrosis # serum/ skin/ lung IL-4, IL-6, IL-10, IL-17, IFN-γ, TNF-α, TGF-β levels # serum IgG, IgM IL-6 KO mice $ dermal thickness N/A N/A $ lung fibrosis $ serum/skin/lung IL-17 levels, $ serum Ig levels $ BALF Th2, Th17 cells # BALF Th1, Treg cells

Scl-cGVHD mouse model Scl-cGVHD mice (30) Express AIF-1 # induce IL-6 N/A N/A secretionon mononuclear cells and fibroblast chemotaxis Scl-cGVHD mice (31) # serum IL-6 levels after bone Anti-mIL-6R mAb prophylaxis $ Severity of Scl-cGVHD marrow transplantation # CD4+CD25+FoxP3+ Treg cells

$: decreased; #: increased; BLM: bleomycin; WT: wild-type; mRNA: messenger RNA; anti mIL-6R mAb: anti-mouse-IL-6 receptor monoclonal antibody; IL- 6KO: IL-6-knock-out; α-SMA: α smooth muscle actin; RmIL-6: recombinant-mouse-IL6; rh-DNA-topo I: recombinant human DNA topoisomerase I; BALF: bronchoalveolar lavage fluid; Scl-cGVHD: sclerodermatous-chronic graft-versus-host disease; AIF-1: allograft inflammatory factor-1; N/A: not available.

2.2. Role of B cell and B cell their intrinsic B cell abnormalities and JAK2, JAK3, and Tyk2) and STAT1- compartment in fibrogenic and autoantibody production (33). B cell STAT-6 (40-41). Their signals yield inflammatory responses activating factor belonging to the tu- cellular proliferation, differentiation, B lymphocyte (B cell) is the most po- mour necrosis factor family (BAFF) is migration, apoptosis, and cell survival, tent antigen-presenting cell (APC) and a TNF-like homeostatic cytokine that depending on the signal, tissue, and among several cells in immune system supports B cell survival and differen- cellular context (42). The IL-6 trans- that secrete IL-6 (19). CD19 a cell- tiation. Excessive BAFF production signalling pathway is mediated by the surface signal transduction molecule corrupts B-cell tolerance and leads to JAK/STAT1-3 pathway (43),but the of B cell, acts as a central critical posi- autoimmunity (34-36). Mouse mod- STAT4 knockout (STAT4-/-) mice sub- tive response regulator that lowers the els that examined CD19 and BAFF in cutaneously injected with bleomycin B cell signalling threshold resulting in fibrogenesis and inflammation were (BLM) showed decreased dermal scle- amplified signalling, clonal expansion summarised in Table II. rosis, CD4, CD8 T cells infiltration, and antibody production of B cells lower levels of IFN-γ, IL-2, TNF-α, (32). Transgenic mice that overexpress 2.3. Factors affecting T cell signalling, and IL-6 relative to STAT+/+ mice. CD19 by 20-170% lose tolerance and resulting in fibrogenesis In contrast, STAT4 -/- / TSK+/ mouse generate autoantibodies. SSc patients Cytokines-cytokine receptor interac- model did not significantly ameliorate also overexpress CD19 by approxi- tions rely on signals through pathways the fibrotic phenotype (44). mately 20%, which may contribute to such as Janus kinases (JAK; JAK1, Regulation of T cell activation and tol-

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Table II. Role of CD19 and BAFF in intrinsic B cell signalling and IL-6.

Animal models Interventions Results

CD19 KO C57BL/6 mice (37) BLM SC injection $ dermal thickness, $lung fibrosis $ numbers of mast cells, macrophages, T cells, B cells dermal infiltration $ serum levels & mRNA of IL-4, IL-6, IL-10, IFN-γ, TNF-α, TGF-β1, MIP-2 $ hyaluronan over-production, $ serum Ig (relatively to CD19 +/+ C57BL/6 mice) CD19 KO C57BL/6 mice-derived B cells (37) ECM breakdown product $ mRNA & protein levels of IL-4, IL-6, IL-10, IFN-γ, TGF-β, MIP-2 stimulation via TLR-4 (relatively to CD19 +/+ C57BL/6 mice) CD19 KO TSK+ mice (38) N/A $ skin fibrosis CD19 KO TSK+ mice-derived B cells (38) N/A $ hyper-γ -globulinemia $ autoantibody production $ IL-6 secretion TSK+ (39) BAFF receptor antagonist $ autoantibody production $dermal IL-6, IL-10 mRNA expression, #IFN-γ expression TSK+ mice-derived B cells (39) BAFF stimulation # ability to produce IL-6

$: decreased; #: increased; CD19 KO: CD19 knock-out; MIP-2: macrophage inflammatory protein-2; Ig: immunoglobulin; ECM: extracellular matrix; TLR-4: Toll-like receptor-4; TSK+ mice: tight-skin mice; N/A: not available. erance requires 4 signal interactions 3. Scleroderma fibroblasts and tion (73). CD40 is expressed on mac- (45). interleukin-6 rophages, dendritic cells, B cells, fibro- 1. Antigen-Major histocompatibility Dermal fibroblasts from early SSc pa- blasts, and endothelial cells. CD40L complex (MHC) on antigen present- tients up-regulate IL-6 secretion sev- (CD154) is expressed on T cells and NK ing cells (APC) interact with T cell eral-fold more than normal fibroblasts cells (74). CD40 expression from fibro- receptor (TCR)-CD3 complexes on (54-60), via the accumulation of IL-6 blasts is higher in early SSc. Ligation T cells mRNA mediated by the constitutive of CD40 by CD40L (CD154) results 2. B7-1(CD80) or B7-2 (CD86) on binding of Nuclear Factor-Kappa B in increased production of IL-6, IL-8, APC interact with CD28 or cytotox- (NF-kB) to the IL-6 promoter gene (55, monocytes chemoattractant protein-1 ic T-lymphocyte antigen 4 (CTLA-4 59, 61-62). However, one study found (MCP-1) and Regulated upon Activa- or CD152) on T cells SSc fibroblasts did not produce more tion Normal T-cell Expressed and pre- 3. Inducible T cell co-stimulator ligand IL-6 than controls (63). Augmenta- sumably Secreted (RANTES) (75-76). (ICOSL) on APC interacts with In- tion of IL-6 mRNA and IL-6 release is IL-6 trans-signalling of fibroblasts ducible T cell co-stimulator (ICOS) modulated by TNF-α with a synergistic through the JAK2/STAT3 or extracel- on T cells effect from the type II IFN -IFN-γ (54, lular signal-regulated kinase/ mitogen- 4. Programme cell death ligand 1 & 56, 59, 64), IL-1α (64-68), IL-1β (59, activated protein kinase (ERK/ MAPK) 2 (PD-, PD-L2) on APC interact 69) and platelet derived growth fac- transduction pathway is responsible with PD-1 on T cells tor (PDGF) (70). Type I IFN; IFN-α2, for a production of procollagen type 1, In BLM-induced dermal sclerosis also augment TLR3 expression on SSc α-smooth muscle actin (α-SMA) and and lung fibrosis mouse model, ICOS fibroblasts primed by TGF-β resulted connective tissue growth factor (CTGF) knock-out (ICOS-/-) mice has less skin in enhance TLR3-induced IL-6 produc- (55, 77). The expression of IL-6 in SSc and lungs fibrosis and lower TGF-β tion (71). SSc fibroblasts constitutively fibroblasts is positively correlated with levels; in contrast, ICOSL knock-out up-regulate IL-1α mRNA and express collagen production (61, 63). Roscovi- (ICOSL-/-) mice had more skin and IL-1α endogenously yielding an auto- tine- a cyclin-dependent kinase inhibi- lung fibrosis and higher TGF-β levels. crine loop with further increases in IL-6 tor caused decreased IL-6 production Double-knock out (ICOS-/-, ICOSL-/-) and PDGF (65-68) which in turn stimu- by SSc fibroblasts below the basal lev- mice result the same as ICOSL-/- mice. late SSc fibroblasts. SSc macrophages, els of normal fibroblasts (78). So apart from the ICOS/ICOSL co- T cells, and B cells are sources of IL- stimulatory pathway, ICOS and ICOSL 1α, IL-6, basic fibroblast growth factor 4. Peripheral blood mononuclear cells might have a role in development of (bFGF), TNF-α, and TGF-β responsi- (PBMC), dendritic cells, T and B tissue sclerosis in this mice model (46). ble for fibroblast proliferation, PDGF lymphocytes, endothelial cells and secretion, and PDGF receptor (PDG- interleukin-6 in scleroderma 2.4. Experimental interventions in FR) expression (64, 72). IL-4 and IL-13 SSc peripheral blood mononuclear scleroderma animal models –a Th2 cytokines promote circulating cells (PBMC) secrete more IL-6 Interventions that ameliorate fibrogen- bone marrow-derived fibrocyte differ- spontaneously and when stimulated esis and affect IL-6 are summarised in entiation whereas IFN-γ, IL-12 –a Th1 compared to controls, especially SSc Table III. cytokines inhibits fibrocyte differentia- PBMC from patients with early disease

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Table III. Experimental interventions affecting fibrogenesis and IL-6.

Animal models Characteristics Interventions Results

BLM-induced dermal sclerosis Overt free radical IV Edaravone $ dermal thickness, lung fibrosis mice and TSK+ mice (47) production (a free radical scavenger) $ T cells, B cells, macrophages, neutrophils dermal infiltration $ IL-6, TGF-β1, TNF-α, IFN-γ, anti topo-I Ab, IgG, IgM BLM-induced dermal sclerosis N/A IP Sirolimus $ skin fibrosis mice and TSK+ mice (48) $ IL-4, IL-6, IL-10, IL-17, TGF-β1, IFN-γ *In human, rapamycin did not differ from treatment with methotrexate but the study was under-powered (49) BLM-induced lung fibrosis N/A Col V prophylaxis $ lung inflammation mice (50) $ expression of BALF IL-6, IL-17, IL-22 *Human oral Col I trial show no skin score improvement (51) BLM-induced dermal sclerosis N/A Anti-TGF-β antibody $ IL-4, IL-6 levels mice (52) treatment *A phase I/II trial of recombinant anti-TGF β1 antibody in early dcSSc patients was ineffective (53)

$: decreased; BLM: bleomycin; IV: intravenous; TSK+ mice: tight-skin mice; IP: intra-peritoneal; BALF: bronchoalveolar lavage fluid; Col V: collagen type V; Col I: collagen type I.

(79-82). One study found SSc alveo- IL-6 and sIL-6R but not significantly organ involvement. B cells from SSc lar macrophages produced more IL-6 more sgp130 (80). Tran-signalling of patients produced more IL-6 and IgG but the results were not significantly IL-6 mediates neutrophil-dependent when stimulated with BAFF (96). different from controls (83). IL-10 endothelial cells activation and apopto- and TNF-α is increased secretion by sis (90). Centromere protein B (CENP- 5. Serum interleukin-6 and C-reactive SSc PBMC (79). TNF-α is correlated B) released from apoptotic endothelial protein and clinical applications in with IL-6 and IL-10 production (79). cells can bind to the surface of smooth scleroderma Increased levels of IL-6, soluble IL-6 muscle cells, and subsequently stimu- 5.1. Serum IL-6 and CRP levels in receptor (sIL-6R), IL-13, macrophage late the migration of smooth muscle scleroderma inflammatory protein (MIP) -1α, and cells and release of IL-6 (91). Topoi- Many studies found serum IL-6 (63, 79, RANTES but decreased levels of IL- somerase I (Topo 1; Scl70) antibody 88, 97-107) and CRP (108-117) in SSc 4, IL-10, TGF-β, and macrophage de- production by autologous peripheral were significantly higher than controls. rived chemokines (MDC) have been blood B cells via the interactions of Serum IL-6 levels are 5-12 times higher described in SSc CD3+ T cells (79, MHC-TCR and CD40/CD40L requires than controls (97, 99). The frequency of 84). Blood SSc monocytes also sponta- IL-2 and IL-6 for topoisomerase I Th1 elevated serum IL-6 and CRP levels in neously secrete IL-6 which is related to and Th2 cell regulation, respectively SSc is from 50-94% for IL-6 (118-121) serum IL-6 levels (85). IL-6 production (92). In addition, IL-6 may mediate the and 20-70% for CRP (20, 114, 122- by stimulated NK cells are elevated in enhanced expression of high-affinity 125). However, most patients with SSc dcSSc patients (86), with increased ex- IL-2 receptor (HIL-2R) on SSc T cells do not have elevated CRP (20, 126). pression of IL-6 mRNA in alveolar T (93). T cells can induce activation of Also, some studies reported no signifi- cells and macrophages (87). TLR-2, 3, normal fibroblasts, increasing their cant differences in serum IL-6 (60, 81, 4-mediated stimulation of SSc mono- collagen production and the expression 85, 127-131) and CRP between SSc cyte-derived dendritic cells (moDC) of several markers of fibrosis includ- patients and healthy controls (132). from early dcSSc patients result in ing IL-6, TGF-β, α- smooth muscle Few studies reported increased IL-6 increased IL-6, TNF-α and IL-10 pro- actin (α-SMA), and endothelin recep- levels from sources other than serum. duction (88, 89). Membrane-bound/ tor (ET-R) by expression of allograft Exhaled breath in SSc had higher IL- and soluble IL-6 receptor (mIL-6R/ inflammatory factor-1 (AIF-1) (94). 6, than controls. IL-6 and IL-2, -4, -10, and sIL-6R) is a functional receptor IL-12 -a Th1 cytokine, produced by TNF-α, and IFN-γ levels have negative of IL-6. IL-6 binds to either mIL-6R SSc PBMC is significantly elevated in correlations with diffusing capacity of or sIL-6R causing homodimerisation SSc patients but does not seem to cor- the lung for carbon monoxide (DLCO) of membrane-bound gp130 (mgp130) relate with Th2 cytokines e.g. IL-4, and total lung capacity (TLC) % pre- then this IL-6-IL-6R-mgp130 com- IL-6, IL-10 and IL-13 (95). BAFF lev- dicted (133) A different study found no plex transfers IL-6 signalling. Soluble els were significantly elevated in both increase in IL-6 in bronchoalveolar lav- gp130 (sgp130) also binds to IL-6-IL- dcSSc, and lcSSc compared to controls age fluid (BALF) in SSc and controls 6R complex, therefore inhibiting bind- and were higher in dcSSc than lcSSc. (85). SSc skin biopsies have more ex- ing of these complexes to mgp130, so BAFF correlated with the skin score pression of IL-6, IL-8, TNF-α, vascular sgp130 is an inhibitor of IL-6 signal- and ESR; where increased changes in cell adhesion molecule-1 (VCAM-1) ling (43). SSc PBMC produces more BAFF were associated with worsening and p- (134).

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Table IV. Correlations of serum IL-6 and CRP levels with parameters.

Serum Interleukin-6 levels Correlation No correlation Positive Negative

Fever (119) FVC, DLCO %predicted (104, 159) Clinical/laboratory findings (127) Interstitial lung disease (79, 119) BAL cell characteristics/ BALF Alveolitis score (140) IL-6 in SSc-alveolitis (85) Arthritis/ Myositis (119) Serum adiponectin (160) Total body skin score (102, 129) LAMPs (161) Extent of skin thickening (129) DcSSc-mRSS, peak skin score (55) WBC count (157), Platelets count (55) ESR (104) CRP (55, 104, 124) Serum IgG (104, 158) Serum P-III-P levels (63) Serum IL-1RA (105)

Serum C-reactive levels Correlation No correlation Positive Negative

MRSS (20) PFT parameters (20, 116) SSc-myopathy (176) Severity of skin, lung, joint (116) Serum albumin (173) Bone mineral density (177) MRI fascial thickening, synovitis (136) Serum vitamin D (174) Aortic stiffness (178) EScSG Activity Index (20, 162) Erythrocyte deformability (175) Arterial wall dysfunction (108) 12-point Activity Index (162) Serum pentraxin-3 (179) Medsger Disease Severity Index (20) Serum amyloid P (180) HAQ Disability Index (20) Serum adiponectin (160) Abnormal 6MWD (163) Serum prolactin (181) ESR (20, 114) Serum YKL-40 (182) ANA titer (114) Serum MMP-3 (147) Serum IL-6 (55, 104, 124) Serum IL-13 (164) Serum sCD40L (165) Plasma microparticles (166) Platelets activation markers (125) Serum vWf (114) Serum NT-proCNP (167) Serum COMP-C3b (168) Serum CTX-I (169) Serum TAP (170) Serum HSP-70 (171) Serum Ang-2 (172) dcSSc: diffuse cutaneous systemic sclerosis; mRSS: modified Rodnan skin score; WBC: white blood cells; ESR: erythrocyte sedimentation rate; CRP: C- reactive protein; IgG: immunoglobulin G; P-III-P: N-terminal procollagen-III propeptide; IL-1RA: interleukin-1 receptor antagonist; FVC: forced vital ca- pacity; DLCO: diffusing capacity of the lung for carbon monoxide; BAL: brochoalveolar lavage; BALF: bronchoalveolar lavage fluid; LAMPs: - associated membrane proteins; MRI: magnetic resonance imaging; EScSG: European Scleroderma Study Group; HAQ: health Assessment Questionnaires; 6MWD: 6-minute walk distance; ANA: antinuclear antibody; sCD40L: soluble CD40 ligand; vWf: von Willebrand factor; NT-proCNP: amino-terminal fragment of pro C-type natriuretic ; COMP-C3b: complex between cartilage oligomeric protein and complement activation product C3b; CTX-1: c-terminal telopeptide of collagen type I; TAP: total anti-oxidant power; HSP-70: heat shock protein-70; Ang-2: angiopoietin-2; PFT: pulmonary function test; SSc-myopathy: scleroderma-associated myopathy; YKL-40: human cartilage glycoprotein-39; MMP-3: matrix metalloproteinase-3.

5.2. IL-6 levels in dcSSc 135, 136). Both IL-6 and CRP trend to 5.3. Clinical applications of IL-6 compared to lcSSc decrease overtime in SSc (20, 99). Solu- and CRP in scleroderma IL-6 levels are higher in dcSSc com- ble IL-6 receptor (sIL-6R) serum levels IL-6 levels are frequently elevated pared to lcSSc in some studies (55, 79, are increased in SSc patients and cor- when CRP levels are in SSc (124), and 128) and not in others (98, 105). CRP related with progression and severity of also in interstitial lung disease (ILD) levels also varied between subsets in the disease (104, 137). Serum anti-IL-6 (102, 104, 140), pulmonary artery one but not another study (113, 114). autoantibody found in SSc serum (138, hypertension (PAH) (102, 141), anti- Early dcSSc had the highest IL-6 lev- 139) binds to IL-6. This IL-6 - anti-IL-6 topoisomerase I positivity (102), anti- els (88, 104, 118) and occasionally also autoantibody complex retains the origi- RNA polymerase III positivity (102), early lcSSc (88, 102, 118). CRP is el- nal IL-6 activity and is able to bind to and CRP is elevated in those with ex- evated more in early dcSSc and in those sIL-6R (138). The autoantibody seems tensive skin involvement, worse pul- with a worse prognosis (20, 110, 126, to transport IL-6 in the serum (138). monary function, higher disease ac-

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Table V. Interventions base on clinical application of IL-6 and CRP in scleroderma.

Authors, year (ref.) Interventions Patients Results

1. Targeted therapy on IL-6 or IL-6 producing B cells Shima Y. 2010 (186) TCZ 8 mg/kg monthly x 6 months 2 dcSSc After 6 months; 42 yr. man with SRC ≥50% $ Total z-score of Vesmeter hardness in both patients; 57 yr. woman with ILD ≥50% $ mRSS in only 1 patients Shima Y. 2013 (187) TCZ 8 mg/kg monthly x 16 months 1 dcSSc After 16 months; 59 yr. woman with SRC $ mRSS (357), improved joints range of motion Bosello S. 2010 (188) RTX 1 g IV every 2 weeks 9 dcSSc After 6 months; Mean age 40.9±11 yr. $ Mean mRSS (21.1±9.012.0±6.1; p=0.001) Mean Dis. Dur. 4.08±6.1 yr. No changes of FVC, DLCO %predicted; and echocardiographic parameters $ Mean serum IL-6 levels (3.7±5.3 pg/ml  0.6±0.9 pg/ ml; p=0.02)

2. Targeted therapy on endothelial/vascular regulatory dysfunction Filaci G. 1999 (100) Group I: Iloprost 20 SSc (16 dcSSc 4 lcSSc) After 12 months; $ serum IL-6 levels Group II: Iloprost + CyA 2.5 MKD Age 12 – 65 yr. Group I: 17.03±17.9 pg/ml  12.3±14.9 pg/ml (p=0.3) Dis. Dur. <2 yr. Group II: 17.50±13.1 pg/ml  3.8±2.5 pg/ml (p=0.007) No significant differences were observed for mean ESR & CRP Sicinska J. 2008 (113) PGE1 vs. placebo 50 SSc (32 dcSSc, 18 lcSSc) After 4 weeks; Mean age 49.5±12.9 yr. $ CRP levels (p=0.05) in PGE1 group Mean Dis. Dur. dcSSc 10.9±7.3 yr. lcSSc 12.0±8.8 yr. Bellisai F. 2011 (189) Bosentan 125 mg twice daily 10 SSc with DU ± PH $ Serum IL-2, IL-6, IL-8, IFN-γ levels

Abou-Raya A 2007 Atorvastatin 40 mg/day vs. 40 SSc After 6 months; $ IL-6 & CRP levels in atorvastatin group (190) placebo Mean age 59.9±10.1 yr. Serum IL-6: atorvastatin 26.1±11.5 pg/ml19.4±12.1 Mean Dis. Dur. 9.8±5.2 yr. pg/ml vs. placebo 25.5±11.8 pg/ml25.8±11.5 pg/ml Serum CRP: atorvastatin 3.79±1.8 mg/l3.14±1.5 mg/l vs. placebo 3.85±1.4 mg/l3.91±1.5 mg/l Del Papa N. 2008 Simvastatin 20 mg/day 20 lcSSc After 12 weeks; (191) x 12 weeks Median age 59 yr. (28-65) $ Serum IL-6 levels from 42±10.3 ng/ml25.7±7.5 ng/ml Median Dis. Dur. 8 yr. (1-28) (p=0.04) After 16 weeks; Rebound serum IL-6 levels to 35±9.1 ng/ml (not different to baseline) Alekperov R.T. 2011 Atorvastatin 10-40 mg/day vs. 50 SSc After 12 months; (192) placebo $ Serum level of CRP & IL-6 in atorvastatin group

3. Immunosuppression Åkesson A. 1994 (193) CYC 2-2.5 MKD x 12 months 18 SSc After 12 months; with prednisone 30 mg/day Median age 47 yr. (24-68) Median (range) ESR from 39 (3-113) mm/hr17 (5-75) x 10 weeks Median Dis. Dur. 2.5 yr. (0.5-17) mm/hr (p<0.05) Median (range) CRP from 16 (12-123) mg/l12 (12-55) mg/l (p<0.01) De Macedo P.A. 2009 CYC 0.5-1.0 g/m2 IV monthly 9 dcSSc After 12 months; $ Mean mRSS from 37.7±4.0829.1± (194) x 18 months Mean age 41.7 yr. 8.13 (p=0.009) Mean Dis. Dur. 2.2 yr. After 18 months; $ Mean CRP from 8.9 mg/dL3.09 mg/dL (p=0.04)

4. Other modalities McNearney T.A. 2013 Transcutaneous electrical nerve 17 SSc (9 dcSSc) After 2 weeks; (195) stimulation at GI acupoints apply Mean age 55 ± 2.28 yr., Improved patient gastric myoelectrical activity (GMA) score daily (30 min. x 3) Mean Dis. Dur. 8.8±1.1 yr. Improved association between GMA and sympathovagal balance $ Plasma IL-6 (p<0.05)

TCZ: Tocilizumab; dcSSc: diffuse cutaneous systemic sclerosis; lcSSc: limited cutaneous systemic sclerosis; SRC: scleroderma renal crisis; ILD: interstitial lung disease; $: decreased; mRSS: modified Rodnan skin score; RTX: Rituximab; Dis. Dur.: Disease duration; CyA: cyclosporine A; MKD: mg/ kg/ day; PGE1: Prostaglandin E1; DU: digital ulcer; PH: pulmonary hypertension; CYC: Cyclophosphamide; GI: gastro-intestinal tract.

S-128 IL-6 and CRP in SSc / C. Muangchan & J.E. Pope REVIEW tivity/ severity, and poorer quality of (171) which is a biomarker for oxida- mab can also reduce IL-6 by destroy- life, PAH, RA overlap, digital ulcers, tive stress and tissue injury; and serum ing CD20 marked B cells. Both drugs renal damage and those with primary angiopoietin-2 (Ang-2) that is abnor- have reports of softening of SSc skin biliary cirrhosis (PBC), calcinosis, mal in SSc-ILD (172). Pulmonary but large RCTs are needed (186-188). myopathy, contractures and antibodies function (20), albumin (173), vitamin Rituximab has a single site trial in SSc (topoisomerase I, RF, anticardiolipin, D levels (174) and erythrocyte deform- ILD (188) and there is a NIH trial of and anti-IL-6 IgG antibody) (20, 114, ability (175) are inversely associated rituximab to treat PAH from SSc that 126, 139, 141-149). The levels of IL-6 with CRP. is ongoing. There is a trial of tocili- in BALF do not differ between SSc zumab in the treatment of early active patients with and without alveolitis 5.4. Factors not associated with CRP dcSSc that is ongoing. There are other (150). Similarly, SSc patients with and Although elevated CRP levels occur in immunosuppressive and targeted thera- without elevated PA pressures on echo- SSc-myopathy (145). An elevated CRP pies reported to lower IL-6 and/or CRP. cardiography have no difference in is not essential for the occurrence of Prednisone can lower both. Interven- CRP levels (151), nor did the presence SSc-myopathy (176). CRP is not corre- tions reported changes of serum levels vs. absence of coronary calcification lated with many factors including bone of IL-6 and CRP were shown in Table V. (152), arthritis (153), and ILD (154, mineral density (BMD) (177), aortic 155). One study reported lower CRP stiffness (178), arterial wall dysfunc- Discussion levels in SSc patients who had elevated tion (108), pentraxin 3 (PTX-3) (179), Not all studies are in agreement about anti-caspase-8 proteinase domain anti- serum amyloid P (SAP) (180), prolac- the role of IL-6 and CRP in SSc prog- bodies which were frequent in females tin (181), matrix metalloproteinase- 3 nosis. There needs to be both ongoing and lcSSc patients (156). (MMP-3) (147), serum YKL-40 or hu- bench research combined with well Correlations of serum IL-6 and CRP man cartilage glycoprotein 39 (HC gp- conducted randomised blinded trials in levels with clinical and laboratory pa- 39) (182) and adiponectin (160). There order to determine if specific medica- rameters are shown in Table IV. is only one study reporting no corre- tions that alter IL-6 will show promise IL-6 levels are usually correlated with lation between serum IL-6 levels and in patients with SSc. worse SSc organ manifestations (55, CRP (119). In conclusion, we have addressed a 79, 102, 104, 119, 129, 140, 157-159), significance of IL-6 in SSc and impor- elevated ESR (104) and CRP (55, 104, 5.5. IL-6 and CRP and survival tance of CRP that could be used as a 124) (Table IV) but there also negative Serum IL-6 and CRP levels also have marker of disease activity, severity and publications (85, 127, 160-161). CRP predictive values to SSc morbidity and worse outcome in SSc and treatment is increased with disease activity (20, mortality. IL-6 levels >2 pg/ml are in- strategies to down regulate IL-6 will 162), severity (20, 116, 136), and dis- creased in digital ulcers and avascular need to be proven in clinical trials. ability (20). 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