Systemic Sclerosis

An Update

Uwe-Frithjof Haustein, MD, PhD

Lab Med. 2011;42(9):562-572.

Antifibrotic Agents

Imatinib mesylate, an inhibitor of the tyrosine kinase, also targets the PDGFR kinase, thus inhibiting the ERK1/2 pathway of FB activation. Various clinical studies have shown it reduces fibrosis of different organs.^[101]

Oral administration of 500 mg bovine collagen type I reduced skin thickness. The rationale is the induction of oral tolerance against the suspected autoantigen collagen as measured by T cell reactivity.^[103] However, the target of this therapy may only be a secondary mechanism.

Attempts to treat with neutralizing anti-TGFβ antibodies (CAT-192) and with peptide inhibitors of TGFβ and CTGF are promising. Penicillamine cannot be recommended, since it causes severe side effects.

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Cite this: Systemic Sclerosis - Medscape - Sep 01, 2011.

Table 1. Systemic Sclerosis Subsets According to LeRoy and Colleagues⁶
Limited Cutaneous SSc
Raynaud's phenomenon for years at presentation Skin sclerosis limited to hands, feet, face, and forearms, or absent Significant late incidence of PHT, trigeminal neuralgia, calcinosis, and telangiectases Dilated nailfold capillary loops, usually without capillary dropouts detected by widefield nailfold capillaroscopy
Diffiuse SSc
Onset of Raynaud's phenomenon within 1 year of onset of skin changes Truncal and acral skin involvement Presence of tendon friction rubs Early and significant incidence of interstitial lung disease, oliguric renal failure, diffuse gastrointestinal disease, and myocardial involvement Presence of anti-DNA topoisomerase I (anti-Scl-70) antibodies Absence of anti-centromere antibodies Nailfold capillary dilatation and destruction detected by widefield nailfold capillaroscopy

Table 2. Cytokines, Chemokines, Growth Factors Involved in Systemic Sclerosis
Mediators	Findings in SSc
Proinflammatory
IL-2, IL-2R	Elevated in serum
IL-6	Elevated in serum
MCP-1	Elevated in lesions, correlation with disease activity
TNF-α	Increased in serum and tissue, up-regulation of TNF-α converting enzyme (TACE) in monocytes, inhibition of collagen synthesis in FB
IFN-α	Increased in tissue, monocyte activation
Pro-fibrotic
TGF-β	Increased in tissue, reduced in serum, increased TRβ1 receptor expression, increased activation of latent TGF-β by integrins
IL-4, IL-13	Increased collagen synthesis, myofibroblast differentiation
PDGF	Receptor stimulation by Auto-ab via tyrosine phosphorylation and stimulation of the ERK pathway
BAFF	Increased in serum

Table 3. Autoantibodies in Systemic Sclerosis
Autoantibody	Target, Function	Pathogenicity
ATA	Topoisomerase, FB surface 100kD molecule, mediates relaxation of supercoiled DNA	Unknown
ACA	Centromeres A,B,C,D kinetochore, interacts with cell division	Unknown
A-RNA-P-A	RNA-polymerase I, II, III protein biosynthesis by ribosomes	Unknown
A-U3RNP(fibrillarin)-A	Fibrillarin, 34kD basic protein, processing of peri-ribosomal RNA	Unknown
AECA	NAG-2, topoisomerase I centromeric protein B	Apoptosis, ECM expression, EC cytotoxicity by direct complement activation
A-FiB-A	Fibrillin-1, NAG-2	ECM expression via TGF-ß pathway, FB activation/ECM expression
A-MMP-A	MMP-1 and -3	Inhibition of ECM degradation
A-PDGF-A	PDGF-R	Collagen expression, production of ROS, tyrosine phosphorylation, and stimulation of the ERK pathway

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Systemic Sclerosis

An Update

Antifibrotic Agents

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