Scleroderma pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:  M. Khurram Afzal, MD [2]

## Overview[edit | edit source]

Scleroderma is an autoimmune connective tissue disease. The hallmark of the underlying pathophysiology is production of autoantibodies against various cellular antigens, small vessel vasculopathy, fibrosis of skin and internal organs, and excess collagen deposition in the skin and internal organs. Circulating autoantibodies found in patients with scleroderma are anti-topoisomerase I (Scl-70) antibody, anti-centromere antibody, anti-RNA polymerase III antibody, anti-nucleolar antibody. Growth factors and cytokines play an important role in the underlying pathogenesis of scleroderma. Increased fibroblast activity leads to the excessive collagen deposition in scleroderma. Although the hallmark of this disease is skin fibrosis, internal organ involvement is a fatal complication and includes, esophageal dysmotility, interstitial lung disease, pulmonary arterial hypertension, scleroderma renal crisis, myocardial fibrosis, pericardial fibrosis and pericardial effusion. Although scleroderma occurs in a sporadic pattern in the general population, variations in the human leukocyte antigen (HLA) genes can predispose an individual to developing scleroderma. On gross pathology, sclerodactyly, skin fibrosis, edema and calcinosis are characteristic findings of scleroderma. On microscopic histopathological analysis, characteristic findings of scleroderma include microvascular damage, perivascular infiltrates of immune cells, loss of microvasculature, perivascular edema, fibrosis, densely packed collagen in the lower dermis and upper subcutaneous layer, atrophy, and loss of cells in the later stages of the disease.

## Pathophysiology[edit | edit source]

### Pathogenesis[edit | edit source]

* Scleroderma, also known as systemic sclerosis (SSc) is an autoimmune connective tissue disease.[1][2]
* Important features of scleroderma include:[3]
* Production of autoantibodies against various cellular antigens
* Small vessel vasculopathy
* Fibrosis of the skin and internal organs
* Excess of collagen deposition in the skin and internal organs
* Other features of Scleroderma include:
* Sclerodactyly (thickened skin of the fingers) is common
* Extensive skin fibrosis may be present
* Raynaud phenomenon
* Esophageal dysmotility
* Pulmonary arterial hypertension
* Cardiac involvement
* Interstitial lung disease
* Inflamatory arthritis
* Digital ulcers
* There is an association between scleroderma and malignancy:[4]
* Patients with RNA polymerase III autoantibodies are at high risk for scleroderma associated malignancy
* Patients with an older age of onset of scleroderma are at higher risk for cancer
* Screening for malignancy is recommended in these patients at risk
* An increase in alpha2-adrenergic activity in vascular smooth muscle is responsible for vasospasm in scleroderma.[5]
* Circulating autoantibodies found in patients with scleroderma include:
* Anti-topoisomerase I (Scl-70) antibody[6][7][8]
* Associated with higher risk of interstitial lung disease
* Increased disease activity
* Anti-centromere antibody
* Present in limited cutaneous scleroderma (CREST syndrome)
* Anti-RNA polymerase III antibody[9]
* Associated with higher prevalence of malignancy in scleroderma patients
* Anti-nuclear antibody (ANA)
* Growth factors and cytokines play a role in the underlying mechanism of disease:[1]
* Transforming growth factor-beta (TGF-beta)[10]
* Platelet-derived growth factor[11]
* Interleukins[12]
* IL-1, IL-6, IL-8, IL-17
* Basic fibroblast growth factor (bFGF)[13]
* Interferon-gamma
* Tumor necrosis factor (TNF) alpha
* Increased fibroblast activity leads to excess collagen deposition[14]
* The mechanism responsible is thought to be increased transcription of collagen specific mRNA[15]
* The transformation of fibroblasts to myofibroblasts leads to the over expression of cytokines and growth factors[16][10]
* Reactive oxygen species also play a role in the differentiation of fibroblasts[17]
* Internal organ involvement:
* Gastrointestinal system[18][19][20]
* Esophageal dysmotility
* Lower esophageal sphincter incompetence
* Pulmonary system
* Interstitial lung disease (pulmonary fibrosis)[21]
* Pulmonary arterial hypertension
* Renal system
* Scleroderma renal crisis[22][23]
* Microalbuminuria
* Elevated plasma creatinine
* Hypertension
* Cardiovascular system[24]
* Pericarditis[25]
* Pericardial effusion
* Myocardial fibrosis[26]
* Myocardial ischemia leading to myocardial infarction[27][28]
* Arrhythmia
* Ventricular arrhythmias
* Due to fibrosis of the myocardium and conduction system

## Genetics[edit | edit source]

Genetics associated with the development of scleroderma include:[29]

* Scleroderma occurs in a sporadic pattern in the general population.
* Variations in human leukocyte antigen (HLA) genes can predispose an individual to developing scleroderma.
* Other genes that increase the risk of developing scleroderma include:
* IRF5
* STAT4
* Genetic variation in the IRF5 gene predisposes an individual to developing diffuse cutaneous systemic scleroderma.
* Genetic variation in the STAT4 gene predisposes an individual to developing limited cutaneous systemic scleroderma.

## Associated Conditions[edit | edit source]

Conditions that are associated with scleroderma include:[2]

* Nephrogenic sclerosing fibrosis
* Scleroderma diabeticorum
* Scleromyxedema
* Erythromyalgia
* Porphyria
* Lichen sclerosis
* Diabetic cheiroarthropathy
* Primary biliary cirrhosis[30]

* Systemic lupus erythematosus (SLE)
* Rheumatoid arthritis
* Polymyositis
* Sjögren's syndrome
* Graft-versus-host disease[31]
* Mixed connective tissue disease
* Malignancy[32][4]

## Gross Pathology[edit | edit source]

* On gross pathology, sclerodactyly, skin fibrosis, edema and calcinosis are characteristic findings of scleroderma.[33][34][2]

## Microscopic Pathology[edit | edit source]

* On microscopic histopathological analysis characteristic findings of scleroderma include:
* Microvascular damage[35]
* Arterioles are primarily affected
* Perivascular edema
* Large gaps between endothelial cells
* Loss of integrity of the endothelial lining
* Platelet aggregation in the vessels
* Vacuolization of the cytoplasm of endothelial cells
* Perivascular infiltrates of mononuclear immune cells in the walls of arterioles[36]
* Obliterative microvascular lesions
* Rarefaction of capillaries
* Small vessel effacement[37]
* Fibrosis[38]
* Densely packed collagen in the lower dermis
* Upper subcutaneous layer also affected
* Loss of reticular structure
* Accumulation of proteoglycans, fibrillar and elastic fibers[39]
* Accumulation of type I collagen[40]
* Atrophy and loss of cells in later stages

## References[edit | edit source]

1. ↑ 1.0 1.1 Gabrielli A, Avvedimento EV, Krieg T (May 2009). "Scleroderma". N. Engl. J. Med. 360 (19): 1989–2003. doi:10.1056/NEJMra0806188. PMID 19420368.
2. ↑ 2.0 2.1 2.2 Pope JE, Johnson SR (August 2015). "New Classification Criteria for Systemic Sclerosis (Scleroderma)". Rheum. Dis. Clin. North Am. 41 (3): 383–98. doi:10.1016/j.rdc.2015.04.003. PMID 26210125.
3. ↑ Barnes J, Mayes MD (March 2012). "Epidemiology of systemic sclerosis: incidence, prevalence, survival, risk factors, malignancy, and environmental triggers". Curr Opin Rheumatol. 24 (2): 165–70. doi:10.1097/BOR.0b013e32834ff2e8. PMID 22269658.
4. ↑ 4.0 4.1 Shah AA, Casciola-Rosen L (November 2015). "Cancer and scleroderma: a paraneoplastic disease with implications for malignancy screening". Curr Opin Rheumatol. 27 (6): 563–70. doi:10.1097/BOR.0000000000000222. PMC 4643720. PMID 26352736.
5. ↑ Flavahan NA, Flavahan S, Liu Q, Wu S, Tidmore W, Wiener CM, Spence RJ, Wigley FM (August 2000). "Increased alpha2-adrenergic constriction of isolated arterioles in diffuse scleroderma". Arthritis Rheum. 43 (8): 1886–90. doi:10.1002/1529-0131(200008)43:8<1886::AID-ANR27>3.0.CO;2-S. PMID 10943881.
6. ↑ Reveille JD, Solomon DH (June 2003). "Evidence-based guidelines for the use of immunologic tests: anticentromere, Scl-70, and nucleolar antibodies". Arthritis Rheum. 49 (3): 399–412. doi:10.1002/art.11113. PMID 12794797.
7. ↑ Hu PQ, Fertig N, Medsger TA, Wright TM (May 2003). "Correlation of serum anti-DNA topoisomerase I antibody levels with disease severity and activity in systemic sclerosis". Arthritis Rheum. 48 (5): 1363–73. doi:10.1002/art.10977. PMID 12746909.
8. ↑ Black CM (1995). "The aetiopathogenesis of systemic sclerosis: thick skin--thin hypotheses. The Parkes Weber Lecture 1994". J R Coll Physicians Lond. 29 (2): 119–30. PMID 7595885.
9. ↑ Shah AA, Rosen A, Hummers L, Wigley F, Casciola-Rosen L (September 2010). "Close temporal relationship between onset of cancer and scleroderma in patients with RNA polymerase I/III antibodies". Arthritis Rheum. 62 (9): 2787–95. doi:10.1002/art.27549. PMC 2946521. PMID 20506513.
10. ↑ 10.0 10.1 Kawakami T, Ihn H, Xu W, Smith E, LeRoy C, Trojanowska M (January 1998). "Increased expression of TGF-beta receptors by scleroderma fibroblasts: evidence for contribution of autocrine TGF-beta signaling to scleroderma phenotype". J. Invest. Dermatol. 110 (1): 47–51. doi:10.1046/j.1523-1747.1998.00073.x. PMID 9424086.
11. ↑ Rajkumar VS, Sundberg C, Abraham DJ, Rubin K, Black CM (May 1999). "Activation of microvascular pericytes in autoimmune Raynaud's phenomenon and systemic sclerosis". Arthritis Rheum. 42 (5): 930–41. doi:10.1002/1529-0131(199905)42:5<930::AID-ANR11>3.0.CO;2-1. PMID 10323448.
12. ↑ Needleman BW, Wigley FM, Stair RW (January 1992). "Interleukin-1, interleukin-2, interleukin-4, interleukin-6, tumor necrosis factor alpha, and interferon-gamma levels in sera from patients with scleroderma". Arthritis Rheum. 35 (1): 67–72. PMID 1731816.
13. ↑ Bashkin P, Doctrow S, Klagsbrun M, Svahn CM, Folkman J, Vlodavsky I (February 1989). "Basic fibroblast growth factor binds to subendothelial extracellular matrix and is released by heparitinase and heparin-like molecules". Biochemistry. 28 (4): 1737–43. PMID 2541764.
14. ↑ LeRoy EC (October 1974). "Increased collagen synthesis by scleroderma skin fibroblasts in vitro: a possible defect in the regulation or activation of the scleroderma fibroblast". J. Clin. Invest. 54 (4): 880–9. doi:10.1172/JCI107827. PMC 301627. PMID 4430718.
15. ↑ Eckes B, Mauch C, Hüppe G, Krieg T (April 1996). "Differential regulation of transcription and transcript stability of pro-alpha 1(I) collagen and fibronectin in activated fibroblasts derived from patients with systemic scleroderma". Biochem. J. 315 ( Pt 2): 549–54. PMC 1217231. PMID 8615828.
16. ↑ Rajkumar VS, Howell K, Csiszar K, Denton CP, Black CM, Abraham DJ (2005). "Shared expression of phenotypic markers in systemic sclerosis indicates a convergence of pericytes and fibroblasts to a myofibroblast lineage in fibrosis". Arthritis Res. Ther. 7 (5): R1113–23. doi:10.1186/ar1790. PMC 1257439. PMID 16207328.
17. ↑ Bellini A, Mattoli S (September 2007). "The role of the fibrocyte, a bone marrow-derived mesenchymal progenitor, in reactive and reparative fibroses". Lab. Invest. 87 (9): 858–70. doi:10.1038/labinvest.3700654. PMID 17607298.
18. ↑ Turner R, Lipshutz W, Miller W, Rittenberg G, Schumacher HR, Cohen S (March 1973). "Esophageal dysfunction in collagen disease". Am. J. Med. Sci. 265 (3): 191–9. PMID 4701683.
19. ↑ Marie I, Dominique S, Levesque H, Ducrotté P, Denis P, Hellot MF, Courtois H (August 2001). "Esophageal involvement and pulmonary manifestations in systemic sclerosis". Arthritis Rheum. 45 (4): 346–54. doi:10.1002/1529-0131(200108)45:4<346::AID-ART347>3.0.CO;2-L. PMID 11501722.
20. ↑ HOSKINS LC, NORRIS HT, GOTTLIEB LS, ZAMCHECK N (September 1962). "Functional and morphologic alterations of the gastrointestinal tract in progressive systemic sclerosis (scleroderma)". Am. J. Med. 33: 459–70. PMID 14449181.
21. ↑ Harrison NK, Myers AR, Corrin B, Soosay G, Dewar A, Black CM, Du Bois RM, Turner-Warwick M (September 1991). "Structural features of interstitial lung disease in systemic sclerosis". Am. Rev. Respir. Dis. 144 (3 Pt 1): 706–13. doi:10.1164/ajrccm/144.3_Pt_1.706. PMID 1892314.
22. ↑ Traub YM, Shapiro AP, Rodnan GP, Medsger TA, McDonald RH, Steen VD, Osial TA, Tolchin SF (November 1983). "Hypertension and renal failure (scleroderma renal crisis) in progressive systemic sclerosis. Review of a 25-year experience with 68 cases". Medicine (Baltimore). 62 (6): 335–52. PMID 6355755.
23. ↑ Nikpour M, Hissaria P, Byron J, Sahhar J, Micallef M, Paspaliaris W, Roddy J, Nash P, Sturgess A, Proudman S, Stevens W (2011). "Prevalence, correlates and clinical usefulness of antibodies to RNA polymerase III in systemic sclerosis: a cross-sectional analysis of data from an Australian cohort". Arthritis Res. Ther. 13 (6): R211. doi:10.1186/ar3544. PMC 3334664. PMID 22189167.
24. ↑ Janosik DL, Osborn TG, Moore TL, Shah DG, Kenney RG, Zuckner J (December 1989). "Heart disease in systemic sclerosis". Semin. Arthritis Rheum. 19 (3): 191–200. PMID 2690346.
25. ↑ Byers RJ, Marshall DA, Freemont AJ (June 1997). "Pericardial involvement in systemic sclerosis". Ann. Rheum. Dis. 56 (6): 393–4. PMC 1752384. PMID 9227172.
26. ↑ Tzelepis GE, Kelekis NL, Plastiras SC, Mitseas P, Economopoulos N, Kampolis C, Gialafos EJ, Moyssakis I, Moutsopoulos HM (November 2007). "Pattern and distribution of myocardial fibrosis in systemic sclerosis: a delayed enhanced magnetic resonance imaging study". Arthritis Rheum. 56 (11): 3827–36. doi:10.1002/art.22971. PMID 17968945.
27. ↑ Nordin A, Jensen-Urstad K, Björnådal L, Pettersson S, Larsson A, Svenungsson E (August 2013). "Ischemic arterial events and atherosclerosis in patients with systemic sclerosis: a population-based case-control study". Arthritis Res. Ther. 15 (4): R87. doi:10.1186/ar4267. PMC 3979018. PMID 23945149.
28. ↑ Chu SY, Chen YJ, Liu CJ, Tseng WC, Lin MW, Hwang CY, Chen CC, Lee DD, Chen TJ, Chang YT, Wang WJ, Liu HN (November 2013). "Increased risk of acute myocardial infarction in systemic sclerosis: a nationwide population-based study". Am. J. Med. 126 (11): 982–8. doi:10.1016/j.amjmed.2013.06.025. PMID 24157289.
29. ↑ "Systemic scleroderma - Genetics Home Reference".
30. ↑ Powell FC, Winkelmann RK, Venencie-Lemarchand F, Spurbeck JL, Schroeter AL (October 1984). "The anticentromere antibody: disease specificity and clinical significance". Mayo Clin. Proc. 59 (10): 700–6. PMID 6384675.
31. ↑ Artlett CM, Smith JB, Jimenez SA (April 1998). "Identification of fetal DNA and cells in skin lesions from women with systemic sclerosis". N. Engl. J. Med. 338 (17): 1186–91. doi:10.1056/NEJM199804233381704. PMID 9554859.
32. ↑ Shah AA, Casciola-Rosen L (2017). "Mechanistic and clinical insights at the scleroderma-cancer interface". J Scleroderma Relat Disord. 2 (3): 153–159. doi:10.5301/jsrd.5000250. PMC 5734659. PMID 29264402.
33. ↑ Shah AA, Wigley FM (April 2013). "My approach to the treatment of scleroderma". Mayo Clin. Proc. 88 (4): 377–93. doi:10.1016/j.mayocp.2013.01.018. PMC 3666163. PMID 23541012.
34. ↑ Steen VD, Ziegler GL, Rodnan GP, Medsger TA (February 1984). "Clinical and laboratory associations of anticentromere antibody in patients with progressive systemic sclerosis". Arthritis Rheum. 27 (2): 125–31. PMID 6607734.
35. ↑ Prescott RJ, Freemont AJ, Jones CJ, Hoyland J, Fielding P (March 1992). "Sequential dermal microvascular and perivascular changes in the development of scleroderma". J. Pathol. 166 (3): 255–63. doi:10.1002/path.1711660307. PMID 1517881.
36. ↑ Fleischmajer R, Perlish JS (February 1980). "Capillary alterations in scleroderma". J. Am. Acad. Dermatol. 2 (2): 161–70. PMID 7364973.
37. ↑ Fleming JN, Nash RA, McLeod DO, Fiorentino DF, Shulman HM, Connolly MK, Molitor JA, Henstorf G, Lafyatis R, Pritchard DK, Adams LD, Furst DE, Schwartz SM (January 2008). "Capillary regeneration in scleroderma: stem cell therapy reverses phenotype?". PLoS ONE. 3 (1): e1452. doi:10.1371/journal.pone.0001452. PMC 2175530. PMID 18197262.
38. ↑ Fleischmajer R, Perlish JS, West WP (December 1977). "Ultrastructure of cutaneous cellular infiltrates in scleroderma". Arch Dermatol. 113 (12): 1661–6. PMID 202203.
39. ↑ Fleischmajer R, Jacobs L, Schwartz E, Sakai LY (June 1991). "Extracellular microfibrils are increased in localized and systemic scleroderma skin". Lab. Invest. 64 (6): 791–8. PMID 2046331.
40. ↑ Perlish JS, Lemlich G, Fleischmajer R (January 1988). "Identification of collagen fibrils in scleroderma skin". J. Invest. Dermatol. 90 (1): 48–54. PMID 3335789.

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