Systemic Sclerosis (SSc)

Systemic sclerosis (SSc) is a chronic autoimmune disease that affects the skin and many internal organs. Skin thickening caused by edema and excessive buildup of collagen-rich extracellular matrix is one of the defining clinical characteristics of SSc. In addition to sclerosis, the pathogenesis of SSc is defined by vasculopathy. It manifests with nailfold capillary abnormalities, Raynaud’s phenomenon, and the presence of antinuclear antibodies like anticentromere, anti-topoisomerase I, and anti-RNA polymerase III antibodies. Histological examination of various organ systems can help reveal each patient’s disease involvement and guide treatment plans.¹

Skin Histology

Involvement of the skin is the most characteristic disease feature affecting almost all individuals with SSc to variable degrees.² And as the skin is often the first organ to show significant disease changes, most patients with SSc initially present to dermatologists.³ 

History, physical examination, test results, and the 2013 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) criteria are used to diagnose SSc. Skin histology is not included in the SSc categorization criteria. However, skin biopsy may occasionally be useful to support the diagnosis of SSc or distinguish it from illnesses with similar clinical symptoms. Additionally, a few studies have compared the histological aspects of various SSc subtypes using skin biopsies.³

Previous research using clinical samples and animal models suggested that the epidermis and subcutaneous adipose tissue are potential drivers of dermal fibrosis in SSc.⁴ Characteristic histological findings seen in skin biopsies that are helpful to differentiate SSc from other diseases include increases in thickness involving the epidermis and subcutis. There may be sclerosis and thickening of collagen bundles in the dermis. In addition, loss of hair follicles with compression of pilosebaceous units may be observed, as well as loss of periadnexal fat and scanty inflammatory infiltrates of lymphocytes and plasma cells.³ 

Read more about SSc pathophysiology

Lung Histology

Interstitial lung disease (ILD) and pulmonary hypertension, which together account for 60% of SSc-related deaths, are the 2 most frequent types of direct lung involvement in SSc.⁵

Interstitial Lung Disease

Patients with SSc rarely undergo surgical lung biopsies because the most frequent cause of diffuse parenchymal lung disease in people with SSc-ILD is fibrotic nonspecific interstitial pneumonia (NSIP). Usual interstitial pneumonia (UIP) is less common than NSIP, but when adequate high-resolution computed tomography findings are noted, lung biopsies are typically not required for confirmation of the diagnosis.⁶ 

Histological examination of surgical lung biopsies reveal a mixed pattern of inflammation and fibrosis in most NSIP cases.⁵ There is effacement of lung architecture due to fibrosis of the alveolo-capillary membrane and the parenchymal interstitium along with marked mononuclear cell infiltration. It is common to have prominent vascular abnormalities with proliferation in the intima that results in the constriction or total obliteration of small blood vessels.⁷

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Pulmonary Hypertension 

Autopsy studies have identified pulmonary vasculature abnormalities in approximately 50% of SSc cases, with changes noted mostly in small and medium muscular arteries. Important histological abnormalities include fibrosis of the intima that affects the small distal vessels adjacent to the alveoli, hyperplasia of the media layer, and fibrosis of the adventitia affecting the pulmonary arterioles. Pulmonary hypertension in SSc differs from idiopathic pulmonary arterial hypertension due to small vessel intimal fibrosis (with involvement of the veins/venules), the presence of a pulmonary veno-occlusive disease pattern, the presence of concentric laminar intimal fibrosis, and the paucity or absence of plexiform lesions.⁵ 

Read more about SSc etiology

Gastrointestinal System Histology

Around 90% of people with SSc exhibit gastrointestinal symptoms, which are the main cause of morbidity. These symptoms include hypomotility, dysmotility, and reduced secretion of digestive enzymes in any gastrointestinal region, from the oral cavity to the anus.⁴ 

Histological biopsies of gastrointestinal lesions demonstrate marked atrophy and fibrosis of the smooth muscles in the gut. Vascular structural changes, including capillary loss and arteriolar stenosis, cause hypoxia in tissues of the gastrointestinal tract, leading to autonomic axonal degeneration. Marked atrophy and fibrosis of the enteric smooth muscles and the disordered enteric nervous system result in hypomotility and dysmotility.⁴

Read more about SSc life expectancy

Kidney Histology

Kidney biopsy is very helpful to determine the nature of the disease, particularly curable renal conditions in patients with SSc such as inflammatory glomerular disease. As patients present with an apparent decrease in glomerular filtration rate (GFR), microscopic hematuria, and proteinuria, kidney biopsy is useful to establish a precise diagnosis and determine a treatment plan.⁸

Histological features of kidney lesions show ischemic changes in the glomeruli with no evidence of glomerulitis. There is severe narrowing and obliteration of the medium-sized arterioles because of subintimal accumulation of loose connective tissue along with intimal and perivascular fibrosis. Marked fibrosis (interstitial, perivascular, and periglomerular) can be observed in long-standing cases.⁷

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Heart Histology

Heart involvement is seen in all patients with SSc; however, it is usually clinically undetectable. Histological examination of autopsy samples from SSc patients with no cardiac symptoms prior to death show evidence of myocardial disease. Histological findings in the heart include inflammation, changes in vessels, and extracellular membrane deposition.⁴ 

Liver Histology

Severe liver complications in SSc are rare. Histological examination of the liver shows portal tract fibrosis with no other abnormalities.⁴ 

References

1. Van Praet JT, Smith V, Haspeslagh M, Degryse N, Elewaut D, De Keyser F. Histopathological cutaneous alterations in systemic sclerosis: a clinicopathological study. Arthritis Res Ther. 2011;13(1):R35. doi:10.1186/ar3267
2. Adigun R, Goyal A, Hariz A. Systemic sclerosis. In: StatPearls [Internet]. Treasure Island, FL: StatPearls Publishing; 2023. Updated May 8, 2022. Accessed April 17, 2023.
3. Showalter K, Gordon JK. Skin histology in systemic sclerosis: a relevant clinical biomarker. Curr Rheumatol Rep. 2020;23(1):3. doi:10.1007/s11926-020-00970-z
4. Asano Y. The pathogenesis of systemic sclerosis: an understanding based on a common pathologic cascade across multiple organs and additional organ-specific pathologies. J Clin Med. 2020;9(9):2687. doi:10.3390/jcm9092687
5. Solomon JJ, Olson AL, Fischer A, Bull T, Brown KK, Raghu G. Scleroderma lung disease. Eur Respir Rev. 2013;22(127):6-19. doi:10.1183/09059180.00005512
6. Nandan A. Scleroderma workup: histologic findings. Medscape. Updated March 1, 2023. Accessed April 17, 2023. 
7. Konopka KE, Myers JL. Interstitial lung disease pathology in systemic sclerosis. Ther Adv Musculoskelet Dis. 2021;13:1759720X211032437. doi:10.1177/1759720X211032437
8. Tonsawan P, Talabthong K, Puapairoj A, Foocharoen C. Renal pathology and clinical associations in systemic sclerosis: a historical cohort study. Int J Gen Med. 2019;12:323-331. doi:10.2147/IJGM.S221471

Reviewed by Kyle Habet, MD, on 4/19/2023.

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Harshi Dhingra, MD

Harshi Dhingra is a licensed medical doctor with specialization in Pathology. She is currently employed as faculty in a medical school with a tertiary care hospital and research center in India. Dr. Dhingra has over a decade of experience in diagnostic, clinical, research, and teaching work, and has written several publications and citations in indexed peer reviewed journals. She holds medical degrees for MBBS and an MD in Pathology.