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SSc-ILD

Overview

Systemic sclerosis (SSc) is a systemic autoimmune disease that is characterized by endothelial dysfunction resulting in a small-vessel vasculopathy, fibroblast dysfunction with resultant excessive collagen production and fibrosis, and immunological abnormalities. While virtually any organ system may be involved in the disease process, fibrotic and vascular pulmonary manifestations of SSc, including interstitial lung disease (ILD) and pulmonary hypertension (PH), are the leading cause of death.1 Patients with SSc are classified as limited cutaneous SSc (lcSSc) or diffuse cutaneous SSc (dcSSc) based on the extent of skin involvement. Patients with dcSSc or Scl-70 (anti-topoisomerase I) antibodies are more likely to develop ILD, whereas patients with lcSSc or anticentromere antibodies tend to have a lower prevalence of pulmonary fibrosis.2 SSc is uncommon and is designated an orphan disease with a high unmet medical need.3 As new therapies targeting these pulmonary conditions emerge, early recognition of lung involvement is essential for the care of these patients.1

Epidemiology

Past studies estimated the yearly incidence of SSc in the United States at under 2 cases per 100,000 individuals and the prevalence in the United States at over 25 cases per 100,000 individuals. A study used a large US managed care organization database to estimate the incidence and prevalence of SSc from 2003 to 2008 among their insured members. The annual age-and-sex-adjusted incidence of SSc ranged from 4.8 to 6.3 cases per 100,000; and the annual prevalence ranged from 13.5 to 18.4 per 100,000.4

On the other hand, a study was done using the Taiwan National Health Insurance Research Dataset and the National Death Registry of Taiwan to calculate the incidence, prevalence and mortality of SSc in Taiwan from 2002 to 2007. The annual incidence of SSc was found to be 1.09 per 100,000; and the mean annual prevalence was 5.63 per 100,000. The 1-, 2- and 5-year survival rates of SSc patients were 94.9%, 92.0% and 83.2%, respectively. SSc patients had a standardized mortality ratio of 3.24 (95% confidence interval of 2.82-3.71) for all-cause mortality as compared with the national population in 2002.5

Clinically relevant pulmonary fibrosis is present in approximately 25% of all SSc patients, but up to 90% of patients with SSc show changes consistent with ILD on high-resolution computed tomography (HRCT) of the chest, and between 40–75% of patients exhibit some pulmonary function test (PFT) abnormality.2 A recent European League Against Rheumatism Scleroderma Trials and Research analysis revealed in a cohort of 3,656 SSc patients that ILD was present in 53% of cases with dcSSc and in 35% of cases with lcSSc.6

SSc-ILD was found to be the primary contributor of mortality in 33% of the SSc patients.7

Pathogenesis

SSc-ILD is thought to be the result of the interplay between fibrosis, autoimmunity, inflammation, and vascular injury. The initial event has been proposed to be an injury to the alveolar epithelium or vasculature, or both, followed by aberrant activation of the immune system, which promotes fibroblast recruitment and activation, extracellular matrix over-production, and eventually the replacement of normal pulmonary architecture by scarring.8 (Figure 1)

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Figure 1. Inflammation, autoimmunity and epithelial and microvascular injury culminate in myofibroblast activation leading to pulmonary fibrosis.8

Tissue injury8: The presence of lung injury is suggested by the detection of high serum concentrations of alveolar epithelial cell products such as surfactant protein D and Krebs von den Lungen-6 (KL-6) in patients with SSc-ILD. Tissue injury results in the release of profibrotic stimuli that induce the differentiation of fibroblasts to myofibroblasts, with the participation of coagulation factors, cytokines, growth factors and inflammatory cells, leading to inflammation and fibrosis.8

Vascular injury8: Several histological changes obvious in patients with SSc, including gaps, vacuolization, and apoptosis of endothelial cells, perivascular fibrosis, and inflammation, all support the hypothesis of vascular injury. A number of functional auto-antibodies were identified as potential culprits for the vascular injury.8

Autoimmunity resulting in inflammation and fibrosis8: Stimulatory antibodies targeting the platelet derived growth factor receptor have been reported in the serum of patients with SSc and could potentially have a role in the fibrosing process. Anti-endothelial antibodies have been detected in the circulation of patients with SSc and shown to induce both endothelial cell activation and apoptosis. Moreover, a central role has been proposed for antibodies against the angiotensin-2 type 1 receptors and endothelin-1 type A receptors. The presence of these antibodies has been associated with vascular symptoms of SSc, including pulmonary arterial hypertension (PAH), and also fibrosis. These antibodies act on their receptors as agonists, promoting the release of transforming growth factor-β and interleukin (IL)-8 by endothelial cells and collagen by fibroblasts.8

B cells seem to be activated and to produce increased amounts of autoantibodies, which accumulate in the lung and cause local damage. Moreover, B cells have been shown to produce transforming growth factor-β and profibrotic Th2 cytokines such as IL-4, IL-6, and IL-13. Serum level of IL-6 is also found to be particularly elevated in patients with SSc-ILD. IL-6 promotes collagen synthesis and fibroblasts and switches macrophage polarization towards a profibrotic M2-like phenotype. The increase of IL-6 level has been associated with a worse prognosis.8

Anti-topoisomerase 1-polarized T cells were identified in the serum of patients with SSc, particularly in patients who also have ILD. These T-cells produce profibrotic cytokines such as IL-4, IL-13, and IL-17. Increased numbers of these T cells are positively correlated with the severity of ILD and are associated with a worse prognosis.8

Risk factors8,9

The demographic factors associated with the presence of SSc-ILD include male sex, African American race, and diffuse skin disease. SSc-ILD is also more common among patients with nailfold capillary abnormalities, digital ulcers, longer disease duration, and PH on screening echocardiogram,8 and those with the presence of anti-Scl-70/anti-topoisomerase I antibody and/or absence of anticentromere antibody.9

Footnotes:

  • Anti-Scl-70, anti-topoisomerase I antibodies; αSMA, α smooth muscle action; CCL, chemokine (C-C motif) ligand; dcSSc, diffuse cutaneous systemic sclerosis; HRCT, high-
    resolution computed tomography; lcSSc, limited cutaneous systemic sclerosis; KL-6, krebs von den lungen-6; IL, interleukin; ILD, interstitial lung disease; M1, M1-type 
    macrophage; M2, M2-type macrophage; PAH, pulmonary arterial hypertension; PFT, pulmonary function test; PH, pulmonary hypertension; SSc, systemic sclerosis; SSc-ILD, 
    systemic sclerosis associated interstitial lung disease; Th, T helper cell; TGF, transformative growth factor; US, United States.

References:

  1. Solomon JJ, et al. Eur Respir Rev. 2013 Mar 1;22(127):6-19.

  2. Schoenfeld SR, Castelino FV. Ther Adv Respir Dis. 2017 Aug;11(8):327-340.

  3. Denton CP, Khanna D. Lancet. 2017 Oct 7;390(10103):1685-1699.

  4. Furst DE, et al. J Rheumatol. 2012 Apr;39(4):784-6.

  5. Kuo CF, et al. Scand J Rheumatol. 2011;40(5):373-8.

  6. Castelino FV, Varga J. Arthritis Res Ther. 2010;12(4):213.

  7. Solomon JJ, Brown KK. Int. J. Clin. Rheumatol. 2011;6(5):503–515.

  8. Perelas A, et al. Lancet Respir Med. 2020 Mar;8(3):304-320.

  9. Cottin V, Brown KK. Respir Res. 2019 Jan 18;20(1):13.

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