Background/Purpose: Systemic sclerosis (SSc) is a rare autoimmune disease with multiple disease manifestations, including cutaneous fibrosis, musculoskeletal inflammation, Raynaud phenomenon, calcinosis and digital ulceration. Internal organ-based disease manifestations also occur, including pulmonary fibrosis, pulmonary hypertension (PH), and cardiac, renal, and gastrointestinal (GI) complications. This review aimed to determine the additional mortality risk and humanistic burden of eight SSc manifestations: interstitial lung disease (ILD) and/or PH, and cardiac, renal, GI, musculoskeletal, peripheral vascular, and skin manifestations.

Methods: We conduced a search of electronic databases (Embase, Medline, PubMed, NHS Economic Evaluation Database). We included recent observational studies (published 2018–2023) comparing SSc patients with/without the manifestations of interest and reporting any of the following outcomes: mortality risk, Kaplan–Meier survival estimates, or humanistic burden (health-related quality of life [HRQoL] and patient-reported outcome or experience measures). Meta-analyses with no publication limits were also included.

Results: A total of 43 studies reporting mortality or burden outcomes were identified; 37 (including 4 meta-analyses) reported mortality outcomes and 9 reported HRQoL outcomes.

Pulmonary, cardiac, renal, and severe GI manifestations were generally associated with a higher mortality risk compared to SSc patients without manifestations. Multivariate Cox regression analyses and meta-analyses estimated that these four manifestations are associated with an approximately 2- to 4-fold increased mortality risk. Most Kaplan–Meier survival estimates reported significantly (p≤0.05) poorer survival. In three of the four studies reporting significantly (p≤0.05) reduced survival for PH, ILD, and concurrent PH-ILD, the presence of PH-ILD was associated with the poorest survival with a hazard ratio of up to 6.1 (95% confidence intervals [CIs]: 3.72, 9.96; p< 0.001) reported, followed by PH and no ILD (hazard ratio of up to 4.81 [95% CIs: 2.68, 8.64; p< 0.001]).

Multiple manifestations were associated with poorer HRQoL outcomes.  GI involvement often affected physical, mental, and social functioning, while Raynaud phenomenon and digital ulcers were significantly associated with lower mental (p≤0.003) and physical (p≤0.009) HRQoL. Skin manifestations also significantly affected physical (p≤0.002), mental (p≤0.021), and emotional (p=0.009) HRQoL.  There was a lack of studies comparing the humanistic burden between SSc patients with and without scleroderma renal crisis, or arthritis, and muscle weakness.

Conclusion: Manifestations of SSc are associated with a substantial mortality and humanistic burden. Even for those manifestations that have no significant impact on mortality, patients often experience poorer quality of life due to physical, mental, emotional, or social functioning impairment. Further studies are needed to determine the humanistic impact of musculoskeletal and renal involvement in SSc. Early detection and treatment of SSc manifestations may reduce the burden associated with these manifestations and potentially improve survival.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-impact-of-systemic-sclerosis-manifestations-on-survival-and-humanistic-burden-a-targeted-literature-review/