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While PPIs mitigate GERD symptoms and protect against lung injury, concerns about their long-term safety, particularly regarding chronic kidney disease (CKD), osteoporosis, and Alzheimer\u2019s disease, are growing. This study aimed to assess whether the adverse effects of PPI are amplified in patients with scleroderma.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods<\/jats:title>\n            <jats:p>This was a retrospective observational analysis that utilized the TriNetX research network, including over 130 million patients globally. The study population comprised 6800 SSc patients on PPIs and 1,889,433 GERD patients on PPIs. Outcomes were evaluated pre- and post-propensity score matching for demographic and clinical factors. Risks of CKD (including stages 3, 4, 5, ESRD, hemodialysis dependence), osteoporosis, vascular dementia, and Alzheimer\u2019s disease were assessed.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>The SSc cohort exhibited higher risks of developing CKD (attributable risk [AR] 2.8%, <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.01) and osteoporosis (AR 9%, <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.01) after matching, compared to the GERD cohort. Notably, CKD stages 4 and 5 showed minimal differences between groups. SSc patients on PPI had lower risks of Alzheimer\u2019s disease (AR\u2009\u2212\u20090.7%, <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.01). While the findings highlight an amplified risk of CKD and osteoporosis in SSc patients, the differences in advanced renal disease were modest.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusion<\/jats:title>\n            <jats:p>PPI therapy remains indispensable in SSc management. While potentially associated with a slight but significant increase in the risks of CKD and osteoporosis, these adverse effects do not negate the critical role of PPIs in mitigating GERD and its serious pulmonary complications. A strategy of targeted monitoring is recommended to maximize safety.<\/jats:p>\n            <jats:p>\n              <jats:table-wrap>\n                <jats:table>\n                  <jats:tbody>\n                    <jats:tr>\n                      <jats:td align=\"left\" colspan=\"2\">\n                        <jats:bold>Key Points<\/jats:bold>\u2022 <jats:italic>Identified Amplified Risks in SSc: This large-scale study reveals that SSc patients on PPIs face significantly higher risks of chronic kidney disease and osteoporosis compared to GERD patients on PPIs, suggesting SSc pathophysiology amplifies PPI-associated adverse effects.<\/jats:italic>\u2022 <jats:italic>Uncovered Neuroprotective Association: Contrary to general population trends, SSc patients on PPIs showed a reduced risk of Alzheimer\u2019s disease, potentially linked to immunosuppressant use, closer monitoring, or unique disease mechanisms\u2014a finding warranting further investigation.<\/jats:italic>\u2022 <jats:italic>Provided Real-World Safety Evidence: Leveraging global data (&gt;\u2009130 million patients), this study offers robust real-world evidence on PPI safety in SSc, reinforcing PPIs\u2019 vital role in GERD\/ILD management while advocating vigilant monitoring for CKD\/osteoporosis.<\/jats:italic>\u2022 <jats:italic>Informed Risk\u2013Benefit Clinical Strategy: The findings underscore the need to balance PPI benefits (reducing GERD\/aspiration-related lung injury) against amplified renal\/bone risks in SSc, guiding individualized treatment and monitoring protocols despite causal limitations of retrospective data.<\/jats:italic>\n                      <\/jats:td>\n                    <\/jats:tr>\n                  <\/jats:tbody>\n                <\/jats:table>\n              <\/jats:table-wrap>\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1007\/s10067-025-07686-4","type":"journal-article","created":{"date-parts":[[2025,9,11]],"date-time":"2025-09-11T23:33:04Z","timestamp":1757633584000},"page":"4061-4070","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Proton pump inhibitors in systemic sclerosis: should we exercise caution? 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