Objective: The aim of this study was to investigate the impact of estrogen and progesterone analog supplementation on the development of autoimmune conditions.Methods: This retrospective observational study used data from the TriNetX network, which comprised over 100 million patients from 89 health care organizations. We compared patients exposed to estrogen and progesterone analogs to those exposed to progesterone‐only therapy, using 1:1 propensity score matching based on age, ethnicity, and additional criteria. The primary outcomes were incidences of various autoimmune conditions.Results: We included 3,338,925 patients in the group who received estrogen and progesterone and 2,090,758 patients in the group who received progesterone only. Prematching, the group who received combined therapy showed increased risks for Sjögren disease (risk ratio [RR] 1.46), rheumatoid arthritis (RR 1.1), and other autoimmune conditions. Postmatching, significant associations persisted for most conditions, with increased risks for systemic sclerosis, systemic lupus erythematosus, giant cell arteritis, Behcet disease, psoriatic arthritis, reactive arthritis, and ankylosing spondylitis. The group who received combination therapy appeared to have lower risks of developing antiphospholipid syndrome (RR 0.7).Conclusion: Combined estrogen and progesterone therapy is associated with an increased risk of several autoimmune conditions. The role of estrogen, despite its protective effects against some conditions, underscores the complex interplay of sex hormones in autoimmunity. Further prospective studies are needed to elucidate underlying mechanisms and evaluate causality.

Emerging evidence suggests a significant association between monocytes and the pathophysiology and prognosis of idiopathic pulmonary fibrosis (IPF). This review aims to systematically evaluate current knowledge regarding blood monocyte counts and their relationship with the etiology, progression, and prognosis of IPF. We conducted a systematic search in the PubMed database for articles published through 17 February 2025, using the MeSH terms “lung diseases, interstitial” and “monocytes,” which yielded 314 results. After filtering for full-text articles in English (n = 242), we included only studies focusing on blood monocyte counts with clinical implications in IPF. Articles relating to other cell types or non-IPF lung diseases were excluded. Our systematic search identified 12 relevant articles. Monocytes play an essential role in regulating inflammatory responses and resolution across multiple diseases, with established but incompletely understood contributions to lung fibrosis development in IPF. Correlations have been demonstrated between elevated blood monocyte counts and the following: (1) the presence and progression of interstitial lung abnormalities, (2) the progression from an indeterminate usual interstitial pneumonia (UIP) pattern on CT scans to definitive IPF, and (3) worse lung function parameters, an increased risk of acute exacerbations, and reduced overall survival in IPF patients. Monocytes serve as critical orchestrators throughout IPF’s natural history—from early interstitial changes to disease progression and acute exacerbations. Targeting monocyte recruitment pathways and reprogramming their differentiation represents a promising therapeutic approach, while circulating monocyte counts offer potential as accessible biomarkers for disease progression and treatment response. Future research should characterize stage-specific monocyte phenotypes to enable precision-targeted interventions.

Background: Systemic sclerosis (SSc) is a chronic autoimmune disorder often accompanied by gastroesophageal reflux disease (GERD), necessitating frequent use of proton pump inhibitors (PPIs). 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’s disease, are growing. This study aimed to assess whether the adverse effects of PPI are amplified in patients with scleroderma. Methods: 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’s disease were assessed. Results: The SSc cohort exhibited higher risks of developing CKD (attributable risk [AR] 2.8%, p < 0.01) and osteoporosis (AR 9%, p < 0.01) 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’s disease (AR − 0.7%, p < 0.01). While the findings highlight an amplified risk of CKD and osteoporosis in SSc patients, the differences in advanced renal disease were modest. Conclusion: 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. Key Points• 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.• Uncovered Neuroprotective Association: Contrary to general population trends, SSc patients on PPIs showed a reduced risk of Alzheimer’s disease, potentially linked to immunosuppressant use, closer monitoring, or unique disease mechanisms—a finding warranting further investigation.• Provided Real-World Safety Evidence: Leveraging global data (> 130 million patients), this study offers robust real-world evidence on PPI safety in SSc, reinforcing PPIs’ vital role in GERD/ILD management while advocating vigilant monitoring for CKD/osteoporosis.• Informed Risk–Benefit 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.

Osteoporosis is a chronic skeletal disorder in which reduced bone strength confers sustained fracture risk, often necessitating long-term pharmacotherapy with a multi-phase approach rather than a single “one and done” drug choice. Contemporary guidelines increasingly advocate a treat-to-target (TTT), goal-directed approach: clinicians define an explicit target, most often a total hip T -score threshold that corresponds to a lower fracture risk than baseline; select initial therapy according to baseline risk; and reassess and adjust treatment intensity until that target is achieved and maintained. Within this framework, sequential strategies are central. Anabolic-first sequences (e.g., abaloparatide or teriparatide followed by alendronate, or romosozumab followed by alendronate or denosumab) consistently produce larger and more durable gains in bone mineral density and fracture risk reduction in very-high-risk patients than antiresorptive monotherapy. Transitions from long-term bisphosphonates to teriparatide are complicated by transient increased remodeling and modest hip BMD responses, whereas switching to romosozumab yields more robust bone mineral density (BMD) gains at the hip. Notably, denosumab discontinuation demands structured bisphosphonate “exit” therapy to avoid rebound bone loss and multiple vertebral fractures. Across all pathways, rare but serious adverse events (e.g., atypical femoral fractures, medication-related osteonecrosis of the jaw, cardiovascular events), patient adherence and persistence, and insurance coverage constraints strongly shape the feasibility and desirability of specific regimens. This narrative review synthesizes mechanistic and clinical evidence underlying TTT osteoporosis care, summarizes the evidence base for sequential osteoporosis pharmacotherapy, and proposes practical strategies to help clinicians choose, transition, and discontinue therapies while preserving skeletal gains and minimizing harm over decades of longitudinal osteoporosis care.