Thyroid peroxidase antibody (TPOAb) positivity is the most important risk factor for hypothyroidism and determines thyroid function follow-up during pregnancy. TPOAb positivity is usually defined by manufacturer cut-offs which typically derived from non-pregnant populations. However, as a state of immune tolerance, pregnancy can affect TPOAb concentrations. To improve the understanding of clinical relevance of TPOAb concentrations during pregnancy, we investigated the association of TPOAbs with maternal thyroid function. We performed an individual participant data meta-analysis embedded in the Consortium on Thyroid and Pregnancy. Participants with multiple gestations, pre-existing thyroid disease, thyroid (interfering) medication usage, or conception by in vitro fertilization were excluded. We used mixed effects regression models to assess the association of TPOAb percentiles calculated in each cohort with maternal thyroid function. The study population comprised 62,634 pregnant women from 24 cohorts. As compared to TPOAb percentiles ≤80, there were progressively higher mean thyroid stimulating hormone (TSH) concentrations across TPOAb percentiles ≥89, with corresponding mean differences ranging from +0.11 SD (95% confidence interval [CI] +0.04 SD, +0.19 SD) at the 89th percentile to +1.04 SD (95% CI+0.96 SD, 1.11 SD) at the 100th percentile. Higher TPOAb percentiles were associated with progressively lower mean free thyroxine (FT4) concentrations across TPOAb percentiles ≥91, with corresponding mean differences ranging from -0.08 SD (95% CI -0.16 SD, -0.01 SD) at the 91st percentile to -0.48 SD (95% CI -0.56 SD, -0.4 SD) at the 100th percentile. From the 89th TPOAb percentile upwards, there were progressively higher risks of TSH >4.0 mU/L, with absolute risks of 2.4%, 4.0%, and 28.1% in cases of ≤80th, 89th, and 100th TPOAb percentiles, respectively. Higher TPOAb percentiles were also associated with lower thyroidal response to human chorionic gonadotropin stimulation and higher risks of overt and subclinical hypothyroidism. In 19 of the included cohorts, there were 0.4-6.3% of pregnant women with TPOAb concentrations lower than the positivity cut-offs but larger than or equal to the 89th-percentile concentrations. The associations of TPOAbs with TSH and with FT4 were most apparent during early pregnancy (P for interaction <0.001 for both TSH and FT4). During pregnancy, TPOAbs were dose-dependently associated with TSH, FT4, and the risk of abnormal thyroid function. With concentrations below currently used positivity cut-offs, TPOAbs could be associated with lower maternal thyroid function, which indicates clinically relevant thyroid autoimmunity. These findings implicates that high normal TPOAb concentrations upon first assessment in pregnancy may warrant active follow-up.

Autoimmune diseases pose significant challenges due to the high risks associated with abnormal immune responses to self-antigens and the limitations of broad-spectrum immunosuppressants. Current therapeutic approaches primarily rely on immunosuppressive drugs, yet their non-specificity and side effects urge researchers to explore novel targets and the advancement of precision medicine. Recent advances in targeted protein degradation (TPD) technologies, including PROTAC, MGD and LYTAC, offer therapeutic potential by precisely eliminating pathogenic proteins. By leveraging cellular degradation machinery such as ubiquitin-proteasome an endolysosomal systems to overcome the undruggable targets, these TPD technologies offer promising therapeutic strategies for precise immune regulation. Preclinical studies demonstrate PROTAC-mediated degradation of IRAK4 reduce inflammatory cytokines. RIPK2 degraders are expected to become a new approach for treating inflammatory diseases. While BTK degraders L18I surpass inhibitors in blocking autoantibodies. There are still challenges to overcome, such as delivery barriers, off-target effects and limited E3 ligase diversity. Emerging solutions such as AI-driven design and modular platforms may improve the specificity and efficacy. This review summarizes the underlying mechanisms, therapeutic breakthroughs, and translational hurdles of TPD technologies, and explores how integrating AI can optimize the technologies. TPD strategies have the potential to revolutionize the treatment of autoimmune diseases by providing more targeted and personalized therapies.