Mind the Rarities: Can Rare Skin Diseases Be Reliably Diagnosed via Diagnostic Reasoning?

Vision--language models (VLMs) have recently shown promise for assisting clinical reasoning in dermatological diagnosis. However, their trustworthiness and clinical utility remain limited by three key challenges: heterogeneous datasets with inconsistent diagnostic labels and concept annotations, the lack of grounded diagnostic rationales for reliable reasoning supervision, and limited scalability when transferring knowledge from small, densely annotated datasets to large collections with sparse labels. To address these challenges, we propose Skin-R1, a dermatology-oriented VLM that integrates textbook-grounded clinical reasoning supervision with reinforcement learning (RL) to improve the accuracy and robustness of diagnostic prediction. First, we construct a textbook-based reasoning generator that synthesizes hierarchy-aware and differential-diagnosis (DDx) diagnostic trajectories derived from authoritative dermatology knowledge. Second, these trajectories are used for supervised fine-tuning (SFT), establishing a clinically grounded reasoning foundation for the model. Finally, we introduce an RL training framework that incorporates the hierarchical structure of dermatological diseases into the reward design, enabling the model to generalize grounded diagnostic reasoning to large-scale datasets with sparse annotations. Extensive experiments across multiple dermatology benchmarks demonstrate that Skin-R1 consistently improves diagnostic accuracy and robustness compared to state-of-the-art Med-VLM baselines. Ablation studies further highlight the critical role of grounded reasoning supervision introduced during the SFT stage.

While recent advancements in Large Language Models have significantly advanced dermatological diagnosis, monolithic LLMs frequently struggle with fine-grained, large-scale multi-class diagnostic tasks and rare skin disease diagnosis owing to training data sparsity, while also lacking the interpretability and traceability essential for clinical reasoning. Although multi-agent systems can offer more transparent and explainable diagnostics, existing frameworks are primarily concentrated on Visual Question Answering and conversational tasks, and their heavy reliance on static knowledge bases restricts adaptability in complex real-world clinical settings. Here, we present SkinGPT-X, a multimodal collaborative multi-agent system for dermatological diagnosis integrated with a self-evolving dermatological memory mechanism. By simulating the diagnostic workflow of dermatologists and enabling continuous memory evolution, SkinGPT-X delivers transparent and trustworthy diagnostics for the management of complex and rare dermatological cases. To validate the robustness of SkinGPT-X, we design a three-tier comparative experiment. First, we benchmark SkinGPT-X against four state-of-the-art LLMs across four public datasets, demonstrating its state-of-the-art performance with a +9.6% accuracy improvement on DDI31 and +13% weighted F1 gain on Dermnet over the state-of-the-art model. Second, we construct a large-scale multi-class dataset covering 498 distinct dermatological categories to evaluate its fine-grained classification capabilities. Finally, we curate the rare skin disease dataset, the first benchmark to address the scarcity of clinical rare skin diseases which contains 564 clinical samples with eight rare dermatological diseases. On this dataset, SkinGPT-X achieves a +9.8% accuracy improvement, a +7.1% weighted F1 improvement, a +10% Cohen's Kappa improvement.

Rare diseases affect millions of individuals worldwide, yet timely diagnosis remains a major public health challenge due to scarcity of specialized clinical expertise. While large language models (LLMs) show promise to support rare disease diagnosis, current models are constrained by insufficient clinical deployability, limited clinically grounded evidence, and scarcity of training data. Here we present RaDaR (Rare Disease navigatoR), an open-source, compact reasoning LLM (32B parameters) for rare disease diagnosis. RaDaR was trained with 49,170 publicly available free-text cases and 104,666 synthetic cases with reasoning-enhanced training. RaDaR showed the strongest performance among evaluated open-source models, including the 671B DeepSeek-R1, across public benchmarks and four external validation centers. In a retrospective cohort, RaDaR prioritized the final diagnosis before documented clinical suspicion in 61.06 percent of cases, corresponding to a potential lead time of 1.87 months and 50.18 percent of the within-center interval. In a randomized physician-assistance trial, RaDaR assistance improved physicians' rare-disease diagnostic accuracy by 21.44 percentage points compared with internet search alone. Synthetic-data ablations suggested that phenotype-anchored narratives provide useful training signal for long-tail rare diseases, with a monotonic scaling trend within the tested data range. Together, RaDaR and its development and validation framework provide a deployable rare-disease reasoning model and a reproducible development framework for diagnostic AI under data scarcity.