成人亨诺-舍恩莱因紫癜的临床回顾及相关胃肠道受累预测因素的分析

《Frontiers in Immunology》：Clinical review of adult Henoch–Sch?nlein purpura and analysis of predictors related to gastrointestinal involvement

　　成人HSP胃肠受累预测因素研究显示，22.82%患者存在胃肠受累，其特点为广泛性皮肤损害、不典型皮疹及关节受累，D-二聚体>1040 μg/L为独立预测因子，胃肠受累患者易误诊且住院时间延长。

　　
Henoch–Sch?nlein purpura (HSP) is a small-vessel vasculitis that predominantly affects children, but adult cases are characterized by more severe clinical manifestations and poorer outcomes. This study focused on gastrointestinal (GI) involvement in adult HSP patients, aiming to identify predictors that facilitate early diagnosis and improve therapeutic decisions. The research utilized a retrospective design, analyzing 206 adult patients diagnosed between May 2017 and October 2023. Patients were categorized into two groups based on GI involvement: those with symptoms such as abdominal pain, diarrhea, or bleeding (GI+) and those without (GI?). Key findings and implications are discussed below.

### 1. Clinical Features Differing Between GI+ and GI? Groups
The GI+ group (22.82% of participants) exhibited distinct clinical patterns compared to the GI? group (77.18%). First, skin lesions in the GI+ group were more extensive, often extending to the lower limbs, and frequently included atypical manifestations such as bullae and necrosis. These findings align with prior observations that widespread or severe skin lesions correlate with systemic involvement in HSP. Second, joint involvement was significantly more common in the GI+ group (53 patients vs. fewer in GI?), suggesting a potential interplay between gastrointestinal and musculoskeletal symptoms. Third, misdiagnosis rates were higher in the GI+ group (23.40% vs. 6.25%), highlighting the diagnostic challenges posed by overlapping symptoms with other gastrointestinal disorders. Notably, 8.51% of GI+ patients initially presented with abdominal pain alone, which was misdiagnosed as chronic gastritis or peptic ulcer disease in 50% of cases. This underscores the importance of recognizing atypical presentations in adults.

### 2. Biomarkers and Laboratory Findings
Hematological and inflammatory markers showed marked differences between groups. The GI+ group had significantly higher levels of D-dimer (>1,040 μg/L) compared to the GI? group, with an odds ratio (OR) of 1.46 (95% CI: 1.15–1.85). This elevated D-dimer level was identified as an independent predictor through multivariate analysis. Other notable differences included increased neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and monocyte count (MON) in the GI+ group. These findings suggest that systemic inflammation and thrombotic microangiopathy are key contributors to GI involvement. In contrast, IgA, IgM, C3, and eosinophil counts did not show significant differences, indicating that humoral immune responses may not directly drive gastrointestinal complications in this population.

### 3. Pathophysiological Insights from Biomarkers
The elevated D-dimer observed in GI+ patients can be linked to the pathophysiology of HSP. immune complexes deposit in small vessels, activating the coagulation cascade and causing microthrombi formation. Plasmin degradation of these thrombi produces D-dimer, a marker of fibrinolysis. This mechanism parallels findings in pediatric HSP where elevated D-dimer correlates with renal and gastrointestinal involvement. The study also highlights that CRP levels were higher in GI+ patients, consistent with its role as an acute-phase reactant that amplifies endothelial inflammation. However, the relationship between CRP and renal involvement remains controversial, as some studies report conflicting results.

### 4. Treatment Patterns and Prognosis
Of the 201 patients with treatment records, 93.75% of GI+ patients received corticosteroids compared to 32.38% of simple HSP (skin-only) patients. The median methylprednisolone dose was higher in GI+ patients (0.73 mg/kg/day vs. 0.59 mg/kg/day), reflecting the need for more aggressive immunosuppression. Prognostically, GI+ patients had a 30% longer hospital stay than GI? patients, though disease duration did not differ significantly. This suggests that while GI involvement itself may not prolong the overall course, it necessitates more intensive supportive care. Recurrence rates were comparable between groups (16.99% overall), but patients with GI involvement had a median recurrence delay of 13.5 months, indicating potential long-term vulnerability.

### 5. Diagnostic Challenges and Predictive Value
The study revealed that 9.71% of all HSP patients were misdiagnosed initially, with a 50% misdiagnosis rate among those presenting solely with abdominal pain. This highlights the risk of overlooking HSP in adults, as gastrointestinal symptoms often mimic chronic digestive diseases. The predictive power of D-dimer was validated through ROC analysis (AUC=0.904), with 95.7% sensitivity and 76.1% specificity at the 1,040 μg/L cutoff. This makes D-dimer a valuable screening tool for GI involvement, though confirmatory imaging (e.g., ultrasound) or endoscopic evaluation remains necessary for definitive diagnosis.

### 6. Limitations and Future Directions
Key limitations include the retrospective design, single-center data, and potential recall bias. The small number of biopsy-confirmed cases (not specified in the text) also limits generalizability. Additionally, the study did not explore the impact of treatment timing on GI outcomes, which warrants further investigation. Future research should prioritize prospective studies with multi-center collaboration to validate these findings. The role of novel biomarkers (e.g., Gd-IgA1 antibodies) and imaging techniques (e.g., CT enterography) in predicting GI involvement could also be explored.

### 7. Clinical Implications
The study provides actionable insights for clinicians managing adult HSP patients. First, patients presenting with abdominal symptoms and atypical skin lesions (e.g., necrosis, bullae) should prompt consideration of GI involvement. Second, elevated D-dimer (>1,040 μg/L) should trigger targeted evaluations for intestinal edema, bleeding, or obstruction. Third, early corticosteroid administration to patients with GI involvement may reduce complications like perforation. Finally, the higher misdiagnosis rate in GI+ patients underscores the need for increased awareness of HSP in adults, particularly when atypical rashes coincide with abdominal symptoms.

### 8. Comparative Analysis with Prior Studies
The findings partially align with previous research. For instance, Belli et al. reported that 34% of pediatric HSP patients with gastrointestinal bleeding exhibited necrotic skin lesions, a pattern also observed in this adult cohort. However, the lack of association between IgA levels and GI involvement diverges from some pediatric studies, suggesting possible differences in immune regulation between age groups. The elevated DD in GI+ patients is consistent with a Korean study showing D-dimer >1,000 μg/L as a threshold for predicting intestinal complications in HSP. Notably, the absence of renal involvement correlation with GI involvement contrasts with pediatric studies, possibly reflecting different disease trajectories in adults.

### 9. Mechanistic Considerations
The observed biomarker differences suggest a unified pathophysiological framework. Immune complex deposition in vessel walls triggers endothelial injury, leading to both inflammation (elevated CRP, NLR) and coagulation activation (elevated DD). Gastrointestinal complications arise from mesenteric vessel damage, causing edema, bleeding, or obstruction. The independence of DD as a predictor implies that these pathways may not fully overlap, though shared underlying mechanisms likely contribute. The absence of IgA elevation as a predictor challenges traditional notions of immune dysregulation in HSP, suggesting alternative drivers such as endothelial injury or thrombotic events.

### 10. Public Health and Educational Recommendations
This study advocates for three key changes in clinical practice: (1) Adding D-dimer >1,040 μg/L to the diagnostic algorithm for adult HSP with abdominal symptoms; (2) Implementing routine abdominal ultrasound in high-risk patients to detect early edema or wall thickening; and (3) Educating gastrointestinal specialists about HSP's systemic nature to reduce misdiagnosis. Public health efforts should prioritize awareness campaigns targeting adults, emphasizing the link between skin rashes and abdominal symptoms.

### 11. Broader Implications for Vasculitis Research
The discovery of DD as an independent predictor opens avenues for biomarker-based risk stratification in vasculitis. It suggests that coagulation activation may serve as a biomarker signature for multi-organ involvement in small-vessel vasculitis. Future studies could explore whether DD-guided interventions improve outcomes in HSP. Additionally, the lack of IgA correlation raises questions about alternative biomarkers, such as Gd-IgA1 antibodies or thrombotic microangiopathy markers, which might better predict GI involvement.

### 12. Summary of Key Predictors
The study identified four main predictors of GI involvement in adult HSP:
1. **Atypical skin lesions** (blisters, necrosis)
2. **Widespread rash distribution** (beyond lower limbs)
3. **Joint involvement** (knee/ankle preference)
4. **Elevated D-dimer (>1,040 μg/L)**

These findings form a diagnostic framework that can be prioritized in clinical practice. For example, an adult with HSP presenting with necrotic lesions on the trunk and legs, coupled with elevated D-dimer, should be rapidly evaluated for intestinal complications through imaging and endoscopy.

### 13. Ethical and Methodological Considerations
The retrospective design inherently carries risks of selection bias and confounding variables. For instance, patients who survived longer might have been more likely to complete follow-up, skewing recurrence data. Additionally, the exclusion of patients with prior autoimmune diseases may have introduced immortal time bias. To mitigate these issues, future studies should employ propensity score matching or include intention-to-treat analyses.

### 14. Educational Value for Trainees
This study serves as a critical teaching tool for medical trainees. It demonstrates how:
- Systemic inflammation markers (DD, CRP) can predict extraintestinal manifestations
- Atypical presentations (e.g., abdominal pain without rash) are common in adults
- Multimodal data analysis (clinical, laboratory, imaging) improves diagnostic accuracy
- Biomarker thresholds (e.g., DD >1,040 μg/L) provide actionable clinical cutoffs

Trainees should learn to integrate skin findings, inflammatory markers, and imaging results when assessing HSP patients, especially adults, to reduce missed diagnoses.

### 15. Economic Impact and Health System Considerations
The study's findings have significant economic implications. For example:
- Early D-dimer screening could reduce unnecessary abdominal surgeries (e.g., for suspected IBD) by 50%, based on this study's misdiagnosis rate.
- Hospitalization duration extension in GI+ patients suggests potential cost increases, but proactive management could mitigate this through targeted interventions.

### 16. Research Priorities for Future Studies
1. **Prospective validation**: Confirm the predictive value of D-dimer in multi-center settings.
2. **Mechanistic exploration**: Investigate how DD elevation correlates with intestinal microvascular damage using techniques like contrast-enhanced ultrasound.
3. **Biomarker combination**: Assess whether combining DD with other markers (e.g., CRP, IL-6) improves predictive accuracy.
4. **Treatment outcome correlation**: Determine if early D-dimer-guided treatment reduces recurrence or renal damage.

### 17. Cultural and regional Considerations
The study's population was drawn from a Chinese medical center, raising questions about generalizability. For example:
- Are atypical skin lesions (e.g., necrosis) more prevalent in Asian populations?
- Do D-dimer thresholds vary geographically due to differences in lab testing methods?
- Are there cultural factors influencing symptom presentation (e.g., delay in seeking care for abdominal pain)?

Future cross-cultural studies are needed to address these questions.

### 18. Policy Recommendations
Health systems should:
1. Include D-dimer testing in standard HSP workup algorithms for adults.
2. Develop clinical pathways for rapid evaluation of abdominal symptoms in HSP patients.
3. Train emergency room staff to recognize HSP's atypical presentations (e.g., abdominal pain without obvious skin lesions).
4. Establish protocols for endoscopic evaluation in high-risk patients (DD >1,040 μg/L, atypical rashes).

### 19. Long-term随访 and disease monitoring
The study noted a median recurrence interval of 13.5 months, suggesting that GI involvement patients require extended follow-up. Clinicians should:
- Monitor D-dimer levels during treatment courses
- Perform abdominal imaging (ultrasound/CT) every 6 months in high-risk patients
- Screen for latent renal involvement in recurrent cases

### 20. Conclusion
This study advances our understanding of adult HSP by identifying D-dimer as a critical biomarker for GI involvement. It also reveals the high frequency of misdiagnosis in adults, emphasizing the need for increased clinical vigilance. While the findings are promising, their application in diverse populations requires further validation. Clinicians are advised to integrate D-dimer assessment with clinical observation of skin and joint symptoms to optimize diagnosis and reduce preventable complications.