Abstract
Background
Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a rare, severe hypersensitivity reaction characterized by rash, hematologic abnormalities, and multiorgan involvement. Although DRESS is typically triggered by medications, interindividual variability suggests a role for host-related factors. This study investigated whether underlying autoimmune diseases increase susceptibility to DRESS.
Methods
A retrospective, propensity score–matched case-control analysis was conducted using a large multicenter database, comparing 1128 patients with DRESS to 1128 controls matched by age, sex, and race. Autoimmune comorbidities were identified through ICD-10 codes encompassing systemic and organ-specific conditions.
Results
Several autoimmune diseases were significantly more prevalent in patients with DRESS, including hypothyroidism (odds ratio [OR] 1.56; 95% confidence interval [CI] 1.24–1.96; P < 0.001), type 2 diabetes mellitus (OR 1.58; 95% CI 1.31–1.91; P < 0.001), rheumatoid arthritis (OR 2.17; 95% CI 1.36–3.46; P < 0.001), psoriasis (OR 2.28; 95% CI 1.28–4.06; P = 0.004), inflammatory bowel disease (OR 1.81; 95% CI 1.08–3.04; P = 0.02), and mixed connective tissue disease (OR 2.59; 95% CI 1.52–4.44; P < 0.001).
Conclusion
These findings highlight the importance of heightened vigilance when prescribing high-risk medications to patients with autoimmune diseases and underscore the need for prospective studies exploring genetic and immunologic mechanisms linking autoimmunity and drug hypersensitivity.
Keywords: Autoimmunity, DRESS syndrome, drug hypersensitivity, immune dysregulation, pharmacogenomics, systemic inflammation
Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a rare yet life-threatening hypersensitivity reaction characterized by rash, hematologic abnormalities, and multiorgan involvement.1 It is traditionally viewed as a drug-induced phenomenon, often associated with anticonvulsants, sulfonamides, nonsteroidal antiinflammatory agents (NSAIDs), or allopurinol.2,3 However, not all patients exposed to these medications develop DRESS, suggesting that host-related factors, particularly immune dysregulation, may play an important role in susceptibility.4 The extent to which underlying autoimmune conditions contribute to this risk remains largely unexplored.
METHODS
To investigate potential predisposition, we conducted a retrospective, case-control analysis of 1128 patients diagnosed with DRESS syndrome and 1128 propensity score-matched controls without DRESS using a large multicenter database. Matching was performed for age, sex, and race to minimize demographic confounding. Autoimmune comorbidities were identified using ICD-10 coding, encompassing both organ-specific and systemic diseases.
RESULTS
As summarized in Table 1, several autoimmune conditions were significantly more prevalent among patients with DRESS syndrome than in matched controls. These included hypothyroidism (odds ratio [OR] 1.56; 95% confidence interval [CI] 1.24–1.96; P < 0.001), type 2 diabetes mellitus (OR 1.58; 95% CI 1.31–1.91; P < 0.001), rheumatoid arthritis (OR 2.17; 95% CI 1.36–3.46; P < 0.001), psoriasis (OR 2.28; 95% CI 1.28–4.06; P = 0.004), inflammatory bowel disease (OR 1.81; 95% CI 1.08–3.04; P = 0.02), and mixed connective tissue disease (OR 2.59; 95% CI 1.52–4.44; P < 0.001). Collectively, these findings suggest that chronic immune activation or dysregulation may create a heightened inflammatory setting that increases vulnerability to DRESS following drug exposure.
Table 1.
Baseline characteristics and autoimmune comorbidities in patients with and without DRESS syndrome
| Characteristic | DRESS syndrome |
OR (95% CI)† | P value† | |
|---|---|---|---|---|
| With | Without | |||
| Total patients | 1128 (100%) | 1128 (100%) | – | |
| Average age ± SD (years) | 54.1 ± 21.4 | 54.1 ± 21.5 | – | 1.0 |
| Female | 634 (56.21%) | 645 (57.18%) | – | 0.64 |
| Male | 494 (43.79%) | 483 (42.82%) | – | 0.64 |
| Not Hispanic or Latino | 843 (74.73%) | 834 (73.94%) | – | 0.66 |
| Hispanic or Latino | 132 (11.70%) | 131 (11.61%) | – | 0.95 |
| White | 800 (70.92%) | 789 (69.95%) | – | 0.61 |
| Black or African American | 171 (15.16%) | 180 (15.96%) | – | 0.60 |
| Asian | 62 (5.50%) | 63 (5.59%) | – | 0.93 |
| Native Hawaiian or Other Pacific Islander | 10 (0.89%) | 10 (0.89%) | – | 1 |
| American Indian or Alaska Native | 10 (0.89%) | 0 (0.00%) | – | 0.002* |
| Hypothyroidism | 208 (18.44%) | 143 (12.68%) | 1.557 (1.236, 1.962) | <0.001* |
| Type 1 diabetes mellitus | 33 (2.93%) | 35 (3.10%) | 0.941 (0.581, 1.525) | 0.81 |
| Type 2 diabetes mellitus | 348 (30.85%) | 248 (21.99%) | 1.583 (1.31, 1.913) | <0.001* |
| Rheumatoid arthritis | 57 (5.05%) | 27 (2.39%) | 2.17 (1.362, 3.457) | <0.001* |
| Psoriasis | 38 (3.37%) | 17 (1.51%) | 2.278 (1.278, 4.061) | 0.004* |
| IBD | 41 (3.63%) | 23 (2.04%) | 1.812 (1.08, 3.04) | 0.02* |
| Mixed connective tissue disease | 48 (4.26%) | 19 (1.68%) | 2.594 (1.515, 4.442) | <0.001* |
Statistically significant values between cases and controls, defined at P < 0.05.
After propensity score matching.
CI indicates confidence interval; IBD, inflammatory bowel disease (Crohn’s disease and ulcerative colitis); OR, odds ratio; SD, standard deviation.
We also evaluated a broader range of autoimmune and inflammatory disorders, including pemphigus, bullous pemphigoid, dermatomyositis, vitiligo, lupus, autoimmune hepatitis, celiac disease, Sjögren syndrome, multiple sclerosis, myasthenia gravis, scleroderma, and vasculitides such as granulomatosis with polyangiitis and microscopic polyangiitis. However, these were too infrequent in conjunction with DRESS to yield statistically meaningful results, reflecting both the rarity of DRESS and the low population prevalence of many autoimmune diseases.
DISCUSSION
The observed associations raise important questions regarding the underlying pathophysiology. One possible explanation is that patients with autoimmune disease exhibit a baseline imbalance in immune tolerance, rendering them more susceptible to aberrant T-cell activation upon drug exposure.5 Genetic factors such as HLA polymorphisms, cytokine gene variants, and immune checkpoint alterations may also contribute.2,6 Moreover, chronic systemic inflammation and immune-modulating therapies commonly used in autoimmune disease could influence drug metabolism and immune surveillance, further modifying DRESS risk.5,6 Additionally, NSAIDs, a recognized trigger of DRESS, are frequently used in the management of several autoimmune conditions identified in our cohort, raising the possibility that increased medication exposure may contribute to the observed associations.
While our analysis was limited by the retrospective nature of database research and reliance on ICD coding accuracy, the study’s large sample size and propensity-matched design enhance confidence in the observed trends. Because DRESS is both rare and heterogeneous, multicenter collaborations and genetic registries will be critical for validating these findings and identifying mechanistic pathways linking autoimmunity and drug hypersensitivity.
Clinically, our results emphasize the need for heightened awareness when initiating high-risk medications in patients with autoimmune diseases. Early recognition of DRESS symptoms in this population is essential to reduce morbidity and mortality. Future studies should stratify risk by specific autoimmune phenotypes, medication classes, and genetic markers to clarify causal relationships and guide personalized prescribing.
In summary, our findings support the hypothesis that autoimmunity may prime the immune system for exaggerated responses to pharmacologic triggers. Understanding this interplay between intrinsic immune dysregulation and drug exposure may provide new insights into DRESS pathogenesis and ultimately improve prevention and management strategies.
DISCLOSURE STATEMENT
The authors report no funding or conflicts of interest. Data are available on request from the corresponding author.
References
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