Out of 1,437 patients, we identified 53 DILI-DRESS cases (29 in the Spanish DILI Registry and 24 in the LATINDILI Network). Thus, the prevalence of DRESS (with confirmed DILI) in these registries was 3.7%. Two SJS/TEN/AGEP cases were excluded from this study. In addition, 881 DILI cases were included. No differences in demographic and clinical characteristics were found between DILI-DRESS cases from the Spanish DILI Registry and LATINDILI Network, except that Latin American patients were younger (mean age 54 years in the Spanish cases vs. 39 years in the Latin American cases; p = 0.006).

Demographics, clinical characteristics, and outcomes of DILI-DRESS and DILI cases were compared in Table 1. DILI-DRESS patients were younger than DILI (mean age 47 vs. 53 years, respectively; p = 0.042). However, when only Spanish cases were analysed, no differences in age were found (mean age 54 years in both groups; p = 0.927). Furthermore, there were significant differences in the pattern of liver damage (p = 0.018). Hepatocellular injury was predominant in DILI (63%), while 56% of DILI-DRESS patients presented with cholestatic/mixed damage. Indeed, the median elevation of ALP was significantly higher in DILI-DRESS cases (median 2.1 × ULN) than in DILI cases (median 1.6 × ULN; p = 0.003). Likewise, gamma-glutamyl transferase (GGT) levels were increased in DILI-DRESS cases compared to DILI (median 7.2 vs. 5.5 times ULN; p = 0.039).

All DILI-DRESS cases had rash, and 85% presented with eosinophilia. Moreover, 55% of these patients had fever, 34% had lymphopenia, and only 14% suffered from arthralgia. When compared to DILI, DILI-DRESS cases had a lower prevalence of positive autoantibody titres (21% and 5.1%, respectively; p = 0.013), and the hospitalization rate was higher (50% vs. 79%, respectively; p < 0.001).

Eleven DILI-DRESS patients underwent liver biopsy. Histological findings showed cholestasis with hepatitis (n = 4), zonal necrosis (n = 3), chronic hepatitis (n = 2, active in one of them), steatohepatitis (n = 1), and unspecific changes in the liver (n = 1).

Even though the damage was moderate in most patients in both groups (55%), those in the DILI-DRESS group developed a severe liver injury more frequently than DILI cases (13% vs. 5.9%, respectively), albeit these differences did not reach statistical significance. Of note, 13 out of 53 DILI-DRESS cases (25%) were treated with corticosteroids. Furthermore, there were no differences in liver-related death. Only one DILI-DRESS patient, due to anti-tuberculosis (TB) drugs died (after liver transplantation). Conversely, death due to non-liver-related causes was higher among the DILI-DRESS patients (5.7%; n = 3), compared to DILI (1.0%; n = 9) (p = 0.026). Information of the 53 DILI-DRESS patients is further detailed in Table 2.

DILI-DRESS patients who developed a severe-fatal injury had predominantly a hepatocellular injury (88%) and marked elevations of serum transaminases and TBL levels at DILI recognition compared to those with mild-to-moderate liver damage. In addition, 63% of cases with a more severe injury presented with eosinophilia, compared to 89% of patients with milder damage.

An exploratory backward stepwise regression analysis was performed to identify factors associated with the development of a worse outcome in DILI-DRESS cases out of the following variables (p-value < 0.1 in univariate analysis): type of liver injury (hepatocellular vs. cholestatic/mixed), eosinophilia, ALT, AST, ALP, TBL, and nR-based Hy's law. Of these, higher TBL levels at DILI recognition (odds ratio [OR] 1.23; 95% confidence interval [CI] 1.04–1.45) and absence of eosinophilia (OR 8.77; 95% CI 1.11–69.20) were found as prognostic factors of worse outcome in DILI-DRESS patients.

The most common agents implicated in DILI-DRESS were carbamazepine (13%), anti- TB medications (isoniazid, rifampicin, and pyrazinamide, either alone or in combination, 13%), amoxicillin-clavulanate (11%), and allopurinol and lamotrigine (7.6% each). On the other hand, amoxicillin-clavulanate (15%), anti-TB (6.6%), ibuprofen (3.5%), and diclofenac (3.1%) were the most frequent causative drugs in DILI cases. Notably, among all cases of carbamazepine-induced liver injury in the two registries (n = 15), 47% of them were DILI-DRESS, as well as four out of six cases due to lamotrigine (67%). However, in cases due to other antiepileptics such as valproic acid or phenytoin (n = 9 each), few of them developed DILI-DRESS (11% and 22%, respectively). Conversely, among the six cases of DILI due to allopurinol, 67% presented with a DILI-DRESS phenotype.

According to the Anatomic Therapeutic Classification groups, anti-infectives for systemic use were the most common drugs in both groups (40% in DILI-DRESS and 34% in DILI). Furthermore, drugs for the nervous system were overrepresented in DILI-DRESS compared to DILI (32% vs. 8.6%, respectively). In contrast, drugs for the cardiovascular system and antineoplastic and immunomodulating agents were more common among DILI patients (Online Resource 1).

An ancillary analysis was performed to compare the clinical characteristics of DILI-DRESS patients according to the most frequent culprit drugs and drug classes, i.e., antiepileptic drugs (carbamazepine, lamotrigine, phenytoin, valproic acid and levetiracetam), anti-TB drugs, amoxicillin-clavulanate, and allopurinol (Table 3). Young women were more prone to present DILI-DRESS caused by antiepileptic or anti-TB medications. DILI-DRESS was induced by amoxicillin-clavulanate after a shorter duration of therapy. Hepatocellular injury was distinctive in DILI-DRESS caused by anti-TB drugs, while the cholestatic/mixed pattern of liver injury was the predominant damage caused by the other drugs. Moreover, it is worth noting that eosinophilia was less prevalent in those DILI-DRESS patients who had taken anti-TB medications and had a poorer outcome.