DRESS is a type IV hypersensitivity syndrome typically triggered by specific medications. It is characterized by prodromal symptoms, the development of a diffuse erythematous maculopapular eruption, lymphadenopathy, and eosinophilia that can lead to significant organ damage. The term DRESS was proposed as an umbrella term in 1996 to encompass several drug-specific reactions, which had been described under a variety of names such as anticonvulsant hypersensitivity syndrome, allopurinol hypersensitivity syndrome, and dapsone hypersensitivity syndrome [3]. DRESS is more commonly seen in adults when compared to children, with recent studies demonstrating a slight female-to-male predominance [4]. Common causative agents are anticonvulsants, allopurinol, antibiotics, and NSAIDs; reactions have usually been reported three weeks to three months after initiation of therapy. This distinguishes it from other types of type IV hypersensitivity drug reactions that usually begin one to two weeks after initial exposure [3, 5, 6]. Interestingly, DRESS has been seen in connection with a variety of autoimmune diseases such as type 1 diabetes mellitus (T1DM), thyroid diseases, hematologic diseases, and rheumatologic disease.

Patients afflicted with DRESS usually have a latency phase that occurs for two to eight weeks, marked by nonspecific systemic symptoms like fever, fatigue, and diffuse lymphadenopathy. Following the prodromal symptoms, patients typically manifest with a morbilliform rash predominantly affecting the face, upper trunk, and upper extremities, with subsequent involvement of the lower extremities [7, 8]. On occasion, there may be an upper-respiratory infection-like prodrome. Periorbital, facial, or neck erythema and edema with pustules may be present at the early stages. Mild mucosal involvement, often in the oral mucosa, rarely progresses to skin detachment in DRESS and has been documented in up to 50% of cases [7]. Palms and soles are classically spared. Lymph nodes may also become affected, with most patients developing tender lymphadenopathy at the beginning of the illness. Some patients also develop severe xerostomia, which makes swallowing difficult [6]. Leukocytosis with atypical lymphocytes and eosinophilia are prominent, and liver abnormalities with increased serum alanine aminotransferase values are characteristic. However, liver function test abnormalities frequently resolve about 3 weeks after, without sequelae. Hepatitis, interstitial pneumonia, interstitial nephritis and carditis represent eosinophilic organ infiltration in DRESS. Dramatic decreases in serum IgG, IgM, and IgA are observed at the early stages of the condition, likely secondary to decreased peripheral B-cell numbers and predominance of regulatory T cells (Tregs) leading to significant immune dysregulation [9]. Notably, IgG levels continue to decrease even after removal of the offending drug over several weeks; however, some reports describe an overshooting phenomenon that increases IgG values similar to other autoimmune conditions. Occasionally, renal involvement can also be seen, with the degree of involvement correlating with mortality. Poor prognosis is seen with eosinophil counts above 6,000 × 10³/μL, thrombocytopenia, pancytopenia, leukocytosis, coagulopathy, and the presence of comorbidities such as CKD [3, 4, 6, 8].

There are various diagnostic criteria used around the world to diagnose DRESS. The Japanese Research Committee on Severe Cutaneous Adverse Reactions (J-SCAR) and RegiSCAR have both proposed diagnostic criteria that are used internationally for diagnosis of DRESS. RegiSCAR is a multinational registry of all SCARs started in 2003 with a network of hospitals in Austria, England, France, Germany, Israel, Italy, the Netherlands and Taiwan (China) [4]. For diagnosis of DRESS, three out of seven criteria must be present and the presence of the first three criteria are needed for diagnosis: acute rash, reaction is suspected to be drug-related, hospitalization, fever (> 38°C), laboratory abnormalities (at least one present-lymphocytes above or below normal, low platelets, eosinophilia), involvement of > 1 internal organ and enlarged lymph nodes > 2 sites [8]. DRESS is often a clinical diagnosis, with biopsies having a limited role in confirming the diagnosis.

T-cell mediated SCARs are believed to occur by three mechanisms: the hapten/pro-hapten model, the pharmacological interactions of drugs with immune receptors (p-i) concept, and the altered peptide repertoire model. In the hapten/pro-hapten model, it is believed that drugs are too small to be immunogenic; thus, they must bind to an endogenous carrier and form a hapten-carrier complex. This complex will then be recognized by antigen-presenting cells (APCs) and subsequently be recognized by a T-cell receptor (TCR), forming a drug-specific immune response. In the p-i concept, it is believed that the drug will bind to HLAs/TCRs, directly stimulating the TCR and then the drug-reactive T cells. The altered peptide repertoire model suggests that a drug can bind to a pocket on an HLA and change its conformation, thereby creating a new set of self-peptides and stimulating T cells [3]. SCARs also appear to be influenced by genetic factors. HLA allele studies have shown associations between HLA-B*57:01 and abacavir-induced hypersensitivity reactions, HLA-B*15:02 and carbamazepine-induced SJS/TEN, and HLA-B*58:01 and allopurinol-induced SCARs (SJS/TEN and DRESS) [3].

SCARs, as type IV hypersensitivity reactions, can be further characterized into IVa, IVb, and IVc based on T cell subset, cytokines, and leukocyte recruitment. DRESS is considered a type IVb reaction and primarily involves T helper 2 (TH2) lymphocyte activation and viral reactivation [10]. Support for this theory arises as discontinuation of the causative drug paradoxically worsens clinical symptoms. Thus, mechanisms cannot be explained only by a drug reaction [3]. Evidence of increased HHV-6 IgG titers and HHV-6 DNA arising two to three weeks after the onset of rash has caused countries in Asia and Europe to adopt testing for the virus as the gold standard, as reactivation has only been detected in DRESS but not in other drug eruptions [11]. Studies have also demonstrated that other herpesviruses can reactivate sequentially, with reactivation events initiated by HHV-6, followed by HHV-7, and then CMV. This sequential reactivation of these herpesviruses would explain why several flares of the disease occur even after discontinuation of the culprit drug, as symptoms would be mediated by an immune response to viral replication [8, 11].

It is important to note that HHV-6 has selective tropism for CD4 T cells. CD134, also called OX40, is a member of the tumor necrosis factor (TNF) family and is expressed on CD4 T cells in acute stages of DRESS. It is a costimulatory receptor and has been identified as a receptor of HHV-6. It is believed that the up-regulation of CD134 allows entry of HHV-6 into the CD T cells in the acute stages of DRESS. CD4 and CD8 T cells play distinct roles in DRESS. CD4 T cells are drug-specific and initiate drug-induced immune responses, while CD8 T cells recognize viral antigens and launch antiviral immune responses, affecting multiple organs and amplifying immune responses [3].

SJS and TEN are rare but highly fatal clinical subtypes of SCARs typically manifesting as a hypersensitive allergic response to infections or medications. Common causative agents include antiepileptics, sulfonamides, antipyretics, antibiotics, analgesics, and allopurinol, although some cases are idiopathic [30–35]. HIV, Mycoplasma pneumonia, and vaccination have also been documented to predispose SJS/TEN-like conditions [33–37]. These manifestations can be further complicated with hepatic, renal, and respiratory dysfunction. The estimated incidence of SJS is approximately 8–9 cases per million people annually, with a mortality rate of 4.8%, while TEN is less frequent at 1–2 cases per million but with a significantly higher mortality rate of 14.8% [30, 33, 34, 36]. Curiously, mortality increases further in SJS/TEN overlap cases, with recent studies reporting mortality as high as 19.4% [37]. Demographic factors also influence risk, with females and younger adults more commonly affected. Racial disparities have also been identified, with incidence rates highest among Black and Asian individuals, with elevated risk also noted in Hispanic, Native American, and multiracial populations compared to white individuals due to HLA-A/B association [34, 35, 37]. Additionally, SJS/TEN is associated with a spectrum of systemic comorbidities, such as malignancies including multiple myeloma, leukemia, non-Hodgkin’s lymphoma, central nervous system cancers, renal and hepatic dysfunction, epilepsy, and autoimmune disorders like systemic lupus erythematosus (SLE) [35, 37].

The diagnosis of SJS/TEN is primarily clinical, based on characteristic mucocutaneous findings and the extent of epidermal detachment. Patients may experience preliminary symptoms preceding skin involvement, characterized by fever, cough, rhinorrhea, conjunctivitis, anorexia, and malaise [35]. General cutaneous manifestations present with symmetrical facial and truncal rashes spreading to extremities, irregularly shaped and sized erythematous or purpuric macules that progress to bullae, widespread epidermal necrolysis, and painful erosions involving both the skin and mucus membranes of the mouth, eyes, and genitalia, which are commonly affected [30, 32, 35, 36, 38]. A positive Nikolsky’s sign, where gentle lateral pressure causes epidermal detachment, is a hallmark clinical finding [30, 34, 35]. Blisters develop quickly, leading to the shedding of extensive areas of the epidermis and revealing the underlying, fluid-secreting dermis. Epidermal separation typically advances over five to seven days, after which a healing phase with re-epithelialization occurs over one to three weeks [35]. Symptom onset typically occurs within four to eight weeks following the initiation of a culprit medication, although latency periods as long as 30 weeks have been reported for drugs with low or atypical risk. In addition to classic high-risk medications, emerging evidence highlights agents which enhance cytotoxic T lymphocyte (CTL) activity, such as checkpoint inhibitors like CTLA-4 antagonists, EGFR inhibitors like cetuximab, and BRAF inhibitors used in melanoma, which can precipitate SJS/TEN by intensifying immune-mediated keratinocyte apoptosis [34, 39]. Management of SJS/TEN primarily involves prompt discontinuation of the offending drug, along with supportive care focused on maintaining fluid and electrolyte balance, ensuring adequate respiratory function, providing nutritional support, controlling pain, and preventing or treating infections [34, 35]. Wound care is also essential, involving careful handling to promote re-epithelialization and prevent secondary infections. One of the most significant predictors of these conditions is the presence of multiple underlying chronic illnesses, suggesting that concurrent use of multiple medications and poor baseline health status contribute substantially to susceptibility [34, 37, 40].

Classification is based on total body surface area (BSA) involvement: SJS involves less than 10% BSA detachment, TEN involves more than 30%, and SJS/TEN overlap is defined by detachment between 10–30% [30, 31, 33–36, 38]. Given the importance of identifying the causative agent, the ALDEN scoring system has emerged as a valuable diagnostic tool which systematically assesses drug exposure timing, known associations, and alternative causes to classify drug causality likeliness. Another score, SCORTEN is the standard clinical score for predicting mortality in SJS/TEN, but it reflects severity at presentation rather than the underlying immune mechanism [34].

In addition to clinical and histopathological criteria, biomarkers have shown promise in early diagnosis and disease monitoring. Serum granulysin, for example, is now proposed as an early diagnostic marker, with rapid immunochromatographic tests available [34, 35]. Granulysin is one of the strongest proposed early mediators and biomarkers of SJS/TEN, while IL-15 appears to act upstream by promoting cytotoxic immune activity and granulysin production. In SLE, the main issue is diagnostic overlap: lupus can mimic SJS/TEN or rarely present with SJS/TEN-like skin disease, so careful differentiation is essential. Overall, the literature supports IL-15 and granulysin as biologically informative markers in SJS/TEN, with SCORTEN remaining the main bedside prognostic tool [34].

While the acute presentation and management of SJS/TEN are well-characterized, growing evidence indicates that survivors may not fully return to immunologic baseline. Instead, the intense immune activation and epithelial injury that define the acute phase may initiate a cascade of long-term immunological consequences. In particular, persistent immune dysregulation following resolution of the acute episode has been associated with the later development of autoimmune disorders. The following section explores the mechanisms and clinical evidence linking SJS/TEN to autoimmune sequelae.

SJS/TEN is classified as a type IVa hypersensitivity reaction, characterized by involvement of TC1 and TH1 cells, natural killer cells, and macrophages in blistering lesions, primarily directed at keratinocytes [10, 30, 34]. Histopathologically, both SJS/ TEN exhibit full-thickness epidermal necrosis involving all epidermal layers, often accompanied by a sparse inflammatory infiltrate in the dermis [34–36]. Unlike other autoimmune blistering diseases, direct immunofluorescence typically reveals no immunoglobulin deposition. Instead, the immunologic response in SJS/TEN is marked by cytotoxic CD8+ T cells (CTLs) and NK-like T cells in early blister fluid, with monocytes predominating in later phases by IFN-γ recruitment [34, 35]. In the pre-blistering phase, however, CD14+ monocytes coexpressing CD80, CD86, and CD137 can also work to promote CTL proliferation and cytotoxicity [34]. These immune cells release a variety of pro-apoptotic and inflammatory mediators that drive keratinocyte death and amplify tissue damage. Granulysin has emerged as a central cytotoxic molecule in this process, with serum levels significantly elevated during the early stages of SJS/TEN, peaking two to four days prior to the development of skin detachment and mucosal erosion symptoms [34, 35]. Similarly, serum FasL exhibits an early spike during disease onset, whereas other markers such as TNF-α, IFN-γ, sTRAIL, and TWEAK remain persistently elevated throughout the disease course. Additional biomarkers such as thymus and activation-regulated chemokine (TARC) or IL-15, which recruit and activate other immune cells, and micro-RNA-124 have been correlated with disease severity, with the latter two levels showing a direct relationship with patient mortality measured by the SCORTEN index [34].

Recent evidence also implicates reactive oxygen species (ROS) generated within keratinocytes as a key contributor to the pathogenesis of TEN, preceding pro-apoptotic pathways [35]. Oxidative stress markers such as GST-π are found in greater abundance in TEN compared to other cutaneous adverse drug reactions, suggesting impaired detoxification and accumulation of electrophilic xenobiotics leading to further ROS production, cellular damage, and activation of apoptotic processes including Fas ligand expression and TNF-α inflammatory cytokine release. Additionally, TNF-α contributes to keratinocyte apoptosis by activating caspases and enhancing Fas/FasL expression, while also stimulating nitric oxide production that disrupts mitochondrial electron transport and exacerbates ROS accumulation. These combined events drive early apoptosis followed by late necrosis, corresponding to histological findings of TEN [35].

AGEP is a T-cell mediated inflammatory condition with abrupt onset of sterile, non-follicular pustules on the background of erythema and edema [43, 44]. AGEP occurs from children to adults with a predominance in those aged 20–60 years [45–47]. There is a predominance in women, which is likely due to sex differences in pharmacokinetics affecting drug metabolism, corresponding with the finding that drug eruptions are more commonly seen in females [45, 48–52]. The majority of the reported patient race is white, followed by Black or African American [53, 54]. AGEP is rare, with a yearly incidence of one to five cases per million per year [43, 55]. Out of all drug-induced rashes such as DRESS or SJS/TEN, AGEP accounts for approximately 17% of cases [56]. Triggers for AGEP are drug-related the majority of the time; most commonly implicated antibiotics include β-lactams and quinolones [46]. Other triggers have also been reported, including allergens, infections, mercury exposures, vaccines, and insect bites [57–67]. In a cross-sectional study, Gallardo et al. [68] found that AGEP patient populations had increased body mass index and previous drug allergies compared to the DRESS patient population. While AGEP is primarily linked to specific medications, social determinants of health such as socioeconomic status and healthcare access may have effects on case incidence, given that individuals with limited access to healthcare may have higher rates of infections, leading to increased antibiotic use. Though AGEP’s connection with autoimmune disorders has not been well studied, there have been studies centered around patients who developed AGEP with a past medical history of autoimmune disorders. A study by Smith et al. [69] looked at the underlying diseases in 21 patients with episodes of AGEP. Out of the 21 patients with AGEP studied, past medical histories include diagnoses of psoriasis, sarcoid, inflammatory bowel disease, autoimmune thyroiditis, and multiple sclerosis, suggesting that patients who develop AGEP appear to have a deregulatory immune T-helper-1 cytokine pattern [69].

AGEP is diagnosed based on both clinical presentation and histologic pathology. The EuroSCAR project has developed a scoring system for AGEP after comparing the clinical presentation of AGEP against other similar cutaneous diseases such as pustular psoriasis, pustular vasculitis, or TEN [43]. Criteria that support AGEP include sterile non-follicular pustules, erythematous background, distribution over the trunk and intertriginous areas, post-pustular desquamation, fever, neutrophils > 7,000/mm³, and spongiform subcorneal and/or intraepidermal pustules with papillary edema [43]. Drug patch tests can also be used when the drug agent causing AGEP is known [80]. A review by Barbaud in 2014 [80] has found that drug patch tests have been shown to be useful for AGEP in 50–58% of cases, whereas skin prick tests and intradermal tests have not shown any known value. On histology, spongiform pustules are commonly located in intracorneal, subcorneal, and/or intraepidermal regions with papillary dermal edema with both neutrophilic and eosinophilic infiltrates [43, 81–83]. Intraepidermal pustules containing eosinophils are mostly in the upper epidermis, bordering the subcorneal pustules [82]. The epidermal layer contains necrotic keratinocytes and spongiosis with neutrophil exocytosis, while the dermal layer contains neutrophilia and eosinophilia with occasional erythrocyte extravasation [81–83].

AGEP is a type IVc reaction caused by massive cell infiltrates of neutrophils in pustules and infiltration in the dermis and epidermis by TH17, ILC3s, and Tc17 [10]. The pathophysiology of AGEP is suggested to be a T-cell mediated inflammatory disease or a type IV reaction, with both CD4 and CD8 T-cells playing vital roles [84–86]. As shown through patch tests and in vitro tests, it is hypothesized that after allergen exposure, CD4 and CD8 T-cells undergo activation after binding to MHC molecules from antigen-presenting cells [70, 85–90]. Activated T-cells, or drug-specific T-cells, subsequently undergo proliferation, then migrate to the dermis and epidermis [70]. The drug-specific cytotoxic T-cells utilize proteins like granzyme B and perforin to induce apoptosis of keratinocytes, resulting in the formation of epidermal vesicles [86]. Drug-specific T-cells in AGEP patients have also been shown to produce more CXCL8/IL-8, a neutrophil chemokine, guiding neutrophils into epidermal vesicles, which form sterile pustules [85, 86, 91]. Studies have also demonstrated that increased levels of granulocyte-macrophage colony-stimulating factor (GM-CSF), INF-γ, IL-17, and IL-22 prevent neutrophil apoptosis, as well as induce further release of CXCL8/IL-8 by keratinocytes [85, 91, 92]. Peripheral blood serum of AGEP patients reveals higher levels of TH17 cells, which are responsible for the production of IL-17 and IL-22, suggesting a role of innate cells in pathophysiology [92]. Other cytokines that are found to be elevated in some AGEP cases include IL-5 and TNF-α [85, 93]. The increased levels of IL-5, a key cytokine in eosinophilic development and activation, can help explain eosinophilia that is seen in 28–52% of cases [85].

Additionally, studies have found a link between mutations in the IL-γ receptor antagonist (IL-36RN) gene and AGEP [94–96]. IL-36 is induced by pro-inflammatory cytokines such as IL-17 and IL-22 [94]. The IL36RN gene codes for the IL-36 receptor antagonist, IL-36Ra, which functions to block pro-inflammatory cytokines like IL-36a, IL-36b, and IL-36γ [95, 96]. Lack of a feedback mechanism in patients with IL36RN gene mutation would lead to an uncontrolled IL-36 pathway, hence increasing production of inflammatory cytokines like IL-6, IL-8, IL-1a, and IL-1 b, contributing to epidermal pustule formation [95, 97]. The initial discovery of the IL36RN gene was found to correlate with generalized pustular psoriasis (GPP) [94, 95]. Due to similar clinical, histological, and immunological features, several studies have attempted to identify link between IL36RN mutations and other GPP-related diseases, namely AGEP [94, 95]. Navarini and colleagues in 2013 found the rate of IL36RN gene mutations to be higher in AGEP groups compared to controls [95].

The limited literature examining potential links between AGEP and autoimmune disease may be attributable to the rarity of AGEP, given its typically self-limited clinical course, and the lack of long-term follow-up studies. Consequently, most investigations have focused on drug triggers and acute immunologic mechanisms rather than subsequent autoimmune outcomes. Current evidence suggests a shared genetic and immunologic predisposition, including CARD14 and IL36RN mutations, rather than a direct AGEP-mediated autoimmune process.