DRESS Syndrome Triggered by Sulphasalazine: Clinicopathological Correlation and Immune-Modulatory Management

INTRODUCTION

Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a rare but potentially life-threatening, drug-induced hypersensitivity reaction. DRESS is characterized by a constellation of symptoms including fever, skin eruption, hematologic abnormalities, and visceral organ involvement.^[1] Its prevalence is estimated at 2.18 to 9.63/1,00,000. The syndrome typically manifests with a delayed onset, often between 2-8 weeks after initiation of the offending drug.^[2]

The most frequently reported culprits in the aetiology of DRESS syndrome include aromatic anticonvulsants such as phenytoin, carbamazepine, phenobarbital, sulphonamides, allopurinol, minocycline, vancomycin, and certain antiretrovirals and antipsychotics.^[3] Sulphasalazine is a sulphonamide derivative commonly used in Rheumatoid Arthritis management.^[4]

The pathophysiology of DRESS is complex. It typically involves a combination of genetic predisposition, particularly human leukocyte antigen (HLA) haplotypes, defective drug detoxification pathways leading to accumulation of reactive metabolites, and viral reactivation.^[5] The RegiSCAR group (European Registry of Severe Cutaneous Adverse Reactions) proposed criteria are commonly used for diagnosis.

The diagnosis of DRESS is often challenging due to variable clinical presentation and overlap with other systemic illnesses. Early recognition is very critical, as delayed diagnosis and continued exposure to the offending agent can lead to severe organ dysfunction and mortality rates as high as 10%.^[6] This case report describes a patient who developed DRESS syndrome following the use of several medications. The current report discusses the diagnostic challenges, therapeutic approach, and need for monitoring serious complications.

CASE REPORT

A 42-year-old woman came to the emergency department with a low-grade, on-and-off fever for the past four days. She had a rash on her face, neck, chest, and thighs. The rash on her face (cheeks, forehead, nose, and chin) appeared three days ago and was itching. The rash on her thighs appeared patchy and erythematous with pus-filled spots on her neck. The patient had pharyngeal erythema and angular cheilitis. She had mentioned superficial mouth ulcers, which resolved spontaneously in a few days. Mucositis was very mild, not correlating with Steven Johnson syndrome (SJS) or TEN. She had swelling all over her body, including a puffy face, for the last 2 days. In addition, she complained of throat pain and difficulty swallowing and had several mouth ulcers [Figure 1a].

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Figure 1: Improvement in facial puffiness from admission to discharge. (a) Facial puffiness at the time of admission and (b) Significant regression at the time of discharge.

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The patient was recently diagnosed with rheumatoid arthritis and was initiated on tablet hydroxychloroquine (200 mg twice daily), sulfasalazine 500 mg once daily, etoricoxib 60 mg once daily, and prednisolone 10 mg once daily.

The vitals measured on admission were pulse rate of 114 beats/min, blood pressure 100/50 mmHg, oxygen saturation of 94%, and respiratory rate of 26 per minute. The periorbital oedema, pharyngeal wall erythema, and mild mucositis were also found. The patient had pharyngeal erythema and angular cheilitis on admission. She had mentioned superficial mouth ulcers, which resolved spontaneously in a few days. The central nervous system, cardiovascular system, and abdomen showed no significant abnormalities. The breath sounds were equal on both sides, and crepitations were present over the lower zones bilaterally.

There was marked leucocytosis with a white blood cell count of 18.9 × 10³/mm³ (normal: 4.5-11 × 10³/mm³) and neutrophilia (80%; normal: 40-60%), with a neutrophil count of 15.4 × 10³/mm³ (normal: 3000-7000/mm³). Although eosinophils were normal, the absolute eosinophil count was elevated at 590/mm³ (normal: 50-400/mm³). The platelet count was normal at 326 × 10³/mm³ (normal: 150-400 × 10³/mm³). The renal function tests showed mildly elevated serum urea (30 mg/dL; normal: 5-18 mg/dL) while creatinine was 1.8 mg/dL on admission, eGFR- 38 mL/min/1.73m², and Creatinine clearance-39 mL/min. Before discharge, the value was 0.8 mg/dl [Figure 1b]. (Normal: 0.6-1.2 mg/dL) suggesting early renal involvement. Elevated SGOT (95 U/L; normal: 10-40 U/L) and SGPT (90 U/L; normal: 7-56 U/L) were found. Additionally, the serum albumin level was 1.2 mg/dL (Normal: 3.5-5.0 mg/dL). The albumin post multiple transfusions of human albumin was 3.0 mg/dL.

All the above indicate possible hepatic dysfunction or systemic inflammation [Table 1]. The ultrasonography of the abdomen and pelvis showed hepatomegaly along with periportal lymphadenopathy.

The skin biopsy [Figure 2] showed changes that are typical of a drug allergy reaction. There was a dense collection of immune cells (lymphocytes, histiocytes, neutrophils) around the blood vessels in the upper skin layers. The papillary dermis was swollen, and some immune cells moved to the basal layer. Many lymphocytes were seen on the basal cells, a sign called interface dermatitis. The epidermis showed mild thinning, with spongiosis and parakeratosis. The keratinocytes were found to be dying in patches in the middle skin layer. Notably, no evidence of vasculitis (blood vessel inflammation) was found. In this case, sulfasalazine was identified as the most likely offending agent. The RegiSCAR scoring of 6 points was suggestive of a definite case of DRESS Syndrome.

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Figure 2: Histopathology image of skin biopsy suggestive of interface dermatitis and consistent with DRESS syndrome. Hematoxylin and eosin stain, (a) low-power view, 4x and (b) represents a higher-power view, 10x magnification. DRESS: Drug reaction with eosinophilia and systemic symptoms

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DISCUSSION

The present case highlights the classical presentation of DRESS syndrome in a middle-aged female with Rheumatoid Arthritis following exposure to sulfasalazine. The patient showed symptoms ∼6 weeks after starting sulfasalazine, which fits the typical time frame for DRESS. The key signs, like rash, fever, facial edema, eosinophilia, and liver involvement, were present, thus meeting the RegiSCAR scoring system.^[3]

The burden of DRESS syndrome cases is majorly reported due to drugs like sulfasalazine, anticonvulsants (phenytoin, carbamazepine), and small molecules, which in turn can lead to T cell-mediated delayed hypersensitivity, viral reactivation, or certain HLA alleles impacting the drug metabolism.^[7]

The exact pathophysiology of DRESS is still under the bridge; it often presents in a similar way to SJS or acute generalized exanthematous pustulosis. The key differences to rule out in this case lie within the onset of symptomatology and a confirmatory skin biopsy. DRESS often has a delayed onset of clinical features with mild mucosal involvement, varying grades of systemic involvement, with a possible aetiology of viral reactivation; differentiating it from SJS, toxic epidermal necrosis, which is characterized by >30% of body surface area detachment, or acute generalized exanthematous pustulosis.^[8,9]

Transient Hepatic dysfunction in the form of a transitory increase in the liver enzymes, hepatomegaly, and periportal lymphadenopathy was reported here. A study also suggests that certain drugs may stimulate the expansion of drug-specific cytotoxic T cells that destroy hepatocytes via a cell-contact-dependent mechanism.^[10]

Renal dysfunction presenting as acute kidney injury (AKI) due to acute immunoallergic interstitial nephritis (AIN) was noted in our patient. Similar cases were reported by previous studies implicating sulfasalazine and other drugs used for rheumatoid arthritis.^[11,12]

The mainstay of treatment here is systemic steroids. This patient was started on the 2^nd line of management with cyclosporine. Earlier studies observed the effectiveness of cyclosporine as a first line of management or in patients with contraindications to steroid usage.^[13,14]

CONCLUSION

This case highlights the need to stay alert for DRESS syndrome in patients showing signs like fever, rash, eosinophilia, and systemic symptoms, especially if they recently started a new medication. Early recognition, immediate offending drug withdrawal, and timely immunosuppressive treatment are key to reducing morbidity and mortality in such cases.