Allopurinol Can Cause Severe Skin Reactions and Multi-Organ Involvement

Primary care physicians encounter patients with hyperuricemia and gout in everyday practice with a prevalence of up to 5.6% (1). Uricostatic drugs such as allopurinol are recommended for the long-term lowering of uric acid following at least one attack of gout or chronic gouty arthritis/uric acid stones. The following case series highlights what to look out for when patients present to their primary care physician with new skin lesions while receiving this treatment.

Patient history

A 43-year-old male patient of Southeast Asian origin (patient I) developed new-onset red macules in the chest region, accompanied by fever. Within 2 days, a generalized maculopapular rash had developed together with pronounced facial edema and abdominal pain. Due to the persistent fever and a feeling of being unwell, he presented to the emergency department and was admitted as an inpatient. A more detailed patient history revealed that due to a gouty tophus, allopurinol treatment had been initiated around 4 weeks before the skin lesions first appeared.

A 63-year-old patient of Southeast Asian origin (patient II) developed new-onset progressive itchy redness in the chest region. In the further course, a maculopapular rash developed, which the primary care physician suspected to be an allergic reaction and treated with antihistamines. Upon feeling unwell and experiencing attacks of fever, the patient presented to an emergency care walk-in clinic and received prednisolone, paracetamol, and FeniHydrocort cream. Due to the abdominal pain that was also present, the patient was admitted as an inpatient for acute cholecystitis and underwent cholecystectomy. Treatment with allopurinol had been initiated approximately 4 weeks previously.

A 49-year-old male patient of Southeast Asian origin (patient III) had noticed an area of intensely pruritic reddened skin in the neck region that spread over the entire integument within few days. Some weeks previously, he had received intravenous antibiotic treatment with penicillin V and amoxicillin/clavulanic acid due to erysipelas of the forefoot. In addition, due to elevated uric acid levels, the patient had been taking allopurinol for about 4 weeks prior to the onset of the first skin lesions. The patient presented to his primary care physician, who discontinued allopurinol and arranged for the patient to be admitted to hospital for a suspected drug eruption.

Clinical findings

All three patients were found to be in a poor general condition and showing generalized maculopapular exanthem with facial edema, in some cases involving the oral mucosa. The exanthem covered more than 50% of the surface of the body and was exfoliative in places (peeling of moist skin), but then resolved upon pronounced desquamation (dry flaking skin) (Figure).

Figure

Patient II with pronounced exanthem and facial swelling in the acute phase of the reaction

Laboratory tests and histology

The differential blood counts of all three patients showed eosinophilia, elevated transaminases, and elevated inflammatory parameters.

Histology revealed lymphohistiocytic inflammatory infiltrates comprising eosinophils, consistent with a drug eruption (Table).

Table

Criteria according to the DRESS validation score of the RegiSCAR study group

The diagnosis was: drug reaction with esosinophilia and systemic symptoms (DRESS).

Treatment and course

All three patients received oral steroid therapy of 0.5–2.0 mg/kg/body weight, which was slowly tapered. We also ordered antipruritic therapy comprising antihistamines and a steroid-containing topical treatment.

Allergy testing

Patch testing is usually recommended 2–4 months after the resolution of skin lesions to verify the triggering agent. However, patch testing is not helpful in the case of allopurinol since the substance is not suited to skin testing (2).

Discussion

DRESS is a severe skin reaction with multi-organ involvement that can be triggered by various drugs and may be potentially life-threatening. The main triggers include:

• Aromatic anti-seizure drugs
• Allopurinol
• Antibacterial sulfonamides
• Sulfasalazine
• Vancomycin
• Minocycline.

The first skin lesions generally appear 2–6 weeks after starting use of the drug.

The clinical picture varies. It usually takes the form of a generalized skin eruption that can be maculopapular, lichenoid, or inflammatory and infiltrative in nature, and sometimes also purpuric. The mucous membranes may also be affected by erythema or erosions. It is accompanied by a deterioration in general condition, fever, hepatopathy, nephropathy, or lymphadenopathy. Eosinophilia or atypical lymphocytes are almost always found (3).

Summary

Our case series illustrates DRESS in three patients of Southeast Asian origin in conjunction with the use of allopurinol. Certain genetic polymorphisms, particularly in the HLA-B*5801 allele, are associated with a higher risk for DRESS following the use of allopurinol, irrespective of the dose used (4). This allele is more commonly found in the Southeast Asian population compared to other ethnic groups (2). Its prevalence in Southeast Asia is > 10%, while in Europe it is 1–5%.

Upon disease onset, all three patients presented to their primary care physician or to an emergency care walk-in clinic. Therefore, primary care physicians in particular should be aware of the possible adverse effects that can be associated with prescribing allopurinol—primarily in patients of Southeast Asian origin—and use alternative drugs such as probenicid or febuxostat as appropriate. In the case of skin lesions and general symptoms, physicians should consider a severe hypersensitivity reaction like DRESS in the differential diagnosis in order to ensure appropriate treatment.

In the studies conducted by the RegiSCAR group, it was observed that allopurinol was initiated despite uric acid levels being within the reference range and in the absence of signs of gout. Therefore, the indication for prescribing allopurinol even in patients of European origin should be assessed more rigorously.

Susan Smakovic, Maren Paulmann, Maja Mockenhaupt

Acknowledgments

We would like to thank our departmental colleagues (in particular, Dr. Scholl and Dr. Trefzer) who co-treated these three patients, as well as Dr. Technau-Hafsi and PD Dr. Meiß for the histological analysis.

Conflict of interests statement
The authors state that no conflicts of interest exist.

Manuscript submitted on 1 May 2024, revised version accepted on

7 November 2024.

Translated from the original German by Christine Rye.

Cite this as
Smakovic S, Paulmann M, Mockenhaupt M: Allopurinol can cause severe skin reactions and multi-organ involvement. Dtsch Arztebl Int 2025; 122: 111–2. DOI: 10.3238/arztebl.m2024.0238

References

1. Jaeschke L, et al.: Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz 2020; 63: 439–51.

2. Ardern-Jones MR, Mockenhaupt M: Curr Opin Allergy Clin Immunol 2019; 19: 283–93.

3. Liß Y, et al.: Allergologie 2013; 36: 28–34.

4. Kardaun SH, et al.: Br J Dermatol 2013; 169: 1071–80.