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Acute generalized exanthematous pustulosis induced by sulfasalazine: Uncommon presentation of a common culprit

1 Department of Dermatology, Command Hospital, Lucknow, Uttar Pradesh, India
2 Department of Pathology, Central Command, Lucknow, Uttar Pradesh, India
3 Department of Dermatology, Central Command Hospital, Lucknow, Uttar Pradesh, India

Date of Submission31-Jan-2022
Date of Acceptance07-Apr-2022
Date of Web Publication13-Jul-2022

Correspondence Address:
Juhi Sharma,
Department of Dermatology, Command Hospital, Lucknow - 226 002, Uttar Pradesh
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/injr.injr_21_22


Acute generalized exanthematous pustulosis (AGEP) is a severe cutaneous adverse drug reaction caused by drugs in the majority of cases. It is characterized by the sudden onset of nonfollicular sterile pustules, papules, and edematous plaques on an erythematous background, predominantly involving the flexures. Sulfa drugs have a notorious reputation of wide range of severe adverse reactions, including AGEP. However, nonantibiotic sulfonamides behave differently from antibiotic sulfonamides in the pattern of adverse drug reactions and seldom cause AGEP. Only one case of AGEP due to salazosulfapyridine has been documented, none due to sulfasalazine. We report a 40-year-old female patient with a known case of reactive arthritis who was started on tablet sulfasalazine 500 mg in escalating doses, 4 days before the onset of nonfollicular sterile pustules, on erythematous background predominantly over flexures. She was diagnosed as a case of definite AGEP with score of 12/12 on the European Study of Severe Cutaneous Adverse Reaction validation scale. As per the Naranjo causality scale, sulfasalazine was the probable drug with a score of 5.

Keywords: Acute generalized exanthematous pustulosis, drug reaction, sulfasalazine

How to cite this URL:
Vashisht D, Kamboj P, Madakshira MG, Sinha P, Hegde A, Sharma J. Acute generalized exanthematous pustulosis induced by sulfasalazine: Uncommon presentation of a common culprit. Indian J Rheumatol [Epub ahead of print] [cited 2022 Dec 5]. Available from:

  Introduction Top

Sulfonamides are responsible for 3% of all the hypersensitivity reactions in the general population.[1] Sulfasalazine is a nonantibiotic sulfonamide drug developed in the 1930s for the treatment of inflammatory joints and bowel disease. Cildag and Senturk reported adverse reactions such as drug reaction with eosinophilia and systemic symptoms, Stevens‒Johnson syndrome (SJS), or toxic epidermal necrolysis (TEN), in almost 8.8% of patients using sulfasalazine.[2] Time interval between the drug intake and the onset of reaction varies with the type of drug reaction. It ranges from 4 to 6 weeks in drug reaction eosinophilia and systemic symptoms (DRESS), 2–4 weeks in SJS/TEN, and 1–10 days in acute generalized exanthematous pustulosis (AGEP). However, AGEP due to sulfasalazine has not been reported. This case report highlights a rare presentation of AGEP following the use of sulfasalazine.

  Case Report Top

A 40-year-old female patient had low backache and anterior uveitis for the past 2 years. She was human leukocyte antigen-B27-positive and an X-ray pelvis showed bilateral sacroiliitis. She was diagnosed with reactive arthritis and started on sulfasalazine 500 mg in escalating doses for 1 month. However, on the 4th day of the treatment, she developed a generalized rash involving her extremities and trunk with flexural preponderance and relative sparing of face, palms, and soles. The patient developed multiple tiny pustules over the existing rash over a period of the next 12 h, associated with a burning sensation that disturbed her sleep. There had been no previous history of sore throat, psoriasis, insect bites, or cutaneous drug reactions. Generalized erythematous plaque with multiple tiny nonfollicular pustules distributed symmetrically and predominately over the flexures of the extremities and trunk was revealed. Mucous membranes, palms, and soles were spared [Figure 1]a and [Figure 1]b. She was febrile and had an axillary temperature of 39°C, but there was no significant lymphadenopathy. Investigations revealed hemoglobin – 10.2 g/dl, erythrocyte sedimentation rate ‒ 45 mm/h, total leukocyte count – 33,400/mm3; differential leukocyte count showed polymorphs – 80%, lymphocytes – 15%, monocytes – 4%, and eosinophils – 1%. Peripheral blood smear showed microcytic hypochromic anemia, neutrophilic leukocytosis, D-dimer – 6817 ng/dl, and lactate dehydrogenase ‒ 378 IU/L. Liver, renal function tests, procalcitonin, antinuclear antibody, rheumatoid arthritis factor, serological tests for dengue, HIV 1 and 2, hepatitis A, B, and C, and reverse transcription-polymerase chain reaction for COVID-19 were negative. A Tzanck smear from a pustule showed a large number of neutrophils and a few eosinophils. Cultures from the pustule, blood, and urine were sterile.
Figure 1: (a) Confluent erythematous plaques studded with pustules over both lower extremities. (b) Multiple nonfollicular pustules over erythematous base. (c) Lesions resolving with exfoliation over forearms

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Skin biopsy of the representative lesion showed multiple foci of spongiosis associated with subcorneal neutrophilic abscess admixed with many eosinophils with evidence of neutrophils and eosinophils beneath the pustules. Dermis showed a perivascular lymphomononuclear cell infiltrate admixed with many eosinophils and neutrophils; Direct immunofluorescence (DIF) was negative for antibodies against immunoglobulins and complement [Figure 2]a and [Figure 2]b.s
Figure 2: (a) ×100 magnification. H and E-stained skin biopsy with epidermis and dermis. The epidermis shows two foci of subcorneal pustules (black arrow) with accompanying spongiosis. The upper dermal capillary plexus show moderate lymphomononuclear cell infiltrate. (b) ×2000 magnification. H and E stain. The subcorneal pustule (black arrow) with spongiosis (star) is better appreciated composed of numerous polymorphonuclear leukocytes and cell debris

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The patient fulfilled the criteria of definite AGEP and had a score of 12/12 as per the European Study of Severe Cutaneous Adverse Reaction (Euro SCAR)3, probably induced by sulfasalazine as validated by Naranjo scale, score of 05.

The patient was managed as a case of AGEP in the intensive care unit. Sulfasalazine was discontinued, and she was started on tapering doses of tablet prednisolone at 1 mg/kg/day, along with intravenous antibiotics. Started responding by the 3rd day, and the lesions were completely exfoliated by the 10th day [Figure 1]c. A patch test was not done on this patient as there was no history of polymedication.

  Discussion Top

The term “AGEP” was coined by Beylot et al.[3] AGEP is characterized by acute-onset pinpoint-sized, nonfollicular, sterile pustules, on edematous, erythematous skin, with a flexural preponderance. The typical rash begins on the face and flexural folds and progresses to involve the trunk and limbs, with minimal or no mucosal involvement. It is associated with a fever above 38°C and a neutrophil count of more than 7 × 109/μl with no internal organ involvement. Lesions usually resolve within 15 days after stopping the offending drug, with characteristic post pustular exfoliation. Histopathology shows spongiosis, subcorneal neutrophilic abscess admixed with eosinophils, and dermis shows perivascular lymphomononuclear cell infiltrate admixed with many eosinophils and neutrophils similar to our case.

Cases have been reported where pustules of AGEP coalesced and resulted in epidermal detachment similar to toxic epidermal necrolysis. However, in SJS-TEN, there is a 2–4 week latency period, cutaneous lesions are targetoid as well as mucosal involvement, and there is a positive Nikolsky's sign. Histopathology of the detached skin shows epidermal separation, paucicellular lymphocytic infiltrate along with necrotic keratinocytes. Similarly, DRESS may have AGEP-like pustules in up to 20% of cases, but it has a latency of 4–6 weeks and is associated with lymphadenopathy, visceral organ involvement, atypical lymphocytes, and eosinophilia.

AGEP is generally attributed to drugs in almost 90% of cases, but occasionally, it can be precipitated by other causes such as viral and bacterial infections.[4] It may be due to contact with chemicals (e.g., mercury) or dyes or as a response to certain organisms (e.g., cytomegalovirus, Chlamydia pneumonia, and  Escherichia More Details coli). Known medication associations include penicillin, macrolides, sulfa antibiotics, and antiepileptic drugs.[5]

Sulfonamides are classified as antibiotics and nonantibiotics. Sulfasalazine is classified as a nonantibiotic sulfonamide but is structurally related to antibiotic sulfonamides. Sulfasalazine is a prodrug that is split in the colon by the bacterial enzyme azoreductase into 5-aminosalicylic acid and the aromatic sulfonamide and sulfapyridine. The immunogenicity of sulfasalazine is due to its breakdown product, sulfapyridine, which contains the arylamine group at the N4 position. Hydroxylamine metabolites, formed through the oxidation of the arylamine group, present in the sulfapyridine group of sulfasalazine, are an essential factor in forming a haptenized structure that acts as a foreign body and initiates the immunologic process. The drug acts as a hapten presented by antigen-presenting cells to trigger the cytotoxic CD4+ and CD8+ T cells, which cause the formation of intraepidermal and subcorneal pustules and produce a high amount of IL8 which is accountable for attracting neutrophils.

Only a solitary case of salazosulfapyridine-induced AGEP has been reported by Kawaguchi et al.[6] However, there are no case reports of AGEP caused by sulfasalazine in the literature. It is surprising that in spite of sulfa drugs being implicated in the vast majority of the adverse drug reaction patterns, AGEP seldom finds its place. The same thoughts have been shared by Roujeau et al.[7]

Our case is “definite AGEP,” with a score of 12/12 on the (Euro SCAR) validation scale, probably induced by sulfasalazine as validated by the Naranjo scale, and a score of 5 with a latency period of 4 days. To our knowledge, this is the first reported case of AGEP associated with sulfasalazine (searched on PubMed with keywords as sulfasalazine and AGEP).

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient (s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

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Conflicts of interest

There are no conflicts of interest.

  References Top

Tilles SA. Practical issues in the management of hypersensitivity reactions: Sulfonamides. South Med J 2001;94:817-24.  Back to cited text no. 1
Cildag S, Senturk T. Sulfasalazine-related hypersensitivity reactions in patients with rheumatic diseases. J Clin Rheumatol 2017;23:77-9.  Back to cited text no. 2
Beylot C, Bioulac P, Doutre MS. Acute generalized exanthematic pustuloses (four cases) (author's transl). Ann Dermatol Venereol 1980;107:37-48.  Back to cited text no. 3
Sidoroff A, Dunant A, Viboud C, Halevy S, Bavinck JN, Naldi L, et al. Risk factors for acute generalized exanthematous pustulosis (AGEP)-results of a multinational case-control study (EuroSCAR). Br J Dermatol 2007;157:989-96.  Back to cited text no. 4
Kostopoulos TC, Krishna SM, Brinster NK, Ortega-Loayza AG. Acute generalized exanthematous pustulosis: Atypical presentations and outcomes. J Eur Acad Dermatol Venereol 2015;29:209-14.  Back to cited text no. 5
Kawaguchi M, Mitsuhashi Y, Kondo S. Acute generalized exanthematous pustulosis induced by salazosulfapyridine in a patient with ulcerative colitis. J Dermatol 1999;26:359-62.  Back to cited text no. 6
Roujeau JC, Bioulac-Sage P, Bourseau C, Guillaume JC, Bernard P, Lok C, et al. Acute generalized exanthematous pustulosis. Analysis of 63 cases. Arch Dermatol 1991;127:1333-8.  Back to cited text no. 7


  [Figure 1], [Figure 2]


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