Stevens-Johnson Syndrome Induced by Allopurinol

doi:10.21203/rs.3.rs-4083722/v1

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Case Report

Stevens-Johnson Syndrome Induced by Allopurinol

https://doi.org/10.21203/rs.3.rs-4083722/v1

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Background and Objective:

Adverse drug reaction leading to Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis(TEN) is a rare and potentially life-threatening adverse effect of allopurinol. Before allopurinol initiation, screening for patients with HLA-B*58:01 is recommended to avoid the risk of complications.

Case description:

An 85-year-old man was admitted to our hospital after initiating allopurinol for treating hyperuricemia, presenting with diffuse maculopapular rash on entire body. The level of inflammatory indicators such as C-reaction protein(CRP), erythrocyte sedimentation rate (ESR) and procalcitonin and the amount of eosinophilic granulocyte were decreased after discontinuation of allopurinol and corticosteroid administration, while deterioration of the situation occurred after quick glucocorticoid withdrawal. Reinstitution of the glucocoritcoids with immunoglobulin showed clinical improvement. Despite the amelioration of SJS, the patient died after 40 days of hospitalization with the acute coronary syndrome.

Conclusion

A case of allopurinol-induced SJS/TEN syndrome suggests that clinicians should prescribe allopurinol to hyperuricemia patients with caution. Detection of HLA-B*58:01 for allopurinol hypersensitivity among high-risk individuals is warranted. Timely treatment with glucocosteroid and immunoglobulin might be helpful in the management of this rare but serious adverse reaction.

Stevens-Johnson Syndrome

Allopurinol

HLA-B*58:01

Adverse drug reaction

Adverse drug reactions resulting in Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare yet potentially life-threatening effects of allopurinol. They are characterized by a diffuse maculopapular erythematous, pruritic rash, as well as skin and mucosal desquamation, with a mortality rate of approximately 30%. This case report presents an instance of allopurinol-induced SJS/TEN syndrome, emphasizing the necessity for physicians to exercise caution when prescribing allopurinol to patients with hyperuricemia. It is recommended to screen patients for the presence of HLA-B*58:01 to mitigate the risk of complications. Furthermore, timely administration of glucocorticoids and immunoglobulins may prove beneficial in managing this rare yet serious adverse reaction. This case serves as a reminder of the critical importance of vigilant monitoring and preemptive measures when prescribing allopurinol to prevent the onset of SJS/TEN syndrome in susceptible individuals.

An 85-year-old male, with a decade-long history of hypertension, renal dysfunction, and paroxysmal atrial fibrillation, was admitted to the respiratory ward at the Seventh Medical Center of PLA General Hospital, presenting with a sore throat, sputum production, fever (38.4°C), dyspnea persisting for four days, and diffuse maculopapular erythematous and pruritic rashes for two days. The erythema and macular rashes initially manifested on his face and neck and subsequently extended to his trunk and back, with hemorrhagic crustations over the lips and oral cavity, resulting in eating difficulties (Fig. 1A, 2A).

Upon physical examination, significant pulmonary moist rales were noted, while chest CT imaging revealed no discernible anomalies. Laboratory analysis unveiled elevated serum alanine aminotransferase (ALT) levels of 128 U/L (reference range: 0–40), aspartate aminotransferase (AST) levels of 136 U/L (reference range: 0–40), and creatinine levels of 196 (44.2–115) µmol/L. The blood cell counts were as follows: initial white blood cell (WBC) count of 7.3210^9/L, eosinophilic granulocyte count of 1.510^9/L, with an eosinophil count (EO%) of 20.5, platelet count of 204*10^9/L, and hemoglobin (HGB) level of 135 g/L. Additionally, inflammatory markers such as C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and procalcitonin were substantially elevated at 240 mg/L (0–8 mg/L), 41 mm/h (0–15 mm/h), and 8.1 ng/mL (0-0.49 ng/mL), respectively. Furthermore, complement C3 and C4 levels were below the reference range. A decrease in lymphocyte count, along with an altered CD4+/CD8 + ratio and CD56+ %, was also observed (0.47 (> 1) and 47.84 (5-39.5%), respectively). Thyroid function tests and autoimmunity markers fell within the reference range. Notably, screenings for hepatitis B surface antigen, hepatitis C antibody, CMV antigen, blood culture, urine culture, cytoplasmic Anti-Neutrophil Cytoplasmic Antibodies (cANCA) and perinuclear ANCA (pANCA) and rheumatoid factor yielded negative results.

Concurrently, a blood sample was submitted for genetic marker testing, specifically HLA-B*58:01, associated with allopurinol-induced severe cutaneous adverse reactions (SCAR), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN), which returned as positive. This comprehensive clinical assessment underscores the diagnosis of allopurinol-induced Stevens-Johnson syndrome and toxic epidermal necrolysis, emphasizing the critical role of thorough patient evaluation and genetic screening in preempting such severe adverse reactions.

Upon suspicion of drug hypersensitivity, immediate discontinuation of allopurinol was executed, following which intravenous methylprednisolone (40 mg, qd) and immunoglobulin (20g, qd) were concomitantly initiated for a duration of 5 days, accompanied by supplementary supportive measures. Given the prominent inflammatory markers and heightened concerns regarding potential infectious etiology contributing to fever and sore throat, Imipenem/Cilastatin (Tienam) was administered to provide coverage against a wide spectrum of gram-positive and gram-negative microorganisms. Approximately 5 days subsequently, significant improvements were observed in the amelioration of pruritus, erythema, and rash, as well as in the laboratory inflammatory markers. The subsequent days saw a sustained decline in eosinophilic granulocyte count, inflammatory indicators, and ALT levels, attributable to the comprehensive and intensive therapeutic regimen. This swift and robust medical intervention reflects the effective management of allopurinol-induced adverse reactions, underscoring the critical role of prompt treatment and supportive care in mitigating severe drug hypersensitivity responses.

Regrettably, the diffuse maculopapular erythematous and pruritic rash exhibited severe exacerbation, with involvement of the lip mucosa subsequent to the alteration in treatment, transitioning from 32mg methylprednisolone to oral administration (Fig. 1B, 2B). This progression was accompanied by an elevation in the white blood cell count to 13.22*10^9/L, including a 14.4% eosinophil count, and episodes of exacerbated dyspnea. Following consultation, a dermatologist recommended a regimen of methylprednisolone at 40 mg, twice daily, in conjunction with immunoglobulin (20g, qd) for an additional 5 days, leading to gradual reduction in the symptoms and signs of hypersensitivity reaction. Subsequently, intravenous methylprednisolone was gradually tapered over a period of 30 days and then maintained at 20mg/d. Sadly, the patient experienced acute coronary syndrome, characterized by troponin levels fluctuating between 0.34 to 2.1ng/ml, alongside persistent renal dysfunction. Tragically, the patient succumbed after 40 days of hospitalization. This poignant clinical course underscores the complexity and gravity of allopurinol-induced adverse reactions, emphasizing the significance of vigilant monitoring and the interdisciplinary management of severe drug hypersensitivity responses.

Allopurinol-induced severe cutaneous adverse drug reactions (SCAR) exhibit a robust correlation with a notably high risk of 7.4% prevalence among carriers of HLA-B*58:01, particularly within Asian and African-American patient populations. These reactions may manifest as a spectrum of hypersensitivity responses, encompassing maculopapular rash, erythema multiforme, Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), as well as hypersensitivity syndrome (HSS) or drug rash with eosinophilia and systemic symptoms (DRESS) [1, 2]. It is noteworthy that these manifestations can coincide and display overlapping features. The extent of skin involvement serves to delineate the severity of the SCAR as follows: (1) erythema multiforme major, confined to 1–2% of the body surface area (BSA); (2) SJS, encompassing less than 10% of the BSA with detachable or detached skin; (3) Overlapping SJS and TEN involving 10–30% of the BSA; and (4) TEN, affecting more than 30% of the BSA. This elucidation of the varying degrees of skin involvement underscores the diverse and potentially life-threatening nature of allopurinol-induced adverse reactions, necessitating heightened awareness and tailored intervention strategies in clinical practice.

Although our patient presented with fever, skin rash, abnormal blood counts including eosinophilia, and involvement of multiple visceral organs such as the lung, liver, and kidneys, all of which are hallmark clinical features of Drug Rash with Eosinophilia and Systemic Symptoms (DRESS), several distinctive aspects led to the consideration of a diagnosis of Stevens-Johnson Syndrome (SJS). Notably, the delayed onset of symptoms following drug exposure (typically 4 weeks after, with a usual range of 2–8 weeks) and persistent or worsening manifestations post-drug withdrawal, align with the characteristic profile of DRESS, accounting for 27%-36.7% of cases attributed to allopurinol[3].However, the clinical presentation, inclusive of similar complications and the presence of diffuse maculopapular erythematous rash with mucosal involvement of the lips and oral cavity, bears closer resemblance to the features classically associated with SJS/TEN. SJS, characterized by severe and life-threatening skin and mucous membrane desquamation, is recognized to engender a mortality rate of approximately 30%. The percentage of allopurinol-induced SJS cases exhibits regional variance, ranging from 5% in Europe to 13% in Singapore[4]. This diagnostic delineation underscores the nuanced clinical distinctions and diverse disease presentations within allopurinol-induced severe cutaneous adverse reactions, reflecting the imperative for differential diagnosis and tailored therapeutic interventions contingent upon the specific disease entity.

Drug-induced adverse reactions are commonly categorized as type A and type B adverse drug reactions. Type A reactions are directly related to the dose and toxicity of the implicated medication and typically ameliorate following discontinuation of the drug. In contrast, Allopurinol-induced Stevens-Johnson Syndrome (SJS) is commonly regarded as an idiosyncratic and typically classified as a type B adverse drug reaction. This classification associates it with an immunologic T cell-mediated reaction, recognized as a delayed drug allergy reaction (DDAR) according to the nomenclature of the World Allergy Organization[5]. The delayed onset of symptoms suggests that the underlying mechanism may be influenced by a direct pharmacologic effect of the drug or the accumulation of oxypurinol, the therapeutic metabolite of allopurinol, excreted by the kidneys.

Notably, the patient's medical history of renal insufficiency and impaired renal clearance may have contributed to a type 3 hypersensitivity response, likely triggered by elevated plasma levels of oxypurinol. This response led to the deposition of complement factors and immunoglobulins along the glomerular basement membrane, resulting in progressive renal impairment and a cyclical pattern of degradation, corroborated by the sustained elevation of creatinine levels and diminished complement factors C3 and C4. Furthermore, type IV hypersensitivity responses to oxypurinol have been posited as the underlying mechanism, characterized by the delayed onset of symptoms 2–8 weeks after exposure to the offending drug (4 weeks in this instance). The role of specific HLA alleles, particularly HLA-B*58:01, and their interaction with oxypurinol in provoking aberrant T-cell activation and amplifying the adaptive immune response are believed to be pivotal in the pathophysiology[7]. Additionally, favorable outcomes were observed following the administration of corticosteroids and immunoglobulins, underscoring the significance of targeted therapeutic interventions in managing allopurinol-induced severe cutaneous adverse reactions.

The established association between the HLA-B58:01 allele and allopurinol-induced Severe Cutaneous Adverse Reactions (SCARs) is well-documented, with an allergy risk elevated by 80–97 times in patients harboring this allele, particularly evident among the Han Chinese population[8]. Despite this knowledge, the exact mechanisms underpinning this relationship remain incompletely elucidated. In addition to HLA-B58:01, other HLA alleles such as HLA-A33:03 and HLA-C33:02 have also been implicated in allopurinol-triggered SCARs encompassing Acute Hypersensitivity Syndrome (AHS), Stevens-Johnson Syndrome (SJS), and Toxic Epidermal Necrolysis (TEN).The subsequent activation and clonal expansion of CD8 + T cells and cytotoxic T lymphocytes play a pivotal role in heightening the immune response through cell-cell interactions and the synthesis of cytolytic proteins and cytokines. The observed downregulation of lymphocytes, decreased ratio of CD4+/CD8+, and upregulated CD56 + in our case provides substantial evidence supporting the involvement of T-cell (CD8+) and NK cell (CD56+)-mediated cytotoxicity, which are prominently featured in SJS/TEN[9].The presence of pre-existing sore throats before the onset of skin rash suggests a potential triggering of the innate immune response by viral infections during the initiation phase of T-cell-mediated drug reactions[10]. Moreover, studies by Nakajima et al. have illustrated that allopurinol can elicit an innate immune response through the MAPK signaling pathway and drive inflammation via NF-kB activation[11–12]. Viral infections have been identified as an additional risk factor for allopurinol-induced delayed drug allergy reactions. These insights underscore the intricate interplay between genetic predisposition, immune pathways, and infectious triggers in the development of severe cutaneous reactions induced by allopurinol[13].Notably, renal insufficiency has been linked to increased mortality rates and prolonged cutaneous reactions. Additionally, the utilization of long-acting diuretics for hypertension management may impose an added burden on the kidneys. In this case, the patient presents several risk factors including gender (male), advanced age, diuretic use, Han Chinese ethnicity, positive HLA-B*58:01 status, allopurinol ingestion at a medium-high dose, and concurrent viral infection, collectively corroborating a poor prognosis.The significance of pre-screening for HLA-B*58:01 prior to the initiation of allopurinol is underscored by the 2020 American College of Rheumatology (ACR) guidelines, particularly advocating for high-risk patients, such as those of Korean, Thai, and Han Chinese descent. This strategic approach aligns with the imperative of personalized medicine, ensuring risk assessment and tailored intervention in vulnerable patient populations[14].

Early diagnosis and immediate withdrawal of the suspected drug, coupled with the initiation of tailored therapeutic interventions, form the cornerstone of management strategies for Severe Cutaneous Adverse Reactions (SCARs) triggered by allopurinol. The presence of genetic markers, such as HLA-B58:01, has been notably articulated in patients with allopurinol-induced Stevens-Johnson Syndrome (SJS), particularly among individuals of Han-Chinese descent. Furthermore, aside from HLA-B58:01, other HLA alleles, including HLA-A33:03 and HLA-C33:02, have also been linked to allopurinol exposure-induced SCARs encompassing Acute Hypersensitivity Syndrome (AHS), SJS and TEN. Consequently, the screening for HLA-B*58:01 emerges as a cost-effective measure in certain Asian populations and in patients with advanced renal failure.Supportive management involving intravenous fluids and antibiotics represents the standard of care in these cases. Corticosteroids or immunoglobulins have proven beneficial in our patient's case. Elderly patients require judicious management, particularly with medications such as allopurinol. These agents should be prescribed thoughtfully, strictly upon confirmation of a gout diagnosis, and not for generalized joint discomfort or asymptomatic hyperuricemia. This underscores the critical significance of evidence-based prescribing practices, particularly in vulnerable patient populations.

SJS/TEN

Stevens-Johnson syndrome and toxic epidermal necrolysis

CRP

C-reaction protein

ESR

erythrocyte sedimentation rate

ALT

alanine aminotransferase

AST

aspartate aminotransferase

WBC

white blood cell

EO%

eosinophil count () of 20.5,cANCA,cytoplasmic Anti-Neutrophil Cytoplasmic Antibodies

pANCA

perinuclear Anti-Neutrophil Cytoplasmic Antibodies

SCAR

severe cutaneous adverse reactions

AHS

Acute Hypersensitivity Syndrome.

Ethics approval and consent to participate

The patient’s consent for the case report was obtained after well informed by patient’s daughter and formal approval was received from the ethics committee of 7^th Medical Center of Chinese PLA General Hospital.

Consent for publication

Written informed consent for publication of their clinical details and/or clinical images was obtained from the guardian of the patient.

Availability of data and materials

The data and materials that support the findings and presentations of this study are available upon reasonable request. Requests for access to these datasets should be directed to the corresponding author De Chang (Email: [email protected]).

Competing interests

None of the co-authors reports any conflict of interest.

Funding

This study was supported by funding from the National Key Research and Development Program of China (No.2021YFC2302300), the National Natural Science Foundations of China (No. 81700069), and Major Project of Eighth Medical Center of Chinese PLA General Hospital (No.2021ZD005).

Authors' contributions

Ying Zhu drafted the manuscript and prepare the figure; Dandan Li &Hong Zhang interpreted the linical data and Jiandong Li & De Changedited the manuscript.

Acknowledgments

Our thanks to the anonymous editors and reviewers for their constructive feedback, which has significantly enhanced the quality of this publication.

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No competing interests reported.

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Stevens-Johnson Syndrome Induced by Allopurinol

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