Critical Review: Systemic Medical Neglect in Lab-Confirmed Antiphospholipid Syndrome (APS) with von Willebrand Factor (vWF) Abnormalities and Stevens-Johnson Syndrome (SJS)

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1. Overview

This review examines the intersection of underdiagnosed autoimmune diseases, coagulation disorders, and drug-induced adverse reactions, with particular emphasis on patients with laboratory-confirmed Antiphospholipid Syndrome (APS) and abnormalities of von Willebrand factor (vWF). Special attention is given to cases of Stevens-Johnson Syndrome (SJS) induced by medications such as allopurinol and methotrexate (MTX), both of which are recognized, although uncommon, causes of this severe hypersensitivity reaction.

The review also explores the potential influence of cytochrome P450 gene polymorphisms, particularly CYP3A4 and CYP11A1 variants, on blood concentrations of hydroxychloroquine and its metabolites, and how these genetic differences may contribute to adverse drug reactions.

Hydroxychloroquine has been associated with Stevens-Johnson Syndrome (SJS), although this is an exceptionally rare adverse effect. SJS is a severe and potentially life-threatening mucocutaneous reaction characterized by widespread blistering, epidermal detachment, and involvement of the mucous membranes, including the eyes, oral cavity, and genital region.

Key considerations regarding the risk of SJS with hydroxychloroquine include:

  • Onset: Symptoms typically develop within the first one to two weeks after initiating treatment and may initially present with flu-like symptoms.
  • Incidence: The risk is considerably lower than that associated with medications such as sulfonamide antibiotics or certain antiepileptic drugs.
  • Clinical action: Patients who develop blistering skin lesions, purulent rashes, or peeling of the skin or mucous membranes while taking hydroxychloroquine should discontinue the medication immediately and seek urgent medical attention.

Common Adverse Effects of Hydroxychloroquine

The most frequently reported adverse effects are generally mild and include:

  • Gastrointestinal: Nausea, diarrhea, vomiting, abdominal pain, and loss of appetite, particularly during the initial phase of treatment.
  • Dermatologic: Skin rash, pruritus, hair loss, and increased photosensitivity.
  • Neurological: Headache, dizziness, and sleep disturbances.

Rare but Serious Adverse Effects

Although uncommon, hydroxychloroquine may cause severe complications involving multiple organ systems:

  • Ocular toxicity (retinopathy): Long-term use may result in retinal damage, potentially leading to irreversible visual impairment. Baseline and regular ophthalmologic examinations are therefore essential.
  • Cardiac toxicity: Hydroxychloroquine may prolong the QT interval, increasing the risk of potentially life-threatening cardiac arrhythmias. This risk is elevated when combined with other QT-prolonging medications, such as azithromycin.
  • Neuropsychiatric effects: Rarely, patients may experience mood changes, confusion, psychosis, or suicidal ideation, most commonly during the first month of therapy.
  • Hematologic and hepatic toxicity: Very rare cases of blood dyscrasias, including anemia, as well as abnormal liver function tests, have been reported.
  • Severe hypersensitivity reactions: Serious cutaneous adverse reactions (SCARs), including Acute Generalized Exanthematous Pustulosis (AGEP), Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), and Stevens-Johnson Syndrome (SJS), may occur.

Despite clear laboratory confirmation, these patients are frequently misdiagnosed, undertreated, or prescribed high-risk medications without appropriate pharmacogenetic or clinical screening. The consequences include irreversible neurologic injury, systemic inflammation, life-threatening dermatologic reactions, and in some cases, preventable death.

2. APS and vWF Dysregulation: A High-Risk but Overlooked Profile

APS is defined by:

  • Clinical criteria: arterial or venous thrombosis, and/or pregnancy morbidity

  • Laboratory criteria: persistent presence of antiphospholipid antibodies (LA, aCL IgG/IgM, or anti-β2GPI IgG/IgM), confirmed on two occasions at least 12 weeks apart 

    In a subset of patients, APS coexists with von Willebrand Factor (vWF) abnormalities, including:

  • Type 2: qualitative platelet adhesion defects

  • Type 5: rare multimer structure variants

This overlap presents a complex clinical profile with both thrombotic and hemorrhagic risks, often dismissed or misinterpreted.

Complications include:

3. Neurologic Injury in APS with vWF Abnormalities: A Dual Mechanism of Harm

Neurological complications of APS arise from thrombotic occlusion and immune-mediated inflammation of cerebral vessels and brain tissue. These effects are exacerbated by coagulopathy from vWF abnormalities.

Symptoms include:

  • Cognitive dysfunction ("brain fog")

  • Seizures

  • Migraines and visual changes

  • Neuropsychiatric symptoms (e.g., mood disorders, psychosis)

  • Stroke or transient ischemic attacks (TIAs)

Mechanisms:

  • Thrombosis limits cerebral perfusion

  • Antiphospholipid antibodies disrupt the blood-brain barrier, leading to neuroinflammation

  • vWF dysfunction impairs platelet function and microcirculatory regulation

Despite this, patients often face misdiagnosis or delayed treatment due to systemic clinical skepticism, particularly when CNS symptoms present without overt thrombosis.

4. Methotrexate and Stevens-Johnson Syndrome (SJS)

Though rare, methotrexate (MTX)—a drug commonly used in autoimmune diseases and oncology—can trigger Stevens-Johnson Syndrome (SJS), a life-threatening mucocutaneous reaction.

In a documented case series, two 14-year-old girls undergoing chemotherapy for osteosarcoma developed SJS following MTX administration. Symptoms included:

  • Purplish macular rash

  • Cutaneous and mucosal erosions

  • Oral and ocular ulcerations

Both patients were treated with systemic corticosteroids (1 mg/kg/day) and recovered.

Key implications:

  • MTX-induced SJS is rare but serious, particularly in immunocompromised or genetically predisposed patients

  • Prompt discontinuation of the drug is critical

  • Re-exposure to the culprit drug is contraindicated

  • Risk must be considered in APS or coagulopathy patients already prone to immune-mediated reactions

5. Allopurinol, HLA-B*5801, and Drug-Induced SJS

Allopurinol, frequently used to manage hyperuricemia, is a well-known trigger for SJS/TEN in individuals carrying the HLA-B*5801 allele—especially common in East Asian populations.

Clinical features of SJS/TEN include:

  • Painful, blistering rash with mucosal involvement

  • Skin detachment

  • Multi-organ dysfunction (e.g., hepatic, renal)

  • Mortality rate up to 30%

Despite the availability of genetic screening, allopurinol is still often prescribed without testing, even in high-risk patients.

References:

6. Inappropriate Use of DOACs in APS

Despite evidence from the TRAPS study and others, Direct Oral Anticoagulants (DOACs), such as rivaroxaban and apixaban, are still prescribed in APS, including in triple-positive patients who are at highest risk.

Associated outcomes:

  • Increased risk of stroke and recurrent thrombotic events

  • Reduced efficacy in preventing arterial thrombosis

  • Misleading safety assumptions due to general DOAC guidelines not applicable to APS

Treatment of the antiphospholipid syndrome with direct oralanticoagulants
https://leitlinien.dgk.org/2020/treatment-of-the-antiphospholipid-syndrome-with-direct-oralanticoagulants/

References:

7. Systemic Patterns of Medical Neglect

Recurring failures in APS management include:

  • Ignoring repeat-testing requirements for aPLs

  • Dismissing vWF abnormalities as incidental

  • Prescribing contraindicated drugs (e.g., allopurinol, MTX, DOACs) without screening

  • Misdiagnosing autoimmune CNS symptoms as psychiatric

  • Failure to involve rheumatology, hematology, neurology early in care

These failures disproportionately affect:

  • Women

  • Ethnic minorities

  • Adolescents and young adults with overlapping autoimmune presentations

The result is often severe, avoidable harm, including long-term neurologic damage and fatal drug reactions.

8. Conclusion: Preventable Harm from Clinical Blind Spots

APS with coagulopathy and immune overlap is a diagnostically and therapeutically manageable condition, yet outcomes are often poor due to systemic medical neglect. The addition of rare but known drug risks such as MTX-induced SJS and allopurinol hypersensitivity further demands vigilant clinical awareness.

When guidelines are ignored, testing protocols skipped, and unsafe medications prescribed, the result is a cascade of avoidable injury—including neurologic disability, mucocutaneous failure, organ dysfunction, and death.

This must change—through education, protocol reform, and above all, clinical vigilance.

Hydroxychloroquine is Plaquenil. Depending on the region or pharmaceutical manufacturer, it is also sold under other brand names such as Sovuna, Quinoric, and Dimard. 

Safety Recommendations

Because of the potential for cumulative retinal toxicity, patients should undergo a comprehensive baseline ophthalmologic examination before or shortly after initiating hydroxychloroquine therapy. Follow-up retinal screening is generally recommended after five years of continuous treatment, or earlier in patients with additional risk factors, such as high cumulative doses, renal impairment, or pre-existing retinal disease. Careful clinical monitoring is also recommended for cardiac, hematologic, hepatic, dermatologic, and neuropsychiatric adverse effects throughout the course of treatment.

References

CYP3A4 and CYP11A1 variants are risk factors for ischemic stroke: a case control study
https://pubmed.ncbi.nlm.nih.gov/32126981/ 

Gastrointestinal | Biotransformation of Drugs and Toxins
https://www.youtube.com/watch?v=zkS7PZUE27g&t=369s

For Healthcare Professionals | FDA’s Examples of Drugs that Interact with CYP Enzymes and Transporter Systems
https://www.fda.gov/drugs/drug-interactions-labeling/healthcare-professionals-fdas-examples-drugs-interact-cyp-enzymes-and-transporter-systems

Neurologic Manifestations of the Antiphospholipid Syndrome — An Update 
Kraus SS, Levine SR. Current Rheumatology Reports (2021)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8200381/

Encephalitis: Symptoms and Causes – Mayo Clinic

Mayo Clinic Health Information Resource 
https://www.mayoclinic.org/diseases-conditions/encephalitis/symptoms-causes/syc-20356136

TRAPS Study – Rivaroxaban in High-Risk APS3.   Pengo V et al., Blood (2018)
https://pubmed.ncbi.nlm.nih.gov/29540395/

Drug Interactions with Grapefruit Juice
https://www.drugs.com/article/grapefruit-drug-interactions.html

Guidelines on the Investigation and Management of Antiphospholipid Syndrome British Journal of Haematology (2012)
https://onlinelibrary.wiley.com/doi/10.1111/j.1365-2141.2012.09125.x

Allopurinol Hypersensitivity Syndrome and Toxicity
https://www.ncbi.nlm.nih.gov/books/NBK548098/

HLA-B*5801 Association with Allopurinol-Induced SJS/TEN   
"A high-resolution HLA and SNP haplotype map for disease association studies"
https://pubmed.ncbi.nlm.nih.gov/16998491/

rs3095318 SNP – Linked to HLA-B*5801 and SJS Risk  SNPedia: rs3095318
https://www.snpedia.com/index.php/Rs3095318

Warfarin Dosing and Management Guidelines (ACCP)  American College of Chest Physicians (CHEST Guidelines) 
https://journal.chestnet.org/article/S0012-3692%2813%2960019-5/fulltext

Hydroxychloroquine Use in Antiphospholipid Syndrome  Erkan D et al., Lupus (2019)
    "Long-term use of hydroxychloroquine in patients with antiphospholipid antibodies"
https://pubmed.ncbi.nlm.nih.gov/30761995/

EULAR Recommendations for Management of APS    
European League Against Rheumatism (EULAR) – 2019 Guidelines
https://ard.bmj.com/content/78/10/1296

SJS/TEN Overview and Clinical Management
https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2023.1213889/full

Methotrexate Induced Stevens-Johnson Syndrome: Two Cases Reports
https://clinmedjournals.org/articles/cmrcr/clinical-medical-reviews-and-case-reports-cmrcr-9-395.php?jid=cmrcr

Antiphospholipid syndrome, ferritin and fever: Hyperferritinemic syndrome, a nosological ally
(PDF) https://rjr.com.ro/rjr-vol-32-no-2-year-2023/

UpToDate: Stevens-Johnson syndrome and toxic epidermal necrolysis
https://www.uptodate.com/contents/stevens-johnson-syndrome-and-toxic-epidermal-necrolysis-clinical-features-diagnosis-and-pathogenesis *(Subscription required)*

Keywords: Antiphospholipid Syndrome (APS), von Willebrand Factor (vWF) Type 2 & 5, Brain Inflammation, Thrombosis, Encephalitis, Drug Reactions, Methotrexate (MTX), HLA-B*5801, Allopurinol, Warfarin, DOACs, Medical Neglect, Stevens-Johnson Syndrome (SJS)

© 2025-2030 Sieglinde W. Alexander. All writings by Sieglinde W. Alexander have a fife year copy right. Library of Congress Card Number: LCN 00-192742 ISBN: 0-9703195-0-9

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