SJS, Lupus, APS, VWF, and Adrenal Insufficiency: A Convergence of Multisystem Disorders with Overlapping Risk

This research in progress documents the case of a woman over 70 who suffered serious harm due to medical neglect and the administration of toxic treatments by healthcare providers.

Introduction

Multisystem diseases such as Stevens-Johnson Syndrome (SJS), Systemic Lupus Erythematosus (SLE), Antiphospholipid Syndrome (APS), and von Willebrand Factor (VWF) disorders can present with overlapping involvement of the skin, heart, blood vessels, immune system, HPA axis/endocrine system. Adrenal insufficiency, often overlooked in critically ill patients, may also be a life-threatening complication, especially in the setting of systemic inflammation or steroid withdrawal. This article explores their interrelation, highlighted by a case of phenytoin-induced fatal hypersensitivity reaction.

HLA-B*5801 Drug interactions cause SJS, rs3095318(A;T)

HLA-B*5801 allele and allopurinol side effects see discussion at rs3095318

CDSN PSORS1C1

Genes

The minor allele rs3095318(T), as defined on the minus strand, is reported to be associated in Japanese populations with the HLA-B*5801 allele and therefore susceptibility to severe side effects from taking allopurinol and perhaps other drugs. Sequence and haplotype analysis supports HLA-C as the psoriasis susceptibility 1 gene.
Reference: A high-resolution HLA and SNP haplotype map for disease association studies in the extended human MHC https://pubmed.ncbi.nlm.nih.gov/16998491/

Allopurinol can cause severe side effects, including life-threatening skin reactions (Stevens-Johnson Syndrome/TEN) and Allopurinol Hypersensitivity Syndrome (AHS/DRESS) with fever, rash, liver/kidney issues, and swollen glands, often in the first weeks or months. Drug interactions with medications like warfarin, azathioprine, or ampicillin can increase risks, especially with poor kidney function, necessitating immediate medical attention for symptoms like yellowing skin, severe rash, extreme fatigue, unusual bleeding, or difficulty breathing.
References: https://www.snpedia.com/index.php/rs1801131

Allopurinol can cause severe reactions:

Especially: Allopurinol Hypersensitivity Syndrome (AHS) and severe skin reactions like Stevens-Johnson Syndrome (SJS) or Toxic Epidermal Necrolysis (TEN), marked by fever, rash, blisters, jaundice, and organ issues (kidney, liver). Other serious effects include blood disorders, kidney damage, and severe allergic reactions. Drug interactions, like with warfarin, azathioprine, thiopurines, or ampicillin, can increase risks, necessitating immediate medical help for symptoms like difficulty breathing, severe rash, unusual bleeding, or yellowing skin/eyes
References: https://www.ncbi.nlm.nih.gov/books/NBK548098/#:~:text=Chronic%20therapy%20with%20allopurinol%20is%20associated%20with,systemic%20symptoms%20%E2%80%94%20DRESS%20syndrome)%20(Case%201).

Other names for allopurinol?

Allopurinol is a generic drug sold under a variety of brand names, including Allohexal, Allosig, Milurit, Alloril, Progout, Ürikoliz, Zyloprim, Zyloric, Zyrik, and Aluron.

1. Stevens-Johnson Syndrome (SJS) – Mucocutaneous Hypersensitivity Reaction

Overview

SJS is a rare, immune-mediated skin and mucosal disorder, typically triggered by drugs such as:

Antiepileptics (phenytoin, carbamazepine)
Antibiotics
Allopurinol, NSAIDs
Warfarin (German: Coumadin or Marcumar) - induced Stevens-Johnson syndrome with severe liver injury https://pubmed.ncbi.nlm.nih.gov/34311601/
Gabapentin Cases of severe skin rashes, including Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms (DRESS), have been reported. https://pubmed.ncbi.nlm.nih.gov/26321400/

Clinical Features

Widespread skin pain and epidermal detachment
Mucosal erosions (ocular, oral, genital)
Fever, systemic inflammation
Onset: 1–3 weeks after drug initiation
Severity: High ferritin levels are associated with a worse prognosis in SJS, according to NIH. A ferritin level over
$10 comma 000 ng/mL$
is highly suggestive of HLH, which can occur in conjunction with SJS

Rare vardenafil-associated Stevens-Johnson syndrome: toxic epidermal necrolysis
https://pmc.ncbi.nlm.nih.gov/articles/PMC8886404/

2. Myocarditis – Cardiac Inflammation

Causes

Infection (e.g., viral)
Autoimmune diseases (e.g., lupus)
Drug hypersensitivity (as seen with phenytoin)

Symptoms

Chest pain, palpitations
Hypotension, arrhythmias
Heart failure and sudden cardiac arrest

Diagnosis

Elevated troponins/BNP
Cardiac MRI
Biopsy if feasible

3. Lupus (SLE) – Autoimmune Multisystem Disease

Systemic Involvement

Skin (malar rash), joints, kidneys, eyes
Hematologic: Anemia, thrombocytopenia
Cardiac: Pericarditis, myocarditis
Endocrine: Possible adrenal involvement (secondary AI)

Overlap with APS and VWF dysfunction

4. Antiphospholipid Syndrome (APS) – Prothrombotic Autoimmune State

Key Features

- Recurrent venous/arterial thrombosis
- Coexists with lupus in ~40% of cases
- Cardiac complications
- Brain inflammation
APS (Antiphospholipid Syndrome) causes brain inflammation and damage through both blood clots (thrombosis) leading to strokes/ischemia, and direct immune attacks, where autoantibodies disrupt the blood-brain barrier, causing inflammation, cytokine release, and neuronal damage, resulting in symptoms like stroke, headaches, cognitive issues, seizures, and movement disorders. It's a dual process involving clotting and immune-mediated inflammation that damages brain tissue and function.
Reference:
Neurologic Manifestations of the Antiphospholipid Syndrome — an Update
https://pmc.ncbi.nlm.nih.gov/articles/PMC8200381/
APS (Antiphospholipid Syndrome) encephalitis involves brain inflammation (encephalitis) caused by autoantibodies attacking the brain, leading to cognitive issues, seizures, movement disorders, and memory loss, often presenting as "brain fog," and requires immunosuppressive treatments like steroids or IVIG, distinct from typical viral causes but sharing inflammatory mechanisms with other autoimmune encephalitides.
Reference:
Encephalitis
https://www.mayoclinic.org/diseases-conditions/encephalitis/symptoms-causes/syc-20356136#:~:text=Encephalitis%20(en%2Dsef%2Duh,such%20as%20mosquitos%20and%20ticks

5. von Willebrand Factor (VWF) Types 2 and 5 – Hemostatic Dysfunction

VWF Type 2

Qualitative defect → dysfunctional VWF
Mucosal bleeding risk, platelet adhesion issues

VWF Type 5

Rare, variant type—combined secretion and function defect
May appear in autoimmune or inflammatory states (e.g., lupus)
Possible link to paradoxical bleeding or thrombosis

6. Adrenal Insufficiency (AI) – Endocrine Failure in Critical Illness

Definition

AI occurs when the adrenal glands fail to produce adequate cortisol, critical for stress response, blood pressure regulation, and immune modulation.

Types

Primary AI: Adrenal destruction (e.g., Addison’s disease)
Secondary AI: Pituitary dysfunction or long-term steroid use
Acute AI in critical illness: May be triggered by:
- Severe inflammation (e.g., SJS/DRESS)
- Hemodynamic instability
- Abrupt withdrawal of corticosteroids

Clinical Signs

Hypotension unresponsive to fluids/inotropes
Hyponatremia, hyperkalemia
Fatigue, confusion, vomiting
Shock

Relevance in This Case

In the context of SJS and myocarditis, AI should be suspected if hypotension persists despite inotropes. Cortisol deficiency exacerbates cardiovascular collapse and contributes to multi-organ failure.

7. Case Report: Fatal Phenytoin-Induced SJS, and Suspected Adrenal Crisis

Patient Presentation

Started on phenytoin (Zentropil) for seizures
Developed fever, mucosal erosions, rash, hypotension
Labs: Normal LFTs, APTT 32s, platelets 143,000/mm³
GCS 4/15, ventilator-dependent, renal dysfunction

Management

Inotropes, IV hydrocortisone 100 mg (possibly for adrenal support)
Phenytoin discontinued, switched to sodium valproate
Despite support, suffered two cardiac arrests; died within 18 hours

Suspected Adrenal Involvement

Persistent hypotension despite fluids and vasopressors
High stress state without endogenous cortisol compensation
Adrenal insufficiency likely contributed to poor outcome

8

Condition	Cardiac Involvement	Skin Involvement	Coagulation Effects	Endocrine Impact	Medication-Triggered
Stevens–Johnson Syndrome (SJS)	Rare (secondary stress effects)	Severe mucocutaneous necrosis	Mucosal bleeding risk	Cortisol depletion due to extreme stress	Yes
Myocarditis or Heart rhythm issues	Primary involvement	None	Possible thrombosis due to inflammation	Secondary adrenal dysfunction in shock	Yes
Systemic Lupus Erythematosus (SLE)	Common (pericarditis, myocarditis)	Common	Bleeding and/or thrombosis	Possible secondary adrenal insufficiency	No
Antiphospholipid Syndrome (APS)	Common (ischemia, valve disease)	Rare	Predominantly thrombotic	May overlap with adrenal insufficiency	No
von Willebrand Factor Disorder (Type 2/5)	None	Mucosal bleeding	Bleeding ± paradoxical clotting	None	No

9. Conclusion

This case highlights the complex interplay between drug hypersensitivity, autoimmune dysfunction, hemostatic imbalance, and endocrine failure:

Phenytoin-induced hypersensitivity can cause both SJS and myocarditis, with possible adrenal suppression.
APS and lupus increase the risk of cardiac, vascular, and coagulopathic complications
VWF type 2 or 5 abnormalities can worsen bleeding in mucosal or inflammatory lesions
Adrenal insufficiency should be considered early in critically ill patients with persistent hypotension, particularly in immune-mediated syndromes.

Until now, we do not fully understand how certain medications provoke such severe multi-organ toxicity. Immune genetics, endothelial injury, hormonal axis disruption, and coagulation system anomalies all contribute.

Food and Drugs to avoid by APS and Lupus

For Antiphospholipid Syndrome (APS) and Lupus, foods to be cautious with include those high in Vitamin K (leafy greens if on warfarin), alfalfa, and potentially garlic, while avoiding excessive alcohol and ultra-processed foods. Medications to watch for include certain birth controls (estrogen-containing), hormone therapy (HRT), some antibiotics, and NSAIDs (like ibuprofen) when on blood thinners like warfarin, as they increase bleeding or clotting risks; always consult your doctor.

The most common trigger for https://pmc.ncbi.nlm.nih.gov/articles/PMC8886404/ is a reaction to certain medications, particularly anticonvulsants, antibiotics, and anti-inflammatory drugs. Other potential triggers include infections, like Mycoplasma pneumoniae, and even certain vaccinations.

Medications:

Anticonvulsants: Lamotrigine, carbamazepine, and phenytoin are frequently implicated.

Antibiotics: Sulfonamides, such as trimethoprim-sulfamethoxazole, are common culprits.

Anti-inflammatory drugs: NSAIDs, especially oxicams, have been linked to SJS.

Other medications: Allopurinol (used for gout), and nevirapine (used for HIV) can also trigger SJS.

It's important to acknowledge that monoclonal antibodies can cause serious reactions in some individuals. https://my.clevelandclinic.org/health/drugs/19712-rituximab-injection

Infections:

Viral infections like herpes, mumps, and flu have been associated with SJS, particularly in children.

Mycoplasma pneumoniae infection can also trigger the condition.

Other Contributing Factors

Vaccinations, malignancy, systemic inflammatory or autoimmune diseases, and exposure to external chemicals have all been associated with the development of Stevens–Johnson syndrome (SJS).

Genetic susceptibility also plays a role; certain human leukocyte antigen (HLA) types may increase individual risk.

APS-Related Brain Swelling (Thrombo-Inflammatory Edema)

Primary Mechanisms

Impaired venous outflow (e.g., cerebral venous thrombosis or diffuse microthrombi)
Endothelial activation and dysfunction driven by antiphospholipid antibodies
Disruption of the blood–brain barrier (BBB)
Development of secondary vasogenic ± cytotoxic edema
Resultant elevation of intracranial pressure (ICP) can lead to secondary encephalopathy due to impaired cerebral perfusion and edema.

Key Pathophysiology

This is not a true inflammatory vasculitis of the vessel wall
Pathology is driven by clot-related venous congestion combined with immune-mediated endothelial activation
Commonly occurs in antiphospholipid syndrome (APS), with or without associated lupus
Symptoms may worsen with pressure or altitude changes (e.g., air travel)

Neurologic and Visual Effects

Raised ICP and venous congestion can impair optic nerve perfusion
Transient or persistent vision interruption may occur, including:
- Blurred or dimmed vision
- Visual field defects
- Episodic visual blackouts or “graying out”
Visual symptoms may fluctuate with changes in intracranial pressure and cerebral venous flow

Reference:

Recovering From Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis
https://jamanetwork.com/journals/jamadermatology/fullarticle/2841453

Long-term morbidity and quality of life in survivors of Stevens-Johnson syndrome/toxic epidermal necrolysis spectrum
https://academic.oup.com/bjd/advance-article/doi/10.1093/bjd/ljaf380/8265391?login=false

Stevens-Johnson Syndrome After Immunization With Smallpox, Anthrax, and Tetanus Vaccines https://www.mayoclinicproceedings.org/article/S0025-6196(11)62605-0/fulltext

Stevens-Johnson Syndrome https://www.ncbi.nlm.nih.gov/books/NBK459323/

Recurrent Stevens–Johnson syndrome in a patient with systemic lupus erythematosus: a case report:
https://pmc.ncbi.nlm.nih.gov/articles/PMC7585900/

Phenytoin-induced Stevens–Johnson syndrome with myocarditis: a rare case report:
https://pmc.ncbi.nlm.nih.gov/articles/PMC5513850/

What drugs by mitochondria?
https://swaresearch.blogspot.com/2024/01/what-drugs-can-damage-mitochondria.html

Personal experience after mRNA vaccine incl. images:

Toxic Skin Condition Post-mRNA COVID-19 Vaccination:
https://swaresearch.blogspot.com/2024/06/stevens-johnson-syndrome-and-toxic.html