1. Therapeutic Framework

The cornerstone of managing Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) is the immediate cessation of the offending drug to halt the underlying antigenic stimulation. Subsequently, the decision to initiate immunomodulatory therapy requires a careful balance between the patient’s disease severity and their inherent risk of infection.

A. Offender Drug Cessation & Timeline

• Immediate Discontinuation: All non-essential medications, particularly those started within the last 8 weeks, should be identified and discontinued, ideally within 24 hours of SJS/TEN onset. Early cessation is directly linked to reduced keratinocyte apoptosis and improved survival.
• Causality Assessment: Document precise start and stop dates for all medications. Utilize validated causality assessment tools, such as the Algorithm of Drug Causality for Epidermal Necrolysis (ALDEN), when available to pinpoint the most likely culprit.
• Initiation Window: For patients with significant disease burden (>10% Body Surface Area involvement) or rapidly progressing lesions, immunotherapy is generally initiated within 48 hours of symptom onset to maximize its potential benefit.

B. Indications & Contraindications for Immunomodulation

• Indications:
  • Established SJS/TEN overlap (10–30% BSA) or TEN (>30% BSA).
  • Rapidly progressing skin detachment, regardless of initial BSA.
  • Early and severe mucosal involvement (e.g., eyes, oral cavity, genitals).
  • High-risk SCORTEN score (Severity-of-Illness Score for TEN) of ≥3.
• Absolute Contraindications:
  • Uncontrolled sepsis or other active, serious infection.
  • Profound hematologic compromise (e.g., Absolute Neutrophil Count <500/μL or Platelets <50×10⁹/L).
  • Known active tuberculosis or other opportunistic infections.
• Relative Contraindications: Severe uncompensated hepatic impairment, uncontrolled diabetes mellitus (requires aggressive management).

2. First-Line Immunotherapies

High-dose systemic corticosteroids are the most widely available and frequently used first-line agents. However, their use is debated, with mixed evidence regarding mortality benefit versus the significant risk of iatrogenic infection.

A. High-Dose Systemic Corticosteroids

• Mechanism: Broadly suppress the immune system by inhibiting NF-κB, which in turn downregulates the production of key inflammatory cytokines like TNF-α and IL-2, and promotes the apoptosis of activated T-cells.
• Common Regimens:
  • Methylprednisolone: 1 gram IV daily for 3 consecutive days.
  • Dexamethasone: 100 mg IV daily for 3 consecutive days.
• Tapering Strategy: Following the initial pulse, the dose is tapered gradually over 10–14 days. A typical approach is to reduce the total daily dose by approximately 25% every 3 days, while closely monitoring for rebound skin flares.
• Safety Monitoring: Requires frequent monitoring of blood glucose (every 6 hours), blood pressure (every 6 hours), mental status changes, and daily clinical assessment for signs of new infection.

3. Second-Line & Adjunctive Agents

When the response to corticosteroids is inadequate by day 3, or if they are contraindicated, other immunomodulatory agents should be considered. The choice among IVIG, cyclosporine, and TNF-α inhibitors depends on patient-specific factors, institutional protocols, and resource availability.

A. Intravenous Immunoglobulin (IVIG)

• Mechanism: Thought to work primarily by blocking the Fas-FasL interaction, a key pathway leading to keratinocyte apoptosis. It may also neutralize pathogenic antibodies and other inflammatory mediators.
• Dosing: Total dose of 2–4 g/kg administered over 3–4 consecutive days (e.g., 0.5–1 g/kg/day).
• Pitfalls & Mitigation:
  • Volume Overload: Infuse slowly (e.g., ≤0.4 g/kg over 6 hours) and monitor fluid status closely, especially in patients with cardiac or renal comorbidities.
  • Acute Kidney Injury (AKI): High-osmolarity sucrose-containing formulations are associated with higher risk. Use sucrose-free products and consider split-dosing in patients with pre-existing renal dysfunction (eGFR <30 mL/min).
  • Anaphylaxis: Although rare, can occur in IgA-deficient patients. Screen if deficiency is known or suspected.

B. Cyclosporine A

• Mechanism: A potent calcineurin inhibitor that blocks the transcription of IL-2, thereby preventing the activation and proliferation of cytotoxic T-cells.
• Dosing: 3–5 mg/kg/day, given as a continuous IV infusion or in divided oral doses, for 7–10 days, followed by a 1–2 week taper.
• Monitoring:
  • Trough Levels: If available, target 150–200 ng/mL to balance efficacy and toxicity.
  • Renal Function: Monitor serum creatinine daily. Reduce dose by 25-50% if creatinine increases by more than 30% from baseline.
  • Blood Pressure: Monitor every 12 hours and manage emergent hypertension with appropriate antihypertensives.

C. TNF-α Inhibitors & Plasmapheresis

• Etanercept: A single RCT showed that two doses of 25 mg SC (or 50 mg in adults >65kg) given one week apart was associated with lower observed mortality and faster re-epithelialization without a significant increase in infections.
• Infliximab: Case reports suggest a single 5 mg/kg IV dose can lead to rapid cessation of disease progression, but high-quality data are lacking.
• Plasmapheresis: Theoretically removes culprit drug metabolites, antibodies, and cytokines. However, there are no robust trials to support its use. It is typically reserved as a rescue therapy in refractory cases or within research protocols.

4. Pharmacokinetic/Pharmacodynamic (PK/PD) Considerations

The systemic inflammation and capillary leak syndrome inherent to SJS/TEN dramatically alter drug pharmacokinetics and pharmacodynamics. This necessitates individualized dosing strategies and vigilant monitoring to ensure efficacy and avoid toxicity.

A. Altered Drug Distribution in Critical Illness

• Increased Volume of Distribution (Vd): Capillary leak leads to a “third spacing” of fluid, increasing the Vd for hydrophilic drugs like methylprednisolone. Standard weight-based doses may result in sub-therapeutic concentrations; consider loading doses.
• Hypoalbuminemia: Decreased serum albumin increases the free (active) fraction of highly protein-bound drugs like cyclosporine, elevating the risk of toxicity even with “therapeutic” total drug levels.

B. Protein Binding & Hepatic Metabolism Changes

• CYP450 Downregulation: Pro-inflammatory cytokines (e.g., TNF-α, IL-6) can suppress the activity of cytochrome P450 enzymes. This can prolong the clearance and half-life of drugs metabolized by this system, including corticosteroids and cyclosporine.
• Monitoring Implications: Standard dosing intervals may lead to drug accumulation. Therapeutic drug monitoring (TDM) and clinical assessment are crucial to guide dose adjustments.

C. Dose Adjustment in Organ Dysfunction & RRT

• Cyclosporine: Requires dose reduction of 25–50% in patients with an eGFR <30 mL/min or those on renal replacement therapy (RRT). Adjustments should be guided by daily creatinine trends and trough levels.
• IVIG: In renal impairment, use slower infusion rates and consider splitting the total dose over more days to mitigate the risk of osmotic nephrosis and AKI.
• Etanercept: No formal dose adjustment is recommended for RRT, but its use should be avoided in the setting of an active, uncontrolled infection.

5. Administration Routes & Devices

The choice of administration route must balance the need for reliable drug delivery against the risks associated with vascular access in patients with compromised skin integrity.

A. Peripheral vs. Central Venous Infusion

• Central Line Preferred: A central venous catheter is strongly recommended for the administration of high-concentration or hyperosmolar agents (e.g., cyclosporine), vesicants, or for prolonged high-volume infusions (e.g., methylprednisolone pulses, IVIG).
• Peripheral IV Acceptable: A peripheral IV may be suitable for short-term administration of less caustic agents like dexamethasone or for single-dose biologics like infliximab, provided the access site is sound.

B. Infusion Compatibility & Safety

• IVIG: To reduce the risk of precipitation, most IVIG products should only be infused with Normal Saline (0.9% NaCl). Avoid co-administration with dextrose-containing solutions.
• Cyclosporine: Known for numerous Y-site incompatibilities. Always consult a compatibility chart and ensure lines are flushed thoroughly before and after administration.

C. Enteral Alternatives When Feasible

• Once the skin has stabilized and the gastrointestinal mucosa has healed, transition from IV to enteral formulations of corticosteroids (e.g., oral prednisone) and cyclosporine.
• Account for differences in bioavailability when converting. For example, oral cyclosporine has a variable bioavailability of approximately 30%, often requiring a higher dose compared to the IV formulation.

6. Monitoring Plan & Toxicity Management

A rigorous, systematic monitoring plan is essential to detect iatrogenic complications early, allowing for timely intervention and dose modification.

A. Laboratory Surveillance

• Baseline and Daily: Complete Blood Count (CBC) with differential, Comprehensive Metabolic Panel (CMP) including creatinine, LFTs, and electrolytes. Obtain cyclosporine trough levels if used.
• Hyperglycemia Watch: During corticosteroid pulses, monitor point-of-care blood glucose every 6 hours, with a target of 110–180 mg/dL.

B. Early Detection of Infections & Sequelae

• Conduct a daily physical examination focusing on new fevers, changes in white blood cell count, and signs of catheter-associated infections.
• Maintain a low threshold for obtaining cultures (blood, urine, wound) for any signs of infection. Use culture-directed antimicrobial therapy; prophylactic antibiotics are generally not recommended due to the risk of promoting resistant organisms.

C. Dose Modification Algorithms

• Cyclosporine Nephrotoxicity: Decrease the cyclosporine dose by 25% if serum creatinine rises by >30% from baseline.
• IVIG-Associated AKI: Hold the IVIG infusion if serum creatinine rises by >50% or if signs of acute volume overload develop.
• Infection During Therapy: If a serious infection emerges, consider an accelerated taper of corticosteroids (e.g., reduce dose by an additional 25%) to restore some immune function.

7. Pharmacoeconomic Analysis

The significant cost differences between immunomodulatory agents heavily influence institutional formulary decisions and the development of treatment protocols, especially in resource-limited settings.

A. Cost per Treatment Course

B. Resource Utilization & Formulary Impact

• Cyclosporine: Requires investment in therapeutic drug monitoring assays and increased pharmacist/physician time for dose adjustments.
• Etanercept: Requires robust cold-chain storage logistics and nursing time for subcutaneous administration.
• IVIG: Demands significant resources, including infusion pumps, extended nursing oversight for slow infusions, and pharmacy time for preparation.

8. Algorithmic Treatment Pathways

A structured, stepwise treatment algorithm based on disease severity ensures that therapies are escalated appropriately and integrated seamlessly with the intensive supportive care that these patients require.

A. Stepwise Escalation Based on Severity

B. Integration with Supportive Care Protocols

Immunomodulatory therapy does not exist in a vacuum. Its success is critically dependent on concurrent, aggressive supportive care. This requires seamless coordination with multiple teams, including burn unit or dermatology wound care specialists, fluid and electrolyte management teams, ophthalmology for ocular surface protection, nutrition support, and pain management services throughout the course of treatment.