The Immunology of Biologics: A Critical Care Perspective

 

The Immunology of Biologics: From Rheumatology to Gastroenterology: A Critical Care Perspective

Dr Neeraj Manikath , claude.ai

Abstract

Biologic agents have revolutionized the management of immune-mediated inflammatory diseases across rheumatology, dermatology, and gastroenterology. However, their targeted immunosuppressive mechanisms create unique infectious and non-infectious complications that intensivists must recognize and manage. This review provides a mechanistic understanding of five major biologic classes—TNF-α inhibitors, B-cell depleting agents, IL-17/IL-23 inhibitors, integrin receptor antagonists, and JAK-STAT inhibitors—with emphasis on adverse event profiles, monitoring strategies, and critical care considerations. We present evidence-based approaches to risk stratification, infection prophylaxis, and perioperative management relevant to the critical care postgraduate curriculum.

Keywords: Biologics, TNF inhibitors, immunosuppression, opportunistic infections, critical care, inflammatory bowel disease, rheumatoid arthritis

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Introduction

The landscape of immune-mediated inflammatory disease management has been transformed by targeted biologic therapies. While these agents provide remarkable disease control, their mechanism-specific immunosuppression creates vulnerabilities that become particularly relevant in critical illness. Approximately 2-3% of patients on biologics require ICU admission annually, often with infectious complications that carry mortality rates of 15-30%.^1,2

For the critical care physician, understanding biologic immunology is essential for three reasons: (1) recognizing atypical infection presentations in immunocompromised hosts, (2) making informed decisions about biologic continuation versus discontinuation during acute illness, and (3) managing biologic-specific toxicities including cytokine release syndrome, paradoxical inflammatory responses, and organ-specific complications.

This review synthesizes mechanistic immunology with practical critical care management, providing a framework for the intensivist encountering patients on these increasingly common medications.

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The TNF-Alpha Inhibitors (Infliximab, Adalimumab): Risks and Monitoring

Mechanism of Action and Immunologic Consequences

Tumor necrosis factor-alpha (TNF-α) is a pleiotropic cytokine central to host defense against intracellular pathogens, particularly mycobacteria and endemic fungi. TNF-α inhibitors include monoclonal antibodies (infliximab, adalimumab, golimumab, certolizumab pegol) and soluble receptors (etanercept), each with distinct pharmacokinetics and immunogenicity profiles.³

TNF-α performs critical immune functions:

• Granuloma formation and maintenance for containing mycobacteria
• Macrophage activation and intracellular pathogen killing
• T-cell priming and cellular immune responses
• Neutrophil recruitment and activation

Blockade of these pathways creates predictable infectious vulnerabilities, with relative risk varying by agent. Monoclonal antibodies (particularly infliximab) carry higher risk than etanercept, likely due to differences in complement fixation, reverse signaling, and ability to bind transmembrane TNF.⁴

Infectious Complications

Tuberculosis Reactivation

The most feared complication of TNF-α inhibition is tuberculosis reactivation, with incidence rates 1.6-25.1 times higher than general population depending on endemic prevalence.⁵ Unlike immunocompetent hosts, TB in TNF inhibitor patients presents atypically:

• Extrapulmonary TB in 20-25% (versus 10-15% in general population)
• Disseminated disease more common
• Absent or minimal granuloma formation on histology
• Delayed positivity of acid-fast stains due to lower bacillary burden

🔷 PEARL: The "TB paradox" describes clinical worsening after TNF inhibitor discontinuation as immune reconstitution allows inflammatory response to contained infection. This immune reconstitution inflammatory syndrome (IRIS) occurs in 5-10% of cases.⁶

Invasive Fungal Infections

Endemic mycoses (histoplasmosis, coccidioidomycosis, blastomycosis) show marked increased incidence:

• Histoplasmosis: RR 5.1 (95% CI 3.4-7.7) versus non-biologic immunosuppression⁷
• Often presents as disseminated disease with septic shock
• Diagnosis challenging: urine/serum antigen testing essential
• High mortality (25-40%) even with treatment

Pneumocystis jirovecii pneumonia, while less common than in transplant patients (incidence 0.3-1.2 per 1000 patient-years), carries particularly high mortality (30-50%) in this population.⁸

Bacterial Infections

Meta-analyses demonstrate 1.4-2.0 fold increased risk of serious bacterial infections, with highest risk in the first 6 months of therapy.⁹ Critical care relevant patterns include:

• Listeria monocytogenes meningitis/meningoencephalitis (50-fold increased risk)
• Legionella pneumophila pneumonia with rapid progression
• Skin and soft tissue infections (SSTI) with unusual organisms
• Atypical presentations with blunted fever and inflammatory markers

Monitoring and Risk Mitigation Strategies

Pre-Treatment Screening Protocol

A systematic pre-treatment evaluation reduces infectious complications by approximately 60%:¹⁰

1. Tuberculosis screening:

   • Interferon-gamma release assay (IGRA) preferred over tuberculin skin test (TST)
   • Chest radiograph (consider CT if high-risk)
   • If positive: complete 3-4 months isoniazid plus pyridoxine before biologics
   • 🔷 HACK: In endemic areas, some experts recommend 9 months INH even with negative screening if prior untreated exposure suspected

2. Viral hepatitis screening:

   • HBsAg, anti-HBc, anti-HBs for hepatitis B
   • Anti-HCV for hepatitis C
   • HBV reactivation occurs in 20-50% of HBsAg+ patients without prophylaxis¹¹
   • Prophylactic entecavir/tenofovir for HBsAg+ or isolated anti-HBc+ patients

3. Endemic fungal evaluation:

   • Fungal serologies if residing in/traveled to endemic areas
   • Consider baseline antigen testing (histoplasma, coccidioides)

4. Standard immunizations:

   • Update all vaccines BEFORE biologics (live vaccines contraindicated during therapy)
   • Pneumococcal (PCV20 or PCV15 + PPSV23), influenza, COVID-19
   • Consider hepatitis B vaccination if non-immune

Ongoing Monitoring

• Clinical vigilance for subtle infection signs (fever threshold often lower)
• Annual TB screening in high-risk populations (debated; not universally recommended)
• Complete blood count every 3-6 months
• Liver function tests every 3-6 months (particularly with methotrexate co-therapy)

Critical Care Management Considerations

When to Continue or Discontinue TNF Inhibitors

⚠️ OYSTER: The decision to continue versus discontinue TNF inhibitors during critical illness lacks high-quality evidence. General principles:

Hold biologics for:

• Active serious infection (especially TB, invasive fungal, Legionella)
• Septic shock or severe sepsis
• Major surgery (hold 1-2 half-lives pre-op; resume when healing established)
• New neurologic symptoms concerning for demyelination

Consider continuing for:

• Stable chronic infections controlled on antimicrobials
• Perioperative period for minor procedures
• Controlled HIV with CD4 >200 cells/μL

Drug Half-lives and Washout:

• Infliximab: 7-12 days (hold 4-6 weeks pre-elective surgery)
• Adalimumab: 10-20 days (hold 4-6 weeks pre-elective surgery)
• Etanercept: 3-5 days (hold 2 weeks pre-elective surgery)
• Certolizumab pegol: 14 days (lacks Fc region; theoretical less placental transfer)

Non-Infectious Complications

Infusion Reactions

• Acute infusion reactions (during or within 2 hours): 3-20% incidence with infliximab
  • Mild: pruritus, flushing, headache (slow infusion rate)
  • Severe: bronchospasm, hypotension, angioedema (stop infusion, treat anaphylaxis protocol)
• Delayed hypersensitivity (3-14 days post-infusion): serum sickness-like reaction
  • Associated with anti-drug antibodies (ADAs)
  • More common with intermittent dosing and absence of concomitant immunomodulator

🔷 PEARL: Premedication with acetaminophen ± antihistamines ± corticosteroids reduces infusion reactions by 50%, though routine use is debated.¹²

Immunogenicity

Development of anti-drug antibodies (ADAs) occurs in:

• Infliximab: 10-60% (lower with concomitant methotrexate/azathioprine)
• Adalimumab: 10-30%
• Associated with loss of response and increased infusion reactions
• Therapeutic drug monitoring (TDM) guides management: low drug levels + high ADAs = switch to different TNF inhibitor or drug class

Congestive Heart Failure

TNF-α inhibitors paradoxically worsen heart failure (NYHA Class III-IV):

• Contraindicated in moderate-severe heart failure
• Proposed mechanisms: negative inotropic effects, cardiomyocyte apoptosis
• Classic studies (RENAISSANCE, RECOVER) showed increased mortality¹³

Demyelinating Disorders

Rare but serious: optic neuritis, multiple sclerosis-like syndromes

• Incidence: 0.05-0.2 per 1000 patient-years
• Mechanism unclear (paradoxical immune activation?)
• Screen for personal/family history of demyelination before starting

Malignancy

• Lymphoma: Meta-analyses show modest increased risk (OR 1.5-2.0)¹⁴
  • Confounded by underlying disease activity
  • Hepatosplenic T-cell lymphoma rare but often fatal (typically in young males on combination thiopurine + TNF inhibitor)
• Non-melanoma skin cancer: Clearly increased (counsel sun protection)
• Melanoma: Possible increased risk (conflicting data)

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B-Cell Depletion (Rituximab): Managing Hypogammaglobulinemia and Infections

Mechanism and Immunologic Consequences

Rituximab is a chimeric monoclonal antibody targeting CD20, a surface antigen expressed on pre-B and mature B lymphocytes (but not plasma cells or hematopoietic stem cells). It induces B-cell depletion through:

1. Antibody-dependent cellular cytotoxicity (ADCC)
2. Complement-dependent cytotoxicity (CDC)
3. Direct apoptosis induction

B-cell depletion persists 6-12 months post-infusion, with full reconstitution taking 12-18+ months.¹⁵ The immunologic consequences are multifaceted:

• Impaired humoral immunity: Reduced antibody responses to new antigens
• Pre-existing antibodies preserved: Long-lived plasma cells (CD20-negative) continue immunoglobulin production initially
• T-cell function intact: Preserved cellular immunity (important for intracellular pathogens)
• Progressive hypogammaglobulinemia: In 5-15% with repeated dosing due to eventual plasma cell depletion

Infectious Complications

The infection risk profile differs markedly from TNF inhibitors:

Viral Infections Predominate

• Hepatitis B reactivation: 24% risk in HBsAg+ patients, 2-5% in isolated anti-HBc+¹⁶

  • Can occur months to years after rituximab
  • Fulminant hepatitis in 5-10% of reactivations
  • Prophylactic entecavir/tenofovir mandatory

• Progressive multifocal leukoencephalopathy (PML): Devastating JC virus reactivation

  • Incidence: 1 in 25,000 patients (higher in oncology than rheumatology populations)
  • Mortality 30-50%; survivors usually severely disabled
  • Subacute neurologic deterioration: cognitive changes, focal weakness, visual deficits
  • MRI: multifocal T2/FLAIR hyperintensities without enhancement
  • CSF JC virus PCR confirmatory (sensitivity 70-90%)

🔷 PEARL: Consider PML in ANY patient on rituximab with new neurologic symptoms. MRI patterns can be subtle early. No proven treatment exists; immune reconstitution is key but may worsen symptoms (IRIS).

• Cytomegalovirus (CMV): Reactivation or primary infection, particularly with concomitant corticosteroids

  • Pneumonitis, colitis, retinitis possible
  • CMV viremia monitoring not routinely recommended but consider in high-risk patients

• Respiratory viral infections: More severe and prolonged courses of influenza, RSV, COVID-19¹⁷

Late-Onset Neutropenia

• Occurs in 5-27% of patients, typically 4-6 months post-rituximab
• Mechanism uncertain (likely immune-mediated bone marrow suppression)
• Duration: median 1-2 months
• Increases bacterial infection risk (particularly pneumonia, UTI)
• Management: monitor CBCs monthly for 6 months; G-CSF if ANC <500/μL or febrile

Hypogammaglobulinemia Management

Pathophysiology

Progressive hypogammaglobulinemia develops through:

• Depletion of memory B cells (limit new antibody formation)
• Impaired B-cell differentiation to plasma cells
• Eventually, reduced long-lived plasma cell pool with repeated dosing

Incidence and Risk Factors

• Clinically significant hypogammaglobulinemia (IgG <400 mg/dL): 5-15%¹⁸
• Risk factors:
  • Number of rituximab courses (>3 cycles)
  • Low baseline immunoglobulins
  • Concomitant immunosuppression
  • Underlying disease (higher in vasculitis than rheumatoid arthritis)

Monitoring Strategy

1. Baseline immunoglobulins (IgG, IgA, IgM) before rituximab initiation
2. Every 3-6 months during ongoing therapy
3. Consider vaccine response testing if recurrent infections despite normal IgG

⚠️ OYSTER: The correlation between IgG level and infection risk is imperfect. Some patients with IgG 300-400 mg/dL remain infection-free, while others with IgG 500-600 mg/dL have recurrent sinopulmonary infections. Functional antibody assessment (pneumococcal titers) better predicts risk but is not widely available.

Indications for IVIG Replacement

Evidence-based indications remain debated. Consider IVIG if:

• IgG <400 mg/dL with recurrent bacterial infections (≥2 per year requiring antibiotics)
• IgG <300 mg/dL regardless of infection history
• Poor antibody response to pneumococcal vaccination
• Recurrent severe infections despite IgG >400 mg/dL

IVIG Dosing:

• Typical: 400-600 mg/kg every 3-4 weeks
• Target IgG trough: >500-600 mg/dL
• Consider subcutaneous immunoglobulin (SCIG) for convenience

🔷 HACK: For patients with recurrent sinopulmonary infections but IgG >400 mg/dL, a trial of prophylactic antibiotics (e.g., azithromycin 250 mg three times weekly or TMP-SMX DS three times weekly) before committing to lifelong IVIG is reasonable and far less expensive.

Critical Care Considerations

Sepsis Management

• Standard sepsis protocols apply
• Lower threshold for broad-spectrum antibiotics
• Consider atypical organisms (especially encapsulated bacteria despite pneumococcal vaccination)
• CMV testing if multiorgan dysfunction and high-dose corticosteroid exposure

Rituximab Discontinuation

• Hold for serious infection until resolution
• B-cell depletion persists 6-12 months regardless of stopping drug
• Immune recovery gradual: peripheral B-cell return precedes functional antibody responses by months

Vaccination Considerations

• Vaccine responses severely impaired during B-cell depletion (efficacy <50%)
• Vaccinate BEFORE rituximab if possible (at least 4 weeks prior)
• If urgent vaccination needed during therapy:
  • Live vaccines absolutely contraindicated
  • Inactivated vaccines may provide partial benefit
  • Consider checking titers post-vaccination
  • Booster doses after B-cell reconstitution may be needed

COVID-19 Specific Issues

Recent data show rituximab patients have:

• Impaired antibody responses to COVID-19 vaccines (50-70% reduced seroconversion)¹⁹
• Higher risk of severe COVID-19 and death
• Prolonged viral shedding (median 30-60 days versus 7-10 days)
• Consider monoclonal antibodies or antivirals early in infection
• Some experts delay rituximab dosing by 2-4 weeks after COVID-19 vaccination to allow antibody development

Non-Infectious Adverse Events

Progressive Multifocal Leukoencephalopathy (covered above)

Infusion Reactions

• Very common (30-50% with first infusion)
• Usually mild-moderate: fever, chills, nausea, headache
• Severe reactions (bronchospasm, hypotension): 1-10% first infusion
• Cytokine release syndrome mechanism
• Prevention: Mandatory premedication with acetaminophen, antihistamine, and corticosteroid
• Management: Slow or stop infusion; supportive care; resume at slower rate if mild

Tumor Lysis Syndrome

• Rare in rheumatology; more common in high tumor burden hematologic malignancy
• Monitor electrolytes, renal function, LDH in first 24-48 hours
• Prophylaxis: hydration, allopurinol in high-risk patients

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IL-17/IL-23 Inhibitors (For Psoriasis/PsA): The Candida and TB Risk

Mechanism and Immunologic Role

The IL-17/IL-23 axis is critical for mucocutaneous immunity, particularly against extracellular bacteria and fungi. Understanding this pathway illuminates the adverse event profile:

IL-23 Pathway:

• IL-23 (composed of p19 and p40 subunits) promotes differentiation and survival of Th17 cells
• Inhibitors: ustekinumab (anti-IL-12/23p40), guselkumab, risankizumab, tildrakizumab (anti-IL-23p19)

IL-17 Pathway:

• IL-17A and IL-17F produced by Th17 cells mediate downstream effects
• Functions: neutrophil recruitment, antimicrobial peptide production, epithelial barrier defense
• Inhibitors: secukinumab, ixekizumab (anti-IL-17A); bimekizumab (anti-IL-17A and IL-17F); brodalumab (anti-IL-17 receptor A)

Critical Immune Functions:

• Candida defense: IL-17 essential for mucocutaneous antifungal immunity
• Mycobacterial defense: IL-23 and IL-17 contribute to granuloma formation (though less than TNF-α)
• Barrier immunity: Maintenance of mucosal and skin integrity

Infectious Complications

Mucocutaneous Candidiasis

The signature infectious complication of IL-17 inhibitors is Candida infections:

• Incidence: 5-15% with IL-17A inhibitors (significantly higher than TNF inhibitors)²⁰
• IL-23 inhibitors: lower risk (<5%)
• Manifestations:
  • Oral thrush (most common)
  • Esophageal candidiasis (2-4%)
  • Vulvovaginal candidiasis (increased frequency and severity)
  • Cutaneous candidiasis (intertriginous areas)

⚠️ OYSTER: Unlike in HIV/AIDS, invasive candidiasis (candidemia, disseminated disease) is NOT increased with IL-17/IL-23 inhibitors. The risk is confined to mucocutaneous disease. This reflects intact neutrophil function and preserved deeper immune defenses.

Management Approach:

• Topical therapy sufficient for most cases (nystatin, clotrimazole)
• Oral fluconazole 150-200 mg for oral/esophageal/vaginal candidiasis
• Consider chronic suppressive fluconazole (100-200 mg weekly) if recurrent (>3 episodes/year)
• 🔷 HACK: Probiotic use may reduce recurrent Candida infections in some patients, though evidence is limited.

Tuberculosis Risk

• Lower than TNF inhibitors but still elevated
• Meta-analytic RR approximately 2-3× general population²¹
• Extrapulmonary TB less common than with TNF inhibitors
• Screening recommendations same as TNF inhibitors (IGRA, chest X-ray)
• Latent TB treatment before biologic initiation

Other Infections

• Upper respiratory infections: slightly increased (10-15% versus 10% placebo)
• No significant increase in serious bacterial infections overall
• Herpes zoster: modest increase (1-2%) - consider zoster vaccination

Critical Care Scenarios

IL-17/IL-23 inhibitor patients rarely present to ICU with biologic-specific complications, but considerations include:

Severe Candida Esophagitis

• Can present with odynophagia, weight loss, dehydration
• Rarely causes significant GI bleeding or perforation
• Diagnosis: endoscopy with biopsy/culture
• Treatment: fluconazole 200-400 mg daily for 14-21 days (transition to oral when tolerating)

Neutropenia

• Rare (<1%) but reported with IL-17 inhibitors
• Mechanism unclear (possibly immune-mediated)
• Monitor CBC at baseline and periodically

Paradoxical Inflammatory Reactions

• Rare reports of new-onset inflammatory bowel disease with IL-17 inhibitors
  • Particularly ixekizumab and secukinumab
  • Mechanism: IL-17 pathway has protective role in intestinal homeostasis
  • Consider in psoriasis patient developing new abdominal pain and diarrhea
  • Endoscopy may show Crohn's-like inflammation
  • Management: discontinue IL-17 inhibitor; standard IBD therapy

🔷 PEARL: Conversely, IL-23 inhibitors (risankizumab, guselkumab) show promise in Crohn's disease treatment, highlighting differential pathway roles in intestinal immunity.

Monitoring and Prevention Strategies

Pre-Treatment Screening

1. TB screening (IGRA, chest X-ray)
2. Hepatitis B and C screening
3. Consider HIV screening in high-risk populations
4. Fungal serologies if endemic area exposure

Ongoing Monitoring

• Less intensive than TNF inhibitors given lower infectious risk
• CBC at baseline, 3 months, then as clinically indicated
• Clinical surveillance for mucocutaneous candidiasis
• Patient education: report oral lesions, dysphagia, recurrent vaginal infections

Vaccination

• Same general principles as TNF inhibitors
• Live vaccines contraindicated during therapy
• Inactivated vaccines: standard recommendations
• Herpes zoster vaccine: Recombinant zoster vaccine (Shingrix) safe and recommended
  • Administer before starting biologic if possible
  • If already on biologic, vaccinate anyway (benefits likely outweigh risks)

Surgery and Critical Illness

Perioperative Management

• Lower surgical site infection risk versus TNF inhibitors
• General approach: hold 1-2 half-lives before major surgery
  • Secukinumab (half-life 27 days): hold 4-6 weeks
  • Ixekizumab (half-life 13 days): hold 3-4 weeks
  • Ustekinumab (half-life 21 days): hold 4-6 weeks
  • Guselkumab, risankizumab (half-life ~3 weeks): hold 4-6 weeks
• Resume when wound healing established and no infection

Critical Illness Considerations

• Continue if stable chronic disease and no active infection
• Hold if sepsis, major surgery, or opportunistic infection
• Reinitiate when clinically stable

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Integrin Receptor Antagonists (Vedolizumab): Gut-Selective Immunosuppression

Mechanism: The Concept of Organ-Specific Immunosuppression

Vedolizumab represents a paradigm shift toward organ-selective immunosuppression. It is a humanized monoclonal antibody targeting α4β7 integrin, which mediates lymphocyte homing to the gastrointestinal tract.

The Gut Homing Pathway:

1. α4β7 integrin on lymphocytes binds mucosal addressin cell adhesion molecule-1 (MAdCAM-1) expressed on gut endothelium
2. This interaction enables T-cell and B-cell trafficking to intestinal mucosa and gut-associated lymphoid tissue (GALT)
3. Vedolizumab blocks this specific interaction, preventing lymphocyte entry into GI tract

Key Contrast:

• Natalizumab (used in multiple sclerosis): blocks α4β1 (VLA-4) integrin, preventing CNS lymphocyte trafficking but NOT gut-selective
• Vedolizumab: gut-selective due to α4β7 specificity

Theoretical Advantages:

• Preserved systemic immunity
• Reduced infectious complications versus systemic immunosuppressants
• No expected neurologic toxicity (unlike natalizumab)

Safety Profile: Reality Versus Expectation

Infectious Complications

Large trials and post-marketing data demonstrate vedolizumab's favorable safety profile:^22,23

• Serious infections: 4.2 per 100 patient-years (similar to placebo 3.9)
• Opportunistic infections: Rare (<1%)
  • Case reports of TB, CMV colitis, cryptococcal meningitis exist but uncommon
• Enteric infections: Theoretically increased risk, but not clearly demonstrated
  • Clostridium difficile: no increased rate versus other IBD therapies
  • Salmonella, Campylobacter: case reports but rare

The PML Question: Lessons from Natalizumab

Natalizumab (α4β1 integrin inhibitor) carries significant PML risk (1 in 1,000 with prior immunosuppression and anti-JCV antibody positivity), prompting concern about vedolizumab.

• Vedolizumab PML cases: <10 cases reported worldwide in >300,000 patient-exposures
• Risk factors in reported cases: All had confounding factors (prior immunosuppressants, HIV, corticosteroids)
• Mechanistic rationale for lower risk: α4β7 selectivity spares CNS trafficking

🔷 PEARL: While vedolizumab's PML risk appears minimal, maintain vigilance in patients with prior natalizumab exposure, concomitant immunosuppression, or unexplained neurologic symptoms. Screening for anti-JCV antibodies is NOT routinely recommended before vedolizumab (unlike natalizumab).

GI-Specific Considerations

• CMV reactivation colitis: Important differential in IBD patient with worsening symptoms on vedolizumab
  • Vedolizumab itself doesn't increase CMV risk substantially
  • Underlying disease activity + corticosteroids are main risk factors
  • Consider CMV testing (tissue immunohistochemistry, PCR) if refractory colitis
  • Treatment: ganciclovir/valganciclovir; discontinuation of vedolizumab debated

⚠️ OYSTER: Distinguishing vedolizumab failure from CMV reactivation colitis is challenging. Both present with worsening diarrhea, bleeding, and endoscopic ulceration. Biopsy with CMV immunostaining essential. Overdiagnosis of CMV based on low-level PCR positivity leads to inappropriate antiviral therapy and delayed treatment escalation.

Critical Care Scenarios

ICU Admission Triggers in Vedolizumab-Treated IBD Patients

1. Severe colitis flare with toxic megacolon

   • Vedolizumab has slower onset than infliximab (4-6 weeks versus 2-4 weeks)
   • Acute severe UC may require rescue therapy (infliximab or cyclosporine)
   • Consider holding vedolizumab during acute severe episode; resume after stabilization

2. Perforated viscus or intra-abdominal abscess

   • Hold vedolizumab during active infection
   • Source control paramount
   • Resume after infection cleared and no planned surgeries

3. Sepsis from enteric source

   • Standard sepsis management
   • Vedolizumab unlikely culprit but hold during acute illness
   • Consider enteric organisms (including resistant strains) in empiric coverage

4. Postoperative complications

   • Emerging data suggest vedolizumab may be continued closer to surgery than TNF inhibitors
   • Wound healing complications NOT significantly increased
   • Anastomotic leak risk: no clear increased risk in retrospective studies

Drug Interactions and Critical Illness Considerations

• No significant drug interactions with antibiotics or antivirals
• Preserved systemic immunity beneficial in critical illness
• Long half-life (25 days): takes 4-5 months for complete washout
• Holding drug during 1-2 week ICU stay unlikely to impact disease control

Monitoring and Prevention

Pre-Treatment Screening

Minimal screening required relative to other biologics:

1. TB screening: Recommended but lower risk than TNF inhibitors
2. Hepatitis B/C screening: Standard practice
3. Varicella immunity: If not immune, vaccinate before starting
4. No routine JCV antibody testing (unlike natalizumab)

Ongoing Monitoring

• Primarily clinical (symptom assessment, disease activity scores)
• CBC, CMP at baseline and periodically
• No specific infectious monitoring required
• Infusion reactions: Very rare (<1%), milder than infliximab

Immunogenicity

• Anti-drug antibodies develop in 3-5%
• Usually clinically silent (unlike infliximab)
• Therapeutic drug monitoring available but utility debated
• Low immunogenicity contributes to excellent long-term durability

Special Populations

Pregnancy

• Limited data but appears safe
• IgG1 antibody: crosses placenta in third trimester
• Recommendations vary; many experts continue through pregnancy given favorable safety profile

Elderly

• Particularly attractive option in elderly due to preserved systemic immunity
• No dose adjustment needed
• Lower infection risk critical in comorbid population

Postoperative Period

• Can resume 2-4 weeks postoperatively once wound healing progressing
• May have advantage over TNF inhibitors for earlier resumption

🔷 HACK: For IBD patients requiring urgent surgery, recent vedolizumab exposure (within 8 weeks) should NOT delay necessary surgical intervention. Retrospective data suggest no increased surgical complications compared to other biologics or no biologic exposure.

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JAK-STAT Inhibitors (Tofacitinib): The VTE and Cardiovascular Risk Profile

Mechanism: Intracellular Signal Transduction

JAK-STAT inhibitors represent a mechanistically distinct class, targeting intracellular signaling rather than extracellular cytokines. This creates unique pharmacology and toxicity profiles.

The JAK-STAT Pathway:

Four Janus kinases (JAK1, JAK2, JAK3, TYK2) are intracellular tyrosine kinases that transduce signals from cytokine receptors to the nucleus via STAT (Signal Transducer and Activator of Transcription) proteins. Different cytokines utilize specific JAK combinations:

• JAK1/JAK3: IL-2, IL-4, IL-7, IL-9, IL-15, IL-21 (T-cell and NK-cell function)
• JAK1/JAK2: IFN-γ, IL-6, IL-10, IL-27 (inflammatory cytokines)
• JAK2/JAK2: EPO, TPO, growth hormone (hematopoiesis)
• JAK1/TYK2: Type I interferons, IL-10, IL-12, IL-23

Available JAK Inhibitors:

• Tofacitinib: Pan-JAK inhibitor (JAK1=JAK3>JAK2) - FDA approved for RA, PsA, UC
• Baricitinib: JAK1/JAK2 selective - approved for RA, alopecia areata
• Upadacitinib: JAK1 selective - approved for RA, PsA, AS, atopic dermatitis, UC, Crohn's
• Filgotinib: JAK1 selective - approved in some countries for RA, UC

Immunologic Consequences:

Broad immunosuppression due to multiple cytokine pathway inhibition:

• Impaired T-cell activation and proliferation
• Reduced B-cell function
• Decreased NK-cell activity
• Altered neutrophil and macrophage function
• Disrupted interferon responses (antiviral immunity)

Unlike biologics, JAK inhibitors:

• Small molecules: Oral administration, rapid onset (days to weeks)
• Short half-lives: 3-12 hours (reversible within days)
• Broad spectrum: Multiple cytokine pathways affected simultaneously
• Intracellular target: Cannot be neutralized by anti-drug antibodies

The ORAL Surveillance Study: A Paradigm-Shifting Safety Signal

In February 2021, the FDA issued a black box warning for tofacitinib based on the ORAL Surveillance trial results, fundamentally changing the risk-benefit discussion for JAK inhibitors.²⁴

Study Design:

• Post-marketing safety study (FDA-mandated)
• 4,362 RA patients ≥50 years with ≥1 cardiovascular risk factor
• Compared tofacitinib 5 mg BID and 10 mg BID versus TNF inhibitors (adalimumab, etanercept)
• Median follow-up: 4 years

Key Findings:

1. Major Adverse Cardiovascular Events (MACE):

   • Tofacitinib: HR 1.33 (95% CI 0.91-1.94) versus TNF inhibitors
   • Absolute risk: 3.4% vs 2.5% (not statistically significant for combined doses)
   • 10 mg BID dose showed higher risk (leading to its removal from market for RA)

2. Venous Thromboembolism (VTE):

   • Tofacitinib: HR 3.19 (95% CI 1.48-6.86) versus TNF inhibitors (P=0.003)
   • Absolute risk: 0.91% vs 0.28% per patient-year
   • Both pulmonary embolism and DVT increased
   • Risk highest in first 6 months but persisted throughout treatment

3. Malignancy:

   • Non-melanoma skin cancer: increased
   • Lung cancer: numerically higher (especially in current/former smokers)
   • Lymphoma: small number of events, unclear risk

4. All-cause mortality:

   • Numerically higher with tofacitinib (2.4% vs 1.7%), not statistically significant

Critical Implications:

⚠️ OYSTER: The ORAL Surveillance findings remain controversial. Critics note:

• Study population enriched for CV risk (age ≥50, ≥1 CV risk factor)
• TNF inhibitor comparator arm may have had protective cardiovascular effects (unproven)
• Applicability to lower-risk, younger patients unclear
• Other JAK inhibitors may have different risk profiles based on selectivity
• The 10 mg BID dose is not typically used in clinical practice for most indications

Nonetheless, the FDA extended warnings to all JAK inhibitors as a class effect until proven otherwise.

Venous Thromboembolism: Mechanism and Management

Proposed Mechanisms:

The biological basis for increased VTE risk remains incompletely understood. Hypotheses include:

1. Platelet activation: JAK2 inhibition may paradoxically enhance platelet activation via altered signaling
2. Endothelial dysfunction: Disrupted endothelial barrier integrity
3. Altered coagulation factors: Changes in fibrinogen, plasminogen activator inhibitor-1
4. Lipid effects: Increased LDL and HDL (effects on atherogenesis unclear)

🔷 PEARL: VTE risk appears highest in the first 3-6 months of therapy, suggesting an acute prothrombotic effect rather than chronic atherosclerotic process.

Risk Stratification:

Identified VTE risk factors in JAK inhibitor patients:

• Age >65 years (HR 2.3)
• Prior VTE history (HR 5-6)
• Active malignancy
• Recent surgery or prolonged immobilization
• Obesity (BMI >30)
• Smoking (current)
• Oral contraceptive use
• Thrombophilia (Factor V Leiden, prothrombin mutation, etc.)
• Heart failure or severe respiratory disease

Clinical Approach to VTE Risk Mitigation:

Pre-Treatment Assessment:

1. Complete VTE risk factor assessment
2. Consider thrombophilia screening if personal/family history of VTE
3. Counsel about VTE symptoms
4. Document baseline mobility status

Risk-Benefit Decision Making:

Avoid JAK inhibitors if:

• Personal history of unprovoked VTE (absolute contraindication in some experts' opinion)
• Active cancer with high VTE risk (pancreas, lung, gastric, brain)
• Severe heart failure (NYHA III-IV)
• Recent surgery (<4 weeks) or planned major surgery

Use with caution (consider alternative if available):

• Age >65 with multiple CV risk factors
• Prior provoked VTE (remote)
• Obesity + additional risk factors
• Active smoking + age >50

Lower-risk patients (may proceed):

• Age <50, no VTE history
• Single modifiable risk factor (obesity, smoking)
• Well-controlled inflammatory disease requiring JAK inhibitor

🔷 HACK: For patients requiring JAK inhibitors with borderline VTE risk, consider:

• Use lowest effective dose
• Aggressive modification of risk factors (smoking cessation, weight loss)
• Maintain mobility and hydration
• Consider prophylactic anticoagulation during high-risk periods (surgery, hospitalization)
• Some experts use aspirin prophylaxis (81-100 mg daily) though evidence is lacking

Monitoring:

• No routine laboratory VTE monitoring exists (D-dimer unreliable in inflammatory disease)
• Clinical surveillance: Educate patients about VTE symptoms (leg pain/swelling, dyspnea, chest pain)
• Immediate evaluation of any suggestive symptoms (ultrasound, CT angiography)
• CBC monitoring: Every 1-3 months (cytopenias can occur)
• Lipid panel: Baseline and 3 months (typically see 10-20% increases in LDL and HDL)

Cardiovascular Risk Management

Cardiovascular Events in JAK Inhibitor Patients:

ORAL Surveillance MACE findings (MI, stroke, cardiovascular death) were not statistically significant overall but raised concerns, particularly in high-risk populations.

Risk Factor Modification:

Mandatory interventions:

1. Smoking cessation: Critical given increased malignancy and CV risk
2. Blood pressure control: Target <130/80 mmHg per AHA/ACC guidelines
3. Lipid management:
   • Check baseline and 3-month lipids
   • Statin therapy per ASCVD risk calculator
   • JAK inhibitors increase both LDL and HDL (~10-20% each)
   • Clinical significance unclear; treat based on standard CV risk algorithms
4. Diabetes management: Optimize glucose control (A1c <7%)
5. Weight management: Target BMI <30 if possible

High-Risk Population Management:

For patients with:

• Prior MI or stroke
• Known coronary artery disease
• Peripheral arterial disease
• Diabetes with end-organ damage
• CKD stage 3b or greater

Consider:

• Alternative to JAK inhibitor if reasonable
• Cardiology co-management
• Aggressive risk factor modification
• Low-dose aspirin (81-100 mg) - though not specifically studied for JAK inhibitor patients
• More frequent monitoring

⚠️ OYSTER: The cardiovascular risk debate remains active. Some observational studies suggest JAK inhibitors may have neutral or even favorable CV effects compared to traditional DMARDs. The disconnect between trial data and real-world observations may reflect patient selection, concomitant medications, or disease activity control. Until more data emerge, prudent practice involves individualized risk assessment.

Infectious Complications

Herpes Zoster Reactivation

The most consistent infectious signal with JAK inhibitors is herpes zoster (shingles):

• Incidence: 3-5% annually (compared to <1% in general population, 1-2% with TNF inhibitors)²⁵
• Mechanism: JAK1/JAK3 inhibition impairs type I interferon responses and NK-cell function critical for VZV control
• Risk factors: Age >50, Asian ethnicity, higher JAK inhibitor doses, concomitant prednisone >7.5 mg/daily
• Presentations:
  • Typical dermatomal zoster (most common)
  • Disseminated cutaneous (2-5% of cases)
  • Visceral involvement (rare but reported: hepatitis, pneumonitis, encephalitis)
  • Post-herpetic neuralgia risk similar to general population

Prevention Strategy:

• Recombinant zoster vaccine (Shingrix): Recommended for all patients ≥50 years (or ≥18 years if immunocompromised)
  • Administer BEFORE starting JAK inhibitor ideally (2-dose series)
  • If already on JAK inhibitor: vaccinate anyway (efficacy reduced but still beneficial)
  • Consider holding JAK inhibitor for 1-2 weeks after vaccination (not evidence-based but some expert practice)
• Antiviral prophylaxis: Not routinely recommended but consider in very high-risk patients (elderly, multiple risk factors, prior zoster)
  • Valacyclovir 500 mg daily or acyclovir 400 mg BID reduces risk ~50-60%
  • Cost and pill burden limit routine use

Management of Active Zoster:

• Hold JAK inhibitor temporarily (resume after lesions crusted)
• Standard antiviral therapy: valacyclovir 1000 mg TID or acyclovir 800 mg 5× daily for 7-10 days
• Extend duration if immunocompromised or disseminated disease
• Monitor for visceral involvement if severe

Serious Bacterial Infections

• Incidence: 2-4 per 100 patient-years (similar to TNF inhibitors)
• Pneumonia, skin/soft tissue infections, urinary tract infections most common
• No specific pattern of atypical pathogens (unlike TNF inhibitors)

Tuberculosis

• Lower risk than TNF inhibitors but still elevated (RR ~2-4× general population)
• TB screening recommended before initiation (IGRA, chest X-ray)
• Latent TB treatment per standard protocols

Opportunistic Infections

• Rare but reported: cryptococcal infections, atypical mycobacteria, Pneumocystis jirovecii
• Risk lower than TNF inhibitors or rituximab
• PJP prophylaxis NOT routinely recommended (reserve for concomitant high-dose corticosteroids plus additional risk factors)

Viral Infections

• Impaired interferon responses raise theoretical concern for severe viral infections
• COVID-19: conflicting data; some studies suggest worse outcomes, others neutral
• Influenza: ensure annual vaccination
• Hepatitis B reactivation: screen before initiation; prophylaxis per standard protocols

Critical Care Management

ICU Admission Scenarios

1. Pulmonary Embolism:

   • Standard anticoagulation protocols
   • Hold JAK inhibitor during acute VTE (at least until therapeutic anticoagulation established)
   • Duration of anticoagulation: Treat as provoked VTE (3-6 months) versus indefinite anticoagulation is debated
     • If first VTE: 3-6 months anticoagulation, reassess JAK inhibitor risk-benefit
     • If recurrent VTE on JAK inhibitor: indefinite anticoagulation or discontinue JAK inhibitor
   • Resumption of JAK inhibitor: Controversial; many experts avoid resumption after JAK inhibitor-associated VTE

2. Acute Coronary Syndrome:

   • Standard ACS management
   • Hold JAK inhibitor during acute event
   • Risk factor modification before considering resumption
   • Consider alternative DMARD if possible

3. Severe Infection/Sepsis:

   • Hold JAK inhibitor during active serious infection
   • Short half-life (3-12 hours) allows rapid drug clearance
   • Can resume 1-2 weeks after infection resolution (once clinically stable)
   • Consider antimicrobial prophylaxis if high-risk for recurrent infection

4. Disseminated Herpes Zoster:

   • Hold JAK inhibitor immediately
   • IV acyclovir 10 mg/kg every 8 hours
   • Assess for visceral involvement (LFTs, chest imaging)
   • Prolonged antiviral course (14-21 days)
   • Cautious resumption of JAK inhibitor after full recovery

Perioperative Management

• Preoperative: Hold 3-7 days before surgery (varies by half-life and procedure)
  • Tofacitinib: hold 3 days (half-life 3 hours)
  • Baricitinib: hold 5-7 days (half-life 12 hours)
  • Upadacitinib: hold 5-7 days (half-life 9-14 hours)
• VTE prophylaxis: Aggressive mechanical and pharmacologic prophylaxis
  • Consider extended prophylaxis (4 weeks) for major orthopedic surgery
  • Lower threshold for pharmacologic prophylaxis even for moderate-risk procedures
• Resumption: When wound healing established and no infection (typically 7-14 days)

Drug Interactions

Important interactions in critical care:

• Strong CYP3A4 inhibitors (clarithromycin, fluconazole): increase tofacitinib levels (reduce dose by 50%)
• Strong CYP3A4 inducers (rifampin): decrease tofacitinib levels (avoid combination)
• Immunosuppressants: Avoid combinations with azathioprine, cyclosporine (increased infection and malignancy risk)
• Live vaccines: Contraindicated during therapy

Laboratory Abnormalities

Cytopenias

• Lymphopenia: Common (5-10%), usually mild
  • Monitor ALC; hold if <500 cells/μL
• Neutropenia: 1-2%
  • Hold if ANC <1000 cells/μL
• Anemia: Rarely worsens despite EPO pathway involvement
  • May improve with disease control
• Thrombocytopenia: Rare (<1%)

Lipid Changes

• LDL increases 10-20% (typically within first 3 months)
• HDL increases 10-20% (parallel to LDL)
• LDL:HDL ratio often unchanged
• Clinical significance uncertain; treat per CV risk stratification

Hepatotoxicity

• Transaminase elevations: 5-10%
• Usually mild (1-2× ULN)
• Hold if ALT/AST >5× ULN; rechallenge cautiously after normalization
• Severe hepatotoxicity rare

Monitoring Schedule:

• Baseline: CBC, CMP, lipids, HBV/HCV/TB screening
• Month 1: CBC, CMP
• Month 3: CBC, CMP, lipids
• Every 3 months: CBC, CMP
• Annually: Lipids, skin examination (for malignancy surveillance)

Special Populations

Elderly (Age >65)

• Highest-risk population per ORAL Surveillance
• Careful risk-benefit assessment
• Start with lowest effective dose
• Aggressive risk factor modification
• Consider alternative if multiple comorbidities

Renal Impairment

• Dose adjustment required for moderate-severe CKD
  • CrCl 30-50: reduce tofacitinib to 5 mg once daily
  • CrCl <30: avoid tofacitinib
• Baricitinib, upadacitinib: check product-specific dosing

Hepatic Impairment

• Mild-moderate (Child-Pugh A/B): dose reduction recommended
• Severe (Child-Pugh C): avoid

Pregnancy and Lactation

• Limited human data; animal studies show fetal harm
• Avoid during pregnancy if possible
• Effective contraception required
• Discontinue if pregnancy occurs
• Excretion in breast milk unknown; avoid breastfeeding

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Comparative Risk Summary and Clinical Decision-Making

Head-to-Head Safety Comparison

Adverse Event	TNF-α Inhibitors	Rituximab	IL-17/IL-23 Inhibitors	Vedolizumab	JAK Inhibitors
Tuberculosis	+++	+	++	+	++
Invasive fungal	+++	++	+	+	++
Bacterial infections	++	++	+	+	++
Herpes zoster	+	+	+	+	+++
Candidiasis	+	+	+++	+	+
Viral infections (general)	++	+++	+	+	++
PML	Rare	+	Rare	Rare	Rare
VTE	+	+	+	+	+++
Cardiovascular events	+	+	+	+	++
Malignancy	++	+	+	+	++
Immunogenicity	++ (varies)	+	+	+	None (small molecule)

Scale: + = minimal/rare; ++ = moderate; +++ = significant concern

Algorithm for Biologic Selection in High-Risk Patients

Patient with Prior VTE or High CV Risk:

• First choice: Vedolizumab (if IBD) or IL-23 inhibitors (if psoriasis/PsA)
• Avoid: JAK inhibitors (especially tofacitinib)
• Caution: TNF inhibitors acceptable with risk factor modification

Patient with Prior TB or Endemic Fungal Exposure:

• First choice: IL-23 inhibitors or vedolizumab
• Avoid: TNF-α inhibitors without completed latent TB treatment
• Caution: IL-17 inhibitors (lower TB risk than TNF inhibitors but still present)

Patient with Recurrent Candidiasis:

• Avoid: IL-17 inhibitors
• First choice: TNF inhibitors, IL-23 inhibitors, vedolizumab, or JAK inhibitors

Patient with Hypogammaglobulinemia or Recurrent Sinopulmonary Infections:

• Avoid: Rituximab
• First choice: TNF inhibitors, IL-17/IL-23 inhibitors, vedolizumab, or JAK inhibitors

Elderly Patient (>65 years) with Multiple Comorbidities:

• First choice: Vedolizumab (if IBD) or IL-23 inhibitors (lowest overall infection risk)
• Caution: TNF inhibitors acceptable
• Avoid: JAK inhibitors (VTE/CV concerns)

Patient Requiring Rapid Disease Control:

• First choice: JAK inhibitors (fastest onset: days to weeks) or IV infliximab
• Slower onset: Vedolizumab (6-12 weeks), IL-23 inhibitors (4-12 weeks), subcutaneous TNF inhibitors (4-8 weeks)

Perioperative Biologic Management: Unified Approach

General Principles:

1. Elective surgery: Hold biologics 1-2 half-lives pre-procedure; resume when wound healing established
2. Urgent/emergent surgery: Proceed without delay; recent biologic exposure should not prevent necessary intervention
3. Infection risk: Highest with TNF inhibitors and JAK inhibitors; lowest with vedolizumab
4. VTE prophylaxis: Extended prophylaxis for JAK inhibitor patients undergoing major surgery

Specific Recommendations:

Biologic	Half-life	Hold Before Surgery	Resume After Surgery
Infliximab	7-12 days	4-6 weeks	2-4 weeks
Adalimumab	10-20 days	4-6 weeks	2-4 weeks
Etanercept	3-5 days	2 weeks	2 weeks
Rituximab	22 days	6 months (if possible)	2-4 weeks
Secukinumab	27 days	4-6 weeks	2-3 weeks
Ustekinumab	21 days	4-6 weeks	2-3 weeks
Vedolizumab	25 days	2-4 weeks (or continue)	2-4 weeks
Tofacitinib	3 hours	3 days	7-14 days
Upadacitinib	9-14 hours	5-7 days	7-14 days

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Critical Care Pearls and Clinical Hacks

🔷 Top 10 Pearls for Intensivists

1. The "Immunosuppression Paradox": Stopping TNF inhibitors during active TB can worsen clinical status due to immune reconstitution. Balance drug continuation versus infection control carefully.

2. Biologic Half-lives Matter: Long-acting biologics (rituximab, vedolizumab, most mAbs) provide immunosuppression for months after last dose. Don't assume immunocompetence just because drug was stopped.

3. Listeria and Legionella Love TNF Inhibitors: Think atypical pathogens in CNS and pulmonary infections. Empiric coverage should include ampicillin (Listeria) and fluoroquinolone/macrolide (Legionella).

4. CMV Colitis Mimics IBD Flare: In IBD patient on vedolizumab or other biologics with worsening colitis, always biopsy for CMV before escalating immunosuppression.

5. PML Has No Treatment: The only intervention is immune reconstitution. High suspicion, early MRI, and lumbar puncture are critical. Any new neurologic symptom in rituximab patient = PML until proven otherwise.

6. JAK Inhibitor VTE is Early: Most VTE events occur within first 6 months. Intensivists should have lower threshold for DVT prophylaxis and imaging in symptomatic patients.

7. Candida in IL-17 Inhibitor Patients Stays Superficial: Don't over-investigate for invasive candidiasis. Treat mucocutaneous disease and move on.

8. Rituximab + Hypogammaglobulinemia + Recurrent Infections ≠ Automatic IVIG: Try prophylactic antibiotics first. IVIG is expensive and burdensome; reserve for refractory cases.

9. Vedolizumab's Gut Selectivity is Real: Most favorable safety profile of all biologics for systemic infections. Consider it a "safer" option in patients with multiple comorbidities requiring IBD treatment.

10. Therapeutic Drug Monitoring Can Guide Management: Low infliximab/adalimumab levels + high anti-drug antibodies = switch to different TNF inhibitor or drug class. Don't keep escalating a failing drug.

⚙️ Top 10 Clinical Hacks

1. Pre-Emptive Fluconazole for IL-17 Inhibitors: Consider fluconazole 100-150 mg weekly in patients with recurrent oral/vaginal candidiasis starting IL-17 inhibitors. Prevents 60-70% of cases.

2. The "Biologic Holiday": For planned major surgery, time biologic dosing so that surgery occurs at drug trough (end of dosing interval). Minimizes perioperative levels without extra holding time.

3. Rapid Rituximab Reconstitution Assessment: Order quantitative immunoglobulins + lymphocyte subsets. If CD19+ B cells >80 cells/μL and IgG normal, immune function likely adequate.

4. VTE Risk Stratification Score (Informal): Assign 1 point each for age >65, obesity, prior VTE, active cancer, heart failure, immobility. Score ≥3 = avoid JAK inhibitors if possible.

5. The "Aspirin Bridge": For JAK inhibitor patients requiring temporary drug hold (surgery, infection), continue low-dose aspirin 81 mg daily to mitigate VTE risk during vulnerable period (no formal evidence but rational).

6. Urgent TB Treatment in Biologics: If high clinical suspicion for TB in critically ill patient, start empiric 4-drug therapy immediately. Don't wait for cultures (may take weeks) or let fear of IRIS delay treatment.

7. Vedolizumab "Push-Through" Strategy: Unlike TNF inhibitors, vedolizumab can often be continued through minor surgeries and infections due to gut selectivity. Risk-benefit often favors continuation to prevent flare.

8. Herpes Zoster Prophylaxis Math: Cost of valacyclovir prophylaxis (~$50/month) versus Shingrix vaccination (~$350 one-time) versus treating zoster (~$100-500 + morbidity). Vaccination wins long-term.

9. Pneumocystis Prophylaxis Threshold: Consider TMP-SMX prophylaxis if: biologic + prednisone ≥20 mg daily × ≥4 weeks, or biologic + multiple immunosuppressants, or biologic + CD4 <200.

10. The "Biologic Swap Timing": When switching biologics due to adverse event, allow 1-2 half-lives of first drug to clear before starting second. Reduces cumulative immunosuppression and infection risk.

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Future Directions and Emerging Concerns

Biosimilars: Safety Equivalence Considerations

As biosimilars enter the market for infliximab, adalimumab, rituximab, and others, critical care physicians should understand:

• Immunogenicity: Biosimilars may have slightly different immunogenicity profiles
• Interchangeability: FDA-designated interchangeable biosimilars can be substituted; others require prescriber approval
• Nocebo effect: Patient concerns about "switching to generic" may manifest as perceived loss of efficacy
• Cost savings: Substantial (30-70% reduction) with equivalent efficacy in trials²⁶

Novel Biologics in Development

• Anti-IL-6: Tocilizumab, sarilumab (increased infection risk, lipid changes, GI perforation in diverticulitis)
• Anti-BAFF/APRIL: Belimumab (lupus) - generally well-tolerated
• Sphingosine-1-phosphate (S1P) modulators: Ozanimod, etrasimod (IBD) - lymphopenia, macular edema, bradycardia
• TYK2 inhibitors: Deucravacitinib (psoriasis) - more selective than pan-JAK inhibitors; safety profile emerging

COVID-19 and Biologics: Lessons Learned

The pandemic provided real-world data on biologic safety during viral pandemic:

• Rituximab: Highest risk for severe COVID-19 and mortality (impaired antibody responses)
• TNF inhibitors: Neutral or possibly protective effects (anti-inflammatory benefits?)
• JAK inhibitors: Mixed data; baricitinib actually used therapeutically in hospitalized COVID-19
• IL-17/IL-23, vedolizumab: Appeared relatively safe

Implications: Consider biologic-specific infection risks when evaluating new infectious disease threats.

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Conclusion

Biologic therapies have transformed outcomes for patients with immune-mediated inflammatory diseases, but their targeted immunosuppression creates unique challenges in critical care settings. The intensivist must understand mechanism-specific vulnerabilities: TNF-α inhibitors' predisposition to granulomatous infections, rituximab's humoral immune impairment, IL-17 inhibitors' mucocutaneous candidiasis risk, vedolizumab's gut-selective immunosuppression, and JAK inhibitors' VTE and cardiovascular signals.

Key principles for critical care management include:

1. High clinical suspicion for atypical and opportunistic infections
2. Mechanism-based risk stratification guides empiric therapy and prophylaxis
3. Individualized decisions about biologic continuation versus discontinuation during acute illness
4. Multidisciplinary collaboration with rheumatology, gastroenterology, and infectious diseases
5. Patient-centered risk-benefit analysis when selecting biologics for high-risk patients

As the biologic armamentarium expands and patient populations age with multiple comorbidities, critical care expertise in managing these complex immunosuppressed patients becomes increasingly vital. Continued pharmacovigilance, mechanistic research, and real-world safety data will refine our approach to optimizing outcomes while minimizing toxicity.

The immunology of biologics is not merely academic—it is the foundation for rational, evidence-based critical care management of an increasingly common patient population.

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Abbreviations

ADA: Anti-drug antibodies
ADCC: Antibody-dependent cellular cytotoxicity
ANC: Absolute neutrophil count
AS: Ankylosing spondylitis
CDC: Complement-dependent cytotoxicity
CMV: Cytomegalovirus
CrCl: Creatinine clearance
CV: Cardiovascular
DMARD: Disease-modifying antirheumatic drug
DVT: Deep vein thrombosis
GALT: Gut-associated lymphoid tissue
G-CSF: Granulocyte colony-stimulating factor
HBsAg: Hepatitis B surface antigen
HBV: Hepatitis B virus
HCV: Hepatitis C virus
IBD: Inflammatory bowel disease
ICU: Intensive care unit
IGRA: Interferon-gamma release assay
IL: Interleukin
INH: Isoniazid
IRIS: Immune reconstitution inflammatory syndrome
IVIG: Intravenous immunoglobulin
JAK: Janus kinase
JC virus: John Cunningham virus
MACE: Major adverse cardiovascular events
MAdCAM-1: Mucosal addressin cell adhesion molecule-1
MI: Myocardial infarction
NK: Natural killer
PJP: Pneumocystis jirovecii pneumonia
PML: Progressive multifocal leukoencephalopathy
PsA: Psoriatic arthritis
RA: Rheumatoid arthritis
SCIG: Subcutaneous immunoglobulin
SSTI: Skin and soft tissue infection
STAT: Signal transducer and activator of transcription
TB: Tuberculosis
TDM: Therapeutic drug monitoring
TNF: Tumor necrosis factor
TST: Tuberculin skin test
UC: Ulcerative colitis
VTE: Venous thromboembolism
VZV: Varicella-zoster virus

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Acknowledgments

The authors acknowledge the contributions of infectious disease specialists, rheumatologists, gastroenterologists, and dermatologists whose clinical insights and research have advanced our understanding of biologic safety profiles in critical care populations.

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Disclosure Statement

The authors declare no conflicts of interest relevant to this manuscript. This review article represents an independent educational resource and is not sponsored by any pharmaceutical entity.

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Correspondence:
[Author details would be inserted here in actual publication]

Article Type: Review Article
Word Count: ~12,500 words
Figures/Tables: 1 comparative table
References: 40

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Self-Assessment Questions

To reinforce learning, consider these clinical scenarios:

Question 1: A 58-year-old woman with rheumatoid arthritis on adalimumab 40 mg every 2 weeks presents with 3 weeks of progressive dyspnea, dry cough, and fever. Chest CT shows multiple cavitary lesions. What is the most appropriate next step?

A) Continue adalimumab and add broad-spectrum antibiotics
B) Hold adalimumab, start empiric TB treatment (RIPE therapy)
C) Hold adalimumab, bronchoscopy for diagnosis only
D) Switch from adalimumab to rituximab

Answer: B. The clinical presentation is highly concerning for tuberculosis (cavitary lesions, subacute course, TNF inhibitor exposure). Empiric treatment should be initiated immediately given high morbidity and mortality. Holding the TNF inhibitor is critical, though immune reconstitution may paradoxically worsen symptoms initially. Bronchoscopy can provide confirmation but should not delay treatment in a critically ill patient.

Question 2: A 45-year-old man with ulcerative colitis on vedolizumab develops worsening bloody diarrhea (12 bowel movements daily) despite escalated dosing. Colonoscopy shows deep ulcerations. CMV PCR from colonic biopsy is positive at 1,500 copies/mg tissue. What is the best management?

A) Discontinue vedolizumab, start IV ganciclovir
B) Continue vedolizumab, add oral valganciclovir
C) Treat CMV with antivirals, reassess colitis after completion
D) Urgent colectomy

Answer: C. This scenario illustrates the "CMV colitis versus refractory UC" dilemma. The moderate-level CMV viremia and severe symptoms favor CMV as a significant contributor. The optimal approach is to treat CMV with ganciclovir/valganciclovir for 2-3 weeks, then reassess. If colitis persists after CMV clearance, then intensify IBD therapy or consider surgery. Vedolizumab continuation during CMV treatment is debated; holding temporarily is reasonable in severe cases.

Question 3: A 62-year-old woman with psoriatic arthritis on tofacitinib 5 mg BID develops acute onset left leg swelling. Ultrasound confirms extensive DVT (popliteal to common femoral vein). She has no prior VTE history. What is the most appropriate long-term management?

A) Anticoagulate for 3 months, resume tofacitinib afterward
B) Anticoagulate indefinitely, resume tofacitinib with close monitoring
C) Anticoagulate for 6 months, permanently discontinue tofacitinib
D) IVC filter placement, continue tofacitinib

Answer: C. Tofacitinib-associated VTE represents a drug-specific, recurrent risk. Most experts recommend permanent discontinuation after a VTE event, switching to an alternative biologic class. While some might argue for indefinite anticoagulation + tofacitinib continuation, this exposes the patient to bleeding risk and doesn't address the underlying prothrombotic drug effect. Three months is insufficient given the ongoing drug exposure. The correct answer reflects the current consensus approach following ORAL Surveillance data.

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For Further Reading:

• American College of Rheumatology Guidelines on Screening for and Prophylaxis of Tuberculosis Prior to Biologic Use
• FDA Drug Safety Communications regarding JAK inhibitor safety warnings
• European League Against Rheumatism (EULAR) recommendations for vaccination in patients on immunosuppressive therapies
• Infectious Diseases Society of America guidelines on opportunistic infections in immunocompromised hosts