Perioperative Management of Rheumatologic Conditions: A Critical Care Perspective

Dr Neeraj Mnaikath , claude.ai

Introduction

The perioperative management of patients with rheumatologic conditions presents unique challenges that require a delicate balance between maintaining disease control and minimizing surgical complications. With the increasing use of biologic disease-modifying antirheumatic drugs (DMARDs) and immunosuppressants, along with the long-term consequences of corticosteroid therapy, critical care physicians must navigate complex decision-making pathways. This review synthesizes current evidence and provides practical guidance for the perioperative care of these challenging patients.

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Timing of Biologic DMARDs and Immunosuppressants

The Balancing Act: Disease Flare versus Infection Risk

The fundamental dilemma in perioperative management of biologic DMARDs centers on two competing risks: disease flare from medication withdrawal versus increased surgical site infection (SSI) and delayed wound healing from continued immunosuppression. The 2017 American College of Rheumatology (ACR)/American Association of Hip and Knee Surgeons (AAHKS) guidelines provide an evidence-based framework, though clinical judgment remains paramount.

Tumor Necrosis Factor Inhibitors (TNFi)

Pearl: The "one dosing cycle rule" – withhold TNF inhibitors for one complete dosing cycle before surgery and resume postoperatively once wound healing is satisfactory and infection is excluded.

Specific Recommendations:

• Etanercept (half-life 4.3 days): Withhold 1 week preoperatively
• Adalimumab (half-life 14 days): Withhold 2 weeks preoperatively
• Infliximab (half-life 9.5 days): Withhold 4-6 weeks preoperatively (given its longer dosing interval)
• Golimumab (half-life 14 days): Withhold 4 weeks preoperatively
• Certolizumab pegol (half-life 14 days): Withhold 2 weeks preoperatively

The INCREASED trial demonstrated that continuing methotrexate during TNFi therapy did not significantly increase infection risk in rheumatoid arthritis patients undergoing elective orthopedic surgery, challenging older paradigms about universal methotrexate discontinuation.

Non-TNF Biologics

Abatacept (T-cell costimulation blocker): Given its half-life of 13 days and monthly dosing, withhold approximately 4 weeks preoperatively. Resume when wounds are healed and infection excluded.

Rituximab (anti-CD20): This agent presents unique challenges given its profound B-cell depletion lasting 6-9 months.

• Hack: Check CD19+ B-cell counts preoperatively if rituximab was administered within 6 months
• If B-cells remain depleted (<5 cells/μL), the patient remains at elevated infection risk regardless of time since last dose
• Ideally, schedule elective surgery when B-cell reconstitution has occurred

Tocilizumab (IL-6 receptor antagonist): Withhold for 1-2 weeks before surgery (IV formulation weekly, SC formulation every 2 weeks). The IL-6 pathway is crucial for wound healing, making adherence to discontinuation guidelines particularly important.

JAK inhibitors (tofacitinib, baricitinib, upadacitinib):

• These small molecules have shorter half-lives (3-6 hours) but require 3-7 days for complete washout
• Pearl: Discontinue 3 days before minor procedures, 7 days before major surgery
• Advantage: Can be resumed quickly postoperatively (24-48 hours after minor procedures once hemostasis assured)

Conventional Synthetic DMARDs

Methotrexate: Current evidence supports continuation in most cases. The ACR 2017 guidelines recommend continuing methotrexate for patients with well-controlled rheumatoid arthritis or psoriatic arthritis undergoing elective orthopedic surgery. However, consider holding for 1-2 weeks in patients with:

• Poor nutritional status
• Chronic kidney disease (reduced clearance)
• Concurrent infection
• Major surgery with anticipated prolonged recovery

Leflunomide: Given its long half-life (14 days) and active metabolite persistence, discontinue 2-4 weeks preoperatively for major surgery. Consider cholestyramine washout (8g TID for 11 days) for urgent surgery.

Sulfasalazine and Hydroxychloroquine: Continue perioperatively – these agents have minimal impact on wound healing and infection risk.

Immunosuppressants for Systemic Conditions

Azathioprine: Can generally be continued for minor procedures. For major surgery, consider holding 1 week preoperatively, particularly in patients with leucopenia or those on high doses (>2 mg/kg/day).

Mycophenolate mofetil: Hold 1 week before surgery and resume when adequate wound healing achieved. Monitor for disease flare in lupus patients.

Cyclosporine and Tacrolimus: These calcineurin inhibitors may be continued perioperatively in transplant patients but require therapeutic drug monitoring. For rheumatologic indications, consider holding 24-48 hours preoperatively for major surgery.

Cyclophosphamide: If on monthly IV pulse therapy, schedule surgery to avoid the nadir period (days 7-14 post-dose). For daily oral therapy, discontinue 7 days preoperatively.

Oyster: The "steroid-sparing" paradox – patients on biologics to reduce steroid burden may have better perioperative outcomes than those who failed biologics and require high-dose steroids for disease control.

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Managing Adrenal Insufficiency in Chronic Steroid Users

Physiology and Risk Assessment

Chronic glucocorticoid therapy suppresses the hypothalamic-pituitary-adrenal (HPA) axis through negative feedback inhibition. The degree and duration of suppression depends on dose, duration, and timing of glucocorticoid administration.

Risk Factors for HPA Axis Suppression:

• Prednisone >5 mg daily (or equivalent) for >3 weeks
• Any dose given in evening (disrupts circadian rhythm)
• Cushingoid appearance
• Previous documented adrenal insufficiency

Pearl: The "3-3-1 rule" for HPA suppression risk:

• 3 weeks of therapy

• 5 mg prednisone daily (the "3" represents 3x physiologic dose)

• Within 1 year of discontinuation

Perioperative Stress Dose Steroids: Evolving Paradigms

The traditional approach of "stress-dose" steroids (hydrocortisone 100 mg IV q8h) has been challenged by recent evidence suggesting lower doses suffice for most surgical procedures.

Contemporary Approach – Procedure-Based Dosing:

Minor Surgery (local anesthesia, <1 hour, minimal tissue trauma):

• Give usual morning steroid dose
• Consider hydrocortisone 25 mg IV at induction if patient appears cushingoid

Moderate Surgery (general anesthesia, inguinal hernia repair, colonoscopy, joint surgery):

• Hydrocortisone 50 mg IV at induction
• Continue usual maintenance dose postoperatively
• No taper necessary

Major Surgery (cardiothoracic, intra-abdominal, major vascular):

• Hydrocortisone 100 mg IV at induction
• Followed by 50 mg IV q8h or continuous infusion 200 mg/24h
• Rapid taper over 24-48 hours if uncomplicated
• Resume oral steroids when tolerating PO intake

Hack: For critically ill patients: If uncertain about steroid history, empiric stress-dose steroids (hydrocortisone 50 mg IV q6h) are safer than risking acute adrenal crisis. The ADRENAL trial in septic shock showed hydrocortisone was safe, and this principle extends to perioperative care.

Diagnosing Perioperative Adrenal Insufficiency

Clinical Features:

• Hypotension refractory to fluids and vasopressors
• Hyponatremia, hyperkalemia
• Hypoglycemia
• Unexplained fever
• Abdominal pain, nausea, vomiting
• Altered mental status

Oyster: Eosinophilia may be absent in acute adrenal crisis despite being a classic finding in chronic insufficiency – don't rely on this sign perioperatively.

Diagnostic Approach:

• Random cortisol <5 μg/dL strongly suggests insufficiency
• Random cortisol >18 μg/dL essentially excludes it
• ACTH stimulation testing not feasible in acute perioperative setting
• Pearl: Don't delay treatment for diagnostic testing in suspected adrenal crisis

Management of Acute Adrenal Crisis

1. Immediate resuscitation:

   • 0.9% saline 1-2 liters rapid IV bolus
   • Hydrocortisone 100 mg IV bolus
   • Correct hypoglycemia (D50W if needed)

2. Continuing therapy:

   • Hydrocortisone 50-100 mg IV q6-8h or continuous infusion
   • Volume resuscitation (may require 2-3 liters in first hour)
   • Identify and treat precipitating factors

3. Transition:

   • When stable, taper to oral hydrocortisone 20 mg AM, 10 mg afternoon
   • Add fludrocortisone 0.1 mg daily if primary insufficiency suspected
   • Endocrinology consultation for outpatient axis testing

Hack: The "hydrocortisone preference" – use hydrocortisone (not dexamethasone or methylprednisolone) for acute crisis management because:

• It has mineralocorticoid activity at high doses
• It doesn't interfere with subsequent cortisol assays
• It has the most rapid onset

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Assessing Infection Risk in Immunocompromised Rheumatology Patients

Stratifying Risk: Beyond Simple Categories

Infection risk in rheumatology patients is multifactorial, depending on the disease itself, cumulative immunosuppression, patient comorbidities, and surgical factors.

Disease-Specific Risk Factors

High-risk rheumatologic conditions:

• Systemic lupus erythematosus (SLE): intrinsic immune dysregulation plus treatments
• Granulomatosis with polyangiitis (GPA): disease activity and cyclophosphamide therapy
• Systemic sclerosis: skin breakdown, aspiration risk, lung involvement

Pearl: Active disease increases infection risk more than well-controlled disease on immunosuppression. The "inflammatory paradox" – achieving disease control may reduce overall perioperative risk despite requiring immunosuppressive therapy.

Medication-Specific Risk Stratification

Highest Risk:

• Rituximab (profound B-cell depletion)
• Cyclophosphamide (lymphopenia, neutropenia)
• High-dose steroids (>20 mg/day prednisone equivalent)
• Combination therapy (biologic + conventional DMARD + steroid)

Moderate Risk:

• TNF inhibitors
• Tocilizumab
• JAK inhibitors
• Abatacept

Lower Risk:

• Methotrexate monotherapy
• Hydroxychloroquine
• Sulfasalazine

Comprehensive Preoperative Infection Assessment

Screening Strategy:

1. Clinical evaluation:

   • Review systems for occult infection
   • Dental examination (source of bacteremia)
   • Skin integrity assessment
   • Hack: Check feet in diabetic patients – overlooked onychomycosis or ulcers are infection niduses

2. Laboratory screening:

   • Complete blood count (lymphopenia <500 cells/μL markedly increases risk)
   • Immunoglobulin levels in rituximab patients
   • HIV testing in high-risk patients (may be asymptomatic with CD4 depletion)
   • Pearl: IgG <400 mg/dL in rituximab-treated patients warrants IVIG consideration

3. Infection-specific screening:

   • Hepatitis B: HBsAg, anti-HBc, anti-HBs before rituximab or any biologic
     • Reactivation risk highest with rituximab
     • Prophylactic entecavir/tenofovir if HBsAg+ or HBcAb+ with undetectable HBsAg
   • Hepatitis C: Anti-HCV, confirm with RNA if positive
     • Consider treatment before immunosuppression intensification
   • Tuberculosis:
     • Interferon-gamma release assay (IGRA) or tuberculin skin test
     • Chest X-ray if IGRA positive or in endemic areas
     • Oyster: IGRA may be falsely negative in severely immunosuppressed patients – clinical judgment paramount
   • Strongyloides: Serology in patients from endemic areas before initiating steroids
     • Ivermectin prophylaxis if positive to prevent hyperinfection syndrome

4. Vaccination status:

   • Ensure pneumococcal, influenza vaccines current
   • Critical Pearl: Give vaccines ≥2 weeks before elective surgery and immunosuppression
   • Live vaccines contraindicated in immunocompromised patients

Perioperative Infection Prevention

Antimicrobial Prophylaxis:

• Standard surgical prophylaxis applies to all patients
• Extended duration NOT generally recommended (increases resistance)
• Consider broader spectrum in severely immunocompromised patients (e.g., piperacillin-tazobactam for intra-abdominal surgery)

Fungal Prophylaxis: Consider in patients with:

• Rituximab + high-dose steroids (>20 mg/day prednisone)
• Cyclophosphamide therapy
• Lymphocyte count <500 cells/μL
• Prolonged ICU stay anticipated

Options: Fluconazole 400 mg daily or micafungin 100 mg IV daily

Pneumocystis jirovecii Pneumonia (PCP) Prophylaxis:

Indications:

• Prednisone ≥20 mg daily for ≥4 weeks
• Rituximab-treated patients
• Cyclophosphamide therapy
• Combination therapy with multiple immunosuppressants
• CD4 count <200 cells/μL

Prophylaxis: Trimethoprim-sulfamethoxazole DS daily or three times weekly Alternative: Dapsone 100 mg daily (check G6PD first), atovaquone, or pentamidine inhalation

Hack: The "steroid-equivalent calculator" – convert all glucocorticoids to prednisone equivalents for consistent risk assessment:

• Hydrocortisone 20 mg = Prednisone 5 mg
• Methylprednisolone 4 mg = Prednisone 5 mg
• Dexamethasone 0.75 mg = Prednisone 5 mg

Postoperative Infection Surveillance

Enhanced Monitoring:

• Temperature checks every 4 hours minimum
• Daily wound inspection
• Low threshold for obtaining cultures
• Pearl: Immunosuppressed patients may have blunted fever response – monitor for subtle signs (tachycardia, mental status changes, increased oxygen requirement)

Atypical Infection Considerations:

• Consider fungal infections (Candida, Aspergillus) in non-resolving pneumonia
• Cytomegalovirus (CMV) reactivation in rituximab patients with prolonged critical illness
• Nocardia or atypical mycobacteria in patients on chronic steroids with pulmonary infiltrates

Oyster: The "sterile inflammation" mimicker – rheumatologic disease flare can present identically to infection (fever, elevated inflammatory markers, leukocytosis). When in doubt:

1. Obtain cultures before antibiotics
2. Consider imaging to identify infection source
3. Consult rheumatology for disease activity assessment
4. Treat infection empirically while awaiting workup

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Integration: A Practical Perioperative Protocol

2-4 Weeks Before Surgery:

• Risk assessment (disease activity, medications, comorbidities)
• Optimize disease control with rheumatology
• Infection screening (TB, hepatitis, HIV if indicated)
• Update vaccinations if feasible
• Plan medication adjustments (timing of biologic discontinuation)
• Assess HPA axis risk, plan stress-dose steroids

1 Week Before Surgery:

• Hold specific biologics per protocol
• Continue methotrexate, hydroxychloroquine
• Confirm stress steroid plan with anesthesia
• Recheck labs if lymphopenic or cytopenias present

Day of Surgery:

• Administer stress-dose steroids appropriate to procedure magnitude
• Standard surgical antibiotic prophylaxis
• Consider extended spectrum in severely immunocompromised

Postoperative Period:

• Taper stress steroids rapidly if uncomplicated (24-48 hours)
• Monitor for infection (blunted symptoms in immunosuppressed)
• Resume biologics only after wound healing confirmed and infection excluded
• Vigilance for opportunistic infections (PCP, fungal, viral reactivation)

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Conclusion

The perioperative management of rheumatologic conditions requires individualized risk-benefit analysis balancing disease control with infection prevention. Recent evidence supports more nuanced approaches: continuing methotrexate in stable patients, using procedure-appropriate stress-dose steroids rather than universal high doses, and timing biologic discontinuation based on pharmacokinetics. Critical care physicians must maintain heightened suspicion for opportunistic infections, adrenal insufficiency, and disease flares in this vulnerable population. Close collaboration with rheumatology, infectious disease, and endocrinology specialists optimizes outcomes.

Final Pearl: When uncertain, err on the side of caution – the consequences of missed adrenal crisis or overwhelming infection far outweigh the risks of brief disease flare or transient immunosuppression.

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References

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