Can you provide detailed guidelines for initiating, continuing, holding, and restarting all rheumatologic drugs (DMARDs, biologics, azathioprine, mycophenolate mofetil, cyclophosphamide, Janus‑kinase inhibitors, rituximab) and glucocorticoids during active infections (including tuberculosis), peri‑operative management, and vaccination practices?

Management of Rheumatologic Medications During Active Infections, Perioperative Period, and Vaccination

Active Infections (Including Tuberculosis)

All rheumatologic medications—DMARDs, biologics, JAK inhibitors, rituximab, azathioprine, mycophenolate, cyclophosphamide, and glucocorticoids—must be held during active infections, with TB requiring complete treatment before initiating immunosuppression.

Tuberculosis Management

• Screen all patients before starting any immunosuppressive therapy by measuring HBsAg and anti-HBc for hepatitis B (which reactivates similarly to TB) 1
• Do not initiate any DMARD, biologic, JAK inhibitor, or other immunosuppressive agent in patients with active TB
• Complete full TB treatment course before starting immunosuppression
• For latent TB: Complete at least 1 month of prophylactic therapy before initiating biologics or targeted synthetic DMARDs
• Glucocorticoids: Maintain lowest possible dose (<10 mg prednisone equivalent daily) during TB treatment; higher doses significantly increase infection risk

Active Infection Protocol

Immediate actions:

• Stop all immunosuppressive medications except glucocorticoids (see below)
• Glucocorticoids: Continue at current dose—do NOT stop abruptly due to adrenal suppression risk; do NOT increase to "stress doses" as this worsens infection outcomes 2
• Treat the infection aggressively with appropriate antimicrobials

Restarting medications after infection resolution:

• Wait until infection is completely resolved with clinical and laboratory confirmation
• Restart sequence: Begin with conventional synthetic DMARDs first, then add biologics/JAK inhibitors 1-2 weeks later if wound healing complete and no signs of recurrent infection
• Rituximab requires special consideration: Given prolonged B-cell depletion, delay restart until infection fully cleared and consider PCP prophylaxis for at least 6 months 1

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Perioperative Management

For elective orthopedic surgery, schedule procedures at the end of each biologic's dosing interval rather than extending withholding periods, as this minimizes disease flare without increasing infection risk. 2

Glucocorticoids (Highest Priority)

• Reduce to <10 mg/day prednisone equivalent 2-3 months before surgery if possible 3, 4
• Keep dose stable 1-2 weeks before and on day of surgery—do NOT use supraphysiologic "stress doses" 2
• Continue current daily dose perioperatively rather than increasing, as higher doses increase hyperglycemia and complications by 8.4% for every 10 mg increase 2
• Exception: Patients with primary adrenal insufficiency require stress-dose coverage

Conventional Synthetic DMARDs

Methotrexate:

• Continue through surgery at doses ≤15 mg/week 3, 4
• Reduce to ≤15 mg/week if currently on higher doses and high infection risk
• Stopping methotrexate increases flare risk more than continuation increases infection risk 5

Leflunomide:

• Perform cholestyramine washout before major surgery due to long half-life 3
• For minor procedures: May continue

Sulfasalazine & Hydroxychloroquine:

• Continue without interruption—very low infection risk 3, 5

Azathioprine, Mycophenolate, Cyclosporine:

• Hold 1-2 days before surgery 3
• Restart when wound healing progressing normally (typically 5-7 days)

Biologic DMARDs

General principle: Schedule surgery at the end of the dosing interval 2, 3

TNF inhibitors:

• Adalimumab (every 2 weeks): Surgery 2 weeks after last dose
• Etanercept (weekly): Surgery 1 week after last dose
• Infliximab (every 8 weeks): Surgery 8 weeks after last dose
• Certolizumab, Golimumab: Follow respective dosing intervals

Other biologics:

• Rituximab: Given 6-month dosing, surgery can proceed at any time; however, vaccine responses are impaired, so complete vaccinations before initiating 6
• Abatacept, Tocilizumab, Sarilumab: Schedule at end of dosing interval
• IL-17/IL-23 inhibitors (ixekizumab, guselkumab): Schedule at end of dosing interval 2

Restarting biologics:

• Resume as soon as wound healing is progressing (typically 10-14 days)
• Earlier restart (within 4 weeks) associated with better outcomes than delayed restart 2

JAK Inhibitors (Tofacitinib, Baricitinib, Upadacitinib, Filgotinib)

• Hold 3-4 days before major surgery due to short half-life 3, 4
• May continue for minor procedures
• Restart when wound healing progressing (typically 5-7 days)
• Consider MACE and thromboembolism risk in high-risk patients 7

Apremilast

• Continue without interruption 3

Critical Perioperative Caveats

• Patients with prior severe infections or prosthetic joint infection: Extend withholding periods beyond standard recommendations 2
• The 2022 ACR/AAHKS guideline acknowledges: Evidence remains low-quality with no randomized trials; recommendations based on observational data 2
• Recent meta-analysis shows: Continuation increases SSI risk (OR 1.27) but dramatically reduces flare risk (OR 0.41) 8
• Individualize based on: Disease activity, infection history, surgical complexity

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Vaccination Guidelines

Continue all immunosuppressive medications except methotrexate during vaccination; for rituximab, time vaccines to end of dosing cycle and delay next dose 2 weeks. 6

Non-Live Vaccines (Influenza, Pneumococcal, COVID-19, Hepatitis B, etc.)

Methotrexate—ONLY medication requiring hold:

• Hold methotrexate for 2 weeks after vaccination to improve vaccine response 6
• This applies to influenza and other non-live vaccines
• Moderate-quality evidence supports this practice 6

All other medications (continue):

• TNF inhibitors, IL-6 inhibitors, abatacept, JAK inhibitors: Continue without interruption 6
• Glucocorticoids ≤20 mg/day prednisone equivalent: Administer vaccines without delay 6
• Glucocorticoids >20 mg/day: Vaccine response may be reduced, but still administer—do NOT delay vaccination 6

Rituximab (special timing):

• Defer non-live vaccines (except influenza) until next rituximab dose is due 6
• Administer vaccine, then delay rituximab for 2 weeks to maximize antibody response 6
• For influenza vaccine: Administer regardless of rituximab timing due to seasonal urgency 6
• Low-quality evidence, but strong consensus given profound B-cell depletion 6

Live Vaccines (MMR, Varicella, Zoster Live, Yellow Fever)

Contraindicated in all patients on:

• Biologics (all TNF inhibitors, IL-6, IL-17, IL-23 inhibitors, abatacept, rituximab)
• JAK inhibitors
• Cyclophosphamide
• Mycophenolate at immunosuppressive doses
• Azathioprine >3 mg/kg/day
• Glucocorticoids >20 mg/day prednisone equivalent for >2 weeks

May administer with caution:

• Methotrexate ≤0.4 mg/kg/week
• Azathioprine ≤3 mg/kg/day
• Glucocorticoids <20 mg/day or short courses
• Hydroxychloroquine, sulfasalazine (not immunosuppressive)

Recombinant zoster vaccine (Shingrix):

• Preferred over live zoster vaccine—safe with all immunosuppressive medications
• Administer to all patients ≥50 years regardless of medication regimen

Vaccination Timing Strategy

Before starting immunosuppression:

• Complete all indicated vaccines at least 2-4 weeks before initiating biologics or JAK inhibitors
• Prioritize: Pneumococcal (PCV20 or PCV15 + PPSV23), influenza, recombinant zoster, hepatitis B, COVID-19

During immunosuppression:

• Annual influenza vaccine (inactivated only)
• COVID-19 boosters per current recommendations
• Pneumococcal boosters per ACIP schedule
• Continue methotrexate hold strategy for optimal response 6

Common Pitfalls

• Do NOT hold biologics or JAK inhibitors for vaccination—only methotrexate requires interruption 6
• Do NOT delay urgent vaccines (e.g., post-exposure prophylaxis) due to immunosuppression
• Do NOT assume all immunosuppressed patients need stress-dose steroids—they don't 2
• Do NOT restart rituximab immediately after vaccination—wait 2 weeks 6

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Hepatitis B Reactivation (Applies to All Immunosuppression)

Screen all patients with HBsAg and anti-HBc before starting any DMARD or biologic—HBV reactivation can be fatal. 1

• HBsAg positive (active infection): Consult hepatology; start antiviral therapy before immunosuppression
• HBsAg negative but anti-HBc positive (prior exposure): High reactivation risk with rituximab, moderate with other biologics; consider prophylactic antivirals
• Monitor for reactivation during and for 6-24 months after completing immunosuppressive therapy 1
• If reactivation occurs: Immediately stop all immunosuppression and start antiviral therapy 1

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Summary Algorithm

Active infection → STOP all immunosuppression (except maintain current steroid dose) → Treat infection → Restart after complete resolution

Perioperative → Reduce steroids to <10 mg/day preoperatively → Continue csDMARDs (except hold aza/MMF/cyclosporine 1-2 days) → Schedule surgery at end of biologic dosing interval → Hold JAK inhibitors 3-4 days → Restart when wound healing progressing

Vaccination → Screen and vaccinate BEFORE starting immunosuppression when possible → Hold only methotrexate for 2 weeks post-vaccine → Time rituximab to end of cycle, delay next dose 2 weeks → Never give live vaccines on immunosuppression