What are the guidelines for using Methotrexate and CIMZIA (Certolizumab pegol) concomitantly in an adult patient with a history of rheumatoid arthritis?

Concomitant Use of Methotrexate and CIMZIA in Rheumatoid Arthritis

Methotrexate combined with certolizumab pegol (CIMZIA) is highly effective and appropriate for adults with rheumatoid arthritis who have inadequate response to methotrexate monotherapy, providing rapid and sustained improvement in disease activity, inhibition of joint damage, and improved physical function. 1, 2

Evidence for Combination Therapy

The combination of CIMZIA 400 mg at weeks 0,2, and 4, followed by 200 mg every 2 weeks plus methotrexate, demonstrates superior efficacy compared to methotrexate alone:

• ACR50 response rates reach 25% absolute improvement at 24 weeks (NNTB of 4), with benefits evident as early as week 1 and sustained through 52 weeks 3, 2
• Radiographic progression is significantly inhibited, with mean Sharp score progression of only 0.4 units at 52 weeks compared to 2.8 units with placebo plus methotrexate 2
• Disease remission (DAS < 2.6) is achieved in 10% more patients (NNTB of 8) compared to methotrexate alone 3
• Physical function improves by 12% absolute improvement on HAQ-DI (NNTB of 8) 3

Dosing Protocol

Start with the loading dose regimen followed by maintenance therapy:

• Loading: CIMZIA 400 mg subcutaneously at weeks 0,2, and 4 2
• Maintenance: CIMZIA 200 mg subcutaneously every 2 weeks thereafter 1, 2
• Methotrexate: Continue stable dose of 15-25 mg weekly (oral or subcutaneous) 4
• Folic acid: Prescribe at least 5 mg per week to reduce gastrointestinal and hepatic toxicity without compromising efficacy 4, 5

The 200 mg every-other-week maintenance dose provides equivalent efficacy to 400 mg with potentially better tolerability 1, 3.

Safety Monitoring Requirements

Implement rigorous monitoring given the combination immunosuppression:

• Baseline assessment: Complete blood count (CBC), liver function tests (ALT/AST), creatinine, hepatitis B/C serology, tuberculosis screening, and chest radiograph 4
• During initiation: Monitor CBC, creatinine, and liver enzymes every 1-1.5 months until stable dose achieved 6
• Maintenance monitoring: CBC and liver function tests every 1-3 months with clinical assessment at each visit 4, 6
• Liver enzyme management: Adjust methotrexate dose if ALT/AST persistently elevated 2-3 times upper limit of normal; discontinue if >3 times upper limit of normal 4

Safety Profile of Combination Therapy

The 5-year safety data from RAPID 1 demonstrates acceptable long-term tolerability:

• Overall adverse event rate: 290.4 per 100 patient-years, with most events mild to moderate 1
• Most common adverse events: urinary tract infections (7.9 per 100 patient-years), nasopharyngitis (7.3), and upper respiratory infections (7.3) 7, 1
• Serious adverse events: 20.3 per 100 patient-years (infections 5.9, malignancies 1.2) 1
• Serious adverse events show a 3% absolute increase (NNTH of 33) compared to methotrexate alone, which is statistically but not clinically significant 3
• Mortality rate: 0.6 per 100 patient-years over 5 years 1

Treatment Persistence

Long-term retention on combination therapy is favorable:

• 55.3% of patients remain on treatment at 5 years (week 256) 1
• When considering only withdrawals due to adverse events or lack of efficacy, retention increases to 68.7% 1
• Withdrawals due to adverse events occur in 2% more patients (NNTH of 58) compared to methotrexate monotherapy 3

Critical Management Considerations

Address these specific scenarios to optimize safety:

• Infections requiring antibiotics: Interrupt both methotrexate and CIMZIA; resume after recovery and antibiotic completion 8
• Bone marrow suppression: Hold methotrexate if WBC <3.5×10⁹/L or neutrophils <2×10⁹/L 8
• Elevated MCV (>105 fL): Withhold or decrease methotrexate dose, as this indicates folate deficiency 5
• Perioperative management: Methotrexate can be safely continued for elective orthopedic surgery, but consider interruption for major surgeries with comorbidities 4, 8
• Renal impairment: Exercise extreme caution, as declining renal function increases methotrexate toxicity risk significantly 9

Drug Interactions to Avoid

Recognize high-risk combinations that increase methotrexate toxicity:

• Avoid cotrimoxazole (trimethoprim-sulfamethoxazole), as it inhibits folate utilization and can cause pancytopenia 9
• Avoid probenecid, which inhibits renal tubular secretion of methotrexate 9
• Use NSAIDs cautiously, particularly in patients with reduced renal function, though interactions may not be clinically significant in most cases 9

Contraindications

Do not use this combination in the following situations:

• Pregnancy or planned pregnancy within 3 months (both partners) 4
• Active serious infections 7
• Breastfeeding 4
• Severe renal impairment without dose adjustment 9

Long-Term Efficacy

Sustained clinical benefits are maintained over 5 years:

• DAS28 remission rates and improvements from baseline persist through week 256 of treatment 1
• No new safety signals emerge with long-term use 1
• The combination provides a favorable risk-benefit profile for extended treatment duration 1