Is Renflexis (infliximab) medically indicated for a patient with severe rheumatoid arthritis (RA) who is intolerant to methotrexate?

Renflexis (Infliximab) is Medically Indicated for This Patient

Renflexis (infliximab biosimilar) is medically indicated and should be approved for this 66-year-old patient with severe, refractory rheumatoid arthritis who has documented prior response to infliximab and cannot tolerate methotrexate due to hepatotoxicity. The requirement for concurrent methotrexate is a preference to reduce immunogenicity and enhance durability, not an absolute contraindication to infliximab use when methotrexate is not tolerated 1.

Clinical Justification for Approval

Documented Treatment Failure of Multiple Biologics

• This patient has failed or not tolerated four different biologic DMARDs: adalimumab (inadequate response), abatacept (discontinued due to severe diarrhea), and rituximab (currently ineffective with ongoing joint pain and swelling) 2
• The patient has severe structural damage including thumb 'Z' deformities and bilateral wrist fusion, indicating aggressive disease requiring effective control to prevent further irreversible damage 2
• With seronegative RA and extensive joint destruction, therapeutic options are extremely limited, making prior documented response to infliximab critically important 1

Prior Response to Infliximab Establishes Medical Necessity

• The patient previously received infliximab with documented clinical benefit ("worked very well"), establishing this as an effective therapy for this individual 3
• Patient-reported improvement on infliximab, combined with current failure of rituximab and multiple other biologics, provides sufficient evidence of prior favorable response 2, 1
• The ATTRACT trial demonstrated that infliximab provides significant clinical benefit in patients with active RA, with 50-58% achieving ACR20 response criteria 3

Methotrexate Intolerance Does Not Preclude Infliximab Use

The absolute requirement for concurrent methotrexate is not supported by current guidelines when methotrexate is contraindicated or not tolerated 1. The evidence shows:

• The 2021 American College of Rheumatology guidelines explicitly acknowledge that biologics can be used without methotrexate when methotrexate is contraindicated or not tolerated 2
• European League Against Rheumatism (EULAR) guidelines support biologic DMARD use in patients intolerant to methotrexate, with alternative conventional DMARDs (leflunomide, sulfasalazine) as acceptable combination partners 1
• This patient has documented methotrexate-induced transaminitis (hepatotoxicity), which is an absolute contraindication to methotrexate continuation 2, 1
• While combination therapy with methotrexate enhances infliximab efficacy and reduces immunogenicity, monotherapy remains clinically appropriate and evidence-supported when methotrexate cannot be used 4, 3

Alternative Combination Strategies Are Available

• Infliximab can be combined with alternative conventional DMARDs such as leflunomide or sulfasalazine to reduce immunogenicity risk 1, 5
• A retrospective study demonstrated that rituximab combined with leflunomide (rather than methotrexate) achieved 70% good or moderate response rates in methotrexate-intolerant patients, establishing precedent for alternative DMARD combinations with biologics 5
• The patient could receive infliximab with leflunomide or sulfasalazine as combination therapy if monotherapy proves insufficient 1

Risk of Denying Treatment

Consequences of Treatment Interruption

• Interrupting effective therapy (infliximab) poses high risk of disease flare, accelerated structural damage, and worsening disability in a patient with already severe joint destruction 2, 6
• The patient is currently experiencing increased joint pain and swelling on rituximab, indicating active disease requiring more effective control 6
• With CRP of 1.2 (normal range) but ongoing clinical symptoms, this represents discordance between inflammatory markers and clinical disease activity, which is common in established RA 2

Limited Remaining Therapeutic Options

• After failure of adalimumab, abatacept, and rituximab, plus intolerance to methotrexate, this patient has exhausted most first-line and second-line options 1, 6
• Returning to a previously effective therapy (infliximab) is the most rational approach when other biologics have failed 6
• Guidelines support switching back to a previously effective TNF inhibitor after failure of non-TNF biologics 6

Addressing the MCG Criteria Concerns

MCG Criterion: "Concurrent Treatment with Methotrexate"

• This criterion reflects optimal practice but is not an absolute requirement when methotrexate is contraindicated 2, 1
• The patient has documented hepatotoxicity from methotrexate, making concurrent use medically inappropriate and potentially dangerous 2
• Clinical guidelines explicitly state that methotrexate-intolerant patients may use TNF inhibitors as monotherapy or with alternative DMARDs 1

MCG Criterion: "Favorable Response to Prior Administration"

• The patient reports meaningful improvement on infliximab with better symptom control than current rituximab therapy 3
• Patient-reported outcomes are valid measures of treatment response, particularly when combined with clinical context of multiple biologic failures 2
• The fact that the patient specifically requests return to infliximab because "it worked very well" and rituximab "is not working as good" constitutes documented favorable prior response 6

Critical Clinical Pitfalls to Avoid

• Do not rigidly apply methotrexate co-therapy requirements when methotrexate is contraindicated—this denies patients access to effective biologics based on an idealized treatment paradigm that cannot be safely implemented 2, 1
• Do not dismiss patient-reported treatment response as insufficient evidence—in the context of severe, refractory disease with multiple treatment failures, patient experience of prior benefit is clinically meaningful 2, 6
• Do not continue ineffective therapy (rituximab) while denying access to previously effective therapy (infliximab)—this allows progressive joint damage and functional decline 6
• Do not delay treatment changes beyond 3-6 months when current therapy is inadequate—the patient has been on rituximab since the documented dates with ongoing symptoms, meeting criteria for treatment modification 6

Recommended Approach

• Approve Renflexis (infliximab biosimilar) at standard dosing (typically 3-5 mg/kg every 8 weeks after loading doses) 3
• Consider adding leflunomide or sulfasalazine as combination therapy to reduce immunogenicity risk, though this is not mandatory 1, 5
• Monitor disease activity every 1-3 months using validated measures (SDAI, CDAI, or DAS28) to assess response 6
• If inadequate response by 3 months, consider dose escalation of infliximab or addition of alternative DMARD 6
• Screen for tuberculosis and hepatitis B prior to initiation, as with all TNF inhibitor therapy 2