Influence of Methotrexate Discontinuation on Immunogenicity After PCV-20 Vaccine in Patients ARDs

Effect of Methotrexate Discontinuation on Immunogenicity of 20-valent Pneumococcal Conjugate Vaccine (PCV20) in Patients With Autoimmune Rheumatic Diseases

This clinical trial aims to evaluate the effect of temporary methotrexate (MTX) discontinuation on the humoral immunogenicity of the 20-valent pneumococcal conjugate vaccine (PCV20) in adult patients with autoimmune rheumatic diseases (ARDs).

Key questions:

• Does suspending MTX for 2 weeks after PCV20 enhance humoral immunogenicity?
• What is the impact of MTX discontinuation on functional opsonophagocytic activity (OPA) and cellular immunity?
• What is the risk of disease flaring with MTX withdrawal?

Patients with autoimmune rheumatic diseases (ARDs) have an increased risk of infections, including invasive pneumococcal disease, due to underlying immune dysregulation and the frequent use of immunosuppressive therapies. Pneumococcal vaccination is strongly recommended in this population; however, methotrexate (MTX), a cornerstone therapy for ARDs, has been consistently associated with reduced vaccine immunogenicity.

Evidence from randomized clinical trials in influenza and COVID-19 vaccination has demonstrated that short-term MTX discontinuation (10-14 days post-vaccination) can significantly enhance humoral immune responses. However, this strategy may be accompanied by an increased risk of mild disease flare. Importantly, no study to date has evaluated the effect of temporary MTX discontinuation on pneumococcal vaccination, representing a critical knowledge gap in the care of immunosuppressed patients.

The 20-valent pneumococcal conjugate vaccine (PCV20) represents the most comprehensive pneumococcal conjugate vaccine currently licensed, covering 20 serotypes responsible for the majority of invasive disease. Unlike polysaccharide vaccines, conjugate vaccines generate T-cell dependent immune responses, leading to higher-quality and longer-lasting protection. Yet, the immunogenicity of PCV20 in patients with ARDs under MTX therapy has not been investigated.

This randomized, double-blind, controlled clinical trial will evaluate the impact of a 2-week MTX discontinuation following PCV20 vaccination in patients with ARDs in remission or low disease activity. A total of 192 adult patients will be enrolled and randomized 1:1 to either suspend MTX for 2 weeks after vaccination or continue MTX treatment as usual.

All participants will receive one dose of PCV20 at baseline (D0). Blood samples will be collected at baseline (D0), 4 weeks post-vaccination (D28), and 6 months post-vaccination (D180). Humoral immunogenicity will be assessed by quantifying IgG antibody concentrations against 12 vaccine serotypes using multiplex Luminex assays. In addition, we will evaluate serotype-specific opsonophagocytic activity (OPA) assays to assess functional antibody responses.

Disease activity will be monitored throughout the study using standardized indices (DAS28 for rheumatoid arthritis, ASDAS for spondyloarthritis, SLEDAI for systemic lupus erythematosus, MMT for myopathies, among others).

Safety assessments will include the recording of local and systemic adverse events in structured diaries and surveillance for disease flares, with predefined management protocols.

The primary endpoint is the seroconversion rate at 4 weeks after PCV20, defined as at least a twofold increase in IgG antibody levels for ≥50% of included serotypes.

Secondary endpoints include persistence of humoral immunity at 6 months, OPA titers, disease flare rates and adverse events.

By directly addressing the effect of MTX on PCV20 immunogenicity and incorporating both functional and cellular immune measures, this trial will generate critical evidence to guide vaccination strategies in immunosuppressed patients with ARDs and has the potential to inform future international guidelines.

Inclusion Criteria:

• Adults (>=18 years ) with confirmed ARD diagnosis (e.g., RA, PsA, axial SpA, primary Sjögren's, SLE, IIM, SSc, MCTD).
• Stable MTX dose ≥12 weeks.
• Prednisone ≤5 mg/day.
• Low disease activity/remission according to specific disease activity criteria.
• Eligible for PCV20 vaccination (no prior PCV20).

Exclusion Criteria:

• Anaphylaxis to vaccine components.
• Acute febrile illness.
• Guillain-Barré, decompensated CHF (NYHA III-IV), demyelinating disease.
• Live virus vaccine ≤4 weeks or inactivated vaccine ≤2 weeks before.
• Blood products in last 6 months.
• Severe infection in last month (including pneumococcal).
• Hospitalization at enrollment.
• Refusal to participate or inability to complete study procedures.