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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
PREVENTION
Masking
DOUBLE
Enrollment
192
All participants will receive a single intramuscular dose (0.5 mL) of PCV20 (Prevnar 20®, Pfizer), administered into the deltoid muscle at baseline (Day 0). PCV20 contains purified capsular polysaccharides of 20 pneumococcal serotypes (1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 14, 15B, 18C, 19A, 19F, 22F, 23F, and 33F), individually conjugated to the nontoxic diphtheria CRM197 carrier protein. The conjugation induces a T-cell dependent immune response, resulting in higher-affinity antibodies and immune memory compared to polysaccharide vaccines.
Reumatology division of Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo
São Paulo, São Paulo, Brazil
RECRUITINGSeroconversion Rate After Vaccination
Proportion of participants who achieve seroconversion, defined as at least a twofold increase in IgG antibody concentrations for ≥50% of PCV20 vaccine serotypes (1, 3, 4, 5, 6B, 7F, 8, 9V, 12F, 14, 19A e 23F) compared to baseline, measured by multiplex Luminex assay.
Time frame: Day 28 (4 weeks post-vaccination).
Opsonophagocytic Activity (OPA) Response
Functional antibody response will be assessed according to the serotype-specific opsonophagocytic activity (OPA), defined as at least a twofold increase in IgG antibody concentrations for ≥50% of vaccine serotypes (6B, 8, 12F, 14, 19A and 23F) compared to baseline.
Time frame: Day 0 to Day 28
Persistence of Humoral Immunity
Persistence of IgG antibody response assessed by Luminex and OPA assays by specific vaccine serotypes.
Time frame: Day 180 (6 months post-vaccination).
Frequency of Disease Flares in Rheumatoid Arthritis
To assess the effect of temporary MTX discontinuation on disease activity in participants with rheumatoid arthritis, as measured by the Disease Activity Score 28 (DAS28). The DAS28 includes a count of tender and swollen joints (out of 28), a measure of general health (VAS), and either ESR or CRP. Scores range from approximately 0.9 to 9.4, with higher scores indicating worse disease activity.
Time frame: Baseline through Day 28.
Frequency of Disease Flares in Spondyloarthritis
To evaluate the impact of MTX discontinuation on disease activity in participants with spondyloarthritis, as measured by the Ankylosing Spondylitis Disease Activity Score (ASDAS). The ASDAS combines patient-reported outcomes (back pain, duration of morning stiffness, peripheral pain/swelling, and global assessment) and an objective measure of inflammation (CRP or ESR). Scores range from approximately 0.6 to 6, with higher values indicating worse disease activity.
Time frame: Baseline through Day 28
Frequency of Disease Flare in Systemic Lupus Erythematosus
To assess the frequency of disease flares in participants with systemic lupus erythematosus following MTX discontinuation, using the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K). SLEDAI-2K scores range from 0 to 105, with higher scores indicating more severe disease activity. A flare is defined as an increase in SLEDAI-2K score from baseline based on pre-established thresholds.
Time frame: Baseline through Day 28
Frequency of Disease Flare in Myopathies
To evaluate the impact of MTX discontinuation on muscle strength in patients with idiopathic inflammatory myopathies, using the Manual Muscle Testing-8 (MMT-8) scale. The MMT-8 score ranges from 0 to 80, with higher scores indicating greater muscle strength and better clinical outcomes. A decrease in score indicates clinical worsening.
Time frame: Baseline through Day 28
Frequency of Disease Flares in Psoriatic Arthritis
To assess the frequency of disease flares following MTX discontinuation in participants with Psoriatic Arthritis, using the Disease Activity Index for Psoriatic Arthritis (DAPSA). Disease flares will be defined as worsening in disease activity classification (e.g., from remission to low, or from low to moderate activity). The DAPSA score ranges as follows: Remission (0-4), Low (5-14), Moderate (15-28) and High (\>28). Higher scores indicate worse disease activity.
Time frame: Baseline through Day 28
Frequency of Disease Flares in Primary Sjögren's Syndrome
To evaluate the frequency of disease flares after MTX discontinuation in participants with primary Sjögren's Syndrome using the EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI). Disease flare will be defined as a clinically significant increase in ESSDAI score. The total ESSDAI score ranges from 0 to 123, with higher scores indicating more severe disease activity.
Time frame: Baseline through Day 28
Frequency of Disease Flares in Behçet's Disease
To determine the frequency of disease flares in patients with Behçet's Disease following MTX discontinuation, using the Behçet's Disease Current Activity Form - Simplified (BDCAF-s). Disease activity will be evaluated based on the presence and severity of clinical features (e.g., oral/genital ulcers, ocular involvement, skin lesions, etc.). Flare will be defined as the appearance or worsening of clinical manifestations as documented in the BDCAF-s.
Time frame: Baseline through Day 28
Frequency of Disease Flares in Systemic Sclerosis
To evaluate the frequency of disease flares in systemic sclerosis after MTX discontinuation using a composite clinical approach. Flare will be defined as the occurrence of one or more of the following: Increase in modified Rodnan Skin Score, Development of new digital ulcers, Worsening dyspnea score, Significant clinical change based on the EULAR disease activity assessment for systemic sclerosis.
Time frame: Baseline through Day 28
Adverse events
Safety will be closely monitored, and all serious adverse events will be classified as related or unrelated to the vaccine. A standardized adverse event diary will be provided to all patients and healthy controls for recording local and systemic reactions during the 4 weeks following each vaccine dose. Local reactions include: injection site pain, redness, swelling, bruising, itching, and induration. Systemic reactions include: fever, fatigue, chills, malaise, drowsiness, loss of appetite, nausea, vomiting, diarrhea, abdominal pain, dizziness, tremors, headache, fatigue, myalgia, muscle weakness, arthralgia, pruritus, and skin rash.
Time frame: Baseline through Day 28
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