Methotrexate as a corticosteroid-sparing agent in leprosy reactions: A French multicenter retrospective study.

INTRODUCTION: Leprosy reactions (LRs) are inflammatory responses observed in 30%-50% of people with leprosy. First-line treatment is glucocorticoids (GCs), often administered at high doses with prolonged courses, resulting in high morbi-mortality. Methotrexate (MTX) is an immunomodulating agent used to treat inflammatory diseases and has an excellent safety profile and worldwide availability. In this study, we describe the efficacy, GCs-sparing effect and safety of MTX in LRs. METHODS: We conducted a retrospective multicentric study in France consisting of leprosy patients receiving MTX for a reversal reaction (RR) and/or erythema nodosum leprosum (ENL) since 2016. The primary endpoint was the rate of good response (GR) defined as the complete disappearance of inflammatory cutaneous or neurological symptoms without recurrence during MTX treatment. The secondary endpoint was the GCs-sparing effect, safety and clinical relapse after MTX discontinuation. RESULTS: Our study included 13 patients with LRs (8 men, 5 women): 6 had ENL and 7 had RR. All patients had had at least one previous course of GCs and 2 previous treatment lines before starting MTX. Overall, 8/13 (61.5%) patients had GR, allowing for GCs-sparing and even GCs withdrawal in 6/11 (54.5%). No severe adverse effects were observed. Relapse after MTX discontinuation was substantial (42%): the median relapse time was 5.5 months (range 3-14) after stopping treatment. CONCLUSION: MTX seems to be an effective alternative treatment in LRs, allowing for GCs-sparing with a good safety profile. Furthermore, early introduction during LRs may lead to a better therapeutic response. However, its efficacy seems to suggest prolonged therapy to prevent recurrence.

Immunogenicity, efficacy, and safety of CoronaVac and Pfizer/BioNTech mRNA vaccines in patients with psoriasis receiving systemic therapies: A prospective cohort study.

BACKGROUND AND OBJECTIVES: Evidence of immune response to COVID-19 vaccine in psoriasis patients on biological agents is lacking. This study aimed to evaluate SARS-CoV-2 antibody levels following vaccination with CoronaVac or Pfizer/BioNTech mRNA in patients using biological agents or methotrexate, high-titer antibody levels achievement rate, and impact of medications on immunogenicity. METHODS: This noninterventional, prospective cohort study included 89 patients and 40 controls vaccinated with two doses of inactivated (CoronaVac) or Pfizer/BioNTech mRNA vaccines. Anti-spike and neutralising antibodies were analysed before and three to six weeks after the second dose. Adverse effects and symptomatic COVID-19 were assessed. RESULTS: Median anti-spike and neutralising antibody titers after CoronaVac were significantly lower in patients than controls (57.92 U/mL vs 125.4 U/mL, and 1/6 vs 1/32, respectively, p < 0.05). Patients were less likely to achieve high-titer anti-spike antibody levels (25.6 % vs 50 %). Infliximab was associated with attenuated vaccine response. Pfizer/BioNTech vaccine induced comparable median anti-spike (2,080 U/mL vs 2,976.5 U/mL,) and neutralising antibody levels (1/96 vs 1/160) in patients and controls, respectively (p > 0.05). High-titer anti-spike and neutralising antibodies development rates were comparable among patients and controls (95.2 % vs 100 %, and 30.4 % vs 50.0 %, respectively, p > 0.05). Nine (10.1 %) COVID-19 cases- all mild - were identified. Psoriasis flare was seen in 6.74 %, mostly after Pfizer/BioNTech vaccine. CONCLUSION: Psoriasis patients treated with biological agents and methotrexate developed similar response to mRNA vaccine but weaker response to inactivated vaccine. Infliximab reduced response to the inactivated vaccine. Adverse effects were more frequent with mRNA vaccine, but none was severe.

The effects of methotrexate on the immune responses to the COVID-19 vaccines in the patients with immune-mediated inflammatory disease: A systematic review of clinical evidence.

COVID-19 vaccines exhibit high levels of immunogenicity in the overall population. Data on the effects of immunomodulators on the consequences of COVID-19 in patients with Immune-mediated inflammatory diseases (IMIDs) remains scarce. This systematic review aimed to evaluate the immune responses to the COVID-19 vaccines in IMID patients receiving methotrexate (MTX) compared to healthy individuals. A comprehensive literature search was carried out using electronic databases such as PubMed, Web of Science, Scopus, Google Scholar, and Embase up to August 2022 to identify eligible RCTs evaluating the effect of MTX on immune responses in patients with COVID-19. The PRISMA checklist protocol was applied for the quality assessment of the selected trials. Our findings demonstrated that MTX lowered the responses of T cells and antibodies in IMID patients compared to healthy controls. We also discovered that young age (<60 years) was the main parameter influencing the antibody response after vaccination, while MTX had little effect. Following vaccination, MTX-hold and age were considered the main factors influencing the antibody response. In patients older than 60 years of age, the time point of 10 days of MTX discontinuation was critical to boosting the humoral response to anti-SARS-CoV-2 IgG. Because many IMID patients did not have adequate humoral and cellular responses, our findings highlighted the importance of second or booster doses of vaccine and temporary MTX discontinuation. As a result, it implies that individuals with IMIDs should be subjected to more research, particularly humoral and cellular immunity efficiency trials after COVID-19 vaccination, until credible information is achieved.

Impact of triple intrathecal prophylaxis in acute lymphoblastic leukemia adults receiving HyperCVAD: A COVID-19 practice change.

Treatment of acute lymphoblastic leukemia (ALL) requires both systemically and locally directed therapies to prevent central nervous system (CNS) recurrence. In response to restrictions brought on by the COVID-19 pandemic, our institution adopted triple intrathecal (IT) chemotherapy for CNS prophylaxis during HyperCVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with high-dose methotrexate and cytarabine). We retrospectively reviewed records of newly diagnosed adult all patients who were consecutively treated with HyperCVAD between January 2011 and July 2022. Outcomes of patients who received triple IT chemotherapy and standard of care (SOC) CNS prophylaxis were compared. The primary endpoint was CNS relapse-free survival (RFS) while secondary endpoints included cumulative incidence of relapse, overall survival, number of outpatient, and total ITs per patient, and CNS treatment-related toxicities. A total of 37 patients including 21 in the triple IT and 16 in the SOC cohorts were evaluated. There were no differences between the triple IT and SOC cohorts with respect to CNS-RFS (89.6% vs. 80.4%; HR, 1.55; 95% CI, 0.45-5.39; p = .49), cumulative incidence of relapse (8.9% vs. 19.6%; HR, 1.14; 95% CI, 0.3-5.3; p = .87), and overall survival (89.6% vs. 85.7%; HR, 0.91; 95% CI, 0.20-4.21; p = .90) at 2-years. Significantly fewer IT doses were administered in the triple IT cohort (p = .011) and the number of additional outpatient appointments to administer IT chemotherapy were markedly reduced as 98.6% of IT doses were administered during scheduled admissions compared to 76.8% (p < .001). The adoption of triple IT chemotherapy did not increase CNS treatment-related toxicities but rather, the inverse was observed. Triple IT chemotherapy during HyperCVAD represents a feasible alternative to SOC CNS prophylaxis, especially during times of resource restriction and when minimization of patient exposures is desired.

The effect of immunomodulators on seroconversion after BNT162b2 and AZD1222 vaccines in patients with immune-mediated inflammatory diseases: a prospective cohort study.

BACKGROUND: Biologic and nonbiologic immunomodulators, used to treat immune-mediated inflammatory diseases (IMIDs), could impair the immune response to COVID-19 vaccines and thus vaccine effectiveness. OBJECTIVES: Our objective was to investigate the association between biologic and nonbiologic immunomodulators and seroconversion following the first and second dose of COVID-19 vaccines in patients with IMIDs. METHODS: Serum samples were collected following the first or second dose of the BNT162b2 or AZD1222 vaccines from patients receiving biologic and/or nonbiologic immunomodulators for one or more of psoriasis, psoriatic arthritis, rheumatoid arthritis, inflammatory bowel disease or systemic lupus erythematosus. Seroconversion was defined as a positive Roche Elecsys® Anti-SARS-CoV-2 S (spike protein subunit S1/receptor binding domain) immunoassay (≥ 0.8 U mL-1). Association between immunomodulator exposure and seroconversion was assessed using logistic regression, adjusting for age and sex. RESULTS: After excluding those with prior COVID-19, post-first vaccine dose samples from 193 participants and post-second dose samples from 312 participants were included in the analysis. Following the first vaccine dose, 17.6% (n = 34) of participants did not seroconvert. Seroconversion was reduced for those on nonbiologic [adjusted odds ratio (OR) 0.29, 95% confidence interval (CI) 0.12-0.69] or combined nonbiologic and biologic treatment (adjusted OR 0.14, 95% CI 0.045-0.45) compared with those on biologic monotherapy. Subgroup analysis demonstrated reduced odds of seroconversion in those on methotrexate (adjusted OR 0.097, 95% CI 0.19-0.49) or prednisolone treatment (adjusted OR 0.044, 95% CI 0.002-1.00) relative to tumour necrosis factor-α inhibitor monotherapy. No participants receiving rituximab (n < 5) seroconverted after the first vaccine dose. Following the second vaccine dose, 1.6% of all participants did not seroconvert. Non-seroconversion was associated with receiving rituximab (n = 3 of 4) compared with those receiving other therapies (n = 2 of 308, P < 0.001). Post hoc analyses demonstrated that non-seroconversion was associated with age [adjusted OR 0.18, 95% CI 0.037-0.93 for those aged 60 years and over (reference category age 18-39 years)], but not sex, ethnicity or vaccine type. CONCLUSIONS: Treatment with nonbiologics, particularly methotrexate, is associated with impaired seroconversion following two BNT162b2 or AZD1222 vaccine doses, in patients with IMIDs. These findings are consistent with those of other published studies. While this could indicate reduced protection against COVID-19, the immunological parameters that correlate most closely with vaccine effectiveness need to be defined to reach this conclusion.

COVID-19 vaccination and recurrent anterior uveitis.

A 35-year-old Asian Indian female previously diagnosed with bilateral anterior uveitis and on oral methotrexate developed bilateral anterior uveitis following first/second dose of coronavirus disease 2019 (COVID-19) vaccination. She had skipped her weekly dose of oral methotrexate following first dose of vaccination. Following the second dose, she reduced her oral methotrexate from 25 to 15 mg on her own, but did not stop like the previous occasion. She had extensive workup for her uveitis in the past with only positive severe acute respiratory syndrome coronavirus (SARS-CoV-2) antibodies. She developed unilateral anterior uveitis after she had COVID-19 in July 2022, which resolved with topical steroids and continuation of immunosuppression. This report illustrates that COVID-19 or its vaccination may presumably play a role in triggering the immune system and can cause recurrent ocular inflammation even in the absence of an extraocular inflammation.

COVID-19 vaccination in psoriasis patients receiving systemic treatment: A prospective single-center study.

Background: The rate of seroconversion after COVID-19 vaccination in patients with moderate to severe psoriasis requiring systemic treatment is poorly understood. Objectives: The aim of this prospective single-center cohort study performed between May 2020 and October 2021 was to determine the rate of seroconversion after COVID-19 vaccination in patients under active systemic treatment for moderate to severe psoriasis. Methods: Inclusion criteria were systemic treatment for moderate to severe psoriasis, known COVID-19 vaccination status, and repetitive anti-SARS-CoV-2-S IgG serum quantification. The primary outcome was the rate of anti-SARS-CoV-2-S IgG seroconversion after complete COVID-19 vaccination. Results: 77 patients with a median age of 55.9 years undergoing systemic treatment for moderate to severe psoriasis were included. The majority of patients received interleukin- (n=50, 64.9%) or tumor necrosis factor (TNF)-α inhibitors (n=16, 20.8%) as systemic treatment for psoriasis; nine patients (11.7%) were treated with methotrexate (MTX) monotherapy, and one patient each received dimethyl fumarate (1.3%), respectively apremilast (1.3%). All included patients completed COVID-19 vaccination with two doses over the course of the study. Serum testing revealed that 74 patients (96.1%) showed an anti-SARS-CoV-2-S IgG seroconversion. While all patients on IL-17A, -12 or -12/23 inhibitors (n=50) achieved seroconversion, three of 16 patients (18.8%) receiving MTX and/or a TNF-α inhibitor as main anti-psoriatic treatment did not. At follow-up, none of the patients had developed symptomatic COVID-19 or died from COVID-19. Conclusions: Anti-SARS-CoV-2-S IgG seroconversion rates following COVID-19 vaccination in psoriasis patients under systemic treatment were high. An impaired serological response, however, was observed in patients receiving MTX and/or TNF-α inhibitors, in particular infliximab.

Safety and efficacy of induction immunochemotherapy with rituximab, methotrexate, ifosfamide, and vincristine (R-MIV) in patients with primary CNS lymphoma including recent COVID-19 pandemic experience.

Clinical data on primary central nervous system (CNS) lymphoma (PCNSL) patients is mostly generated from prospective studies, and many frail real-world patients are not included. Recently,the diagnosis and treatment of PCNSL patients was confounded by the COVID-19 pandemic. In particular, treatment with high-dose cytarabine was linked to increased risk of pneumonia and virus persistence. We report on outcome of the induction regimen R-MIV (rituximab, methotrexate, ifosfamide, and vincristine) involving intensive administration of high-dose methotrexate (3.5 g/m2 ) with ifosfamide, every 2 weeks and rituximab once per week for six doses. The median age and performance status (PS) for 64 patients was 58 years and 2 (PS 3; 22%) respectively. The overall response rate by magnetic resonance imaging/computed tomography (MRI/CT) was 73% (n = 46/63), with an additional 17.5% (n = 11/63) patients without measurable disease at baseline. Grade 3-4 haematological toxicity was low for R-MIV (neutropenia: 25% and thrombocytopenia: 1%). Three patients (4.7%) died from treatment-related toxicity. Co-existence of SARS-CoV-2 infection with cytomegalovirus reactivation and the varicella-zoster virus in two patients was fatal. Fifty patients (78%) were eligible for consolidation. Median progression-free and overall survival were not reached (median follow-up: 44 months). In conclusion, the R-MIV regimen is feasible in routine practice, effective and safe, even during the COVID-19 pandemic.

Waning humoral and cellular immunity after COVID-19 vaccination in patients with psoriasis treated with methotrexate and biologics: a cohort study.

BACKGROUND: mRNA-based COVID-19 vaccines have short- and long-term efficacy in healthy individuals, but their efficacy in patients with psoriasis receiving immunomodulatory therapy is less studied. OBJECTIVES: To investigate long-term immunity after COVID-19 vaccination in patients with psoriasis receiving immunomodulatory therapy. METHODS: A prospective cohort study including patients (n = 123) with psoriasis receiving methotrexate (MTX) or biologics and controls (n = 226). Only mRNA-based COVID-19 vaccines administered with standard intervals between doses were investigated. Markers of immunity included SARS-CoV-2 spike glycoprotein-specific IgG and IgA, neutralizing capacity, and interferon-γ release from T cells stimulated with peptides of the SARS-CoV-2 spike glycoprotein. RESULTS: The proportion of IgG responders was lower 6 months after vaccination in patients receiving anti-tumour necrosis factor (TNF) treatment compared with controls. Anti-TNF treatment was associated with lower IgG levels (ß = -0.82, 95% confidence interval -1.38 to -0.25; P = 0.001). The median neutralizing index was lower in the anti-TNF group [50% inhibition (interquartile range [IQR] 37-89)] compared with controls [98% inhibition (IQR 96-99)]; P < 0.001. Cellular responses were numerically lowest in the anti-TNF group. CONCLUSIONS: Treatment with anti-TNF has an impact on the immunity elicited by mRNA-based COVID-19 vaccination in patients with psoriasis, resulting in a faster waning of humoral and cellular markers of immunity; however, the clinical implications are unknown.

Impact of the COVID-19 pandemic on prescription refills for immune-mediated inflammatory disorders: a time series analysis (January 2019 to January 2021) using the English Prescribing Dataset.

OBJECTIVE: To investigate monthly prescription refills for common immunosuppressive/immunomodulatory therapy (sulfasalazine, hydroxychloroquine, azathioprine, methotrexate, leflunomide) prescriptions in England during the complete first wave of the COVID-19 pandemic. Secondary analysis examined unit cost analysis and regional use. DESIGN AND SETTING: A national cohort of community-based, primary care patients who anonymously contribute data to the English Prescribing Dataset, dispensed in the community in England, were included. Descriptive statistics and interrupted time series analysis over 25 months (14 months before, 11 months after first lockdown) were evaluated (January 2019 to January 2021, with March 2020 as the cut-off point). OUTCOME MEASURES: Prescription reimbursement variance in period before the pandemic as compared with after the first lockdown. RESULTS: Fluctuation in monthly medicines use is noted in March 2020: a jump is observed for hydroxychloroquine (Mann-Whitney, SE 14.652, standardised test statistic 1.911, p value=0.059) over the study period. After the first lockdown, medicines use fluctuated, with wide confidence intervals. Unit-cost prices changed substantially: sulfasalazine 33% increase, hydroxychloroquine 98% increase, azathioprine 41% increase, methotrexate 41% increase, leflunomide 20% decrease. London showed the least quantity variance, suggesting more homogeneous prescribing and patient access compared with Midlands and East of England, suggesting that some patients may have received medication over/under requirement, representing potential resource misallocation and a proxy for adherence rates. Changepoint detection revealed four out of the five medicines' use patterns changed with a strong signal only for sulfasalazine in March/April 2020. CONCLUSIONS: Findings potentially present lower rates of adherence because of the pandemic, suggesting barriers to care access. Unit price increases are likely to have severe budget impacts in the UK and potentially globally. Timely prescription refills for patients taking immunosuppressive/immunomodulatory therapies are recommended. Healthcare professionals should identify patients on these medicines and assess their prescription-day coverage, with planned actions to flag and follow-up adherence concerns in patients.

Methotrexate inhibition of SARS-CoV-2 entry, infection and inflammation revealed by bioinformatics approach and a hamster model.

Background: Drug repurposing is a fast and effective way to develop drugs for an emerging disease such as COVID-19. The main challenges of effective drug repurposing are the discoveries of the right therapeutic targets and the right drugs for combating the disease. Methods: Here, we present a systematic repurposing approach, combining Homopharma and hierarchal systems biology networks (HiSBiN), to predict 327 therapeutic targets and 21,233 drug-target interactions of 1,592 FDA drugs for COVID-19. Among these multi-target drugs, eight candidates (along with pimozide and valsartan) were tested and methotrexate was identified to affect 14 therapeutic targets suppressing SARS-CoV-2 entry, viral replication, and COVID-19 pathologies. Through the use of in vitro (EC50 = 0.4 µM) and in vivo models, we show that methotrexate is able to inhibit COVID-19 via multiple mechanisms. Results: Our in vitro studies illustrate that methotrexate can suppress SARS-CoV-2 entry and replication by targeting furin and DHFR of the host, respectively. Additionally, methotrexate inhibits all four SARS-CoV-2 variants of concern. In a Syrian hamster model for COVID-19, methotrexate reduced virus replication, inflammation in the infected lungs. By analysis of transcriptomic analysis of collected samples from hamster lung, we uncovered that neutrophil infiltration and the pathways of innate immune response, adaptive immune response and thrombosis are modulated in the treated animals. Conclusions: We demonstrate that this systematic repurposing approach is potentially useful to identify pharmaceutical targets, multi-target drugs and regulated pathways for a complex disease. Our findings indicate that methotrexate is established as a promising drug against SARS-CoV-2 variants and can be used to treat lung damage and inflammation in COVID-19, warranting future evaluation in clinical trials.

Immunogenicity of inactivated COVID-19 vaccine in patients with autoimmune inflammatory rheumatic diseases.

Progress has been made in COVID-19 vaccine development, with encouraging safety and efficacy data. The purpose of this study was to investigate the immunogenicity of inactivated COVID-19 vaccine in patients with autoimmune inflammatory rheumatic diseases (AIIRD). Patients with AIIRD (n = 101) were included in this study. All patients received 2 doses of inactivated COVID-19 vaccine. Serum anti-S1/RBD protein IgG was detected 2-16 weeks after the second vaccination. Seropositivity was defined as IgG ≥ 1.00 bound antibody unit S/CO. Immunogenicity of inactivated COVID-19 vaccine was assessed by seropositivity rate and the levels of serum IgG antibody against anti-S1/RBD protein, compared with the general population (n = 46). There was no difference by statistical significance in the seropositivity rate between patients with AIIRD (82.2%) and SLE (86.1%) and the control group (93.5%), p > 0.05. The level of anti-S1/RBD protein IgG antibodies in patients with AIIRD (median [IQR], 8.8 [2.2-17.3]) and SLE (median [IQR], 9.6 [2.4-20.4]) was comparable to that in the control group (median [IQR], 7.2 [3.1-14.2]), p > 0.05. Patients treated with glucocorticoids(GCs) (median dose, [IQR]: 2.5 mg/day [IQR 2.5-5.0]) or hydroxychloroquine(HCQ) or GCs + HCQ without other immunomodulatory medications, had an appropriate immunogenic response(88.1%) with high levels of anti-S1/RBD protein IgG(median [IQR], 12.1 [6.5-20.4]). Neither of patients treated with rituximab had positive serum antibodies, which was statistically significant, compared with the control group (p < 0.01). Compared with the control group, methotrexate(MTX) and iguratimod(IGU) was significantly reduced the level of anti-S1/RBD protein IgG antibodies. Inactivated COVID-19 vaccine had appropriate immunogenicity in patients with AIIRD. Immunogenicity of inactivated COVID-19 vaccine was severely impaired by rituximab, and also suppressed by MTX and IGU, while low doses of GC and HCQ had negligible effect.

Effect of interrupting methotrexate treatment on COVID-19 booster vaccine response.

Overview of: Abhishek A, Boyton RJ, Peckham N, et al Effect of a 2-week interruption in methotrexate treatment versus continued treatment on COVID-19 booster vaccine immunity in adults with inflammatory conditions (VROOM study): a randomised, open label, superiority trial. Lancet Respir Med 2022;10:840-50.

Pausing methotrexate prevents impairment of Omicron BA.1 and BA.2 neutralisation after COVID-19 booster vaccination.

OBJECTIVE: The level of neutralising capacity against Omicron BA.1 and BA.2 after third COVID-19 vaccination in patients on paused or continuous methotrexate (MTX) therapy is unclear. METHODS: In this observational cohort study, neutralising serum activity against SARS-CoV-2 wild-type (Wu01) and variant of concern Omicron BA.1 and BA.2 were assessed by pseudovirus neutralisation assay before, 4 and 12 weeks after mRNA booster immunisation in 50 rheumatic patients on MTX, 26 of whom paused the medication. 44 non-immunosuppressed persons (NIP) served as control group. RESULTS: While the neutralising serum activity against SARS-CoV-2 Wu01 and Omicron variants increased 67-73 fold in the NIP after booster vaccination, the serum activity in patients receiving MTX increased only 20-23 fold. Patients who continued MTX treatment during vaccination had significantly lower neutralisation against all variants at weeks 4 and 12 compared with patients who paused MTX and the control group, except for BA.2 at week 12. Patients who paused MTX reached comparably high neutralising capacities as NIP, except for Wu01 at week 12. The duration of the MTX pause after-not before-was associated with a significantly higher neutralisation capacity against all three variants, with an optimal duration at 10 days after vaccination. CONCLUSION: Patients pausing MTX after COVID-19 booster showed a similar vaccine response to NIP. Patients who continued MTX demonstrated an impaired response indicating a potentially beneficial second booster vaccination. Our data also suggest that a 1 week MTX break is sufficient if the last administration of MTX occurs 1-3 days before vaccination.

Reduced humoral response to a third dose (booster) of SARS-CoV-2 mRNA vaccines by concomitant methotrexate therapy in elderly patients with rheumatoid arthritis.

BACKGROUND: Several health authorities recommend a third (booster) vaccination to protect patients with rheumatic and musculoskeletal diseases from severe COVID-19. Methotrexate has been shown to reduce the efficacy of the first and second dose of SARS-CoV-2 mRNA vaccines. So far, it remains unknown how concomitant methotrexate affects the efficacy of a COVID-19 booster vaccination. METHODS: We compared the humoral immune response to SARS-CoV-2 vaccination in 136 patients with rheumatoid arthritis (RA) treated with methotrexate and/or biological or targeted synthetic (b/tsDMARDs). IgG targeting the receptor binding domain (RBD) of SARS-CoV-2 spike protein was measured at a median of 52.5 (range 2-147) days after a third dose of the SARS-CoV-2 mRNA vaccines BNT162b2 or mRNA-1273. RESULTS: Anti-RBD IgG was significantly reduced in elderly patients receiving concomitant treatment with methotrexate as compared with elderly patients receiving monotherapy with b/tsDMARDs or methotrexate (64.8 (20.8, 600.3) binding antibody units per mL (BAU/mL) vs 1106.0 (526.3, 4965.2) BAU/mL vs 1743.8 (734.5, 6779.6) BAU/mL, median (IQR), p<0.001, Kruskal-Wallis test). In younger patients (< 64.5 years), concomitant methotrexate had no significant impact on the humoral immune response. CONCLUSIONS: Concomitant methotrexate increases the risk of an insufficient humoral immune response to SARS-CoV-2 vaccination in elderly patients with RA. Pausing methotrexate during the third vaccination period may be considered for this group of patients.