key: cord-0706784-yzx2mqwe
authors: Rubbert-Roth, Andrea; Schmiedeberg, Kristin; von Kempis, Johannes
title: Pausing drugs and spacing vaccines: an open question – Authors' reply
date: 2021-09-22
journal: Lancet Rheumatol
DOI: 10.1016/s2665-9913(21)00276-9
sha: 714e69ad53379eafd8c5539f3961b3751d009b44
doc_id: 706784
cord_uid: yzx2mqwe

nan

We read with interest the Article by Andrea Rubbert-Roth and colleagues, 1 which reported that among 53 patients with rheumatoid arthritis on various biological, conventional synthetic, and targeted synthetic disease-modifying anti-rheumatic drugs (DMARDs), antibody responses to COVID-19 vaccination was reduced compared with healthy controls.

The authors reported that their data implied that successful vaccination of patients with rheumatoid arthritis who are taking DMARDs might depend on an interval of 3-6 weeks between vaccinations, but we propose that a longer interval might be of benefit to some patients. Methotrexate is known to reduce the immunogenicity of influenza and pneumococcal vaccinations, 2 and Haberman and colleagues suggested that this fact might also be true of COVID-19 vaccination in patients with immunemediated inflammatory diseases. 3 It is possible that a short discontinuation of methotrexate might increase the immune response that is induced by COVID-19 vaccination. Indeed, one study of seasonal influenza vaccination in patients with rheumatoid arthritis receiving methotrexate noted that, in people with stable disease (mean Disease Activity Score 28-CRP=2·3 [SD 1·1]), a discontinuation of the drug for 2 weeks after vaccination resulted in greater humoral responses, without a convincing increase in flares (5·1% vs 10·6%; p=0·070) or use of rescue medications (4·5% vs 6·3%; p=0·49). 4 For an interval of 3 weeks between vaccine doses, methotrexate would need to be withheld for a total of 5 weeks. An interval of 12 weeks between doses of COVID-19 vaccine (ie, the recommended maximum interval in the UK) 5 would allow methotrexate to be safely discontinued for 2 weeks after to first dose, resumed for 10 weeks, and discontinued for a further 2 weeks after the second dose before returning to usual therapy. Another option would be the use of a single-dose vaccine, such as the Ad26.COV2.S vaccine (Janssen), which would require a pause in methotrexate therapy for just 2 weeks. In stable patients, this pause might allow optimisation of a vaccine-induced immune response without significant risk of disease flare. The external validity of these data is poor, and further research is required, particularly in patients with organ-threatening diseases (eg, antineutrophil cytoplasmic antibody-associated vasculitis and systemic lupus erythematosus). While we await large studies to support these findings, we suggest temporary methotrexate discontinuation as a pragmatic approach to maximising vaccine effectiveness in patients with a low risk of flare. MR 

We thank Mia Rodziewicz and colleagues for their interest in our Comment 1 on the immunogenicity of mRNA-based vaccines against SARS-CoV-2 in patients with rheumatoid arthritis and their discussion regarding the interval between the two vaccine doses. Most of our patients (44 [83%] of 53) received the mRNA-based BNT162b2 (Pfizer-BioNTech) vaccine and nine (17%) patients received the mRNA-1273 vaccine (Moderna); the interval between the first and second dose was 3-6 weeks according to Swiss federal regulations, which were based on the intervals that were proposed by the manufacturers. In contrast to mRNA-based vaccines, the ChAdOx1 nCoV-19 vaccine (AstraZeneca), which is used in the UK, consists of the replication-deficient simian adenovirus vector ChAdOx1 and the full-length structural surface glycoprotein (ie, spike protein) of SARS-CoV-2. To achieve a protective anti-SARS-CoV-2 immune response, two vaccine doses are considered to be necessary. In the case of a vectorbased vaccine, concern exists regarding the use of an early homologous boost, because an anti-vectordirected immune response might interfere with the effectiveness of the second vaccine dose to induce a potent anti-SARS-CoV-2-directed e684

www.thelancet.com/rheumatology Vol 3 October 2021 (HLH) from those with systemic juvenile idiopathic arthritisassociated macrophage activation syndrome (systemic JIA-MAS). 1 The authors identified that high serum concentrations of S100A12 and IL-18 and increased ratios of IL-18 to the chemokine (C-X-C motif) ligand (CXCL)9 and CXCL10 could differentiate between systemic JIA-MAS and HLH. 1 These findings could have substantial clinical implications if they allow for early diagnosis and accurate characterisation of hyperinflammatory syndromes that require rapid but vastly different treatments.

Notably, biomarkers were unable to differentiate primary from secondary HLH in this study. 1 However, the cohort of patients with secondary HLH included a diversity of pathogenic triggers, including Epstein-Barr virus (EBV; n=15), cytomegalovirus (n=5), bacteria (n=8), other viruses (n=9), metabolic syndrome (n=1), and unknown causes (n=6). Due to this heterogeneity, the ability of Kessel and colleagues to identify subtle differences in cytokines and chemokines might have been restricted, and this could have been further complicated by unidentified host factors driving the severity of these common infections. A similar article by Weiss and colleagues 2 not only showed the efficacy of increased IL-18 and IL-18 to CXCL9 ratios in differentiating between systemic JIA-MAS and HLH, but also found that these markers could not distinguish between primary and infectionassociated HLH. Weiss and colleagues' infection-triggered HLH cohort (n=20) was a similarly heterogeneous population to that in Kessel and colleagues' study.

These studies were not powered to detect unique biomarker profiles between pathogen subsets that trigger HLH; however, they provide proof-ofconcept that this might be possible. Infectious pathogens drive HLH pathophysiology through a variety of AR-R reports consulting fees from AbbVie, Gilead, Lilly, BMS, and Sanofi; honoraria from AbbVie, Pfizer, Sanofi, UCB, BMS, Lilly, Gilead, and Roche; payment for expert testimony from AbbVie and Gilead; support for travel or meeting attendance from Sanofi, Roche, and AbbVie; and compensation for participation on a data safety monitoring board from R-Pharm. KS reports support for travel or meeting attendance from AbbVie. JvK reports consulting fees from AbbVie, BMS, Pfizer, and Sanofi; honoraria from Lilly; and support for travel or meeting attendance from Pfizer. immune response. A pooled analysis of four randomised large trials with the ChAdOx1 nCoV-19 vaccine that included 24 422 participants (aged 18-55 years) showed that binding antibody responses were more than two-fold higher after an interval of 12 weeks or more than after an interval of less than 6 weeks (ie, geometric mean ratio 2·32 [95% CI 2·01-2·68]). 2 Slower kinetics and a lower magnitude of vaccine-induced anti-S1 antibodies have been reported in patients with rheumatic diseases receiving immunosuppressive therapies. 3 Vaccines that are based on mRNA require intracellular uptake, processing, and protein formation, in contrast to influenza vaccines, which are derived from viral cell culture or based on recombinant techniques. This contrast is one of the reasons why recommendations that are based on results from studies with the influenza vaccine in patients with rheumatic disorders receiving immunosuppressive therapies might not apply to the use of mRNA vaccines in these patients. No data are available regarding whether stopping DMARDs, including methotrexate, before COVID-19 vaccination, after vaccination, or both will improve immunogenicity. Discontinuation of DMARDs might put patients at risk for flares that might ultimately require glucocorticoids or an escalation of DMARD treatment.

Alternatively, the use of a third dose of an mRNA-based vaccine might increase vaccine immunogenicity in patients who are immunosuppressed, as described in a cohort of recipients of solid-organ transplants. 4 Measuring anti-S1 titres might help to select patients who are suitable for a third vaccine dose, as thresholds potentially corresponding to neutralisation of viral infectivity have been suggested. 5 Further data are needed to develop an optimised vaccine strategy against SARS-CoV-2 in patients with autoimmune diseases who are treated with immunosuppressive therapies.

We read with interest the Article in The Lancet Rheumatology by Christoph Kessel and colleagues 1 highlighting the capability of biomarker profiles to differentiate between patients with primary or secondary haemophagocytic lymphohistiocytosis

Anti-SARS-CoV-2 mRNA vaccine in patients with rheumatoid arthritis

Single-dose administration and the influence of the timing of the booster dose on immunogenicity and efficacy of ChAdOx1 nCoV-19 (AZD1222) vaccine: a pooled analysis of four randomised trials

Methotrexate hampers immunogenicity to BNT162b2 mRNA COVID-19 vaccine in immune-mediated inflammatory disease

Three doses of an mRNA Covid-19 vaccine in solid-organ transplant recipients

Performance of the rapid-high-throughput automated electrochemiluminescence immunoassay targeting total antibodies to the SARS-CoV-2 spike protein receptor binding domain in comparison to the neutralization assay