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. 2023 May 17;23(1):332.
doi: 10.1186/s12879-023-08298-6.

Primary SARS-CoV-2 infection in patients with immune-mediated inflammatory diseases: long-term humoral immune responses and effects on disease activity

Koos P J van Dam #  1 , Adriaan G Volkers #  2 , Luuk Wieske  1   3 , Eileen W Stalman  1 , Laura Y L Kummer  1   4 , Zoé L E van Kempen  5 , Joep Killestein  5 , Sander W Tas  6 , Laura Boekel  7 , Gerrit J Wolbink  7 , Anneke J van der Kooi  1 , Joost Raaphorst  1 , R Bart Takkenberg  2 , Geert R A M D'Haens  2 , Phyllis I Spuls  8 , Marcel W Bekkenk  8 , Annelie H Musters  8 , Nicoline F Post  8 , Angela L Bosma  8 , Marc L Hilhorst  9 , Yosta Vegting  9 , Frederike J Bemelman  9 , Alexandre E Voskuyl  10 , Bo Broens  10 , Agner Parra Sanchez  6   10 , Cécile A C M van Els  11   12 , Jelle de Wit  11 , Abraham Rutgers  13 , Karina de Leeuw  13 , Barbara Horváth  14 , Jan J G M Verschuuren  15 , Annabel M Ruiter  15 , Lotte van Ouwerkerk  16 , Diane van der Woude  16 , Renée C F Allaart  16 , Y K Onno Teng  17 , Pieter van Paassen  18 , Matthias H Busch  18 , Papay B P Jallah  18 , Esther Brusse  19 , Pieter A van Doorn  19 , Adája E Baars  19 , Dirk Jan Hijnen  20 , Corine R G Schreurs  20 , W Ludo van der Pol  21 , H Stephan Goedee  21 , Maurice Steenhuis  4 , Sofie Keijzer  4 , Jim B D Keijser  4 , Olvi Cristianawati  4 , Anja Ten Brinke  4 , Niels J M Verstegen  4 , S Marieke van Ham  4   22 , Theo Rispens  4 , Taco W Kuijpers  23 , Mark Löwenberg #  2 , Filip Eftimov #  24 ; T2B! Immunity against SARS-CoV-2 study group
Affiliations

Primary SARS-CoV-2 infection in patients with immune-mediated inflammatory diseases: long-term humoral immune responses and effects on disease activity

Koos P J van Dam et al. BMC Infect Dis. .

Abstract

Background: Patients with immune-mediated inflammatory diseases (IMIDs) on immunosuppressants (ISPs) may have impaired long-term humoral immune responses and increased disease activity after SARS-CoV-2 infection. We aimed to investigate long-term humoral immune responses against SARS-CoV-2 and increased disease activity after a primary SARS-CoV-2 infection in unvaccinated IMID patients on ISPs.

Methods: IMID patients on active treatment with ISPs and controls (i.e. IMID patients not on ISP and healthy controls) with a confirmed SARS-CoV-2 infection before first vaccination were included from an ongoing prospective cohort study (T2B! study). Clinical data on infections and increased disease activity were registered using electronic surveys and health records. A serum sample was collected before first vaccination to measure SARS-CoV-2 anti-receptor-binding domain (RBD) antibodies.

Results: In total, 193 IMID patients on ISP and 113 controls were included. Serum samples from 185 participants were available, with a median time of 173 days between infection and sample collection. The rate of seropositive IMID patients on ISPs was 78% compared to 100% in controls (p < 0.001). Seropositivity rates were lowest in patients on anti-CD20 (40.0%) and anti-tumor necrosis factor (TNF) agents (60.5%), as compared to other ISPs (p < 0.001 and p < 0.001, respectively). Increased disease activity after infection was reported by 68 of 260 patients (26.2%; 95% CI 21.2-31.8%), leading to ISP intensification in 6 out of these 68 patients (8.8%).

Conclusion: IMID patients using ISPs showed reduced long-term humoral immune responses after primary SARS-CoV-2 infection, which was mainly attributed to treatment with anti-CD20 and anti-TNF agents. Increased disease activity after SARS-CoV-2 infection was reported commonly, but was mostly mild.

Trial registration: NL74974.018.20, Trial ID: NL8900. Registered on 9 September 2020.

Keywords: Antibodies; Autoimmune disease; Covid-19; Disease activity; Flare; Immune-mediated inflammatory diseases; Immunity; Immunosuppression; SARS-CoV-2; TNF.

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Conflict of interest statement

Joep Killestein, has speaking relationships with Merck, Biogen, TEVA, Sanofi, Genzyme, Roche and Novartis. AmsterdamUMC, location VUmc, MS Center Amsterdam has received financial support for research activities from Merck, Celgene, Biogen, GlaxoSmithKline, Immunic, Roche, Teva, Sanofi, Genzyme, and Novartis. Geert D’Haens has been a consultant for AbbVie, Agomab, AstraZeneca, AM Pharma, AMT, Arena Pharmaceuticals, Bristol Meiers Squibb, Boehringer Ingelheim, Celltrion, Eli Lilly, Exeliom Biosciences, Exo Biologics, Galapagos, Index Pharmaceuticals, Kaleido, Roche, Gilead, GlaxoSmithKline, Gossamerbio, Pfizer, Immunic, Johnson & Johnson, Origo, Polpharma, Procise Diagnostics, Prometheus Laboratories, Prometheus Biosciences, Progenity, and Protagonist; and has received speaker’s bureau fees from AbbVie, Arena Pharmaceuticals, Galapagos, Gilead, Pfizer, BMS, and Takeda. Phyllis Spuls is involved in performing clinical trials with many pharmaceutical industries that manufacture drugs used for the treatment of e.g. psoriasis and atopic dermatitis, for which financial compensation is paid to the department/hospital and is one of the main investigator of the TREAT registry taskforce and SECURE-AD registry. Barbara Horváth reports fees from Janssen-Cilag (Advisory Boards, Educational grants, Consultations, Investigator Initiative Studies), AbbVie (Advisory Boards, Educational grants, Consultations, Investigator Initiative Studies), Novartis Pharma (Advisory Boards, Consultations, Investigator Initiative Studies), UCB Pharma (Advisory Boards, Consultations), Leo Pharma (Consultations), Solenne B.V. (Investigator Initiative Studies), Celgene (Consultations, Investigator Initiative Studies), Akari therapeutics (Consultations, Investigator Initiative Studies), Philips (Consultation), Roche (Consultation), Regeneron (Consultation) and Sanofi (Consultation), Argenx (Advisory Boards, Consultations) which fees were paid to the institution. Jan Verschuuren receives financial support from Target to B consortium, Prinses Beatrix Spierfonds, and has been involved in trials or consultancies for Argenx, Alexion, Rapharma. He is coinventor on patent applications based on MuSK-related research. The LUMC received royalties from IBL and Argenx for MG research. All reimbursements were received by the LUMC. The authors are members of the European Reference Network for Rare Neuromuscular Diseases [ERN EURO-NMD]. DirkJan Hijnen is investigator for AbbVie, LEO pharma, MedImmune/AstraZeneca, Novartis, Sanofi/Regeneron; consultancies for Regeneron/Sanofi, LEO pharma, MedImmune/AstraZeneca, Novartis, Incyte, Janssen, Pfizer. Mark Löwenberg has served as speaker and/or principal investigator for: Abbvie, Alimentiv, Bristol Myers Squibb, Celgene, Covidien, Dr. Falk, Ferring Pharmaceuticals, Galapagos, Gilead, GlaxoSmithKline, Janssen-Cilag, Merck Sharp & Dohme, Pfizer, Protagonist therapeutics, Receptos, Takeda, Tillotts, Tramedico. He has received research grants from AbbVie, Merck Sharp & Dohme, Dr Falk, Achmea healthcare, Galapagos and ZonMW. Filip Eftimov reports (governmental) grants from ZonMw (the Netherlands Organization for Health Research and Development) to study immune responses after SARS-CoV-2 vaccination in autoimmune diseases. He also received grants from Prinses Beatrix Spierfonds, CSL Behring, Kedrion, Terumo BCT, Grifols, Takeda Pharmaceutical Company, and Guillain-Barré Syndrome-Chronic Inflammatory Demyelinating Polyneuropathy (GBS-CIDP) Foundation; consulting fees from UCB Pharma and CSl Behring; and honoraria from Grifols. Diane van der Woude has received research grants from Inova diagnostics, FOREUM (Foundation for Research in Rheumatology) and ZonMw (the Netherlands Organization for Health Research and Development), as well as consulting fees from Galapagos. All other authors had no conflicts of interest. The authors/Several authors of this publication are members of the Netherlands Neuromuscular Center (NL-NMD) and the European Reference Network for rare neuromuscular diseases EURO-NMD.

Figures

Fig. 1
Fig. 1
Study flowchart. ISP Immunosuppressant, PCR Polymerase chain reaction, SARS-CoV-2 Severe acute respiratory syndrome coronavirus 2
Fig. 2
Fig. 2
Seropositivity per specific ISP group. Seropositivity percentages of analyzed samples for A) ISP vs controls, B) specific ISP groups within the ISP group, with corresponding 95% CI’s. CI Confidence interval, ISP Immunosuppressant, TNF Tumor necrosis factor
Fig. 3
Fig. 3
Effect of time since infection on anti-RBD antibody titer. Relation between SARS-CoV-2 RBD-specific antibody titer from all serum samples (dots) and time in days from SARS-CoV-2 infection to obtaining the serum sample. The colored lines are regression lines of titers, for patients with anti-TNF (rs = -0.27; p = 0.05), other ISP (rs = -0.29; p < 0.01), and controls (rs = -0.32; p < 0.01). Colored dots reflect samples of patients with anti-TNF, other ISP, and controls. AU Arbitrary units, ISP Immunosuppressant, RBD Receptor-binding domain, rs Spearman’s rho, TNF Tumor necrosis factor
Fig. 4
Fig. 4
Disease activity after primary SARS-CoV-2 infection per IMID. Bar chart showing proportions of increase in IMID activity after SARS-CoV-2 primo infection per IMID. Different categories of severity of the increase in IMID activity are shown in colors. Proportions are all derived from the IMID group size, shown on the Y-axis. IBD Inflammatory bowel disease, IMID Immune-mediated inflammatory disorder, MS Multiple sclerosis, NMO Neuromyelitis optica, SLE Systemic lupus erythematosus
See this image and copyright information in PMC

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