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Vaccination against SARS-CoV-2 in rheumatic diseases: Safety issues

https://doi.org/10.47360/1995-4484-2022-21-31

Abstract

The problem of coronavirus disease 2019 (Coronavirus diseases, COVID-19) two years later still remains relevant both socially and medically. As one of the methods of combating the current COVID-19 pandemic, most experts rely on the widespread use of vaccination. However, the use of vaccines against SARS-CoV-2 in patients with rheumatic diseases (RD) raises a number of issues related to the effectiveness, immunogenicity, and safety of immunization, including leveling the risks of exacerbation of the underlying disease or the development of new autoimmune phenomena. For this reason it is very important to analyze data on the above-mentioned aspects in real time, especially given that patients of the rheumatology circle were excluded from the clinical development programs of vaccines against SARS-CoV-2. This review presents the results of last year’s research on the safety of vaccination against COVID-19 in patients with RS. A brief description of the main anticovedic vaccines is given. Post-vaccination adverse events were quite frequent after the first, second or both doses of vaccines in patients with RS, which is consistent with the data obtained in the general population. In general, the frequency of exacerbation of RD after vaccination against COVID-19 seems to be quite low (5–7%) and has no significant associations with a specific vaccine or anti-rheumatic therapy. At the same time, unambiguous interpretation of these data is difficult for at least three reasons: a) in many studies, only the symptoms developing after the first dose of the vaccine were taken into account; b) the time-limited post-vaccination follow-up period; c) significant discrepancies in the interpretation of exacerbations of the disease. Within the framework of the problem under consideration, there are still a lot of questions, the answers to which should be obtained in large prospective controlled studies.

About the Authors

B. S. Belov
V.A. Nasonova Research Institute of Rheumatology
Russian Federation

Boris Belov

115522, Moscow, Kashirskoye Highway, 34A


Competing Interests:

нет



A. M. Lila
V.A. Nasonova Research Institute of Rheumatology; Russian Medical Academy of Continuous Professional Education of the Ministry of Healthcare of the Russian Federation
Russian Federation

Alexander M. Lila

115522, Moscow, Kashirskoye Highway, 34A

125993, Moscow, Barrikadnaya str., 2/1, building 1


Competing Interests:

нет



E. L. Nasonov
V.A. Nasonova Research Institute of Rheumatology; I.M. Sechenov First Moscow State Medical University of the Ministry of Health Care of Russian Federation (Sechenov University)
Russian Federation

Evgeny L. Nasonov

115522, Moscow, Kashirskoye Highway, 34A

119991, Moscow, Trubetskaya str., 8, building 2


Competing Interests:

нет



References

1. Conway R, Grimshaw AA, Konig MF, Putman M, DuarteGarcía A, Tseng LY, et al. SARS-CoV-2 infection and COVID-19 outcomes in rheumatic disease: A systematic literature review and meta-analysis. Arthritis Rheumatol. 2021 Nov 22. doi: 10.1002/art.42030

2. Bertoglio IM, Valim JML, Daffre D, Aikawa NE, Silva CA, Bonfá E, et al. Poor prognosis of COVID-19 acute respiratory distress syndrome in lupus erythematosus: Nationwide crosssectional population study of 252 119 patients. ACR Open Rheumatol. 2021;3(11):804-811. doi: 10.1002/acr2.11329

3. Raiker R, Pakhchanian H, DeYoung C, Gupta L, Kardeş S, Ahmed S, Kavadichanda C. Short term outcomes of COVID-19 in lupus: Propensity score matched analysis from a nationwide multi-centric research network. J Autoimmun. 2021;125:102730. doi: 10.1016/j.jaut.2021.102730

4. Gupta S, Nakabo S, Chu J, Hasni S, Kaplan MJ. Association between anti-interferon-alpha autoantibodies and COVID-19 in systemic lupus erythematosus. medRxiv. 2020 Nov 3:2020.10.29.20222000. doi: 10.1101/2020.10.29.20222000

5. Bastard P, Rosen LB, Zhang Q, Michailidis E, Hoffmann HH, Zhang Y, et al. Autoantibodies against type I IFNs in patients with life-threatening COVID-19. Science. 2020;370(6515):eabd4585. doi: 10.1126/science.abd4585

6. Beigel JH, Tomashek KM, Dodd LE, Mehta AK, Zingman BS, Kalil AC, et al. Remdesivir for the treatment of COVID-19 – Final report. N Engl J Med. 2020;383(19):1813-1826. doi: 10.1056/NEJMoa2007764

7. WHO Solidarity Trial Consortium; Pan H, Peto R, HenaoRestrepo AM, Preziosi MP, Sathiyamoorthy V, et al. Repurposed antiviral drugs for COVID-19 – Interim WHO Solidarity Trial results. N Engl J Med. 2021;384(6):497-511. doi: 10.1056/NEJMoa2023184

8. Status of COVID-19 Vaccines within WHO EUL/PQ evaluation process. URL: https://extranet.who.int/pqweb/sites/default/files/documents/Status_COVID_VAX_23Dec2021.pdf [Accessed: 5th January 2020].

9. WHO lists 9th COVID-19 vaccine for emergency use with aim to increase access to vaccination in lower-income countries. URL: https://www.who.int/news/item/17-12-2021-who-lists-9thcovid-19-vaccine-for-emergency-use-with-aim-to-increaseaccess-to-vaccination-in-lower-income-countries [Accessed: 5th January 2020].

10. COVID-19 vaccine tracker and landscape. URL: https://www.who.int/publications/m/item/draft-landscape-of-covid-19-candidate-vaccines [Accessed: 5th January 2020].

11. Craven J. COVID-19 vaccine tracker. URL: https://www.raps.org/news-and-articles/news-articles/2020/3/covid-19-vaccine-tracker [Accessed: 5th January 2020].

12. English-Russian glossary of key terms on vaccinology and immunization (In Russ.). URL: https://alvilogistics.ru/static/links/WHO_RUS.pdf [Accessed: 5th January 2020].

13. Polack FP, Thomas SJ, Kitchin N, Absalon J, Gurtman A, Lockhart S, et al. Safety and Efficacy of the BNT162b2 mRNA COVID-19 vaccine. N Engl J Med. 2020;383(27):2603-2615. doi: 10.1056/NEJMoa2034577

14. Connolly CM, Ruddy JA, Boyarsky BJ, Barbur I, Werbel WA, Geetha D, et al. Disease flare and reactogenicity in patients with rheumatic and musculoskeletal diseases following two-dose SARSCoV-2 messenger RNA vaccination. Arthritis Rheumatol. 2022;74(1):28-32. doi: 10.1002/art.41924

15. Furer V, Eviatar T, Zisman D, Peleg H, Paran D, Levartovsky D, et al. Immunogenicity and safety of the BNT162b2 mRNA COVID-19 vaccine in adult patients with autoimmune inflammatory rheumatic diseases and in the general population: A multicentre study. Ann Rheum Dis. 2021;80(10):1330-1338. doi: 10.1136/annrheumdis-2021-220647

16. Fragoulis GE, Bournia VK, Mavrea E, Evangelatos G, Fragiadaki K, Karamanakos A, et al. COVID-19 vaccine safety and nocebo-prone associated hesitancy in patients with systemic rheumatic diseases: A cross-sectional study. Rheumatol Int. 2021 Nov 5:1-9. doi: 10.1007/s00296-021-05039-3

17. Barbhaiya M, Levine JM, Bykerk VP, Jannat-Khah D, Mandl LA. Systemic rheumatic disease flares after SARS-CoV-2 vaccination among rheumatology outpatients in New York City. Ann Rheum Dis. 2021;80(10):1352-1354. doi: 10.1136/annrheumdis-2021-220732

18. Geisen UM, Berner DK, Tran F, Sümbül M, Vullriede L, Ciripoi M, et al. Immunogenicity and safety of anti-SARS-CoV-2 mRNA vaccines in patients with chronic inflammatory conditions and immunosuppressive therapy in a monocentric cohort. Ann Rheum Dis. 2021;80(10):1306-1311. doi: 10.1136/annrheumdis-2021-220272

19. Ramirez GA, Della-Torre E, Moroni L, Yacoub MR, Dagna L; OSR-COVAX study group. Correspondence on “Immunogenicity and safety of anti-SARS-CoV-2 mRNA vaccines in patients with chronic inflammatory conditions and immunosuppressive therapy in a monocentric cohort”. Ann Rheum Dis. 2021;80(10):e159. doi: 10.1136/annrheumdis-2021-220539

20. Cherian S, Paul A, Ahmed S, Alias B, Manoj M, Santhosh AK, et al. Safety of the ChAdOx1 nCoV-19 and the BBV152 vaccines in 724 patients with rheumatic diseases: A post-vaccination crosssectional survey. Rheumatol Int. 2021;41(8):1441-1445. doi: 10.1007/s00296-021-04917-0

21. Medeiros-Ribeiro AC, Aikawa NE, Saad CGS, Yuki EFN, Pedrosa T, Fusco SRG, et al. Immunogenicity and safety of the CoronaVac inactivated vaccine in patients with autoimmune rheumatic diseases: A phase 4 trial. Nat Med. 2021;27(10):1744-1751. doi: 10.1038/s41591-021-01469-5

22. Fan Y, Geng Y, Wang Y, Deng X, Li G, Zhao J, et al. Safety and disease flare of autoimmune inflammatory rheumatic diseases: A large real-world survey on inactivated COVID-19 vaccines. Ann Rheum Dis. 2021 Nov 25:annrheumdis-2021-221736. doi: 10.1136/annrheumdis-2021-221736

23. Pinte L, Negoi F, Ionescu GD, Caraiola S, Balaban DV, Badea C, et al. COVID-19 vaccine does not increase the risk of disease flare-ups among patients with autoimmune and immune-mediated diseases. J Pers Med. 2021;11(12):1283. doi: 10.3390/jpm11121283

24. Braun-Moscovici Y, Kaplan M, Braun M, Markovits D, Giryes S, Toledano K, et al. Disease activity and humoral response in patients with inflammatory rheumatic diseases after two doses of the Pfizer mRNA vaccine against SARS-CoV-2. Ann Rheum Dis. 2021;80(10):1317-1321. doi: 10.1136/annrheumdis-2021-220503

25. Rotondo C, Cantatore FP, Fornaro M, Colia R, Busto G, Rella V, et al. Preliminary data on post market safety profiles of COVID 19 vaccines in rheumatic diseases: Assessments on various vaccines in use, different rheumatic disease subtypes, and immunosuppressive therapies: A two-centers study. Vaccines (Basel). 2021;9(7):730. doi: 10.3390/vaccines9070730

26. Esquivel-Valerio JA, Skinner-Taylor CM, Moreno-Arquieta IA, Cardenas-de la Garza JA, Garcia-Arellano G, GonzalezGarcia PL, et al. Adverse events of six COVID-19 vaccines in patients with autoimmune rheumatic diseases: A cross-sectional study. Rheumatol Int. 2021;41(12):2105-2108. doi: 10.1007/s00296-021-05017-9

27. Sattui SE, Liew JW, Kennedy K, Sirotich E, Putman M, Moni TT, et al. Early experience of COVID-19 vaccination in adults with systemic rheumatic diseases: Results from the COVID-19 Global Rheumatology Alliance Vaccine Survey. RMD Open. 2021;7(3):e001814. doi: 10.1136/rmdopen-2021-001814

28. Boekel L, Kummer LY, van Dam KPJ, Hooijberg F, van Kempen Z, Vogelzang EH, et al. Adverse events after first COVID-19 vaccination in patients with autoimmune diseases. Lancet Rheumatol. 2021;3(8):e542-e545. doi: 10.1016/S2665-9913(21)00181-8

29. Bartels LE, Ammitzbøll C, Andersen JB, Vils SR, Mistegaard CE, Johannsen AD, et al. Local and systemic reactogenicity of COVID-19 vaccine BNT162b2 in patients with systemic lupus erythematosus and rheumatoid arthritis. Rheumatol Int. 2021;41(11):1925-1931. doi: 10.1007/s00296-021-04972-7

30. Felten R, Kawka L, Dubois M, Ugarte-Gil MF, Fuentes-Silva Y, Piga M, Arnaud L. Tolerance of COVID-19 vaccination in patients with systemic lupus erythematosus: The international VACOLUP study. Lancet Rheumatol. 2021;3(9):e613-e615. doi: 10.1016/S2665-9913(21)00221-6

31. Izmirly PM, Kim MY, Samanovic M, Fernandez-Ruiz R, Ohana S, Deonaraine KK, et al. Evaluation of immune response and disease status in systemic lupus erythematosus patients following SARS-CoV-2 vaccination. Arthritis Rheumatol. 2021 Aug 4:10.1002/art.41937. doi: 10.1002/art.41937

32. Zavala-Flores E, Salcedo-Matienzo J, Quiroz-Alva A, BerrocalKasay A. Side effects and flares risk after SARS-CoV-2 vaccination in patients with systemic lupus erythematosus. Clin Rheumatol. 2021 Nov 16:1-9. doi: 10.1007/s10067-021-05980-5

33. Sciascia S, Costanzo P, Radin M, Schreiber K, Pini M, Vaccarino A, et al. Safety and tolerability of mRNA COVID-19 vaccines in people with antiphospholipid antibodies. Lancet Rheumatol. 2021;3(12):e832. doi: 10.1016/S2665-9913(21)00320-9

34. Hasseli R, Hoyer B, Lorenz H, Pfeil A, Richter J, Regierer A, et al. Safety of COVID-19 vaccines after first vaccination in patients with rheumatic diseases in a patient reported survey. Arthritis Rheumatol. 2021;73(Suppl 10):0100.

35. Michaud K, Cornish A, Freifeld A, Katz P, Wipfler K. COVID-19 mRNA vaccine side effects among individuals with rheumatic disease. Arthritis Rheumatol. 2021;73(Suppl 10):0116.

36. Gomez-Puerta J, Sapena N, Sarmiento-Monroy J, Azuaga A, Ruiz-Esquide V, Frade-Sosa B, et al. The safety profile of SARSCoV-2 vaccines among patients with immune-mediated rheumatic diseases. Arthritis Rheumatol. 2021;73(Suppl 10):0114.

37. Carbone A, Vukatana G, Vandelli E, Trevisani M, Rossi E, Mulè R, Fusconi M. Flares and side effects after COVID-19 vaccination in patients with rheumatic diseases. Arthritis Rheumatol. 2021;73(Suppl 10):1550.

38. Bulanov NM, Novikov PI, Gulyaev SV, Smitienko IO, Meshkov AD, Borodin OO, et al. Tolerability and safety of GamCOVID-Vac (Sputnik V) vaccine in adult patients with autoimmune rheumatic diseases. Clinical Pharmacology and Therapy. 2021;30(4):23-28 (In Russ.). doi: 10.32756/0869-5490-2021-4-23-28

39. Machado PM, Lawson-Tovey S, Strangfeld A, Mateus EF, Hyrich KL, Gossec L, et al. Safety of vaccination against SARSCoV-2 in people with rheumatic and musculoskeletal diseases: results from the EULAR Coronavirus Vaccine (COVAX) physician-reported registry. Ann Rheum Dis. 2021 Dec 31:annrheu mdis-2021-221490. doi: 10.1136/annrheumdis-2021-221490

40. Ramirez GA, Asperti C, Cucca V, Yacoub MR. Challenges to vaccination against SARS-CoV-2 in patients with immunemediated diseases. Vaccines (Basel). 2021;9(10):1147. doi: 10.3390/vaccines9101147

41. Khan N, Mahmud N. Effectiveness of SARS-CoV-2 vaccination in a veterans affairs cohort of patients with inflammatory bowel disease with diverse exposure to immunosuppressive medications. Gastroenterology. 2021;161(3):827-836. doi: 10.1053/j.gastro.2021.05.044

42. Sequeira JF, Cesic D, Keser G, Bukelica M, Karanagnostis S, Khamashta MA, Hughes GR. Allergic disorders in systemic lupus erythematosus. Lupus. 1993;2(3):187-191. doi: 10.1177/096120339300200311

43. Kronzer VL, Crowson CS, Sparks JA, Vassallo R, Davis JM 3rd. Investigating asthma, allergic disease, passive smoke exposure, and risk of rheumatoid arthritis. Arthritis Rheumatol. 2019;71(8):1217-1224. doi: 10.1002/art.40858

44. Mahil SK, Bechman K, Raharja A, Domingo-Vila C, Baudry D, Brown MA, et al. The effect of methotrexate and targeted immunosuppression on humoral and cellular immune responses to the COVID-19 vaccine BNT162b2: A cohort study. Lancet Rheumatol. 2021;3(9):e627-e637. doi: 10.1016/S2665-9913(21)00212-5

45. Simon D, Tascilar K, Fagni F, Krönke G, Kleyer A, Meder C, et al. SARS-CoV-2 vaccination responses in untreated, conventionally treated and anticytokine-treated patients with immune-mediated inflammatory diseases. Ann Rheum Dis. 2021;80(10):1312-1316. doi: 10.1136/annrheumdis-2021-220461

46. Engler RJ, Nelson MR, Klote MM, VanRaden MJ, Huang CY, Cox NJ, et al. Half- vs full-dose trivalent inactivated influenza vaccine (2004-2005): Age, dose, and sex effects on immune responses. Arch Intern Med. 2008;168(22):2405-2414. doi: 10.1001/archinternmed.2008.513

47. Pons-Estel BA, Catoggio LJ, Cardiel MH, Soriano ER, Gentiletti S, Villa AR, et al. The GLADEL multinational Latin American prospective inception cohort of 1,214 patients with systemic lupus erythematosus: Ethnic and disease heterogeneity among “Hispanics”. Medicine (Baltimore). 2004;83(1):1-17. doi: 10.1097/01.md.0000104742.42401.e2

48. Hernández Cruz B, Alonso F, Calvo Alén J, Pego-Reigosa JM, López-Longo FJ, Galindo-Izquierdo M, et al. Differences in clinical manifestations and increased severity of systemic lupus erythematosus between two groups of Hispanics: European Caucasians versus Latin American mestizos (data from the RELESSER registry). Lupus. 2020;29(1):27-36. doi: 10.1177/0961203319889667

49. Assawasaksakul T, Sathitratanacheewin S, Vichaiwattana P, Wanlapakorn N, Poovorawan Y, Kittanamongkolchai W. Immunogenicity, safety and reactogenicity of a heterogeneous booster following the CoronaVac inactivated SARS-CoV-2 vaccine in patients with SLE: A case series. RMD Open. 2021;7(3):e002019. doi: 10.1136/rmdopen-2021-002019

50. Allen-Philbey K, Stennett A, Begum T, Johnson AC, Dobson R, Giovannoni G, et al. Experience with the COVID-19 AstraZeneca vaccination in people with multiple sclerosis. Mult Scler Relat Disord. 2021;52:103028. doi: 10.1016/j.msard.2021.103028

51. Klugar M, Riad A, Mekhemar M, Conrad J, Buchbender M, Howaldt HP, Attia S. Side effects of mRNA-based and viral vector-based COVID-19 vaccines among german healthcare workers. Biology (Basel). 2021;10(8):752. doi: 10.3390/biology10080752

52. Pormohammad A, Zarei M, Ghorbani S, Mohammadi M, Razizadeh MH, Turner DL, Turner RJ. Efficacy and safety of COVID-19 vaccines: A systematic review and meta-analysis of randomized clinical trials. Vaccines (Basel). 2021;9(5):467. doi: 10.3390/vaccines9050467

53. Nasonov EL. Coronavirus disease 2019 (COVID-19) and autoimmunity. Nauchno-prakticheskaya revmatologiya = Rheumatology Science and Practice. 2021;59(1):5-30 (In Russ.). doi: 10.47360/1995-4484-2021-5-30

54. Bingham CO 3rd, Pohl C, Woodworth TG, Hewlett SE, May JE, Rahman MU, et al. Developing a standardized definition for disease “flare” in rheumatoid arthritis (OMERACT 9 Special Interest Group). J Rheumatol. 2009;36(10):2335-2341. doi: 10.3899/jrheum.090369

55. Signal assessment report on embolic and thrombotic events (SMQ) with COVID-19 vaccine (ChAdOx1-S [recombinant]) – Vaxzevria (previously COVID-19 Vaccine AstraZeneca) (Other viral vaccines) EPITT no:19683. URL: https://www.ema.europa.eu/en/documents/prac-recommendation/signal-assessment-reportembolic-thrombotic-events-smq-covid-19-vaccine-chadox1-srecombinant_en.pdf [Accessed: 5th January 2020].

56. Use of the AstraZeneca COVID-19 (AZD1222) vaccine: Updated JCVI statement, 7 May 2021. URL: https://www.gov.uk/government/publications/use-of-the-astrazeneca-covid-19-vaccine-jcvi-statement-7-may-2021/use-of-the-astrazenecacovid-19-azd1222-vaccine-updated-jcvi-statement-7-may-2021 [Accessed: 5th January 2020].

57. MHRA issues new advice, concluding a possible link between COVID-19 Vaccine AstraZeneca and extremely rare, unlikely to occur blood clots. URL: https://www.gov.uk/government/news/mhra-issues-new-advice-concluding-a-possible-linkbetween-covid-19-vaccine-astrazeneca-and-extremely-rareunlikely-to-occur-blood-clots [Accessed: 5th January 2020].

58. Moreno-Torres V, Gutiérrez Á, Valdenebro M, Ortega A, Cítores MJ, Montero E. Catastrophic antiphospholipid syndrome triggered by mRNA COVID-19 vaccine. Clin Exp Rheumatol. 2021 Dec 7.

59. Curtis JR, Johnson SR, Anthony DD, Arasaratnam RJ, Baden LR, Bass AR, et al. American College of Rheumatology guidance for COVID-19 vaccination in patients with rheumatic and musculoskeletal diseases: Version 3. Arthritis Rheumatol. 2021;73(10):e60-e75. doi: 10.1002/art.41928

60. Hazlewood GS, Pardo J, Barnabe C, Schieir O, Barber CEH, Bernatsky S, et al. Canadian Rheumatology Association recommendation for the use of COVID-19 vaccination for patients with autoimmune rheumatic diseases. J Rheumatol. 2021;48(8):1330-1339. doi: 10.3899/jrheum.210288

61. Santosa A, Xu C, Arkachaisri T, Kong KO, Lateef A, Lee TH, et al. Recommendations for COVID-19 vaccination in people with rheumatic disease: Developed by the Singapore Chapter of Rheumatologists. Int J Rheum Dis. 2021;24(6):746-757. doi: 10.1111/1756-185X.14107

62. Park JK, Lee EB, Shin K, Sung YK, Kim TH, Kwon SR, et al. COVID-19 vaccination in patients with autoimmune inflammatory rheumatic diseases: Clinical guidance of the Korean College of Rheumatology. J Korean Med Sci. 2021;36(12):e95. doi: 10.3346/jkms.2021.36.e95

63. Arnold J, Winthrop K, Emery P. COVID-19 vaccination and antirheumatic therapy. Rheumatology (Oxford). 2021;60(8):3496-3502. doi: 10.1093/rheumatology/keab223

64. Soy M, Keser G, Atagunduz P, Mutlu MY, Gunduz A, Koybaşi G, et al. A practical approach for vaccinations including COVID-19 in autoimmune/autoinflammatory rheumatic diseases: A non-systematic review. Clin Rheumatol. 2021;40(9):3533-3545. doi: 10.1007/s10067-021-05700-z

65. Furer V, Rondaan C, Agmon-Levin N, van Assen S, Bijl M, et al. Point of view on the vaccination against COVID-19 in patients with autoimmune inflammatory rheumatic diseases. RMD Open. 2021;7(1):e001594. doi: 10.1136/rmdopen-2021-001594

66. Ferretti F, Cannatelli R, Benucci M, Carmagnola S, Clementi E, Danelli P, et al. How to manage COVID-19 vaccination in immune-mediated inflammatory diseases: An expert opinion by IMIDs Study Group. Front Immunol. 2021;12:656362. doi: 10.3389/fimmu.2021.656362

67. Nasonov EL, Lila AM, Mazurov VI, Belov BS, Karateev AE, Dubinina TV, et al. Coronavirus disease 2019 (COVID-19) and immune-mediated rheumatic diseases. Recommendations of the Association of Rheumatologists of Russia. Nauchno-prakticheskaya revmatologiya = Rheumatology Science and Practice. 2021;59(3):239-254 (In Russ.) doi: 10.47360/1995-4484-2021-239-254


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Belov B.S., Lila A.M., Nasonov E.L. Vaccination against SARS-CoV-2 in rheumatic diseases: Safety issues. Rheumatology Science and Practice. 2022;60(1):21–31. (In Russ.) https://doi.org/10.47360/1995-4484-2022-21-31

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