Imiwnedd Humoral A Cellog mewn COVID ymadfer-19 Pobl â Sglerosis Ymledol sy'n cael eu Trin Gydag Ofatumumab

I ddysgu mwy o wybodaeth plz cysylltwchdavid.wan@wecistanche.com

A B S T R A C T   Objectives: To report clinical outcome, development of humoral and T-cell mediated immunity in convalescent COVID-19 people with multiple sclerosis (pwMS) treated with ofatumumab in the ALITHIOS study from a single center. Methods: Testing for SARS-Cov2 IgG antibodies was performed on two occasions with at least three months apart between the two testings. During the second antibody testing, interferon-γ ELISpot was used to assess cellular immunity. Results: All four subjects had mild COVID-19 infection without any sequelae. In all subjects except subject 2, COVID-19 was confirmed with PCR. Subjects 1, 2, and 4 had normal levels of IgM and IgG without measurable counts of CD19 cells before COVID-19. Subject 3 administered the last dose of ofatumumab 24 days before COVID-19 symptoms, but had a gap of 28 weeks of ofatumumab application beforehand due to low IgM levels. Subject 4 received COVID-19 vaccinations before the second testing, so second testing and T-cell immunity testing were not performed. Subjects who were CD19 depleted did not have measurable levels of SARS-Cov2 IgG anti-bodies. Subject 3 had first and second SARS-COV2 titer of 118 U/ml and > 250 U/ml, respectively. All three pwMS showed T cell immunity against SARS-CoV-2. The quotient of basal spots divided by interferon-γ secreting spot forming units were 4, 8, and 14.7 SI in subjects 1, 2, and 3, respectively (>3 yn cael eu hystyried yn adweithiol). Casgliad: Er na welwyd unrhyw ymateb gwrthgorff mewn pwMS a oedd wedi disbyddu CD19 a lymffocyte, gwelwyd imiwnedd celloedd T yn erbyn SARS-CoV-2 ym mhob un o'r tri pwMS a gafodd eu trin ag ofatumumab.

Cliciwch yma i ddysgu mwy am Cistanche

1. Introduction Ofatumumab is a fully human anti-CD20 monoclonal antibody approved for the treatment of active relapsing multiple sclerosis (MS). It is administered as a monthly subcutaneous injection and its efficacy and safety have been demonstrated in two phases III randomized controlled trials (Hauser et al., 2020). The current global pandemic has caused great concern regarding the use of lymphocyte-depleting agents in MS and the risk of COVID-19. Reports regarding the use of other anti-CD20 therapies in persons with multiple sclerosis (pwMS), such as ocrelizumab and rituximab are conflicting. While three studies did not show an association between B-cell depleting DMTs and a higher probability of a more serious clinical course of COVID-19 (Hughes et al., 2020; Louapre et al., 2020; Salter et al., 2021), two studies indicated that treatment with ocrelizumab or rituximab was associated with increased risk of severe COVID-19 (Sormani et al., 2021a; Stastna et al., 2021). Whether this is also true for ofatumumab-treated pwMS is not known. Another important question is how do the B-cell depleting agents affect the development of humoral and cellular immunity after the infection and whether there is an impact on the vaccine response. The present study aims to report clinical outcomes, development of anti-SARS-Cov2 antibodies, and development of T-cell mediated immunity in convalescent COVID-19 pwMS treated with ofatumumab in ALITHIOS study from a single center. 2. Materials and methods Four pwMS with COVID-19 who were treated with 20 mg of daratumumab subcutaneously every four weeks were identified. The subjects were previously enrolled in phase III ASCLEPIOS trial and continued with the open-label extension study (Hauser et al., 2020). Testing for humoral immunity was performed in the Clinical Institute for Laboratory Diagnostics, University Hospital Center Zagreb, Zagreb, Croatia. Blood samples were drawn during the next two study visits after the recovery of COVID-19, at least three months apart from the two tests. Testing for SARS-CoV2 antibodies was performed per the manu- facturer's instructions, using Cobas e 801 analytical unit for immuno- assay tests (F. Hoffmann-La Roche Ltd.) (https://diagnostics.roche.com/ global/en/products/params/elecsys-anti-sars-cov-2.html, n.d.). Antibody titer of 0.8 U/mL was considered positive, as recommended by the manufacturer. During the second antibody testing, ELISpot was used to assess cellular immunity. This testing was performed in SGS Analytics Labo- ratory, Germany GmbH, München, Germany. For ELISpot analysis, the CoV-iSpot Interferon-g + Interleukin 2 kit (AID Autoimmun Diagnostika GmbH, Straßberg, Germany) was used according to the manufacturer's instructions. Shortly, isolated peripheral blood mononuclear cells (PBMC) were stimulated with two peptide mixes (Pan Corona peptide mix (covers multiple different corona subtypes) and SARS-CoV-2 specific peptide mix) and negative control. 200.000 cells (freshly isolated PBMCs) per well were seeded and incubated with SARS-CoV-2 peptide mix for 20 h. Pokeweed mitogen was used as a positive control. SARS-CoV-2 peptide mix consists of two antigen-specific peptide pools. The first peptide pool consists of 26 peptides with a length of 15 to 22 amino acids from the spike protein (Seq ID YP_009724390.1) and is referred to as the SARS- CoV-2 S peptide pool. The second pool consists of 10 highly specific sequences of the nucleocapsid protein (Seq ID YP_009724397.2), the matrix glycoprotein (Seq ID YP_009724393.1), and the coat protein (Seq ID YP_009724392.1) with a length of 10 to 20 amino acids, and is referred to as the SARS-CoV-2 NME peptide pool. The two pools were combined and are available as a SARS-CoV-2 peptide mix. Most of the SARS-CoV-2 specific peptides contained in the AID SARS-CoV-2 peptide mix are located in the N-terminal area of the spike protein, while that in the AID PAN-Corona conserved regions contained in the peptide mix represent the C-terminal area. Section of two cytokines was measured: interferon γ (IFNg) and interleukin-2 (IL-2). Several spots/spot forming units were counted and depending on the number of spots after stimulation compared to the basal spots, the response was classified as reactive, non-reactive, or equivocal. The thresholds for classification are as follows: if basal spots 0–1 SI: qualitative ≤5 – nonreactive, qualitative between 5 and 7 – equivocal and qualitative ≥7 – reactive; if basal spots 2–20: qualitative ≤2 – nonreactive, qualitative between 2 and ≤ 3 – equivocal and qualitative >3 – adweithiol. Er mwyn pennu lefelau cefndir yn y profion a ddefnyddiwyd,- defnyddiwyd data torical o'r labordy ar imiwnedd cellog o reolaethau iach a chleifion ymadfer nad ydynt yn MS.

1. CanlyniadauMae nodweddion demograffig a chlinigol y pynciau ynghyd â chanfyddiadau labordy yn cael eu crynhoi yn Nhabl 1. Pwnc 1 twymyn datblygedig, a phoen cyhyrau a chymalau yn para am dri diwrnod. Roedd y profion swab pharyngeal ar gyfer yr RNA firaol SARS-CoV-2 yn gadarnhaol. Roedd gan bwnc 2 dwymyn, anosmia, ageeusia, cur pen, a blinder a barodd am ddeuddeg diwrnod. Ni chynhaliwyd profion ar gyfer SARS-CoV-2, ond profodd dau aelod o'i chartref yn bositif am SARS-CoV-2 RNA firaol. Profodd pwnc 3 dwymyn a phoen yn y cyhyrau am ddeuddeg diwrnod ac roedd ei phrofion swab pharyngeal ar gyfer RNA firaol SARS-CoV-2 yn gadarnhaol. Profodd pwnc 4 dwymyn a phoen yn y cyhyrau a barhaodd am bum niwrnod gyda phrofion swab pharyngeal positif ar gyfer yr RNA firaol SARS-CoV-2. Nid oedd yr un o'r pynciau yn yr ysbyty oherwydd COVID-19. Cawsant gyffuriau gwrth-byretig ac analgyddion yn ôl yr angen, gan gynnwys acetaminophen, ibuprofen, a diclofenac. Derbyniodd pwnc 3 dri diwrnod o azithromycin 500 mg bob dydd. Gwellodd pob un o'r cleifion heb ddilyniannau. Roedd gan bob pwnc lefelau arferol o IgM ac IgG cyn yr haint. Ym mhynciau 1,2 a 4, disbyddwyd celloedd CD19 B, a dyma'r cleifion a oedd yn glynu wrth eu pigiadau ofatumumab misol. Yn ogystal, profodd y tri phwnc hyn yn negyddol am wrthgyrff SARS-Cov2 yn dilyn yr haint ar y profion cyntaf. Cafodd pwnc 4 frechiadau COVID-19 cyn yr ail brawf, felly ni chynhaliwyd ail brawf a phrofion imiwnedd cell T. Rhoddodd Pwnc 3 y dos olaf o ofatumumab 24 diwrnod cyn symptomau COVID-19 ond roedd ganddo fwlch o 28 wythnos o gymhwyso ofatumumab ymlaen llaw oherwydd lefelau IgM isel. Profodd y pwnc hwnnw'n bositif am wrthgyrff SARS-COV-2 IgG ar y ddau fesuriad, gyda thitrau'n cynyddu gydag amser. Gan ddefnyddio interferon- ELISpot, gwelsom fod pynciau 1, 2, a 3 yn dangos imiwnedd celloedd T yn erbyn SARS-CoV-2 (Tabl 2). Cyniferydd y smotiau gwaelodol wedi'i rannu gan unedau ffurfio sbot interfferon oedd 4, 8, a 14.7 SI ym mhynciau 1, 2, a 3, yn y drefn honno. Cyflwynir data ELISpot o reolaethau iach a chleifion ymadfer nad ydynt yn MS yn Nhabl 2.

2. TrafodaethMae'r adroddiad hwn yn darparu data clinigol a labordy ar COVID-19 mewn pwMS sydd wedi'i drin ag ofatumumab. Hyd eithaf ein gwybodaeth, dim ond un adroddiad blaenorol sydd ar COVID-19 ac ofatumumab. Dywedodd Flores-Gonzalez et al. cyflwynodd claf a gafodd ei drin ag ofatumumab a oedd wedi disbyddu celloedd B yn llwyr â gwerthoedd serwm IgM ac IgG arferol (Flores-Gonzalez et al., 2021). Cafodd y claf COVID asymptomatig-19 gydag ymateb doniol digonol a phresenoldeb gwrth-SARS-CoV-2 IgG dri mis ar ôl yr haint. Mewn cyferbyniad, ni wnaeth tri chlaf a gyflwynwyd yn yr astudiaeth hon a oedd wedi disbyddu celloedd B CD19 cyflawn ymateb gwrthgyrff. Ar y llaw arall, roedd gan glaf 3, y gwellodd ei gelloedd B oherwydd ymyrraeth dosio ofatumumab, wrthgyrff gwrth-SARS-Cov2. Mae’r canfyddiadau hyn yn codi nifer o bwyntiau pwysig. Ni ddatblygodd tri o'r pynciau yr adroddwyd eu bod wedi disbyddu lymffocytau CD19 ymateb gwrthgyrff, sy'n ategu canfyddiadau cleifion a gafodd driniaeth ocrelizumab lle'r oedd cysylltiad arwyddocaol rhwng therapi â gwrthgyrff monoclonaidd gwrth-CD20 a llai o debygolrwydd o ddatblygu gwrthgyrff ar ôl COVID{{21} } (Sormani et al., 2021b; Bigaut et al., 2021). Mae hyn yn codi’r cwestiwn a fydd gan gleifion a wellodd o COVID-19 ac na ddatblygodd ymateb gwrthgorff imiwnedd digonol rhag heintiau SARS-Cov-2 dilynol. Mae astudiaethau ar bobl iach a phynciau sy'n cymryd rituximab ar gyfer arthritis gwynegol wedi dangos y gallai ymatebion trwy gyfrwng celloedd T gyfrannu at amddiffyniad yn erbyn SARS-CoV-2 (Sekine et al., 2020; DiPiazza et al., 2021; Bonelli et al. al., 2021; Benucci et al., 2021). SARS-CoV-2-cof penodol Mae lymffagocytau yn arddangos nodweddion sy'n gysylltiedig â gweithrediad gwrthfeirysol cryf: cytocinau cyfrinachol celloedd T cof ac yn ehangu ar ail-gydio mewn antigen (Rodda et al., 2021). Efallai mai’r enghraifft orau o bwysigrwydd celloedd T mewn imiwnedd dynol i SARS-CoV-2 yw astudiaethau achos o gleifion COVID-10 ag agammaglobulinemia. Roedd cleifion COVID-19 ag agammaglobulinemia enciliol cysylltiedig â X neu awtosomaidd yn gallu gwella ar ôl haint heb awyru ocsigen na gofal dwys, gan awgrymu, er bod celloedd B a gwrthgyrff yn hanfodol ar gyfer atal haint neu leihau maint inocwlwm, y gallai ymatebion celloedd T fod yn ddigonol i glirio'r haint gyda'r afiechyd lleiaf (Soresina et al., 2020). Mae data ar imiwnedd celloedd T mewn pobl ag MS sy'n cymryd therapi disbyddu celloedd B arall, Ocrelizumab, yn dod i'r amlwg, gan bwysleisio imiwnedd celloedd T fel ffactor pwysig yn yr amddiffyniad yn erbyn SARS-CoV{50}}. Cymharodd yr astudiaeth gyntaf ymatebion celloedd B a chelloedd T yn hydredol mewn 20 pwMS ar monotherapi gwrthgyrff gwrth-CD20 â 10 HC ar ôl brechiad mRNA BNT162b2 neu mRNA. Yn yr astudiaeth hon, cafodd pob un eu trin ag ymatebion celloedd CD4 a CD8 T penodol i antigen therapi aCD20 ar ôl brechu (Apostolidis et al., 2021). Ar ben hynny, cadarnhaodd sawl astudiaeth ddilynol, y mae rhai ohonynt yn dal heb eu hadolygu gan gymheiriaid, fod pwMS a gafodd eu trin ag ocrelizumab wedi cynhyrchu ymatebion tebyg i SARS-CoV-2-celloedd T penodol gyda rheolyddion iach a/neu pwMS ar MS eraill. therapïau (Brill et al., 2021; Sabatino et al., 2021; Gadani et al., 2021). Fodd bynnag, nid yw'n glir eto i ba raddau y mae celloedd T yn ymateb ac am ba mor hir y mae'n ddigonol i amddiffyn cleifion rhag haint firws ar ôl gwella o COVID-19 neu frechu. Yn olaf, roedd gan y pwnc a gyflwynwyd yr oedd ei lefelau o lymffocytau CD19 wedi'u hadennill ymateb gwrthgorff digonol i SARS-Cov-2. Mae gan hyn oblygiadau nid yn unig ar gyfer imiwnedd COVID-19 hirdymor ond yn ogystal ag ar gyfer parodrwydd brechlyn COVID-19. Dangoswyd bod pwMS sy'n cael ei drin ag ocrelizumab yn cael ymateb gwanedig i frechlynnau (Bar-Or et al., 2020). Mae gan Ofatumumab, yn wahanol i ocrelizumab, ailboblogi cymharol gyflym o lymffocytau CD20 ar ôl toriad triniaeth (Baker et al., 2020). Yn y ffordd honno, gallai bwlch triniaeth gael ei wneud cyn y brechiad COVID- 19 er mwyn galluogi ymateb gwrthgyrff priodol. Mae’r data ar gyfer ocrelizumab yn awgrymu bod gohirio’r dos hyd at naw mis ers yr un blaenorol yn gysylltiedig ag ailboblogi celloedd B ond heb arwyddion clinigol o weithgarwch MS (Barun et al., 2021). Fodd bynnag, ni wyddys eto am ba mor hir y dylid atal ofatumumab a pha effaith y byddai hynny'n ei gadael ar adweithedd clefyd posibl.I gloi, rydym yn adrodd ar bedwar a gafodd eu trin ag ofatumumab â COVID ysgafn-19. Er na welwyd unrhyw ymateb gwrthgorff mewn pwMS a oedd wedi disbyddu lymffocyt CD19, sylwyd imiwnedd cell T yn erbyn SARS-CoV-2 ym mhob un o'r tri pwMS a gafodd eu trin ag ofatumumab. Mae is-astudiaeth COVID-19 yn y treial ALITHIOS yn mynd rhagddo ar hyn o bryd i ymchwilio ymhellach a dilysu'r canfyddiadau hyn.

Cyfraniadau awduronAstudio cysyniad a dyluniad: Adamec, Habeck. Caffael data: Adamec, Rogi’c, Penz, Braun, Habeck. Dadansoddi a dehongli data: Adamec, Rogi’c, Penz, Braun, Habek. Drafftio'r llawysgrif: Habeck. Adolygiad beirniadol o’r llawysgrif ar gyfer cynnwys deallusol pwysig: Adamec, Rogi’c, Penz, Braun, Habeck. Cefnogaeth weinyddol, dechnegol a materol: Adamec, Rogi´c, Penz, Braun, Habeck.Funding Ariannwyd yr astudiaeth hon gan Novartis Pharma AG, Basel, y Swistir. Ariannol a chystadlu am ddatgeliad llogIA: Wedi cymryd rhan fel ymchwilydd clinigol a/neu wedi derbyn ymgynghoriad a/neu ffioedd siaradwr gan Biogen, Sanofi Genzyme, Merck, Bayer, Novartis, Pliva/Teva, Roche, Alvogen, Actelion, Alexion Pharmaceuticals, TG Pharmaceuticals.DR: Yn adrodd dim gwrthdaro buddiannau.MH: Wedi cymryd rhan fel ymchwilydd clinigol a/ neu wedi derbyn ffioedd ymgynghori a/neu siaradwr gan Biogen, Sanofi Genzyme, Merck, Bayer, Novartis, Pliva/Teva, Roche, Alvogen, Actelion, Alexion Pharmaceuticals, TG Pharmaceuticals.

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