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July 2020; 7 (4) Clinical/Scientific NotesOpen Access

Guillain-Barré syndrome and chronic inflammatory demyelinating polyradiculoneuropathy after alemtuzumab therapy in kidney transplant recipients

Marieke van der Zwan, Dennis A. Hesselink, Esther Brusse, Pieter A. van Doorn, Martijn W.F. van den Hoogen, Annelies E. de Weerd, Bart C. Jacobs
First published April 16, 2020, DOI: https://doi.org/10.1212/NXI.0000000000000721
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  1. Marieke van der Zwan, MD,
  2. Dennis A. Hesselink, MD, PhD,
  3. Esther Brusse, MD, PhD,
  4. Pieter A. van Doorn, MD, PhD,
  5. Martijn W.F. van den Hoogen, MD, PhD,
  6. Annelies E. de Weerd, MD and
  7. Bart C. Jacobs, MD, PhD
  1. From the Department of Internal Medicine (M.Z., D.A.H., M.W.F.H., A.E.W.), Division of Nephrology and Transplantation; Rotterdam Transplant Group (M.Z., D.A.H., M.W.F.H., A.E.W.); Department of Neurology (E.B., P.A.D., B.C.J.); and Immunology (E.B., P.A.D., B.C.J.), Erasmus MC, University Medical Center Rotterdam, the Netherlands.
  1. Correspondence
    Dr. van der Zwan m.vanderzwan{at}erasmusmc.nl
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  1. Netherlands journal of medicine, associate editor, from 2017 onwards

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  1. Scientific advisory board for Chiesi Pharma SpA.

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  1. Speaker honorariums from Astellas Pharma and Chiesi Pharma SpA.

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  1. Astellas Pharma.

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  1. (1) I serves as an (unpaid)member of the Medical Advisory Board of the Dutch ADCA patient foundation (non- profit entity).

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  1. (1) Dutch ADCA patient foundation.

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Scientific Advisory Boards:

  1. Advisory committee (GBS). Annexion. 2019 Advisory committee (GBS). Hansa Pharmaceuticals 2019 Advisory committee (CIDP). Argenx 2019 Advisory committee (CIDP). Octapharma. 2017, 2019

Gifts:

  1. NONE

Funding for travel or speaker honoraria:

  1. CSL honorarium symposium talk (2019)

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  1. Journal of Neurological Sciences, Journal of Neuromuscular Diseases: member of editorial board

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  1. Research support investigator initiated trials: Sanguin Blood supply (SID-GBS study) Takeda (DRIP study)

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Funding for travel or speaker honoraria:

  1. 1. Astellas Pharma, funding for travel to conference 2. Amgen, funding for travel to conference 3. Sanofi, speaker honoraria 4. Vifor, speaker honoraria 5. Genzyme, funding for travel to conference 6. MSD, speaker honoraria

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  1. 1. Novartis 2. Shire

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Funding for travel or speaker honoraria:

  1. Funding for travel from Baxter International Inc for a scientific meeting.

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  1. Journal of the Peripheral Nervous System, member of the editorial board, 2011 - 2018.

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  1. (1) unrestricted research funding, eSPIN Award 2013, Grifols (2) unrestricted research funding, 2014, CSL-Behring (3) Interlaken Leadership Award 2014, CSL-Behring (4) unrestricted research funding, 2014, Baxalta (5) unrestricted research funding, 2017/2019, Annexon (6) unrestricted research funding, 2019, Hansa Medical AB

Research Support, Government Entities:

  1. Netherlands Organization for Health Research and Development

Research Support, Academic Entities:

  1. (1) ZikaPLAN, Horizon 2020 (EU)

Research Support, Foundations and Societies:

  1. (1) Erasmus MC grant, PI, 2007-2011 (2) Prinses Beatrix Prinses Beatrix Spierfonds (W.OR07- 27), PI, 2007-2009 (3) Prinses Beatrix Prinses Beatrix Spierfonds (W.OR07- 28), PI, 2007-2011 (4) GBS-CIDP Foundation International, PI, 2009 (5) GBS-CIDP Foundation International, PI, 2011 (6) Prinses Beatrix Fonds (W.OR11-27), PI, 2011 (7) Prinses Beatrix Spierfonds (W.OR12-04), PI, 2012 (8) Prinses Beatrix Spierfonds (W.OR14-04), Co-PI, 2014 (9) Prinses Beatrix Spierfonds (W.OR16-18), PI, 2016 (10) Prinses Beatrix Spierfonds (prof chair), PI, 2016-19 (11) Prinses Beatrix Spierfonds (W.OR19-24), PI, 2019

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Alemtuzumab is approved for the treatment of relapsing-remitting MS and is used off-label for patients with chronic lymphocytic leukemia and as induction and antirejection therapy in kidney transplant recipients.1 Guillain-Barré syndrome (GBS) or chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) complicating alemtuzumab treatment was reported in 9 patients with hematologic malignancy or MS.1,–,3 The risk of GBS or CIDP in solid organ transplant recipients treated with alemtuzumab is unknown.

Rabbit antithymocyte globulin (rATG) is another T cell–depleting drug used to treat acute kidney allograft rejection. Only 1 patient was reported who developed GBS after rATG treatment for aplastic anemia.4 We found no reports of GBS or CIDP complicating rATG treatment in kidney transplant recipients. Here, we investigated the frequency, type, and outcome of GBS and CIDP in a single-center cohort of kidney transplant recipients treated with either alemtuzumab or rATG.

Methods

Study design

A retrospective analysis was performed of a cohort of kidney transplant recipients who received either alemtuzumab (Campath, Sanofi-Genzyme, Cambridge, MA) or rATG (Thymoglobulin, Sanofi-Genzyme) between 2002 and 2018 in the Erasmus MC, Rotterdam. Alemtuzumab was administered as a single dose of 30 mg subcutaneously and rATG in a dose of 4 mg/kg and nog g/kg.

Statistical methods

Continuous variables are presented as median and interquartile ranges (IQRs). The 95% CIs were calculated with the modified Wald method. For statistical analysis, SPSS version 21 (SPSS Inc., Chicago, IL) was used.

Standard protocol approvals, registrations, and patient consents

The study was approved by the Erasmus MC Medical Ethical Review Board (number 2018-1430).

Results

Between 2002 and 2018, 2,788 patients received a kidney transplant at our center. Alemtuzumab was administered to 143 (5.1%) patients and rATG to 108 (3.9%) patients. The total follow-up period of patients treated with alemtuzumab was 3.0 years (IQR 1.7–4.1 years) for a total of 444.3 person-years. A tacrolimus-based immunosuppressive regimen was given to 92% of patients. Three patients (2.1%, 95% CI 0.4%–6.3%) developed GBS or CIDP after alemtuzumab. Two patients fulfilled the diagnostic criteria for GBS, and 1 fulfilled the diagnostic criteria for CIDP. The clinical presentation and diagnostic findings of these patients are presented in the table. Laboratory tests, including clinical chemistry, serology, and virology, demonstrated no alternative diagnoses, and there was no recent Campylobacter jejuni or cytomegalovirus infection (PCR negative for cytomegalovirus). The total follow-up period for rATG-treated patients was 8.2 (IQR 6.3–11) years for a total of 829.4 person-years. Seventy-eight percent of patients received a tacrolimus-based immunosuppressive regimen. None of the patients treated with rATG (0%, 97.5% CI 0–4.1%) developed GBS or CIDP.

View this table:
Table

Clinical characteristics, diagnosis, and outcome of patients with GBS and CIDP after alemtuzumab

Discussion

This study shows that 2.1% of patients treated with alemtuzumab developed GBS or CIDP. This is higher than the incidence rate of these neuropathies in the general population and of kidney transplant recipients not treated with alemtuzumab.5,–,7 Secondary autoimmunity after alemtuzumab appears to be mainly B cell driven. A mismatched reconstitution of T and B cells after alemtuzumab can lead to an expansion of B cells in the absence of appropriate T-cell regulation. This may enable the escape of autoreactive B cells and production of pathogenic autoantibodies to self-antigens, which can lead to secondary autoimmunity, such as thyroiditis, idiopathic thrombocytopenic purpura, GBS, or CIDP.1

None of the patients treated with rATG developed GBS or CIDP. A possible explanation for the difference in the risk of developing these neuropathies with alemtuzumab is that the depletion of immune cells lasts longer after alemtuzumab.1 Alternatively, rATG may protect from GBS and CIDP.

Limitations of the current study are that we were unable to define the frequency of GBS and CIDP in kidney transplant recipients not treated with T cell–depleting therapy. Second, no causality between alemtuzumab and the risk of GBS or CIDP was demonstrated, and our findings may therefore relate to chance. Third, cytomegalovirus could have played a role in the development of GBS or CIDP because patients 1 and 3 were seropositive for cytomegalovirus at the time of transplantation. However, no signs of a reactivation were observed at the time the patients were diagnosed with GBS and CIDP. Fourth, we cannot exclude that the increased incidence of GBS and CIDP among alemtuzumab-treated patients may relate to the fact that in this group, more patients used tacrolimus as maintenance immunosuppression compared with the rATG cohort. Fifth, this observation is based on kidney transplant recipients who have several reasons to have an underlying neuropathy (i.e., renal insufficiency and diabetes mellitus), and it is uncertain whether it is also applicable to patients with MS.

In conclusion, alemtuzumab therapy in kidney transplant recipients may be associated with the development of GBS and CIDP. Clinicians should be alert for these neurologic complications in kidney transplant recipients treated with alemtuzumab.

Study funding

No sources of funding were used in the preparation of this manuscript.

Disclosure

DA Hesselink has received grant support, lecture, and consulting fees from Astellas Pharma and Chiesi Pharmaceuticals, a lecture fee from Hikma Pharma, and grant support from Bristol-Myers Squibb. PA van Doorn has received grant support from Baxter, Sanquin Plasma Products, and Grifols. MvdH has received grant lecture and consulting fees from Astellas Pharma, Amgen, Genzyme, MSD, Roche, Sanofi, and Vifor Pharmaceuticals. BC Jacobs has received grant support from Annexon Biosciences, Baxter, CSL Behring, Hansa Biopharma, and Grifols. The other authors declare no conflicts of interest. Go to Neurology.org/NN for full disclosures.

Appendix Authors

Table

Footnotes

  • Go to Neurology.org/NN for full disclosures. Funding information is provided at the end of the article.

  • The Article Processing Charge was funded by the authors.

  • Received November 25, 2019.
  • Accepted in final form March 13, 2020.

This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

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  5. 5.↵
    1. Willison HJ,
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    . Guillain-Barre syndrome. Lancet 2016;388:717–727.
    OpenUrlCrossRefPubMed
  6. 6.↵
    1. Ostman C,
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    . Guillain-Barre syndrome post renal transplant: a systematic review. Transpl Infect Dis 2019;21:e13021.
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    1. Echaniz-Laguna A,
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