Skip to main content

Advertisement

SpringerLink
Log in

Anti-cyclic citrullinated peptide antibody in the cerebrospinal fluid in patients with rheumatoid arthritis who have central nervous system involvement

  • Case Based Review
  • Published:
Clinical Rheumatology Aims and scope Submit manuscript

A Correction to this article was published on 22 June 2020

This article has been updated

Abstract

Central nervous system (CNS) involvement, including encephalopathy, encephalitis, leptomeningitis, and pachymeningitis, in rheumatoid arthritis (RA) is rather rare. We report the case of a 61-year-old female with a history of RA in remission for 7 years, who presented with numbness, weakness of the left upper limb, dysarthria, and headache. Magnetic resonance imaging (MRI) of the brain showed meningeal enhancement in the frontal, parietal, and temporal lobes. Cerebrospinal fluid (CSF) examination detected high levels of both rheumatoid factor (RF) and anti-cyclic citrullinated peptide antibody (ACPA), with a high ACPA-immunoglobulin G index (> 2.0). She was diagnosed with rheumatoid meningitis. Following combined therapy with oral prednisolone and intravenous infusion of cyclophosphamide, her symptoms promptly improved. After treatment, RF and ACPA levels in the CSF were reduced, and MRI showed improvement of the meningeal structures. This case, along with existing literature, suggests that the ACPA level in the CSF may serve as a useful marker for diagnosing of CNS involvement in RA, as well as an index of effectiveness of the associated treatment.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Change history

  • 22 June 2020

    The authors regret that the original published version of the above article contained errors. The authors requested that these be noted.

References

  1. Maher JA (1954) Dural nodules in rheumatoid arthritis. AMA Arch Pathol 58:354–359

    CAS  PubMed  Google Scholar 

  2. Markenson J, McDougal J, Tsairis P, Lockshin MD, Christian CL (1979) Rheumatoid meningitis: a localized immune process. Ann Intern Med 90:786–789. https://doi.org/10.7326/0003-4819-90-5-786

    CAS  PubMed  Google Scholar 

  3. Ronald CK, George HC (1981) The neuropathology of rheumatoid disease. Hum Pathol 12:5–15

    Google Scholar 

  4. Kitamura E, Kondo Y, Kanazawa N, Akutsu T, Nishiyama K, Iizuka T (2019) Autoimmune encephalitis as an extra-articular manifestation of rheumatoid arthritis. Intern Med 58:1007–1009

    PubMed  Google Scholar 

  5. Jones SE, Belsley NA, Mcloud TC, Mullins ME (2006) Rheumatoid meningitis: radiologic and pathologic correlation. AJR Am J Roentgenol 186:1181–1183

    PubMed  Google Scholar 

  6. Mori K, Sasaki K, Oketani K, Nakamura S (1969) An autopsy case of rheumatoid encephalopathy. Rinsho Shinkeigaku (Clinical Neurology) 9:613 (conference proceedings)

  7. Zolcinski M, Bazan-Socha S, Zwolinska G, Musial J (2008) Central nervous system involvement as a major manifestation of rheumatoid arthritis. Rheumatol Int 28:281–283

    CAS  PubMed  Google Scholar 

  8. Radic M, Kaliterna DM, Radic J (2013) Overview of vasculitis and vasculopathy in rheumatoid arthritis—something to think about. Clin Rheumatol 32:937–942

    PubMed  Google Scholar 

  9. Laskari K, Ahmadi-Simab K, Lamken M, Csernok E, Gross WL, Hellmich B (2010) Are anti-cyclic citrullinated peptide autoantibodies seromarkers for rheumatoid vasculitis in a cohort of patients with systemic vasculitis? Ann Rheum Dis 69:469–471

    CAS  PubMed  Google Scholar 

  10. Chowdhry V, Kumar N, Lachance DH, Salomao DR, Luthra HS (2005) An unusual presentation of rheumatoid meningitis. J Neuroimaging 15:286–288. https://doi.org/10.1111/j.1552-6569.2005.tb00325.x

    PubMed  Google Scholar 

  11. Kato T, Hoshi K, Sekijima Y, Matsuda M, Hashimoto T, Otani M, Suzuki A, Ikeda S (2003) Rheumatoid meningitis: an autopsy report and review of the literature. Clin Rheumatol 22:475–480. https://doi.org/10.1007/s10067-003-0788-0

    PubMed  Google Scholar 

  12. Chou RC, Henson JW, Tian D, Hedley-Whyte ET, Reginato AM (2006) Successful treatment of rheumatoid meningitis with cyclophosphamide but not infliximab. Ann Rheum Dis 65:1114–1116. https://doi.org/10.1136/ard.2005.042093

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Claassen J, Dwyer E, Maybaum S, Elkind MS (2006) Rheumatoid leptomeningitis after heart transplantation. Neurology 66:948–949. https://doi.org/10.1212/01.wnl.0000203516.48914.50

    PubMed  Google Scholar 

  14. Graus F, Titulaer MJ, Balu R, Benseler S, Bien CG, Cellucci T, Cortese I, Dale RC, Gelfand JM, Geschwind M, Glaser CA, Honnorat J, Höftberger R, Iizuka T, Irani SR, Lancaster E, Leypoldt F, Prüss H, Rae-Grant A, Reindl M, Rosenfeld MR, Rostásy K, Saiz A, Venkatesan A, Vincent A, Wandinger KP, Waters P, Dalmau J (2016) A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol 15:391–404. https://doi.org/10.1016/S1474-4422(15)00401-9

    PubMed  PubMed Central  Google Scholar 

  15. Ichiose S, Oohashi N, Watabe R, Satou S, Hoshi K, YahikoZawa H, Watanabe M (2013) A 57-year-old female case of rheumatoid meningitis with mental symptoms for which anti-cyclic citrullinated peptides antibody in the cerebrospinal fluid was useful for diagnosis. Med J Nagano Red Cross Hosp 27:110–111. (conference proceedings)

  16. Shibahara T, Matsushita T, Matsuo R, Fukushima Y, Fukuda K, Sugimori H, Kamouchi M, Kitazono T, Ago T (2016) Anti-cyclic citrullinated peptide antibody positive meningoencephalitis in the preclinical period of rheumatoid arthritis. Case Rep Neurol 8:156–160. https://doi.org/10.1159/000447627

    PubMed  PubMed Central  Google Scholar 

  17. Lubomski M, Sy J, Buckland M, Lee AS, Richards B, Thompson E, Fulham M, Breen N, Morris K, Halmagyi GM (2019) Rheumatoid leptomeningitis presenting with an acute neuropsychiatric disorder. Pract Neurol 19:68–71. https://doi.org/10.1136/practneurol-2018-001978

    PubMed  Google Scholar 

  18. Nissen MS, Nilsson AC, Forsberg J, Milthers J, Wirenfeldt M, Bonde C, Byg KE, Ellingsen T, Blaabjerg M (2019) Use of cerebrospinal fluid biomarkers in diagnosis and monitoring of rheumatoid meningitis. Front Neurol 10:666

    PubMed  PubMed Central  Google Scholar 

  19. Asano K, Kamimura N, Tsuchihashi Y, Watanabe D, Takahashi R (2019) A 71-year-old female with rheumatoid meningitis who presented with characteristic imaging findings on brain MRI and was useful for diagnosis by anti-CCP antibody in cerebrospinal fluid. Rinsho Shinkeigaku (Clinical Neurology) 59:299. (conference proceedings)

  20. Suzuki A, Inoue H, Saitou T, Aoki A, Nanzato K (2016) A 40-year-old female case of rheumatoid meningitis for which anti-cyclic citrullinated peptides antibody in the cerebrospinal fluid was useful. Rinsho Shinkeigaku (Clinical Neurology) 56:513 (conference proceedings)

    Google Scholar 

  21. Kawabata Y, Miyaji Y, Nakano T, Joki H, Tanaka F (2015) Aseptic meningitis in a patient with cerebrospinal fluid anti-agalactocyl IgG antibody-positive preclinical rheumatoid arthritis: a case report. Rinsho Shinkeigaku (Clinical Neurology) 55:904–908. https://doi.org/10.5692/clinicalneurol.cn-000754

    Google Scholar 

  22. Abe T, Mishima K, Uchino A, Sasaki A, Tanahashi N, Takao M (2016) A case of anti-cyclic citrullinated peptides antibody positive rheumatoid meningitis without arthritis at the onset of neurological symptoms. Rinsho Shinkeigaku (Clinical Neurology) 56:627–632 https://doi.org/10.5692/clinicalneurol.cn-000915

    Google Scholar 

  23. Ellman P, Cudkowicz L, Elwood JS (1954) Widespread serous membrane involvement by rheumatoid nodules. J Clin Pathol 7:239–244

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Shimada K, Matsui T, Kawakami M, Hayakawa H, Futami H, Michishita K, Takaoka H, Ikenaka T, Komiya A, Nakayama H, Hagiwara F, Sugii S, Furukawa H, Ozawa Y, Thoma S (2009) Diffuse chronic leptomeningitis with seropositive rheumatoid arthritis: report of a case successfully treated as rheumatoid leptomeningitis. Mod Rheumatol 19:556–562

    PubMed  Google Scholar 

  25. Matsushima M, Yamaguchi H, Niino M, Akimoto-Tsuji S, Yabe I, Onishi K, Sasaki H (2010) MRI and pathological findings of rheumatoid meningitis. J Clin Neurosci 17:129–132. https://doi.org/10.1016/j.jocn.2009.01.033

    PubMed  Google Scholar 

  26. Pascale B, Jean R, Christian B (2014) Rheumatoid meningitis presenting with stroke-like episodes. Neurology 82:1564–1565. https://doi.org/10.1212/WNL.0000000000000366

    Google Scholar 

  27. Bathon JM, Moreland LW, DiBartolomeo AG (1989) Inflammatory central nervous system involvement in rheumatoid arthritis. Semin Arthritis Rheum. 18:258–266. https://doi.org/10.1016/0049-0172(89)90047-4

    CAS  PubMed  Google Scholar 

  28. Magaki S, Chang E, Hammond RR, Yang I, Mackenzie IR, Chou BT, Choi SI, Jen JC, Pope WB, Bell DA, Vinters HV (2016) Two cases of rheumatoid meningitis. Neuropathology 36:93–102. https://doi.org/10.1111/neup.12238

    PubMed  Google Scholar 

  29. Mukaino A, Kinoshita I, Asai M, Toriyama F, Nakata R, Motomura M, Matsuo T, Hayashi T (2013) A case of meningeal disseminated sarcoidosis with marked hypoglycorrhachia in the CSF. Rinsho Shinkeigaku (Clinical Neurology) 53:367–371. https://doi.org/10.5692/clinicalneurol.53.367

    Google Scholar 

  30. Calabrese LH, Mallek JA (1988) Primary angiitis of the central nervous system. Report of 8 new cases, review of the literature, and proposal for diagnostic criteria. Medicine (Baltimore) 67:20–39. https://doi.org/10.1097/00005792-198801000-00002

    CAS  Google Scholar 

  31. Inan AS, Masatlioglu S, Ozyurek SC, Engin D, Erdem I (2011) Unusual central nervous system involvement of rheumatoid arthritis: successful treatment with steroid and azathioprine. Rheumatol Int 31:1383–1385

    PubMed  Google Scholar 

  32. Choi SJ, Park YH, Kim JA, Han JH, Choe GY, Kim SY (2017) Pearls & Oy-sters: asymmetric meningeal involvement is a common feature of rheumatoid meningitis. Neurology 88:e108–e110. https://doi.org/10.1212/WNL.0000000000003744

    PubMed  Google Scholar 

  33. Yücel AE, Kart H, Aydin P, Ağildere AM, Benli S, Altinörs N, Demirhan B (2001) Pachymeningitis and optic neuritis in rheumatoid arthritis: successful treatment with cyclophosphamide. Clin Rheumatol 20:136–139. https://doi.org/10.1007/PL00011193

    PubMed  Google Scholar 

  34. Schmid L, Müller M, Treumann T, Arnold W, Möller B, Aeberli D, Villiger PM (2009) Induction of complete and sustained remission of rheumatoid pachymeningitis by rituximab. Arthritis Rheum 60:1632–1634. https://doi.org/10.1002/art.24577

    CAS  PubMed  Google Scholar 

  35. Huys AC, Guerne PA, Horvath J (2012) Rheumatoid meningitis occurring during adalimumab and methotrexate treatment. Joint Bone Spine 79:90–92. https://doi.org/10.1016/j.jbspin.2011.07.008

    PubMed  Google Scholar 

  36. Klareskog L, Rönnelid J, Lundberg K, Padyukov L, Alfredsson L (2008) Immunity to citrullinated proteins in rheumatoid arthritis. Annu Rev Immunol. 26:651–675. https://doi.org/10.1146/annurev.immunol.26.021607.090244

    CAS  PubMed  Google Scholar 

  37. Felgenhauer K (1982) Differentiation of the humoral immune response in inflammatory diseases of the central nervous system. J Neurol 228:223–237. https://doi.org/10.1007/bf00313413

    CAS  PubMed  Google Scholar 

  38. De Bosscher K, Vanden Berghe W, Haegeman G (2003) The Interplay between the Glucocorticoid Receptor and Nuclear Factor-κB or Activator Protein-1: Molecular Mechanisms for Gene Repression. Endocrine Reviews 24(4):488–522

    PubMed  Google Scholar 

  39. Hurd ER, Giuliano VJ (1975) The effect of cyclophosphamide on b and t lymphocytes in patients with connective tissue diseases. Arthritis Rheum 18:67–75. https://doi.org/10.1002/art.1780180113

    CAS  PubMed  Google Scholar 

  40. Cambridge G, Leandro MJ, Edwards JC, Ehrenstein MR, Salden M, Bodman-Smith M, Webster AD (2003) Serologic changes following B lymphocyte depletion therapy for rheumatoid arthritis. Arthritis Rheum 48:2146–2154. https://doi.org/10.1002/art.11181

    PubMed  Google Scholar 

  41. Alessandri C, Bombardieri M, Papa N, Cinquini M, Magrini L, Tincani A, Valesini G (2004) Decrease of anti-cyclic citrullinated peptide antibodies and rheumatoid factor following anti-TNFalpha therapy (infliximab) in rheumatoid arthritis is associated with clinical improvement. Ann Rheum Dis 63:1218–1221. https://doi.org/10.1136/ard.2003.014647

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Chen HA, Lin KC, Chen CH, Liao HT, Wang HP, Chang HN, Tsai CY, Chou CT (2006) The effect of etanercept on anti-cyclic citrullinated peptide antibodies and rheumatoid factor in patients with rheumatoid arthritis. Ann Rheum Dis 65:35–39. https://doi.org/10.1136/ard.2005.038851

    CAS  PubMed  Google Scholar 

  43. Noguchi A, Yasuda S, Hisada R, Kato M, Oku K, Bohgaki T, Suzuki M, Matsumoto Y, Atsumi T (2019) Anti-cyclic citrullinated peptide antibody titers decrease in rheumatoid arthritis patients treated with tocilizumab: a pilot study. Mod Rheumatol 21:1–6. https://doi.org/10.1080/14397595.2019.1583784

    Google Scholar 

  44. Papadopoulos NG, Tsiaousis GZ, Pavlitou-Tsiontsi A, Giannakou A, Galanopoulou VK (2008) Does the presence of anti-CCP autoantibodies and their serum levels influence the severity and activity in rheumatoid arthritis patients? Clin Rev Allergy Immunol 34:11–15. https://doi.org/10.1007/s12016-007-8018-1

    CAS  PubMed  Google Scholar 

  45. Bobbio-Pallavicini F, Alpini C, Caporali R, Avalle S, Bugatti S, Montecucco C (2004) Autoantibody profile in rheumatoid arthritis during long-term infliximab treatment. Arthritis Res Ther 6:R264–R272. https://doi.org/10.1186/ar1173

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Clark RA, Gallin JI, Fauci AS (1979) Effects of in vivo prednisone in vitro eosinophil and neutrophil adherence and chemotaxis. Blood 53:633–641

    CAS  PubMed  Google Scholar 

  47. Reiber H, Peter JB (2001) Cerebrospinal fluid analysis: disease-related data patterns and evaluation programs. J Neurol Sci 184:101–122. https://doi.org/10.1016/S0022-510X(00)00501-3

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors are grateful to Ms. Manami Koyama for supporting data collection in this study.

Author information

Authors and Affiliations

  1. National Hospital Organization Tokyo Medical Center, 2-5-1 Higashigaoka, Meguro-ku, Tokyo, 152-8902, Japan

    Misako Higashida-Konishi, Keisuke Izumi, Masako Tsukamoto, Hiroaki Ohya, Nozomi Takasugi, Satoshi Hama, Yutaro Hayashi, Mari Ushikubo, Kumiko Akiya, Araki Kazuhiro, Yutaka Okano & Hisaji Oshima

  2. Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan

    Keisuke Izumi

Authors
  1. Misako Higashida-Konishi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Keisuke Izumi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Masako Tsukamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hiroaki Ohya
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Nozomi Takasugi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Satoshi Hama
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yutaro Hayashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Mari Ushikubo
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Kumiko Akiya
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Araki Kazuhiro
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Yutaka Okano
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Hisaji Oshima
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Misako Higashida-Konishi, M.D. designed the study; had full access to all of the data used for analyses in this study; contributed to acquisition, analysis, and interpretation of data; and wrote the initial draft of the manuscript. Keisuke Izumi, M.D., Ph.D. designed the study, contributed to analysis and interpretation of data, and assisted in drafting the manuscript. All the other authors contributed to data interpretation and critically reviewed the manuscript. All authors approved the final version of the manuscript and agree to be responsible for the accuracy and integrity of the work.

Corresponding author

Correspondence to Keisuke Izumi.

Ethics declarations

Disclosures

None.

Ethics approval

All procedures performed in the study were in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Consent to participate

The patient provided written informed consent.

Consent for publication

The patient agreed to display all material presented here in any form or medium, in a journal or in any other kind of publication.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Higashida-Konishi, M., Izumi, K., Tsukamoto, M. et al. Anti-cyclic citrullinated peptide antibody in the cerebrospinal fluid in patients with rheumatoid arthritis who have central nervous system involvement. Clin Rheumatol 39, 2441–2448 (2020). https://doi.org/10.1007/s10067-020-05044-0

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10067-020-05044-0

Keywords

Search

Navigation