Skip to main content

Advertisement

Log in

Immunoglobulin deficiencies in treated patients suffering from rheumatoid arthritis

  • Observational Research
  • Published:
Rheumatology International Aims and scope Submit manuscript

Abstract

Immunoglobulins and antibodies to immunoglobulins (autoimmunoglobulins) have been identified to be implicated in the pathogenesis of rheumatoid arthritis (RA). Immunoglobulin deficiencies have been suggested to account for the increased risk of infections in RA patients. This study was carried out to determine the prevalence of immunoglobulin deficiencies in patients with RA and the identification of putative contributing factors. Immunoglobulin levels in blood samples of patients with rheumatoid arthritis were evaluated by an immunonephelometric assay. Demographic and disease related data (including age, sex, smoking habits, disease duration and activity, inflammatory markers) were assessed, and associations were identified by regression analysis. 539 patients were enrolled between 2011 and 2013. The most common immunoglobulin (Ig) deficiencies were those of IgM (24.5%) and IgG (19.9%). Most frequent deficiencies of subclasses were observed for IgG1 (42.3%), followed by IgG4 (10.4%), IgG2 (7.2%), and IgG3 (5.4%). Regression analyses revealed that deficiencies of IgM, IgG, IgG1, and IgG2 were more prevalent in older patients. In addition, smoking was associated with IgG2 deficiency, and IgA deficiency was associated with female sex. Occurrence of infections was significantly increased in patients with IgG, IgG2, and IgG4 deficiencies. RA patients displayed high rates of IgG and IgM deficiencies. In consequence, the assessment of immunoglobulin status should precede the application of immune modulating drugs to prevent a potential risk of infectious diseases. Prospective studies are needed to investigate the influence of immune modulating drugs on IgG and IgG subclass levels.

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

Access this article

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

Instant access to the full article PDF.

Similar content being viewed by others

Availability of data and material

Access of data is possible on the homepage of the Ambulantes Rheumazentrum Erfurt.

Code availability

Not applicable.

References

  1. Lee DM, Weinblatt ME (2001) Rheumatoid arthritis. Lancet 358(9285):903–911. https://doi.org/10.1016/s0140-6736(01)06075-5

    Article  CAS  PubMed  Google Scholar 

  2. Classen M, Diehl V, Kochsiek K, Hallek M, Böhm M, Schmiegel W (2009) Innere Medizin. Elsevier

  3. Aho K, Heliovaara M, Knekt P, Reunanen A, Aromaa A, Leino A, Kurki P, Heikkila R, Palosuo T (1997) Serum immunoglobulins and the risk of rheumatoid arthritis. Ann Rheum Dis 56(6):351–356

    Article  CAS  Google Scholar 

  4. Doran MF, Crowson CS, Pond GR, O’Fallon WM, Gabriel SE (2002) Frequency of infection in patients with rheumatoid arthritis compared with controls: A population-based study. Arthritis Rheum 46(9):2287–2293. https://doi.org/10.1002/art.10524

    Article  PubMed  Google Scholar 

  5. Doran MF, Crowson CS, Pond GR, O’Fallon WM, Gabriel SE (2002) Predictors of infection in rheumatoid arthritis. Arthritis Rheum 46(9):2294–2300. https://doi.org/10.1002/art.10529

    Article  PubMed  Google Scholar 

  6. Strangfeld A, Eveslage M, Schneider M, Bergerhausen HJ, Klopsch T, Zink A, Listing J (2011) Treatment benefit or survival of the fittest: what drives the time-dependent decrease in serious infection rates under TNF inhibition and what does this imply for the individual patient? Ann Rheum Dis 70(11):1914–1920. https://doi.org/10.1136/ard.2011.151043

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Leddy JP, Deitchman J, Bakemeier RF (1970) IgG subclasses measurement of radioimmunoassay in normal and hypogammaglobulinaemic sera. Arthritis Rheum 13:331–332

    Google Scholar 

  8. Shakib F, Stanworth DR, Drew R, Catty D (1975) A quantitative study of the distribution of IgG sub-classes in a group of normal human sera. J Immunol Methods 8(1–2):17–28

    Article  CAS  Google Scholar 

  9. van der Giessen M, Rossouw E, van Veen TA, van Loghem E, Zegers BJ, Sander PC (1975) Quantification of IgG subclasses in sera of normal adults and healthy children between 4 and 12 years of age. Clin Exp Immunol 21(3):501–509

    PubMed  PubMed Central  Google Scholar 

  10. Oxelius VA (1978) Crossed immunoelectrophoresis and electroimmunoassay of human IgG subclasses. Acta pathologica et microbiologica Scandinavica Section C, Immunology 86C(3):109–116

    CAS  PubMed  Google Scholar 

  11. French MA, Harrison G (1984) Serum IgG subclass concentrations in healthy adults: a study using monoclonal antisera. Clin Exp Immunol 56(2):473–475

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Madassery JV, Kwon OH, Lee SY, Nahm MH (1988) IgG2 subclass deficiency: IgG subclass assays and IgG2 concentrations among 8015 blood donors. Clin Chem 34(7):1407–1413

    Article  CAS  Google Scholar 

  13. Schauer U, Stemberg F, Rieger CH, Borte M, Schubert S, Riedel F, Herz U, Renz H, Wick M, Carr-Smith HD, Bradwell AR, Herzog W (2003) IgG subclass concentrations in certified reference material 470 and reference values for children and adults determined with the binding site reagents. Clin Chem 49(11):1924–1929

    Article  CAS  Google Scholar 

  14. Liu F, Wang Q, Qiu YR, Li MM (2003) Analysis of the relation between serum immunoglobulin and auto-antibody levels in patients with rheumatoid. Acad J First Med Coll PLA 23(5):472–473

    Google Scholar 

  15. Chanez P, Burge PS, Dahl R, Creemers J, Chuchalin A, Lamarca R, Garcia Gil E (2010) Aclidinium bromide provides long-acting bronchodilation in patients with COPD. Pulm Pharmacol Ther 23(1):15–21. https://doi.org/10.1016/j.pupt.2009.08.001

    Article  CAS  PubMed  Google Scholar 

  16. Neumann C, Proft F, Hammitzsch A, Gruenke M, Schulze-Koops H (2013) Hypogammaglobulinemia is a frequent finding in patients under immunosuppressive therapy but does not correlate with susceptibility to infections. Ann Rheum Dis 72(3):338

    Google Scholar 

  17. Deutsche Gesellschaft für Rheumatologie (2012) German guidelines for the sequential medical treatment of rheumatoid arthritis 2012: adapted EULAR recommendations and update of a treatment algorithm. AWMF-Register Nr 060/004

  18. Bukhari M, Wiles N, Lunt M, Harrison B, Scott D, Symmons D, Silman A (2003) Influence of disease-modifying therapy on radiographic outcome in inflammatory polyarthritis at five years: results from a large observational inception study. Arthr Rheumatol 48(1):46–53

    Article  CAS  Google Scholar 

  19. Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO 3rd, Birnbaum NS, Burmester GR, Bykerk VP, Cohen MD, Combe B, Costenbader KH, Dougados M, Emery P, Ferraccioli G, Hazes JM, Hobbs K, Huizinga TW, Kavanaugh A, Kay J, Kvien TK, Laing T, Mease P, Menard HA, Moreland LW, Naden RL, Pincus T, Smolen JS, Stanislawska-Biernat E, Symmons D, Tak PP, Upchurch KS, Vencovsky J, Wolfe F, Hawker G (2010) 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum 62(9):2569–2581. https://doi.org/10.1002/art.27584

    Article  Google Scholar 

  20. Bull B, Caswell M, Ernst E, Jou J, Kallner A, Koepke J, Lewis S, Lowe G, Rampling M, Stuart J (1993) ICSH recommendations for measurement of erythrocyte sedimentation-rate. J Clin Pathol 46(3):198–203

    Article  Google Scholar 

  21. Prevoo ML, van ’t Hof MA, Kuper HH, van Leeuwen MA, van de Putte LB, van Riel PL, (1995) Modified disease activity scores that include twenty-eight-joint counts. Development and validation in a prospective longitudinal study of patients with rheumatoid arthritis. Arthritis and rheumatism 38(1):44–48

    Article  CAS  Google Scholar 

  22. Wells G, Becker JC, Teng J, Dougados M, Schiff M, Smolen J, Aletaha D, van Riel PL (2009) Validation of the 28-joint Disease Activity Score (DAS28) and European League Against Rheumatism response criteria based on C-reactive protein against disease progression in patients with rheumatoid arthritis, and comparison with the DAS28 based on erythrocyte sedimentation rate. Ann Rheum Dis 68(6):954–960. https://doi.org/10.1136/ard.2007.084459

    Article  CAS  PubMed  Google Scholar 

  23. Barden J, Mullinax F, Waller M (1967) Immunoglobulin levels in rheumatoid arthritis: comparison with rheumatoid factor titers, clinical stage and disease duration. Arthritis Rheum 10(3):228–234

    Article  CAS  Google Scholar 

  24. Claman H, Merrill D (1966) Serum immunoglobulins in rheumatoid arthritis. J Lab Clin Med 67(5):850–854

    CAS  PubMed  Google Scholar 

  25. Marcolongo R, Carcassi A, Frullini F, Bianco G, Bravi A (1967) Levels of serum immunoglobulins in patients with rheumatoid arthritis. Ann Rheum Dis 26(5):412–418

    Article  Google Scholar 

  26. Veys E, Claessens H (1968) Serum levels of IgG, IgM, and IgA in rheumatoid arthritis. Ann Rheum Dis 27(5):431

    Article  CAS  Google Scholar 

  27. Lock R, Unsworth D (2003) Immunoglobulins and immunoglobulin subclasses in the elderly. Ann Clin Biochem 40(2):143–148

    Article  CAS  Google Scholar 

  28. Gonzalez-Quintela A, Alende R, Gude F, Campos J, Rey J, Meijide L, Fernandez-Merino C, Vidal C (2008) Serum levels of immunoglobulins (IgG, IgA, IgM) in a general adult population and their relationship with alcohol consumption, smoking and common metabolic abnormalities. Clin Exp Immunol 151(1):42–50

    Article  CAS  Google Scholar 

  29. Roseman C, Truedsson L, Kapetanovic MC (2012) The effect of smoking and alcohol consumption on markers of systemic inflammation, immunoglobulin levels and immune response following pneumococcal vaccination in patients with arthritis. Arthritis Res Ther 14(4):R170

    Article  CAS  Google Scholar 

  30. Schur PH, Borel H, Gelfand EW, Alper CA, Rosen FS (1970) Selective gamma-G globulin deficiencies in patients with recurrent pyogenic infections. N Engl J Med 283(12):631–634

    Article  CAS  Google Scholar 

  31. Schmidt R, Baumann U (2011) Humorale Immundefekte. Primäre und Sekundäre Imundefekte. Uni-Med, 3. neubearb. Auflage 2011. .

  32. Gottenberg JE, Ravaud P, Bardin T, Cacoub P, Cantagrel A, Combe B, Dougados M, Flipo R, Godeau B, Guillevin L (2010) Risk factors for severe infections in patients with rheumatoid arthritis treated with rituximab in the autoimmunity and rituximab registry. Arthr Rheumatol 62(9):2625–2632

    Article  CAS  Google Scholar 

  33. Shaffu S, Royle J, Neame R (2013) AB0332 Rituximab & immunoglobulin level monitoring in rheumatoid arthritis–a clinical audit. Ann Rheum Dis 72(Suppl 3):A888–A889

    Article  Google Scholar 

  34. Van Vollenhoven RF, Emery P, Bingham CO, Keystone EC, Fleischmann R, Furst DE, Macey K, Sweetser M, Kelman A, Rao R (2010) Longterm safety of patients receiving rituximab in rheumatoid arthritis clinical trials. J Rheumatol 37(3):558–567

    Article  Google Scholar 

  35. Buch MH, Smolen JS, Betteridge N, Breedveld FC, Burmester G, Dörner T, Ferraccioli G, Gottenberg J-E, Isaacs J, Kvien TK (2011) Updated consensus statement on the use of rituximab in patients with rheumatoid arthritis. Ann Rheum Dis 70(6):909–920

    Article  CAS  Google Scholar 

  36. De La Torre I, Leandro MJ, Valor L, Becerra E, Edwards JC, Cambridge G (2012) Total serum immunoglobulin levels in patients with RA after multiple B-cell depletion cycles based on rituximab: relationship with B-cell kinetics. Rheumatology 51(5):833–840

    Article  Google Scholar 

Download references

Funding

The study conduct was supported by CSL Behring. GKM Gesellschaft für Therapieforschung mbH (Munich, Germany) provided assistance in statistical analysis and writing of the manuscript.

Author information

Authors and Affiliations

Authors

Contributions

SK: data collection and analysis, writing of paper; H-JW: biochemical analysis of blood samples, writing of paper; RB: idea of the study, development of study protocol, supervision of work; PK: idea of the study, development of study protocol, supervision of work.

Corresponding author

Correspondence to Sara Kaestner.

Ethics declarations

Conflicts of interest/competing interests

None of the authors has any conflict of interest.

Ethics approval

The study was approved by the local ethics committee (2927–09/10).

Consent to participate

All participants signed a written informed consent before their data were included in the study.

Consent for publication

All authors consented to the publication of this study.

Additional information

Publisher's Note

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

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 16 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kaestner, S., Wolff, HJ., Braeuer, R. et al. Immunoglobulin deficiencies in treated patients suffering from rheumatoid arthritis. Rheumatol Int 41, 1273–1280 (2021). https://doi.org/10.1007/s00296-021-04871-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00296-021-04871-x

Keywords

Navigation