Skip to main content

Hydroxychloroquine Therapy and Serum Immunoglobulin Levels in Women with IgG Subclass Deficiency and Systemic Lupus Erythematosus, Sjögren Syndrome, and Rheumatoid Arthritis: A Retrospective Study

Abstract

Hydroxychloroquine (HCQ) therapy decreased immunoglobulin (Ig) levels in patients with Sjögren syndrome (SS) and rheumatoid arthritis (RA) in previous studies. We found no report of Ig levels of women with IgG subclass deficiency (IgGSD) and systemic lupus erythematosus (SLE), SS, or RA treated with HCQ. We retrospectively evaluated IgG, IgG subclass, IgA, and IgM levels and other characteristics of women at IgGSD diagnosis who did and did not take HCQ for SLE, SS, or RA. There were 132 women (48 subnormal IgG1 only, 49 combined subnormal IgG1/IgG3, and 35 subnormal IgG3 only). Mean age was 49 ± 13 years. Twenty-two women with SLE, SS, RA, or combination thereof reported HCQ ≥ 200 mg/day ≥ 6 months. In each IgGSD subtype, median Ig levels of women who took HCQ were not significantly lower than those of women who did not take HCQ. Women with combined subnormal IgG1/IgG3 who took HCQ had greater median IgG2 than women who did not take HCQ (4.89 g/L (range 4.43, 4.94) vs. 2.57 g/L (1.21, 6.44), respectively; p = 0.0123). Regressions on IgG1, IgG2, and IgG3 revealed positive associations with HCQ therapy (p = 0.0043, 0.0037, and 0.0139, respectively). There were no significant Ig associations with age, SLE, SS, or RA as independent variables. HCQ therapy of SLE, SS, or RA in women with IgGSD was not associated with significantly lower IgG, IgG subclass, IgA, or IgM levels. IgG1, IgG2, and IgG3 were positively associated with HCQ therapy, after adjustment for other variables.

This is a preview of subscription content, access via your institution.

References

  • Armstrong RA (2014) When to use the Bonferroni correction. Ophthalmic Physiol Opt 34:502–508

    PubMed  Article  Google Scholar 

  • Badcock LJ, Clarke S, Jones PW et al (2003) Abnormal IgA levels in patients with rheumatoid arthritis. Ann Rheum Dis 62:83–84

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Barrett DJ, Ayoub EM (1986) IgG2 subclass restriction of antibody to pneumococcal polysaccharides. Clin Exp Immunol 63:127–134

    CAS  PubMed  PubMed Central  Google Scholar 

  • Barton JC, Bertoli LF, Barton JC (2014) Comparisons of CVID and IgGSD: referring physicians, autoimmune conditions, pneumovax reactivity, immunoglobulin levels, blood lymphocyte subsets, and HLA-A and -B typing in 432 adult index patients. J Immunol Res 2014:542706

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  • Barton JC, Bertoli LF, Barton JC et al (2016) Selective subnormal IgG3 in 121 adult index patients with frequent or severe bacterial respiratory tract infections. Cell Immunol 299:50–57

    CAS  PubMed  Article  Google Scholar 

  • Barton J, Barton C, Bertoli L (2019) Duration of frequent or severe respiratory tract infection in adults before diagnosis of IgG subclass deficiency. PLoS ONE 14:e0216940

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Barton JC, Barton JC, Bertoli LF (2022) Hydroxychloroquine therapy and other observations in 132 women with three common IgGSD subtypes. Open Science Framework https://osf.io/hbfdc/. Accessed 02 may 2022

  • Barton JC, Barton JC, Bertoli LF et al (2020a) Characterization of adult patients with IgG subclass deficiency and subnormal IgG2. PLoS ONE 15:e0240522

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Barton JC, Barton JC, Bertoli LF et al (2020b) HLA-A and -B type and haplotype frequencies in IgG subclass deficiency subgroups. Arch Immunol Ther Exp 68:14

    CAS  Article  Google Scholar 

  • Barton JC, Barton JC, Bertoli LF et al (2021) Factors associated with IgG levels in adults with IgG subclass deficiency. BMC Immunol 22:53

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Blanco F, Kalsi J, Ravirajan CT et al (1992) IgG subclasses in systemic lupus erythematosus and other autoimmune rheumatic diseases. Lupus 1:391–399

    CAS  PubMed  Article  Google Scholar 

  • Bodewes ILA, Gottenberg JE, van Helden-Meeuwsen CG et al (2020) Hydroxychloroquine treatment downregulates systemic interferon activation in primary Sjögren’s syndrome in the JOQUER randomized trial. Rheumatology 59:107–111

    CAS  PubMed  Article  Google Scholar 

  • Bousfiha A, Jeddane L, Picard C et al (2018) The 2017 IUIS phenotypic classification for primary immunodeficiencies. J Clin Immunol 38:129–143

    PubMed  Article  Google Scholar 

  • Concordia Pharmaceuticals Inc. (2017) Plaquenil®: Hydroxychloroquine sulfate tablets, USP (package insert information). https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/009768s037s045s047lbl.pdf. Accessed 01 jul 2022

  • Crisp HC, Quinn JM (2019) Quantitative immunoglobulins in adulthood. Allergy Asthma Proc 30:649–654

    Article  CAS  Google Scholar 

  • de la Torre MC, Toran P, Serra-Prat M et al (2016) Serum levels of immunoglobulins and severity of community-acquired pneumonia. BMJ Open Respir Res 3:e000152

    PubMed  PubMed Central  Article  Google Scholar 

  • Eriksson P, Andersson C, Ekerfelt C et al (2004) Relationship between serum levels of IL-18 and IgG1 in patients with primary Sjogren’s syndrome, rheumatoid arthritis and healthy controls. Clin Exp Immunol 137:617–620

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Fauchais AL, Ouattara B, Gondran G et al (2010) Articular manifestations in primary Sjögren’s syndrome: clinical significance and prognosis of 188 patients. Rheumatology 49:1164–1172

    PubMed  Article  Google Scholar 

  • Fox RI, Chan E, Benton L et al (1988) Treatment of primary Sjögren’s syndrome with hydroxychloroquine. Am J Med 85:62–67

    CAS  PubMed  Article  Google Scholar 

  • Gabay C, Bel M, Combescure C et al (2011) Impact of synthetic and biologic disease-modifying antirheumatic drugs on antibody responses to the AS03-adjuvanted pandemic influenza vaccine: a prospective, open-label, parallel-cohort, single-center study. Arthritis Rheum 63:1486–1496

    CAS  PubMed  Article  Google Scholar 

  • Gibbs JG, Pratt EL, Fisher LH et al (2006) Recurrent pneumonia associated with hydroxychloroquine. J Allergy Clin Immunol 117:S170–S171

    Article  Google Scholar 

  • Gonzalez-Quintela A, Alende R, Gude F et al (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 151:42–50

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Grönwall C, Hardt U, Gustafsson JT et al (2017) Depressed serum IgM levels in SLE are restricted to defined subgroups. Clin Immunol 183:304–315

    PubMed  Article  CAS  Google Scholar 

  • Hammarström L, Vorechovsky I, Webster D (2000) Selective IgA deficiency (SIgAD) and common variable immunodeficiency (CVID). Clin Exp Immunol 120:225–231

    PubMed  PubMed Central  Article  Google Scholar 

  • Khokar A, Gupta S (2019) Clinical and immunological features of 78 adult patients with primary selective IgG subclass deficiencies. Arch Immunol Ther Exp 67:325–334

    CAS  Article  Google Scholar 

  • Kim JH, Park S, Hwang YI et al (2016) Immunoglobulin G subclass deficiencies in adult patients with chronic airway diseases. J Korean Med Sci 31:1560–1565

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Knight AK, Cunningham-Rundles C (2005) Oxcarbazepine-induced immunoglobulin deficiency. Clin Diagn Lab Immunol 12:560–561

    CAS  PubMed  PubMed Central  Google Scholar 

  • Lacombe C, Aucouturier P, Preud’homme JL (1997) Selective IgG1 deficiency. Clin Immunol Immunopathol 84:194–201

    CAS  PubMed  Article  Google Scholar 

  • Lin GG, Li JM (2009) IgG subclass serum levels in systemic lupus erythematosus patients. Clin Rheumatol 28:1315–1318

    PubMed  Article  Google Scholar 

  • Lin G, Li J (2010) Elevation of serum IgG subclass concentration in patients with rheumatoid arthritis. Rheumatol Int 30:837–840

    CAS  PubMed  Article  Google Scholar 

  • Mantovani AP, Monclaro MP, Skare TL (2010) Prevalence of IgA deficiency in adult systemic lupus erythematosus and the study of the association with its clinical and autoantibody profiles. Rev Bras Reumatol 50:273–282

    PubMed  Article  Google Scholar 

  • Parker AR, Skold M, Harding S et al (2019) Pneumococcal vaccination responses in adults with subnormal IgG subclass concentrations. BMC Immunol 20:29

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  • Pavelka K Jr, Sen KP, Peliskova Z et al (1989) Hydroxychloroquine sulphate in the treatment of rheumatoid arthritis: a double blind comparison of two dose regimens. Ann Rheum Dis 48:542–546

    PubMed  PubMed Central  Article  Google Scholar 

  • Pelka K, Matyja-Bednarczyk A, Wojas-Pelc A et al (2021) Hydroxychloroquine does not impair antibody response to 13-valent pneumococcal conjugate vaccine in patients with cutaneous lupus erythematosus-A pilot study. Dermatol Ther 34:e15013

    CAS  PubMed  Article  Google Scholar 

  • Schauer U, Stemberg F, Rieger CH et al (2003) Levels of antibodies specific to tetanus toxoid, Haemophilus influenzae type b, and pneumococcal capsular polysaccharide in healthy children and adults. Clin Diagn Lab Immunol 10:202–207

    CAS  PubMed  PubMed Central  Google Scholar 

  • Siber GR, Schur PH, Aisenberg AC et al (1980) Correlation between serum IgG-2 concentrations and the antibody response to bacterial polysaccharide antigens. N Engl J Med 303:178–182

    CAS  PubMed  Article  Google Scholar 

  • Söderström T, Söderström R, Avanzini A et al (1987) Immunoglobulin G subclass deficiencies. Int Arch Allergy Immunol 82:476–480

    Article  Google Scholar 

  • Swain S, Selmi C, Gershwin ME et al (2019) The clinical implications of selective IgA deficiency. J Transl Autoimmun 2:100025

    PubMed  PubMed Central  Article  Google Scholar 

  • van der Heijden EH, Hartgring SA, Kruize AA et al (2019) Additive immunosuppressive effect of leflunomide and hydroxychloroquine supports rationale for combination therapy for Sjögren’s syndrome. Expert Rev Clin Immunol 15:801–808

    PubMed  Article  Google Scholar 

  • Van Kessel DA, Horikx PE, Van Houte AJ et al (1999) Clinical and immunological evaluation of patients with mild IgG1 deficiency. Clin Exp Immunol 118:102–107

    PubMed  PubMed Central  Article  Google Scholar 

  • Veys EM, Gabriel PA, Coigne E et al (1976) Rheumatoid factor and serum IgG, IgM and IgA levels in rheumatoid arthritis with vasculitis. Scand J Rheumatol 5:1–6

    CAS  PubMed  Article  Google Scholar 

  • World Medical Association (2013) World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA 310:2191–2194

    Article  CAS  Google Scholar 

  • Zhang H, Li P, Wu D et al (2015) Serum IgG subclasses in autoimmune diseases. Medicine 94:e387

    CAS  PubMed  PubMed Central  Article  Google Scholar 

Download references

Acknowledgements

Not applicable.

Funding

The authors did not receive outside support from any organization for the submitted work.

Author information

Authors and Affiliations

Authors

Contributions

JaCB: conceptualization, data curation, formal analysis, investigation, methodology, project administration, visualization, writing—original draft preparation, and writing—review and editing. JClB: data curation, formal analysis, investigation, visualization, and writing—original draft preparation. LFB: formal analysis, resources, visualization, writing—original draft preparation, and writing—review and editing.

Corresponding author

Correspondence to James C. Barton.

Ethics declarations

Conflict of Interests

The authors have no competing interests to report.

Additional information

Publisher's Note

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

About this article

Verify currency and authenticity via CrossMark

Cite this article

Barton, J.C., Barton, J.C. & Bertoli, L.F. Hydroxychloroquine Therapy and Serum Immunoglobulin Levels in Women with IgG Subclass Deficiency and Systemic Lupus Erythematosus, Sjögren Syndrome, and Rheumatoid Arthritis: A Retrospective Study. Arch. Immunol. Ther. Exp. 70, 14 (2022). https://doi.org/10.1007/s00005-022-00652-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s00005-022-00652-x

Keywords

  • Rheumatoid arthritis
  • Sjögren syndrome
  • Systemic lupus erythematosus