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The remission of rheumatoid arthritis during pregnancy

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Abstract

Rheumatoid arthritis (RA) is an autoimmune disease that is favorably influenced by pregnancy but relapses after delivery. A variety of circulating factors has been considered as candidates for inducing gestational improvement of RA; however, the factors/pathways responsible remain still elusive. This review discusses recent research on the effect of pregnancy on RA with a focus on immunregulation, cytokine secretion, HLA antigens, microchimerism, and innate immunity. The complex hormonal and immunological alterations of pregnancy may temporarily correct the disturbed immunregulation of RA.

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References

  1. Klareskog L, Padyukov L, Rönnelid J, Alfredsson L (2005) Genes, environment and immunity in the development of rheumatoid arthritis. Curr Opin Immunol 18:650–655

    Article  CAS  Google Scholar 

  2. Panayi GS (2005) B cells: a fundamental role in the pathogenesis of rheumatoid arthritis? Rheumatology 44(Suppl 2):ii3–ii7

    Article  PubMed  CAS  Google Scholar 

  3. Fournier C (2005) Where do T cells stand in rheumatoid arthritis? J Bone Spine 72:527–532

    Article  Google Scholar 

  4. Williams RO, Feldmann M, Maini RN (2000) Cartilage destruction and bone erosion in arthritis: the role of tumor necrosis factor alpha. Ann Rheum Dis 59(Suppl 1):i75–i80

    Article  PubMed  CAS  Google Scholar 

  5. Gerli R, Lunardi C, Vinante F, Bistoni O, Pizzolo G, Pitzalis C (2001) Role of CD30+ T cells in rheumatoid arthritis: a counter-regulatory paradigm for Th1-driven diseases. Trends Immunol 2:72–77

    Article  Google Scholar 

  6. Doan T, Massarotti E (2005) Rheumatoid arthritis: an overview of new and emerging therapies. J Clin Pharmacol 45:751–762

    Article  PubMed  CAS  Google Scholar 

  7. Hench PS (1938) The ameliorating effect of pregnancy on chronic atrophic (infectious Rheumatoid) arthritis, fibrositis, and intermittent hydrarthrosis. Mayo Clin Proc 13:161–167

    Google Scholar 

  8. Østensen M, Husby G (1983) A prospective clinical study of the effect of pregnancy on rheumatoid arthritis and ankylosing spondylitis. Arthritis Rheum 26:1155–1159

    Article  PubMed  Google Scholar 

  9. Barrett JH, Brennan P, Fiddler M, Silman AJ (1999) Does rheumatoid arthritis remit during pregnancy and relapse postpartum? Arthritis Rheum 42:1219–1227

    Article  PubMed  CAS  Google Scholar 

  10. Nelson JL, Østensen M (1997) Pregnancy and rheumatoid arthritis. Rheum Dis Clin North Am 23:195–212

    Article  PubMed  CAS  Google Scholar 

  11. Skomsvoll JF, Østensen M, Irgens LM, Baste V (1999) Perinatal outcome in pregnancies of women with connective tissue disease and inflammatory rheumatic disease in Norway. Scand J Rheumatol 28:352–356

    Article  PubMed  CAS  Google Scholar 

  12. Bowden AP, Barrett JH, Fallow W, Silman AJ (2001) Women with inflammatory polyarthritis have babies of lower birth weight. J Rheumatol 28:355–359

    PubMed  CAS  Google Scholar 

  13. Persellin RH (1981) Inhibitors of inflammatory and immune responses in pregnancy serum. Clin Rheum Dis 7:769–780

    Google Scholar 

  14. Kobayashi H, Mori T, Suzuki A, Nishimura T, Nishimoto H, Harada M (1979) Suppression of mixed lymphocyte reaction by progesterone and estradiol-17β. Am J Obstet Gynecol 134:255–259

    PubMed  CAS  Google Scholar 

  15. Oka M (1958) Activity of rheumatoid arthritis and plasma 17-hydoxycorticosteroids during pregnancy and following parturition. Acta Rheumatol Scand 4:243–248

    PubMed  CAS  Google Scholar 

  16. Unger A, Kay A, Griffin AJ, Panayi G (1983) Disease activity and pregnancy associated alpha2-glycoprotein in rheumatoid arthritis during pregnancy. Br Med J 286:750–752

    CAS  Google Scholar 

  17. Quinn C, Mulpeter K, Casey EB, Feighery CF (1993) Changes in levels of IgM RF and α 2 PAG correlate with increased disease activity in rheumatoid arthritis during the puerperium. Scand J Rheumatol 22:273–279

    PubMed  CAS  Google Scholar 

  18. Alavi A, Arden N, Spector TD, Axford JS (2000) Immunoglobulin G glycosylation and clinical outcome in rheumatoid arthritis during pregnancy. J Rheumatol 27:1379–1385

    PubMed  CAS  Google Scholar 

  19. Masi AT, Feigenbaum SL, Chatterton RT (1995) Hormonal and pregnancy relationships to rheumatoid arthritis: convergent effects with immunologic and microvascular systems. Semin Arthritis Rheum 25:1–27

    Article  PubMed  CAS  Google Scholar 

  20. Elenkov IJ, Hoffman J, Wilder RL (1997) Does differential neuroendocrine control of cytokine production govern the expression of autoimmune diseases in pregnancy and the postpartum period? Mol Med Today 3:379–383

    Article  PubMed  CAS  Google Scholar 

  21. Simpson E (2006) A historical perspective on immunological privilege. Immunol Rev 213:12–22

    Article  PubMed  Google Scholar 

  22. Hunt JS (2006) Stranger in a strange land. Immunol Rev 213:36–47

    Article  PubMed  CAS  Google Scholar 

  23. Wegmann TG, Lin H, Guilbert L, Mosmann TR (1993) Bidirectional cytokine interactions in the maternal–fetal relationship: is successful pregnancy a TH2 phenomenon? Immunol Today 14:352–356

    Article  Google Scholar 

  24. Austgulen R, Arntzen KJ, Odegaard R (1998) Circulating levels of cytokines and cytokine receptors in normal human pregnancy. Scand J Rheumatol 27(Suppl 107):18

    Google Scholar 

  25. Kupferminc MJ, Peaceman AM, Aderka D (1995) Soluble tumor necrosis factor receptors in maternal plasma and second-trimester amniotic fluid. Am J Obstet Gynecol 173:900–905

    Article  PubMed  CAS  Google Scholar 

  26. Østensen M, Förger F, Nelson JL, Schuhmacher A, Hebisch G, Villiger PM (2005) Pregnancy in patients with rheumatic disease: anti-inflammatory cytokines increase in pregnancy and decrease post partum. Ann Rheum Dis 64:839–844

    Article  PubMed  CAS  Google Scholar 

  27. Matthiesen L, Ekerfelt C, Berg G, Ernerudh J (1998) Increased numbers of circulating interferon-γ and interleukin-4 secreting cells during normal pregnancy. Am J Reprod Immunol 39:362–367

    PubMed  CAS  Google Scholar 

  28. Munoz-Valle JF, Vazquez-Del Mercato M, Garcia-Iglesias T, Orozco-Barocio G, Bernard-Medina G, Martinez-Bonilla G, Bastidas-Ramirez BE, Navarro AD, Bueno M, Martinez-Lopez E, Best-Aguilera CR, Kamachi M, Armendariz-Borunda J (2003) Th1/Th2 cytokine profile, metalloproteinase-9 activity and hormonal status in pregnant rheumatoid arthritis and systemic lupus erythematosus patients. Clin Exp Immunol 131:377–384

    Article  PubMed  CAS  Google Scholar 

  29. Elenkov IJ, Wilder RL, Bakalov VK, Link AA, Dimitrov MA, Fisher S, Crane M, Kanik KS, Chrousos GP (2001) IL-12, TNFα, and hormonal changes during late pregnancy and early postpartum: implications for autoimmune disease activity during these times. J Clin Endocrinol Metab 86:4933–4938

    Article  PubMed  CAS  Google Scholar 

  30. Nolten WE, Rueckert PA (1981) Elevated free cortisol index in pregnancy: possible regulatory mechanisms. Am J Obstet Gynecol 139:492–498

    PubMed  CAS  Google Scholar 

  31. Correale J, Arias M, Gilmore W (1998) Steroid hormone regulation of cytokine secretion by proteolipid protein-specific CD4+ T cell clones isolated from multiple sclerosis patients and normal control subjects. J Immunol 161:3365–3374

    PubMed  CAS  Google Scholar 

  32. Neeck G, Federlin K, Graef V, Rusch D, Schmidt KL (1990) Adrenal secretion of cortisol in patients with rheumatoid arthritis. J Rheumatol 17:24–29

    PubMed  CAS  Google Scholar 

  33. Chikanza IC, Petrou K, Kingsley G, Chrousos GP, Panayi GS (1992) Defective hypothalamic response to immune and inflammatory stimuli in patients with rheumatoid arthritis. Arthritis Rheum 35:1281–1288

    PubMed  CAS  Google Scholar 

  34. Cutolo M, Sulli A, Seriolo B, Accardo S, Masi AT (1995) Estrogens, the immune response and autoimmunity. Clin Exp Rheumatol 13:217–226

    PubMed  CAS  Google Scholar 

  35. Da Silva JAP, Colville-Nash P, Spector TD, Scott DL, Willoghby DA (1993) Inflammation-induced cartilage degradation in female rodents. Arthritis Rheum 36:1007–1013

    Article  PubMed  Google Scholar 

  36. Karpuzoglu-Sahin E, Hissong BD, Ansar Ahmed S (2001) Interferon-gamma levels are upregulated by 17-beta-estradiol and diethylstilbestrol. J Reprod Immunol 52:113–127

    Article  PubMed  CAS  Google Scholar 

  37. Takao T, Kumagi C, Hisakawa N, Matsumoto R, Hashimoto K (2005) Effect of 17beta-estradiol on tumor necrosis factor-alpha-induced cytotoxicity in the human peripheral T lymphocytes. J Endocrinol 184:191–197

    Article  PubMed  CAS  Google Scholar 

  38. Szekeres-Bartho J, Faust Z, Varga P (1995) The expression of a progesterone-induced immunomodulatory protein in pregnancy lymphocytes. Am J Reprod Immunol 34:342–348

    PubMed  CAS  Google Scholar 

  39. Piccini MP, Giudizi MG, Biagiotti R, Beloni L, Giannarini L, Sampognaro S, Parrochi P, Manetti R, Annunziato F, Livi C (1995) Progesterone favors the development of human T helper cells producing Th2-type cytokines and promotes both IL-4 production and membrane CD30 expression in established Th1 cell clones. J Immunol 155:128–133

    Google Scholar 

  40. Chrousos GP, Torpy DJ, Gold PW (1998) Interactions between the hypothalamic–pituitary–adrenal axis and the female reproductive system: clinical implications. Ann Intern Med 129:229–240

    PubMed  CAS  Google Scholar 

  41. Popert AJ (1962) Pregnancy and adrenocortical hormones. Br Med J I:967–972

    PubMed  CAS  Google Scholar 

  42. Barrett JH, Brennan P, Fiddler M, Silman AJ (2000) Breast-feeding and postpartum relapse in women with rheumatoid and inflammatory arthritis. Arthritis Rheum 43:1010–1015

    Article  PubMed  CAS  Google Scholar 

  43. Nagy E, Berczi I, Wren G, Asa SL, Kovacs K (1983) Immunomodulation by bromocriptine. Immunopharmacology 6:231–243

    Article  PubMed  CAS  Google Scholar 

  44. Jiang S, Lechler RI, He XS, Huang JF (2006) Regulatory T cells and transplantation tolerance. Hum Immunol 67:765–776

    Article  PubMed  CAS  Google Scholar 

  45. Morgan ME, Flierman R, van Duivenvoorde LM, Witteveen HJ, van Ewijk W, van Laar JM, de Vries RRP, Toes REM (2005) Effective treatment of collagen-induced arthritis by adoptive transfer of CD25+ regulatory T cells. Arthritis Rheum 52:2212–2221

    Article  PubMed  CAS  Google Scholar 

  46. Baecher-Allan C, Brown JA, Freeman GJ, Hafler DA (2001) CD4+CD25high regulatory cells in human peripheral blood. J Immunol 167:1245–1253

    PubMed  CAS  Google Scholar 

  47. Cao D, Brjesson O, Larsson P, Rudin A, Gunnarsson I, Klareskog L, Malmström V, Trollmo C (2006) FOXP3 identifies regulatory CD25brightCD4+ T cells in rheumatic joints. Scand J Immunol 63:444–452

    Article  PubMed  CAS  Google Scholar 

  48. Lawson CA, Brown AK, Bejarano V, Douglas SH, Burgoyne CH, Greenstein AS, Boylston AW, Emery P, Ponchel F, Isaacs JD (2006) Early rheumatoid arthritis is associated with a deficit in the CD4+CD25high regulatory T cell population in peripheral blood. Rheumatology 45:1210–1217

    Article  PubMed  CAS  Google Scholar 

  49. Cao D, Malmstrom V, Baecher-Allan C, Hafler D, Klareskog L, Trollmo C (2003) Isolation and functional characterization of regulatory CD25brightCD4+ T cells from the target organ of patients with rheumatoid arthritis. Eur J Immunol 33:215–223

    Article  PubMed  CAS  Google Scholar 

  50. De Kleer IM, Wedderburn LR, Taams LS, Patel A, Varsani H, Klein M et al. (2004) CD4+CD25bright regulatory T cells actively regulate inflammation in the joints of patients with the remitting form of juvenile idiopathic arthritis. J Immunol 172:6435–6443

    PubMed  Google Scholar 

  51. Ehrenstein MR, Evans JG, Singh A, Moore S, Warnes G, Isenberg DA, Mauri C (2004) Compromised function of regulatory T cells in rheumatoid arthritis and reversal by anti-TNFα therapy. J Exp Med 200:277–285

    Article  PubMed  CAS  Google Scholar 

  52. Valencia X, Stephens G, Goldbach-Mansky R, Wilson M, Shevach EM, Lipsky PE (2006) TNF downmodulates the function of human CD4+CD25hi T-regulatory cells. Blood 108:253–261

    Article  PubMed  CAS  Google Scholar 

  53. Aluvihare VR, Kallikourdis M, Betz AG (2004) Regulatory T cells mediate maternal tolerance to the fetus. Nat Immunol 3:266–271

    Article  CAS  Google Scholar 

  54. Sasaki Y, Miyazaki S, Sakai M, Saito S (2003) CD4+CD25+ regulatory T cells are increased in the human early pregnancy deciduas and have immunosuppressive activity. Am J Reprod Immunol 49:356

    Google Scholar 

  55. Somerset DA, Zheng Y, Kilby MD, Sansom DM, Drayson MT (2004) Normal human pregnancy is associated with an elevation in the immune suppressive CD4+CD25+ regulatory T cell subset. Immunology 112:38–43

    Article  PubMed  CAS  Google Scholar 

  56. Polanczyk MJ, Hopke C, Huan J, Vandenbark AA, Offner H (2005) Enhanced FoxP3 expression and Treg cell function in pregnant and estrogen-treated mice. J Neuroimmunol 170:85–92

    Article  PubMed  CAS  Google Scholar 

  57. Prieto GA, Rosenstein Y (2006) Oestradiol potentiates the suppressive function of human CD4+CD25+ regulatory T cells by promoting their proliferation. Immunology 118:58–65

    Article  PubMed  CAS  Google Scholar 

  58. Ranella A, Vassiliadis S, Mastora C, Valentina M, Dionyssopoulou E, Athanassakis I (2005) Constitutive intracellular expression of human leukocyte antigen (HLA)-DO and HLA-DR but not HLA-DM in trophoblast cells. Hum Immunol 66:43–55

    Article  PubMed  CAS  Google Scholar 

  59. Hunt JS, Langat DK, McIntire RH, Morales PJ (2006) The role of HLA-G in human pregnancy. Reprod Biol Endocrinol 4:S1–S10

    Article  CAS  Google Scholar 

  60. Le Rond S, Azema C, Krawice-Radanne I, Durrbach A, Guettier C, Carosella ED, Rouas-Freiss N (2006) Evidence to support the role of HLA-G5 in allograft acceptance through induction of immunosuppressive/ regulatory T cells. J Immunol 176:3266–3276

    PubMed  Google Scholar 

  61. Brennan P (1997) HLA sharing and history of miscarriage among women with rheumatoid arthritis. Am J Hum Genet 60:738–739

    PubMed  CAS  Google Scholar 

  62. Gonzalez DA, de Leon AC, Moncholi CV, de Cordova JC, Hernandez LB (2004) Arthritis in mice: allogeneic pregnancy protects more than syngeneic by attenuating cellular immune response. J Rheumatol 31:30–34

    PubMed  Google Scholar 

  63. Chaouat G, Tranchot Diallo J, Volumenie JL, Menu E, Gras G, Delage G, Mognetti B (1997) Immune suppression and Th1/Th2 balance in pregnancy revisited: a (very) personal tribute to Tom Wegmann. Am J Reprod Immunol 37:427–434

    PubMed  CAS  Google Scholar 

  64. Nelson JL, Hughes KA, Smith AG, Nisperos BB, Branchaud AM, Hansen JA (1993) Maternal–fetal disparity in HLA class II alloantigens and the pregnancy-induced amelioration of rheumatoid arthritis. N Engl J Med 329:466–471

    Article  PubMed  CAS  Google Scholar 

  65. Van der Horst-Bruinsma IE, de Vries RRP, de Buck PDM, van Schendel PW, Breedveld FC, Schreuder G MT, Hazes JMW (1998) Influence of HLA-class II incompatibility between mother and fetus on the development and course of rheumatoid arthritis of the mother. Ann Rheum Dis 57:286–290

    Article  PubMed  Google Scholar 

  66. Brennan P, Barrett J, Fiddler M, Thomson W, Payton T, Silman A (2000) Maternal–fetal HLA incompatibility and the course of inflammatory arthritis during pregnancy. J Rheumatol 27:2843–2848

    PubMed  CAS  Google Scholar 

  67. Lo YM, Lau TK, Chan LY, Leung TN, Chang AM (2000) Quantitative analysis of the bidirectional fetomaternal transfer of nucleated cells and plasma DNA. Clin Chem 46:1301–1309

    PubMed  CAS  Google Scholar 

  68. Lo YM, Zhang J, Leung TN, Lau TK, Chang AM, Hjelm NM (1999) Rapid clearance of fetal DNA from maternal plasma. Am J Hum Genet 64:218–224

    Article  PubMed  CAS  Google Scholar 

  69. Liblau RS, Singer SM, McDewitt HO (1995) Th1 and Th2 CD4+ T cells in the pathogenesis of organ-specific autoimmune diseases. Immunol Today 16:34–38

    Article  PubMed  CAS  Google Scholar 

  70. Ekerfelt C, Matthiesen L, Berg G, Ernerudh J (1997) Paternal leukocytes selectively increase secretion of Il-4 in peripheral blood during normal pregnancies: demonstrated by a novel one-way MLC measuring cytokine secretion. Am J Reprod Immunol 38:320–326

    PubMed  CAS  Google Scholar 

  71. Yan Z, Lambert NC, Østensen M, Adams KM, Guthrie KA, Nelson JL (2006) Prospective study of fetal DNA in serum and disease activity during pregnancy in women with inflammatory arthritis. Arthritis Rheum 54:2069–2073

    Article  PubMed  CAS  Google Scholar 

  72. Adams KM, Yan Z, Stevens AM, Nelson JL (2006) The changing maternal “self” hypothesis: a mechanism for maternal tolerance of the fetus. Placenta 27:07003

    Google Scholar 

  73. Crocker IP, Baker PN, Fletcher J (2000) Neutrophil function in pregnancy and rheumatoid arthritis. Ann Rheum Dis 59:555–564

    Article  PubMed  CAS  Google Scholar 

  74. Abumaree MH, Stone PR, Chamley LW (2006) The effects of apoptotic, deported human placental trophoblast on macrophages: possible consequences for pregnancy. J Reprod Immunol 72:33–45

    Article  PubMed  CAS  Google Scholar 

  75. Ostensen M, Revhaug A, Volden G, Berge L, Husby G, Giercksky KE (1987) The effect of pregnancy on functions of inflammatory cells in healthy women and in patients with rheumatic disease. Acta Obstet Gynecol Scand 66:247–253

    PubMed  CAS  Google Scholar 

  76. Sacks GP, Studena K, Sargent K, Redman CW (1998) Normal pregnancy and preeclampsia both produce inflammatory changes in peripheral blood leukocytes akin to those of sepsis. Am J Obstet Gynecol 179:80–86

    Article  PubMed  CAS  Google Scholar 

  77. Davis D, Kaufmann R, Moticka EJ (1998) Nonspecific immunity in pregnancy: monocyte surface Fcγ receptor expression and function. J Reprod Immunol 40:119–128

    Article  PubMed  CAS  Google Scholar 

  78. Crouch SPM, Crocker IP, Fletcher J (1995) The effect of pregnancy on polymorphonuclear leucocyte function. J Immunol 155:5436–5443

    PubMed  CAS  Google Scholar 

  79. Buyon JP, Korchak HM, Rutherford LE, Ganguly M, Weissmann G (1984) Female hormones reduce neutrophil responsiveness in vitro. Arthritis Rheum 27:623–630

    Article  PubMed  CAS  Google Scholar 

  80. Kindzelskii AL, Huang JB, Chaiworapongsa T, Fahmy RM, Kim YM, Romero R, Petty HR (2002) Pregnancy alters glucose-6-phosphate dehydrogenase trafficking, cell metabolism, and oxidant release of maternal neutrophils. J Clin Invest 110:1801–1811

    Article  PubMed  CAS  Google Scholar 

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  1. Clinic for Rheumatology and Clinical Immunology, University Hospital of Berne, CH-3010, Bern, Switzerland

    Monika Østensen & Peter M. Villiger

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  1. Monika Østensen
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  2. Peter M. Villiger
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Correspondence to Monika Østensen.

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Østensen, M., Villiger, P.M. The remission of rheumatoid arthritis during pregnancy. Semin Immunopathol 29, 185–191 (2007). https://doi.org/10.1007/s00281-007-0072-5

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