New research analyzing pro- and anti-inflammatory cytokines in pregnant women with rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA), and ankylosing spondylitis (AS) may help provide a better understanding about why certain rheumatic diseases remit during pregnancy.1 The findings appear in the June issue of Annals of Rheumatic Disease.
The longitudinal study analyzed plasma and serum samples from pregnant patients with RA, JIA, and AS and healthy pregnant and nonpregnant women collected once in each trimester and 6, 12, and 24 weeks after delivery. The results indicate that there were significantly higher concentrations of the anti-inflammatory soluble tumor necrosis factor receptor (sTNFR) and interleukin-1 receptor antagonist (IL1Ra) in pregnant versus non-pregnant participants. Moreover, an increase in IL1Ra from second to third trimester correlated with improved disease activity in patients with RA and AS. While RA is known to improve during pregnancy, AS remains active and is mitigated only in late pregnancy.
"The increase of cytokine inhibitors IL1Ra and sTNFR was related to pregnancy and was independent of an underlying disease," conclude the researchers led by Monike Oestensen, MD, professor of rheumatology and clinical immunology and allergy at University Hospital in Bern, Switzerland. "These anti-inflammatory mediators seem to affect disease activity."
During the study, 17 of 19 patients with RA and five of six with JIA showed improvement, but the disease remained active in the remaining three patients. In the nine-person AS cohort, there was a varying disease course with active disease in first and second trimester observed in eight pregnancies. Four AS patients improved in the third trimester. Aggravation of symptoms occurred in 22 patients with RA/JIA and in eight patients with AS between 6- and 12-weeks postpartum. All patients and healthy controls had uncomplicated pregnancies and delivered healthy children.
Pregnant patients with RA were found to have higher levels of CD30 during pregnancy than other groups of healthy pregnant women and nonpregnant patients with inflammatory disease. CD30 is a receptor normally expressed on the T helper 2 (Th2) subset of activated T cells that produce cytokines that enhance humoral immunity, such as IL4 and IL10. IL10 downregulates the production of proinflammatory cytokines involved in cell-mediated immunity by T helper 1 (Th1) cells. In RA, a Th1-type response is dominant, whereas a Th2 response prevails in AS. The higher levels of CD30 observed in pregnant women with RA suggests a shift towards the Th2 response, though CD30 levels did not correlate with disease activity measurements in this study.
In the authors' attempts to measure levels of these cytokines in the study population, only low levels of IL10 were detected sporadically, whereas IFN-γ and IL-1β were below detection level. Because most of the clinical disease markers did not correlate with changes of circulating cytokines, the extent to which these cytokine levels are related to improvement of disease activity during the third trimester is not clear, the researchers write.
Editorialists led by Rainer H. Straub, MD, of the laboratory of neuroendocrinoimmunology and department of internal medicine at University Hospital in Regensburg, Germany, point out that the theory that pregnancy benefits RA was advanced as far back as 1871.2 "The accidental finding that pregnancy is favourable in these diseases suggests that hormonal factors and neurotransmitters are important players in modulation of the arthritic process," they argue.
The new study and others like it "indicate that favorable changes during pregnancy reverse after delivery, leading to increased disease activity. The question is whether or not pregnancy is accompanied by hormonal changes which modulate immune mechanisms," the editorialists write.
New therapies may be on the horizon
While pregnancy-specific immune changes occur predominantly at the maternal-fetal interface, these changes also elicit systemic effects in the maternal circulation and at sites distant from the uterus. "Although all studies in humans are associative in nature, this hypothesis is based on relatively good clinical evidence," they write. "Future therapeutic studies with pharmacologically high doses of oestriol or progesterone in RA, AS, or psoriatic arthritis may shed new light on this intriguing question."
The new study takes us "one step further in defining the mechanisms" responsible for flare or remission of certain rheumatic diseases during pregnancy, says Fred D. Finkelman, MD, director of the division of immunology at the University of Cincinnati College of Medicine in Ohio.
If it were known precisely what is it about pregnancy that causes changes in cytokines, it could create a whole new therapeutic approach for inflammatory disease, he says. "The best example is the second estrogen receptor."
Earlier this year, CIAOMed reported on novel estrogen receptor beta-agonist, ERB-041, which may offer a new treatment modality in RA, Crohn's disease, endometriosis, and potentially other autoimmune inflammatory diseases. In preclinical and Phase I data presented at the American College of Rheumatology 2005 Innovative Therapies in Autoimmune Disease Meeting in Washington, DC, ERB-041 was found to be safe and well tolerated, with no change in endocrine parameters over the 14-day trial period.3 "There is substantial excitement about this," Dr. Finkelman says.
References:
- Ostensen M, Forger F, Nelson JL, Schuhmacher A, Hebisch G, Villiger PM. Pregnancy in patients with rheumatic disease: anti-inflammatory cytokines increase in pregnancy and decrease post partum. Ann Rheum Dis. 2005;64:839-844.
- Straub RH, Buttgereit F, Cutolo M. Benefit of pregnancy in inflammatory arthritis. Ann Rheum Dis. 2005;64:801-803.
- Harris H. Estrogen Receptor beta: a new target for anti-inflammatory therapy? Presented at: American College of Rheumatology 2005 Innovative Therapies in Autoimmune Disease Meeting; March 4-6, 2005; Washington, DC.