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The Effects of Pregnancy on Autoimmune Diseases
JOBNAME: Mar 96 PAGE: 1 SESS: 11 OUTPUT: Wed Jun 12 21:59:40 1996 /xypage/worksmart/tsp000/0635/2 CLINICAL IMMUNOLOGY AND IMMUNOPATHOLOGY
Vol. 78, No. 2, February, pp. 99–104, 1996 Article No. 0018
SHORT ANALYTICAL REVIEW The Effects of Pregnancy on Autoimmune Diseases JILL P. BUYON,* J. LEE NELSON,†
AND
MICHAEL D. LOCKSHIN‡
*Department of Rheumatic Diseases, Hospital for Joint Diseases, New York University School of Medicine, New York, New York 10003; †Fred Hutchinson Cancer Research Center, Seattle, Washington 98104; and ‡National Institute of Arthritis, Musculoskeletal, and Skin Diseases, National Institutes of Health, Bethesda, Maryland 20892
INTRODUCTION
and a decrease in biliary excretion. Notably, increased circulating levels of estrogen (which are 100-fold higher than those during the menstrual cycle) mediate a marked elevation in the hepatic synthesis of proteins, such as those of the complement system and coagulation cascade (excluding factors XI and XIII). Fibrinogen concentrations increase resulting in a higher erythrocyte sedimentation rate. It is widely held that maternal immunologic adaptations, initiated to downregulate antifetal responses, are required to maintain and nurture the semiallogeneic conceptus, yet available data are inconsistent. Regulation may be operative at the placenta and not measurable systemically. The circulating number of natural killer cells is apparently normal during pregnancy, but the cytolytic activity of these cells is decreased (3). Although the number of circulating T lymphocytes is unchanged, some investigators have demonstrated a decline in the proportion of CD4+ subsets, which may result in immunosuppression (4). Specific functions, such as thymidine incorporation after concanavalin A stimulation of human T lymphocytes and oxidative responses of monocytes/macrophages, are inhibited by concentrations of progesterone known to occur in the placenta (10−6–10−5) (5). Antibody responses and production remain normal during pregnancy as does the number of circulating B cells and plasma cells. The levels of IgG, IgM, and IgA appear to be comparable to those of the nonpregnant state (6). Normal pregnancy is generally not associated with an increase in autoantibody production (7), but there are exceptions; for instance a recent report of rising titers of anti-SSA/Ro and SSB/La during pregnancy (8). In contrast, in many women with autoimmune thyroiditis, the levels of antithyroglobulin and antimicrosomal antibodies have been noted to decrease during gestation, seemingly independent of hemodilution (9). Maternal plasma may decrease neutrophil phagocytosis. Although some in vitro evidence suggests that pregnancy is an immunosuppressed state, on balance there is little clinical evidence that the pregnant woman is sig-
To ensure a successful pregnancy the mother must circumvent those immunological processes developed to ensure recognition and elimination of nonself molecules. Accordingly, a bidirectional interaction between the maternal immune system and fetus during pregnancy may result in the redirection of maternal immunity away from cell-mediated immunity and toward enhanced humoral responsiveness (1). In this model the conceptus protects itself by secreting TH2 cytokines which downregulate TH1 cytokines (1). The course of an autoimmune disease might then be altered as immunological adaptations facilitate successful intrauterine implantation of the blastocyst and maintenance of the fetal semiallograft. Similarly, an autoimmune disease may influence the outcome of pregnancy. As improvement in the morbidity and mortality of autoimmune diseases continues and more patients feel well enough to have families, these issues assume increasing importance. Commonly encountered diseases are rheumatoid arthritis (RA) with a frequency of about 1% in the general adult population, 3:1 female to male ratio, and peak incidence age 65–74 years, and systemic lupus erythematosus (SLE) which has a striking female predilection of 10:1, frequency of 1 per 700 women, and peak incidence around age 30. The antiphospholipid syndrome and neonatal lupus syndrome also occur but do not have well-quantitated incidences or gender associations. BIOLOGY OF HUMAN PREGNANCY
Myriad physiological adaptations occur during the course of a normal pregnancy (2). Some may confound the clinical assessment of women with autoimmune disorders. Specific adaptations include a physiologic anemia, maximal in the second trimester due to the increase of 40–50% in plasma volume with only a slight increase in red cell mass, an increase in minute ventilation secondary to an increase in tidal volume and decline in residual lung volume, an increased sensitivity to carbon dioxide, a decrease in glucose tolerance, 99
0090-1229/96 $12.00 Copyright © 1996 by Academic Press, Inc. All rights of reproduction in any form reserved.
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nificantly immunocompromised. Whether the shift away from TH1 responses adversely affects the course of pregnant women infected with HIV or antibiotic resistant TB is uncertain. At least four types of trophoblast come into contact with maternal cells and tissues. Attention has focused on those trophoblast antigens that are capable of stimulating maternal immune responses. Normal trophoblastic tissue does not constitutively express classical HLA antigens (HLA-A, -B, -C, -DR, and -DQ) at the fetal–maternal interface (10). HLA genes encode molecules known to function as classical transplantation antigens and govern immune responses. The mother is exposed to fetal HLA antigens during gestation, either by escaped fetal cells into the maternal circulation or by other means. The mother develops antibodies to paternal HLA class I and II (11) which, still unexplained, are not deleterious to the fetus and may in fact favorably affect the course of maternal autoimmune disease. A class I HLA gene that is expressed primarily in the extravillous cytotrophoblast is HLA-G (12). Studies have demonstrated polymorphism in HLA-G. Although the function of HLA-G remains undefined, this molecule is potentially capable of presenting a wide variety of peptides to the T cell receptor (TCR) and may elicit an allogeneic response. RHEUMATOID ARTHRITIS
Since the observations of Hench in 1938 (13), it has been well appreciated that pregnancy is associated with improvement in the clinical signs and symptoms of RA in more than 70% of patients (14–16). However, with few exceptions, disease recurs postpartum for the majority of women by 8 weeks after delivery. Sex hormones, particularly estrogen, were considered likely candidates for pregnancy-induced remission. Disappointingly, studies aimed at improving RA by means of treatment with exogenous estrogens have not shown benefit (17). The rise of cortisol during pregnancy does not appear to explain the amelioration of RA (18). Because an immune response to paternally inherited fetal HLA occurs during normal pregnancy, the relationship of maternal–fetal HLA in pregnancies characterized by remission or improvement was compared to pregnancies in which disease was active (19). Maternal–fetal disparity in alleles of HLA-DRB1,-DQA, and -DQB occurred in 26 of 34 pregnancies characterized by remission or improvement (76%) but in only 3 of 12 pregnancies characterized by continuing active arthritis (25%). The strongest association with improvement in arthritis was with maternal–fetal disparity for DQa. In contrast, disparities for HLA-A, HLA-B, and HLA-C antigens were not significantly different in the two groups. HLA molecules, in addition to presenting foreign antigens, also present peptides derived from other self-HLA molecules (20). This raises the possibility
that HLA self-peptides presented by other HLA molecules are involved in the pathogenesis of autoimmunity. Based on these observations Nelson et al. (24) suggest that presentation of fetal DQa peptides might correct autoimmunity in patients with RA either by induction of maternal-regulatory T cells or by affecting the maternal T cell receptor repertoire. Apart from a beneficial effect of pregnancy on existing RA, there is also evidence suggesting that pregnancy may decrease the risk of developing RA, or at least postpone the onset. A twofold increased risk of RA in nulliparous women has been reported (21, 22). However, no increase in the incidence of RA was found among 220 nuns (23). The majority of studies indicate there is no increase in adverse pregnancy outcomes, either spontaneous abortion or stillbirths in women who subsequently develop RA (24) or who have RA. SYSTEMIC LUPUS ERYTHEMATOSUS
In contrast to the rule of “remission” during pregnancies of women with RA, the influence of pregnancy on disease activity in women with SLE is variable. There are two principal areas of concern. The first is that the clinical and serologic expression of SLE may be altered by pregnancy. Although earlier literature emphasized a high risk of disease exacerbations during pregnancy, recent investigations have not reached similar conclusions (25). The assumption that pregnancy induces a disease flare is tainted because SLE is a chronic disease punctuated by episodes of acute illness and spontaneous remission. The second concern is that the placenta and fetus may become targets of specific attack by maternal autoantibodies, resulting in a generalized failure of the pregnancy or specific syndromes of passively acquired autoimmunity such as neonatal lupus. Several studies to date provide a consensus; pregnancy outcome is optimal when disease is in complete clinical remission for 6–12 months (26, 27). Whether flare rates increase during or after pregnancy is still unsettled because individual patient series vary in the characteristics of patients accepted for study and in the definitions of flare (28). Current definitions of flare are imprecise and accepted instruments used to measure disease activity such as the systemic lupus erythematosus disease activity index (SLEDAI) or systemic lupus activity measurement (SLAM) do not account for the physiologic adaptations of pregnancy and have not been validated for pregnant lupus patients. Suggestions for “valid” criteria attributable to a flare are characteristic dermatologic involvement, arthritis, hematuria, fever not secondary to infection, lymphadenopathy, leukopenia, alternative-pathway hypocomplementemia (29), and rising titers of antibodies to DNA. In contrast, “invalid” markers of disease activity include alopecia, facial or palmar blush, arthralgia, musculo-
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skeletal aching, mild anemia, and fatigue, each of which may be present as part of the expected course of pregnancy. Additionally, thrombocytopenia and proteinuria emerge in the setting of preeclampsia and cannot be unambiguously attributed to active lupus. In those studies in which simultaneously followed, nonpregnant patients were evaluated, the flare rates for both groups were similar (25–27, 30–34). Despite a high overall flare rate in some series approaching 60% (26, 30), recorded flares were usually not severe. In general, if all possible abnormalities are presumed due to SLE, disease exacerbation occurs in approximately 25% (32). If only SLE-specific abnormalities are considered, disease exacerbations occur in <13% (32). In counseling a patient about the maternal risks of a prospective pregnancy, a major issue is the presence and/or deterioration of renal disease which is not likely to be first manifest during pregnancy in the absence of any prior detectable involvement. However, in a patient with fixed glomerular lesions, the normal increase in glomerular filtrate rate may result in protein excretion greater than 300 mg/24 hr, the upper limit accepted for an otherwise normal pregnancy. In some cases there will be coexistent hypertension which then must be differentiated (if possible) from preeclampsia. In others, proteinuria will more clearly represent an exacerbation of lupus nephritis as suggested by cellular casts in the urinary sediment. Activation of the alternative complement pathway with a concomitant decrease in CH50 accompanies disease flares in SLE, which is a laboratory finding that may be useful in distinguishing active lupus nephritis from preeclampsia or pregnancy-induced hypertension (29). Preliminary investigations reveal that nitric oxide levels are significantly increased in pregnant lupus patients who flare compared to those who remain stable. However, these levels did not distinguish between proteinuria attributable to a disease flare or preeclampsia and were significantly higher than levels obtained in preeclamptic women without SLE. These data suggest that in lupus either elevated nitric oxide levels mask the expected decrease associated with preeclampsia and/or there is a different pathophysiologic mechanism for pregnancy-induced hypertension and proteinuria compared to preeclamptic women without SLE (35). The presence of active lupus nephritis and/or preeclampsia increases the risk for preterm delivery and fetal death. Moreover, newly active nephritis in the first trimester is associated with a poor fetal outcome. Renal biopsy before gestation is not predictive of progressive nephropathy during pregnancy and change of histology in repeat biopsy can occur. Women in remission prior to pregnancy are the most likely to have an uncomplicated course during pregnancy despite the presence of severe histopathologic changes and heavy proteinuria in the early stages of their disease (36, 37).
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THE ANTI-PHOSPHOLIPID ANTIBODY SYNDROME AND PREGNANCY LOSS
The presence of high-titer IgG anti-phospholipid antibodies (aPL), ascertained by ELISA, and/or positive tests for the presence of the so-called “lupus anticoagulant,” is strongly associated with recurrent midtrimester fetal loss. In women with prior successful pregnancies or those pregnant for the first time, the risk for current loss is less than in women with prior losses but studies suggest risk is still proportional to the autoantibody level (38). In a prospective study of 389 nulliparous women, an elevated IgG anti-cardiolipin antibody level at the first prenatal visit was the only antiphospholipid measurement significantly associated with fetal loss (39). The presence of an isolated elevation of IgM anti-cardiolipin antibodies is not generally associated with recurrent fetal loss. Except for manifestations of active SLE, lupus patients with aPL do not appear to have different pregnancy courses from patients with the primary anti-phospholipid antibody syndrome. Experimental data suggest that “anti-phospholipid” antibodies are not directed against anionic phospholipids, as initially hypothesized, but are part of a larger group of autoantibodies which recognize phospholipidbinding proteins. At present, the best-characterized antigenic target is b2-glycoprotein I (b2GPI) (40–42). b2GPI, also designated apolipoprotein H, is associated with lipoprotein fractions in normal human plasma such as chylomicrons and very low- and high-density lipoproteins (43). b2GPI inhibits contact activation of the intrinsic coagulation pathway (44), platelet prothrombinase activity (45), and ADP-induced platelet aggregation (46). Because b2GPI has been shown to possess multiple inhibitory functions in coagulation pathways, its interaction with anti-phospholipid antibodies may eventually lead to an explanation for the prothrombotic diathesis and fetal loss. Although the measurement of anti-phospholipid antibodies by ELISA is now well standardized these new observations on b2GPI will require large-scale testing, the outcome of which may substantially alter current recommendations. At the placental level the pathology appears to be atherosis of the maternal spiral arteries, the consequence of which is decreased uteroplacental blood flow and retarded placental growth (reviewed in (47)). Once documentation of aPL has been made in a woman with recurrent fetal loss (excluding anatomic, chromosomal, and hormonal abnormalities), there are several rational protocols to consider. To date, there is no single best recommendation. In one collaborative randomized trial in which women with aPL-associated recurrent fetal loss received either 20 mg prednisone twice daily and 80 mg aspirin daily or 10,000 units heparin twice daily and low-dose aspirin daily, a live birth rate of 75% was obtained with each regimen (48).
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However, “serious” maternal morbidity and preterm delivery (frequently associated with premature rupture of membranes or preeclampsia) were significantly higher in the prednisone-treated women. In a separate nonrandomized, retrospective study (49) four regimens were evaluated; (a) prednisone and low-dose aspirin; (b) heparin and low-dose aspirin; (c) prednisone, heparin, and low-dose aspirin; and (d) other combinations of these medications or immunoglobulin. The overall neonatal survival rate was 73% and there were no significant differences in outcome among the four treatment groups. New animal models, including infusion or induction of high-titer antibodies by various strategies, offer hope for specifically incriminating aPL and provide a means for devising better therapies. NEONATAL LUPUS
This illness of the fetus and neonate is currently considered a model of passively acquired autoimmunity in which immune abnormalities in the mother lead to the production of antibodies to SSA/Ro-SSB/La ribonucleoproteins which cross the placenta and presumably injure fetal tissue (reviewed in (50)). The most serious manifestation is damage to the cardiac conducting system resulting in congenital heart block (CHB). Cutaneous involvement (frequently photosensitive), and to a lesser extent hepatic and hematologic involvement, are also associated with maternal and fetal anti-SSA/ Ro-SSB/La antibodies and are now grouped under the heading of neonatal lupus syndromes. Cardiac and dermatologic manifestations are the hallmarks of the syndrome and can occur separately or together. Neonatal lupus was so termed because the dermatologic lesions of the neonate resembled those seen in SLE. The name neonatal lupus is a misnomer in that only a third of mothers of affected children actually have SLE, and the neonatal disease is frequently only manifest as heart block, a problem rarely reported in adults with lupus. To date, complete heart block is irreversible. In contrast, the noncardiac manifestations are transient, resolving at about 6 months of life coincident with the disappearance of maternal autoantibodies from the neonatal circulation. The incidence of neonatal lupus in an offspring of a mother with anti-SSA/Ro antibodies is estimated at 1 or 2% (51). Although there is no serologic profile that is unique to mothers of affected children, compared with mothers of healthy children, anti-SSA/Ro antibodies are usually of high titer and associated with anti-SSB/ La antibodies (52). Anti-52-kDa antibodies are more prevalent by immunoblot in sera of mothers of children with heart block, although all these sera are likely to have anti-60-kDa antibodies by immunoprecipitation. Reports of discordant dizygotic and monozygotic twins and low recurrence rates (53) (4 of 33 pregnancies in 31
women in our series) indicate that factors (likely fetal) in addition to anti-SSA/Ro and SSB/La antibodies contribute to the development of neonatal lupus. Experiments using a rabbit model have provided insights into the pathogenicity of maternal anti-SSA/Ro and anti-SSB/La antibodies. Perfusion of rabbit hearts with isolated IgG fractions from sera containing antiSSA/Ro-SSB/La antibodies results in the electrocardiographic demonstration of atrioventricular (AV) block (54). We have reproduced these conduction abnormalities in an 18-week heart from a human abortus (55). Moreover, sera with anti-SSA/Ro-SSB/La reactivities induce a reduction in the L-type calcium channel current (ICa) in patch clamp experiments of isolated rabbit ventricular myocytes. Thus, the inhibitory effect of ICa at the single myocyte level correlates with the induction of AV block in the EKG of whole working hearts. These data support a major role of ICa in the electrogenesis and propagation of the action potential at the AV node and indicate that anti-SSA/Ro-SSB/La antibodies may interact (directly or indirectly) with these putative ion channels. Importantly, the AV node, which is absent and replaced by fibrotic or adipose tissue in autopsy studies of CHB, is rich in conducting cells that contain high concentrations of calcium channels. Substantial mortality and morbidity are associated with CHB; a third die, some in utero, and the majority of children require pacing (53). Because CHB is most often identified in the mid to late second trimester intrauterine therapy is possible, but guidelines are empiric. The rationale for treatment of identified heart block and prevention of potential heart block is to diminish an inflammatory insult to the heart and to lower the titer of maternal autoantibodies. Several intrauterine therapeutic regimens have been attempted including dexamethasone, which is not metabolized by the placenta and is available to the fetus in an active form, and plasmapheresis (56). Anecdotal reports suggest that associated pleuropericardial effusions and ascites resolve presumably secondary to a decrease in fetal cardiac inflammation independent of a decrease in maternal or fetal antibody titer. Encouragingly, heart block, once established, is not absolutely immutable, because incomplete block has reverted to sinus rhythm and third-degree blocks have transiently improved (57). The administration of maternal prednisone (at least in low and moderate doses) early in pregnancy does not prevent the development of CHB. Given the rarity of neonatal lupus, prophylactic therapies are not justified. Frequent echocardiograms (twodimensional and M-mode techniques) between 16 and 30 weeks of gestation, the presumed window of cardiac vulnerability, to identify an incomplete block or myocardial dysfunction may be the optimal approach.
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Despite a now reasonably large body of developed information, critical gaps are apparent. Pregnancy is the only naturally occurring event in which an individual is exposed to nonself HLA. How the HLA mismatched fetus escapes rejection remains a biologic enigma. More definitive evidence is needed to determine if TH2 bias occurs in normal human pregnancy and how this impacts on established autoimmune diseases. With regard to specific autoantibody-associated placental and fetal disease, why aren’t all pregnancies affected when the putative maternal antibodies are present? Future studies of maternal–fetal immunology, inclusive of information on cytokine regulation, should yield insights not only into the maintenance of normal pregnancy but also into the disproportionate increase of autoimmune diseases in females and the variable course of these diseases during pregnancy. REFERENCES 1. Wegmann, T. G., Lin, H., Guilbert, L., and Mosmann, T. R., Bidirectional cytokine interactions in the maternal-fetal relationship: Is successful pregnancy a TH2 phenomenon? Immunol. Today 14, 353–356, 1993. 2. Branch, D. W., Physiologic adaptations of pregnancy. Am. J. Repro. Immunol. 28, 120–122, 1992. 3. Gregory, C. D., Shah, L. P., Lee, H., Scottm, I. V., and Golding, P. R., Cytotoxic reactivity of human natural killer (NK) cells during normal pregnancy. A longitudinal study. J. Clin. Lab. Immunol. 18, 175–181, 1985. 4. Scridama, V., Pacini, F., Yang, S. L., Moawad, A., Reilly, M., and DeGroot, L. J., Decreased levels of helper T cells. A possible cause of immunodeficiency in pregnancy. N. Engl. J. Med. 307, 353–356, 1982. 5. Sites, D. P., and Siiteri, P. K., Steroids as immunosuppressants in pregnancy. Immunol. Rev. 75, 117–138, 1983. 6. Maurolis, G. B., Buckley, R. H., and Younger, J. B., Serum immunoglobulin concentrations during normal pregnancy. Am. J. Obstet. Gynecol. 109, 971–976, 1971. 7. Patton, P. E., Coulam, C. B., and Bergstralth, E., The prevalence of autoantibodies in pregnant and non-pregnant women. Am. J. Obstet. Gynecol. 157, 1345–1350, 1987. 8. Dorner, T., Chaoui, R., Feist, E., Keyber, G., Goldner, B., Yamamoto, K., and Hiepe, F., Significantly increased maternal and fetal autoantibody levels to 52kD Ro (SS-A) and La (SS-B) in complete congenital heart block. J. Autoimmun. in press, 1996. 9. Amino, N., Kuro, R., and Tanizawa, O., et al., Changes of serum anti-thyroid antibodies during and after pregnancy in autoimmune thyroid diseases. Clin. Exp. Immunol. 31, 30–37, 1978. 10. Hunt, J. S., Andrews, G. U., and Wood, G. W., Normal trophoblast resist induction of class I HLA. J. Immunol. 138, 2481– 2487, 1987. 11. Payne, R., Leukocyte agglutinins in human sera. Arch. Intern. Med. 99, 587–591, 1957. 12. van der Ven, K., and Ober, C., HLA-G polymorphisms in AfricanAmericans. J. Immunol. 153, 5628–5633, 1994. 13. Hench, P. S., The ameliorating effect of pregnancy on chronic atrophic (infectious rheumatoid) arthritis, fibrositis, and intermittent hydrathrosis. Proc. Staff Meet. Mayo Clinic 13, 161–167, 1938.
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Received September 14, 1995; accepted October 18, 1995
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(apo-H) inhibits the release reaction of human platelet during ADP-induced aggregation. Atherosclerosis 63, 109–114, 1987. Branch, D. W., Thoughts on the mechanism of pregnancy loss associated with the anti-phospholipid syndrome. Lupus 3, 275– 280, 1994. Cowchock, F. S., Reece, E. A., Balaban, D., Branch, D. W., and Plouffle, L., Repeated fetal losses associated with antiphospholipid antibodies: A collaborative randomized trial comparing prednisone with low-dose heparin treatment. Am. J. Obstet. Gynecol. 166, 1318–1323, 1992. Branch, D. W., Silver, R. M., Blackwell, J. L., Reading, J. C., and Scott, J. R., Outcome of treated pregnancies in women with antiphospholipid syndrome: an update of the Utah experience. Obstet. Gynecol. 80, 614–620, 1992. Buyon, J. P., Neonatal lupus syndromes. In “Systemic Lupus Erythematosus” (R. Lahita, Ed.), Churchill Livingstone, 1992. Lee, L. A., Neonatal lupus erythematosus. J. Invest. Dermatol. 100, 9S–13S, 1993. Buyon, J. P., Winchester, R. J., Slade, S. G., Arnett, F., Copel, J., Friedman, D., and Lockshin, M. D., Identification of mothers at risk for congenital heart block and other neonatal lupus syndromes in their children: Comparison of ELISA and immunoblot to measure anti-SSA/Ro and anti-SSB/La antibodies. Arthritis Rheum. 36, 1263–1273, 1993. Waltuck, J., and Buyon, J. P., Autoantibody associated complete heart block: Outcome in mothers and children. Ann. Intern. Med. 120, 544–551, 1994. Garcia, S., Nascimento, J. H. M., Bonfa, E., Levy, R., Oliveira, S. F., Tavares, A. V., and Campos deCarvalho, A. C., Cellular mechanism of the conduction abnormalities induced by serum from anti-Ro/SSA-positive patients in rabbit hearts. J. Clin. Invest. 93, 718–724, 1994. Boutjdir, M., Zhang, Z. H., Chen, L., El-Sherif, N., Tseng, C. E., Di Donato, F., Rashbaum, W., and Buyon, J. P., Electrophysiologic characterization of purified IgG from a mother whose child has congenital heart block (CHB) on L-type calcium currents (Ica). Arthritis Rheum., 38, S230, 1995. [Abstract] Rider, L., Buyon, J., Rutledge, J., and Sherry, D., Postnatal treatment of neonatal lupus: Case report and review of the literature. J. Rheum. 20, 1208–1211, 1993. Copel, J., Buyon, J., and Kleinman, C., Successful in utero therapy of fetal heart block. Am. J. Obstet. Gynecol., in press, 1995.
Vol. 78, No. 2, February, pp. 99–104, 1996 Article No. 0018
SHORT ANALYTICAL REVIEW The Effects of Pregnancy on Autoimmune Diseases JILL P. BUYON,* J. LEE NELSON,†
AND
MICHAEL D. LOCKSHIN‡
*Department of Rheumatic Diseases, Hospital for Joint Diseases, New York University School of Medicine, New York, New York 10003; †Fred Hutchinson Cancer Research Center, Seattle, Washington 98104; and ‡National Institute of Arthritis, Musculoskeletal, and Skin Diseases, National Institutes of Health, Bethesda, Maryland 20892
INTRODUCTION
and a decrease in biliary excretion. Notably, increased circulating levels of estrogen (which are 100-fold higher than those during the menstrual cycle) mediate a marked elevation in the hepatic synthesis of proteins, such as those of the complement system and coagulation cascade (excluding factors XI and XIII). Fibrinogen concentrations increase resulting in a higher erythrocyte sedimentation rate. It is widely held that maternal immunologic adaptations, initiated to downregulate antifetal responses, are required to maintain and nurture the semiallogeneic conceptus, yet available data are inconsistent. Regulation may be operative at the placenta and not measurable systemically. The circulating number of natural killer cells is apparently normal during pregnancy, but the cytolytic activity of these cells is decreased (3). Although the number of circulating T lymphocytes is unchanged, some investigators have demonstrated a decline in the proportion of CD4+ subsets, which may result in immunosuppression (4). Specific functions, such as thymidine incorporation after concanavalin A stimulation of human T lymphocytes and oxidative responses of monocytes/macrophages, are inhibited by concentrations of progesterone known to occur in the placenta (10−6–10−5) (5). Antibody responses and production remain normal during pregnancy as does the number of circulating B cells and plasma cells. The levels of IgG, IgM, and IgA appear to be comparable to those of the nonpregnant state (6). Normal pregnancy is generally not associated with an increase in autoantibody production (7), but there are exceptions; for instance a recent report of rising titers of anti-SSA/Ro and SSB/La during pregnancy (8). In contrast, in many women with autoimmune thyroiditis, the levels of antithyroglobulin and antimicrosomal antibodies have been noted to decrease during gestation, seemingly independent of hemodilution (9). Maternal plasma may decrease neutrophil phagocytosis. Although some in vitro evidence suggests that pregnancy is an immunosuppressed state, on balance there is little clinical evidence that the pregnant woman is sig-
To ensure a successful pregnancy the mother must circumvent those immunological processes developed to ensure recognition and elimination of nonself molecules. Accordingly, a bidirectional interaction between the maternal immune system and fetus during pregnancy may result in the redirection of maternal immunity away from cell-mediated immunity and toward enhanced humoral responsiveness (1). In this model the conceptus protects itself by secreting TH2 cytokines which downregulate TH1 cytokines (1). The course of an autoimmune disease might then be altered as immunological adaptations facilitate successful intrauterine implantation of the blastocyst and maintenance of the fetal semiallograft. Similarly, an autoimmune disease may influence the outcome of pregnancy. As improvement in the morbidity and mortality of autoimmune diseases continues and more patients feel well enough to have families, these issues assume increasing importance. Commonly encountered diseases are rheumatoid arthritis (RA) with a frequency of about 1% in the general adult population, 3:1 female to male ratio, and peak incidence age 65–74 years, and systemic lupus erythematosus (SLE) which has a striking female predilection of 10:1, frequency of 1 per 700 women, and peak incidence around age 30. The antiphospholipid syndrome and neonatal lupus syndrome also occur but do not have well-quantitated incidences or gender associations. BIOLOGY OF HUMAN PREGNANCY
Myriad physiological adaptations occur during the course of a normal pregnancy (2). Some may confound the clinical assessment of women with autoimmune disorders. Specific adaptations include a physiologic anemia, maximal in the second trimester due to the increase of 40–50% in plasma volume with only a slight increase in red cell mass, an increase in minute ventilation secondary to an increase in tidal volume and decline in residual lung volume, an increased sensitivity to carbon dioxide, a decrease in glucose tolerance, 99
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nificantly immunocompromised. Whether the shift away from TH1 responses adversely affects the course of pregnant women infected with HIV or antibiotic resistant TB is uncertain. At least four types of trophoblast come into contact with maternal cells and tissues. Attention has focused on those trophoblast antigens that are capable of stimulating maternal immune responses. Normal trophoblastic tissue does not constitutively express classical HLA antigens (HLA-A, -B, -C, -DR, and -DQ) at the fetal–maternal interface (10). HLA genes encode molecules known to function as classical transplantation antigens and govern immune responses. The mother is exposed to fetal HLA antigens during gestation, either by escaped fetal cells into the maternal circulation or by other means. The mother develops antibodies to paternal HLA class I and II (11) which, still unexplained, are not deleterious to the fetus and may in fact favorably affect the course of maternal autoimmune disease. A class I HLA gene that is expressed primarily in the extravillous cytotrophoblast is HLA-G (12). Studies have demonstrated polymorphism in HLA-G. Although the function of HLA-G remains undefined, this molecule is potentially capable of presenting a wide variety of peptides to the T cell receptor (TCR) and may elicit an allogeneic response. RHEUMATOID ARTHRITIS
Since the observations of Hench in 1938 (13), it has been well appreciated that pregnancy is associated with improvement in the clinical signs and symptoms of RA in more than 70% of patients (14–16). However, with few exceptions, disease recurs postpartum for the majority of women by 8 weeks after delivery. Sex hormones, particularly estrogen, were considered likely candidates for pregnancy-induced remission. Disappointingly, studies aimed at improving RA by means of treatment with exogenous estrogens have not shown benefit (17). The rise of cortisol during pregnancy does not appear to explain the amelioration of RA (18). Because an immune response to paternally inherited fetal HLA occurs during normal pregnancy, the relationship of maternal–fetal HLA in pregnancies characterized by remission or improvement was compared to pregnancies in which disease was active (19). Maternal–fetal disparity in alleles of HLA-DRB1,-DQA, and -DQB occurred in 26 of 34 pregnancies characterized by remission or improvement (76%) but in only 3 of 12 pregnancies characterized by continuing active arthritis (25%). The strongest association with improvement in arthritis was with maternal–fetal disparity for DQa. In contrast, disparities for HLA-A, HLA-B, and HLA-C antigens were not significantly different in the two groups. HLA molecules, in addition to presenting foreign antigens, also present peptides derived from other self-HLA molecules (20). This raises the possibility
that HLA self-peptides presented by other HLA molecules are involved in the pathogenesis of autoimmunity. Based on these observations Nelson et al. (24) suggest that presentation of fetal DQa peptides might correct autoimmunity in patients with RA either by induction of maternal-regulatory T cells or by affecting the maternal T cell receptor repertoire. Apart from a beneficial effect of pregnancy on existing RA, there is also evidence suggesting that pregnancy may decrease the risk of developing RA, or at least postpone the onset. A twofold increased risk of RA in nulliparous women has been reported (21, 22). However, no increase in the incidence of RA was found among 220 nuns (23). The majority of studies indicate there is no increase in adverse pregnancy outcomes, either spontaneous abortion or stillbirths in women who subsequently develop RA (24) or who have RA. SYSTEMIC LUPUS ERYTHEMATOSUS
In contrast to the rule of “remission” during pregnancies of women with RA, the influence of pregnancy on disease activity in women with SLE is variable. There are two principal areas of concern. The first is that the clinical and serologic expression of SLE may be altered by pregnancy. Although earlier literature emphasized a high risk of disease exacerbations during pregnancy, recent investigations have not reached similar conclusions (25). The assumption that pregnancy induces a disease flare is tainted because SLE is a chronic disease punctuated by episodes of acute illness and spontaneous remission. The second concern is that the placenta and fetus may become targets of specific attack by maternal autoantibodies, resulting in a generalized failure of the pregnancy or specific syndromes of passively acquired autoimmunity such as neonatal lupus. Several studies to date provide a consensus; pregnancy outcome is optimal when disease is in complete clinical remission for 6–12 months (26, 27). Whether flare rates increase during or after pregnancy is still unsettled because individual patient series vary in the characteristics of patients accepted for study and in the definitions of flare (28). Current definitions of flare are imprecise and accepted instruments used to measure disease activity such as the systemic lupus erythematosus disease activity index (SLEDAI) or systemic lupus activity measurement (SLAM) do not account for the physiologic adaptations of pregnancy and have not been validated for pregnant lupus patients. Suggestions for “valid” criteria attributable to a flare are characteristic dermatologic involvement, arthritis, hematuria, fever not secondary to infection, lymphadenopathy, leukopenia, alternative-pathway hypocomplementemia (29), and rising titers of antibodies to DNA. In contrast, “invalid” markers of disease activity include alopecia, facial or palmar blush, arthralgia, musculo-
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skeletal aching, mild anemia, and fatigue, each of which may be present as part of the expected course of pregnancy. Additionally, thrombocytopenia and proteinuria emerge in the setting of preeclampsia and cannot be unambiguously attributed to active lupus. In those studies in which simultaneously followed, nonpregnant patients were evaluated, the flare rates for both groups were similar (25–27, 30–34). Despite a high overall flare rate in some series approaching 60% (26, 30), recorded flares were usually not severe. In general, if all possible abnormalities are presumed due to SLE, disease exacerbation occurs in approximately 25% (32). If only SLE-specific abnormalities are considered, disease exacerbations occur in <13% (32). In counseling a patient about the maternal risks of a prospective pregnancy, a major issue is the presence and/or deterioration of renal disease which is not likely to be first manifest during pregnancy in the absence of any prior detectable involvement. However, in a patient with fixed glomerular lesions, the normal increase in glomerular filtrate rate may result in protein excretion greater than 300 mg/24 hr, the upper limit accepted for an otherwise normal pregnancy. In some cases there will be coexistent hypertension which then must be differentiated (if possible) from preeclampsia. In others, proteinuria will more clearly represent an exacerbation of lupus nephritis as suggested by cellular casts in the urinary sediment. Activation of the alternative complement pathway with a concomitant decrease in CH50 accompanies disease flares in SLE, which is a laboratory finding that may be useful in distinguishing active lupus nephritis from preeclampsia or pregnancy-induced hypertension (29). Preliminary investigations reveal that nitric oxide levels are significantly increased in pregnant lupus patients who flare compared to those who remain stable. However, these levels did not distinguish between proteinuria attributable to a disease flare or preeclampsia and were significantly higher than levels obtained in preeclamptic women without SLE. These data suggest that in lupus either elevated nitric oxide levels mask the expected decrease associated with preeclampsia and/or there is a different pathophysiologic mechanism for pregnancy-induced hypertension and proteinuria compared to preeclamptic women without SLE (35). The presence of active lupus nephritis and/or preeclampsia increases the risk for preterm delivery and fetal death. Moreover, newly active nephritis in the first trimester is associated with a poor fetal outcome. Renal biopsy before gestation is not predictive of progressive nephropathy during pregnancy and change of histology in repeat biopsy can occur. Women in remission prior to pregnancy are the most likely to have an uncomplicated course during pregnancy despite the presence of severe histopathologic changes and heavy proteinuria in the early stages of their disease (36, 37).
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THE ANTI-PHOSPHOLIPID ANTIBODY SYNDROME AND PREGNANCY LOSS
The presence of high-titer IgG anti-phospholipid antibodies (aPL), ascertained by ELISA, and/or positive tests for the presence of the so-called “lupus anticoagulant,” is strongly associated with recurrent midtrimester fetal loss. In women with prior successful pregnancies or those pregnant for the first time, the risk for current loss is less than in women with prior losses but studies suggest risk is still proportional to the autoantibody level (38). In a prospective study of 389 nulliparous women, an elevated IgG anti-cardiolipin antibody level at the first prenatal visit was the only antiphospholipid measurement significantly associated with fetal loss (39). The presence of an isolated elevation of IgM anti-cardiolipin antibodies is not generally associated with recurrent fetal loss. Except for manifestations of active SLE, lupus patients with aPL do not appear to have different pregnancy courses from patients with the primary anti-phospholipid antibody syndrome. Experimental data suggest that “anti-phospholipid” antibodies are not directed against anionic phospholipids, as initially hypothesized, but are part of a larger group of autoantibodies which recognize phospholipidbinding proteins. At present, the best-characterized antigenic target is b2-glycoprotein I (b2GPI) (40–42). b2GPI, also designated apolipoprotein H, is associated with lipoprotein fractions in normal human plasma such as chylomicrons and very low- and high-density lipoproteins (43). b2GPI inhibits contact activation of the intrinsic coagulation pathway (44), platelet prothrombinase activity (45), and ADP-induced platelet aggregation (46). Because b2GPI has been shown to possess multiple inhibitory functions in coagulation pathways, its interaction with anti-phospholipid antibodies may eventually lead to an explanation for the prothrombotic diathesis and fetal loss. Although the measurement of anti-phospholipid antibodies by ELISA is now well standardized these new observations on b2GPI will require large-scale testing, the outcome of which may substantially alter current recommendations. At the placental level the pathology appears to be atherosis of the maternal spiral arteries, the consequence of which is decreased uteroplacental blood flow and retarded placental growth (reviewed in (47)). Once documentation of aPL has been made in a woman with recurrent fetal loss (excluding anatomic, chromosomal, and hormonal abnormalities), there are several rational protocols to consider. To date, there is no single best recommendation. In one collaborative randomized trial in which women with aPL-associated recurrent fetal loss received either 20 mg prednisone twice daily and 80 mg aspirin daily or 10,000 units heparin twice daily and low-dose aspirin daily, a live birth rate of 75% was obtained with each regimen (48).
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However, “serious” maternal morbidity and preterm delivery (frequently associated with premature rupture of membranes or preeclampsia) were significantly higher in the prednisone-treated women. In a separate nonrandomized, retrospective study (49) four regimens were evaluated; (a) prednisone and low-dose aspirin; (b) heparin and low-dose aspirin; (c) prednisone, heparin, and low-dose aspirin; and (d) other combinations of these medications or immunoglobulin. The overall neonatal survival rate was 73% and there were no significant differences in outcome among the four treatment groups. New animal models, including infusion or induction of high-titer antibodies by various strategies, offer hope for specifically incriminating aPL and provide a means for devising better therapies. NEONATAL LUPUS
This illness of the fetus and neonate is currently considered a model of passively acquired autoimmunity in which immune abnormalities in the mother lead to the production of antibodies to SSA/Ro-SSB/La ribonucleoproteins which cross the placenta and presumably injure fetal tissue (reviewed in (50)). The most serious manifestation is damage to the cardiac conducting system resulting in congenital heart block (CHB). Cutaneous involvement (frequently photosensitive), and to a lesser extent hepatic and hematologic involvement, are also associated with maternal and fetal anti-SSA/ Ro-SSB/La antibodies and are now grouped under the heading of neonatal lupus syndromes. Cardiac and dermatologic manifestations are the hallmarks of the syndrome and can occur separately or together. Neonatal lupus was so termed because the dermatologic lesions of the neonate resembled those seen in SLE. The name neonatal lupus is a misnomer in that only a third of mothers of affected children actually have SLE, and the neonatal disease is frequently only manifest as heart block, a problem rarely reported in adults with lupus. To date, complete heart block is irreversible. In contrast, the noncardiac manifestations are transient, resolving at about 6 months of life coincident with the disappearance of maternal autoantibodies from the neonatal circulation. The incidence of neonatal lupus in an offspring of a mother with anti-SSA/Ro antibodies is estimated at 1 or 2% (51). Although there is no serologic profile that is unique to mothers of affected children, compared with mothers of healthy children, anti-SSA/Ro antibodies are usually of high titer and associated with anti-SSB/ La antibodies (52). Anti-52-kDa antibodies are more prevalent by immunoblot in sera of mothers of children with heart block, although all these sera are likely to have anti-60-kDa antibodies by immunoprecipitation. Reports of discordant dizygotic and monozygotic twins and low recurrence rates (53) (4 of 33 pregnancies in 31
women in our series) indicate that factors (likely fetal) in addition to anti-SSA/Ro and SSB/La antibodies contribute to the development of neonatal lupus. Experiments using a rabbit model have provided insights into the pathogenicity of maternal anti-SSA/Ro and anti-SSB/La antibodies. Perfusion of rabbit hearts with isolated IgG fractions from sera containing antiSSA/Ro-SSB/La antibodies results in the electrocardiographic demonstration of atrioventricular (AV) block (54). We have reproduced these conduction abnormalities in an 18-week heart from a human abortus (55). Moreover, sera with anti-SSA/Ro-SSB/La reactivities induce a reduction in the L-type calcium channel current (ICa) in patch clamp experiments of isolated rabbit ventricular myocytes. Thus, the inhibitory effect of ICa at the single myocyte level correlates with the induction of AV block in the EKG of whole working hearts. These data support a major role of ICa in the electrogenesis and propagation of the action potential at the AV node and indicate that anti-SSA/Ro-SSB/La antibodies may interact (directly or indirectly) with these putative ion channels. Importantly, the AV node, which is absent and replaced by fibrotic or adipose tissue in autopsy studies of CHB, is rich in conducting cells that contain high concentrations of calcium channels. Substantial mortality and morbidity are associated with CHB; a third die, some in utero, and the majority of children require pacing (53). Because CHB is most often identified in the mid to late second trimester intrauterine therapy is possible, but guidelines are empiric. The rationale for treatment of identified heart block and prevention of potential heart block is to diminish an inflammatory insult to the heart and to lower the titer of maternal autoantibodies. Several intrauterine therapeutic regimens have been attempted including dexamethasone, which is not metabolized by the placenta and is available to the fetus in an active form, and plasmapheresis (56). Anecdotal reports suggest that associated pleuropericardial effusions and ascites resolve presumably secondary to a decrease in fetal cardiac inflammation independent of a decrease in maternal or fetal antibody titer. Encouragingly, heart block, once established, is not absolutely immutable, because incomplete block has reverted to sinus rhythm and third-degree blocks have transiently improved (57). The administration of maternal prednisone (at least in low and moderate doses) early in pregnancy does not prevent the development of CHB. Given the rarity of neonatal lupus, prophylactic therapies are not justified. Frequent echocardiograms (twodimensional and M-mode techniques) between 16 and 30 weeks of gestation, the presumed window of cardiac vulnerability, to identify an incomplete block or myocardial dysfunction may be the optimal approach.
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Despite a now reasonably large body of developed information, critical gaps are apparent. Pregnancy is the only naturally occurring event in which an individual is exposed to nonself HLA. How the HLA mismatched fetus escapes rejection remains a biologic enigma. More definitive evidence is needed to determine if TH2 bias occurs in normal human pregnancy and how this impacts on established autoimmune diseases. With regard to specific autoantibody-associated placental and fetal disease, why aren’t all pregnancies affected when the putative maternal antibodies are present? Future studies of maternal–fetal immunology, inclusive of information on cytokine regulation, should yield insights not only into the maintenance of normal pregnancy but also into the disproportionate increase of autoimmune diseases in females and the variable course of these diseases during pregnancy. REFERENCES 1. Wegmann, T. G., Lin, H., Guilbert, L., and Mosmann, T. R., Bidirectional cytokine interactions in the maternal-fetal relationship: Is successful pregnancy a TH2 phenomenon? Immunol. Today 14, 353–356, 1993. 2. Branch, D. W., Physiologic adaptations of pregnancy. Am. J. Repro. Immunol. 28, 120–122, 1992. 3. Gregory, C. D., Shah, L. P., Lee, H., Scottm, I. V., and Golding, P. R., Cytotoxic reactivity of human natural killer (NK) cells during normal pregnancy. A longitudinal study. J. Clin. Lab. Immunol. 18, 175–181, 1985. 4. Scridama, V., Pacini, F., Yang, S. L., Moawad, A., Reilly, M., and DeGroot, L. J., Decreased levels of helper T cells. A possible cause of immunodeficiency in pregnancy. N. Engl. J. Med. 307, 353–356, 1982. 5. Sites, D. P., and Siiteri, P. K., Steroids as immunosuppressants in pregnancy. Immunol. Rev. 75, 117–138, 1983. 6. Maurolis, G. B., Buckley, R. H., and Younger, J. B., Serum immunoglobulin concentrations during normal pregnancy. Am. J. Obstet. Gynecol. 109, 971–976, 1971. 7. Patton, P. E., Coulam, C. B., and Bergstralth, E., The prevalence of autoantibodies in pregnant and non-pregnant women. Am. J. Obstet. Gynecol. 157, 1345–1350, 1987. 8. Dorner, T., Chaoui, R., Feist, E., Keyber, G., Goldner, B., Yamamoto, K., and Hiepe, F., Significantly increased maternal and fetal autoantibody levels to 52kD Ro (SS-A) and La (SS-B) in complete congenital heart block. J. Autoimmun. in press, 1996. 9. Amino, N., Kuro, R., and Tanizawa, O., et al., Changes of serum anti-thyroid antibodies during and after pregnancy in autoimmune thyroid diseases. Clin. Exp. Immunol. 31, 30–37, 1978. 10. Hunt, J. S., Andrews, G. U., and Wood, G. W., Normal trophoblast resist induction of class I HLA. J. Immunol. 138, 2481– 2487, 1987. 11. Payne, R., Leukocyte agglutinins in human sera. Arch. Intern. Med. 99, 587–591, 1957. 12. van der Ven, K., and Ober, C., HLA-G polymorphisms in AfricanAmericans. J. Immunol. 153, 5628–5633, 1994. 13. Hench, P. S., The ameliorating effect of pregnancy on chronic atrophic (infectious rheumatoid) arthritis, fibrositis, and intermittent hydrathrosis. Proc. Staff Meet. Mayo Clinic 13, 161–167, 1938.
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Received September 14, 1995; accepted October 18, 1995
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