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SYSTEMIC LUPUS ERYTHEMATOSUS Introduction Systemic lupus erythematosus (SLE) is the most common serious autoimmune disease affecting women of reproductive age. It is an idiopathic chronic inflam- matory disease that affects skin, joints, kidneys, lungs, serous membranes, nervous system, liver, and other organs of the body. Like other autoimmune diseases, its course is characterized by periods of remission and relapse. Frequent presenting symptoms include extreme fatigue, weight loss, myalgia, arthralgia, and fever (Table 42-1). Epidemiology The annual incidence of SLE is 5 to 10 per 100,000 individuals, depending on the population studied. The overall prevalence is 1 in 2,500 to 1 in 6,500. The inci- dence and prevalence vary among populations; SLE is approximately two to four times more frequent in blacks and Hispanics. 1 The disease is at least five to 10 times more common among adult women than adult men, 2 and the prevalence in women is 1 in 245 (black women) to 1 in 2,400. The lifetime risk of developing SLE for a white woman is one in 700. 1 The peak age of onset is between 15 and 25 years, and the mean age of time of diagnosis is 30 years. Although pediatric SLE occurs, most cases of SLE are associated with adolescence or young adulthood. Approximately 10 percent of patients with SLE also have an affected relative. 3 In addition to this, concordance between twins is reportedly greater than 50 percent. 4 Collagen Vascular Diseases CALLA HOLMGREN AND D. WARE BRANCH CHAPTER 42 Systemic Lupus Erythematosus 1080 Introduction 1080 Epidemiology 1080 Clinical Manifestations 1081 Systemic Lupus Erythematosus and Pregnancy 1082 Treatment of Systemic Lupus Erythematosus in Pregnancy 1087 Antiphospholipid Syndrome 1088 Introduction 1088 1080 KEY ABBREVIATIONS Anti-double-stranded DNA Anti-ds DNA Antinuclear antibodies ANA Antiphospholipid antibodies aPL Antiphospholipid syndrome APS Congenital complete heart block CCHB Diffuse proliferative DPGN glumerulonephritis Food and Drug Administration FDA Gestational hypertension GH Human leukocyte antigen HLA Interleukin-1 IL-1 Intrauterine growth restriction IUGR Intravenous immune globulin IVIG Juvenile rheumatoid arthritis JRA Lupus anticoagulant LA Lupus nephritis LN Mycophenolate mofentil MMF Neonatal lupus erythematosus NLE Non-steroidal anti-inflammatory NSAIDs drugs Nuclear ribonucleoprotein nRNP Preterm birth PTB Preterm premature rupture of PPROM the membranes Recurrent pregnancy loss RPL Rheumatoid arthritis RA Rheumatoid factor RF Single-stranded DNA ssDNA Systemic lupus erythematosus SLE Systemic sclerosis SSc Transforming growth factor-β TGF-β Tumor necrosis factor-α TNF-α Epidemiology 1088 Pathophysiology 1088 Diagnosis 1089 Pregnancy in Women with Antiphospholipid Syndrome 1090 Management 1090 Rheumatoid Arthritis 1092 Introduction 1092 Pathophysiology 1092 Clinical Manifestations and Laboratory Findings 1093 Pregnancy and Rheumatoid Arthritis 1094 Systemic Sclerosis 1096 Introduction 1096 Pathogenesis 1096 Clinical Manifestations and Diagnosis 1096 Pregnancy 1097

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Page 1: sindrome antifosfolipido

SYSTEMIC LUPUS ERYTHEMATOSUS

Introduction

Systemic lupus erythematosus (SLE) is the most common serious autoimmune disease affecting women of reproductive age. It is an idiopathic chronic infl am-matory disease that affects skin, joints, kidneys, lungs, serous membranes, nervous system, liver, and other organs of the body. Like other autoimmune diseases, its course is characterized by periods of remission and relapse. Frequent presenting symptoms include extreme fatigue, weight loss, myalgia, arthralgia, and fever (Table 42-1).

Epidemiology

The annual incidence of SLE is 5 to 10 per 100,000 individuals, depending on the population studied. The overall prevalence is 1 in 2,500 to 1 in 6,500. The inci-dence and prevalence vary among populations; SLE is approximately two to four times more frequent in blacks and Hispanics.1 The disease is at least fi ve to 10 times more common among adult women than adult men,2 and the prevalence in women is 1 in 245 (black women) to 1 in 2,400. The lifetime risk of developing SLE for a white woman is one in 700.1 The peak age of onset is between 15 and 25 years, and the mean age of time of diagnosis is 30 years. Although pediatric SLE occurs, most cases of SLE are associated with adolescence or young adulthood.

Approximately 10 percent of patients with SLE also have an affected relative.3 In addition to this, concordance between twins is reportedly greater than 50 percent.4

Collagen Vascular DiseasesCALLA HOLMGREN AND D. WARE BRANCH

CHAPTER 42

Systemic Lupus Erythematosus 1080Introduction 1080Epidemiology 1080Clinical Manifestations 1081Systemic Lupus Erythematosus and

Pregnancy 1082Treatment of Systemic Lupus

Erythematosus in Pregnancy 1087Antiphospholipid Syndrome 1088

Introduction 1088

1080

KEY ABBREVIATIONS

Anti-double-stranded DNA Anti-ds DNAAntinuclear antibodies ANAAntiphospholipid antibodies aPLAntiphospholipid syndrome APSCongenital complete heart block CCHBDiffuse proliferative DPGN glumerulonephritisFood and Drug Administration FDAGestational hypertension GHHuman leukocyte antigen HLAInterleukin-1 IL-1Intrauterine growth restriction IUGRIntravenous immune globulin IVIGJuvenile rheumatoid arthritis JRALupus anticoagulant LALupus nephritis LNMycophenolate mofentil MMFNeonatal lupus erythematosus NLENon-steroidal anti-infl ammatory NSAIDs drugsNuclear ribonucleoprotein nRNPPreterm birth PTBPreterm premature rupture of PPROM the membranesRecurrent pregnancy loss RPLRheumatoid arthritis RARheumatoid factor RFSingle-stranded DNA ssDNASystemic lupus erythematosus SLESystemic sclerosis SScTransforming growth factor-β TGF-βTumor necrosis factor-α TNF-α

Epidemiology 1088Pathophysiology 1088Diagnosis 1089Pregnancy in Women

with Antiphospholipid Syndrome 1090

Management 1090Rheumatoid Arthritis 1092

Introduction 1092Pathophysiology 1092

Clinical Manifestations and Laboratory Findings 1093

Pregnancy and Rheumatoid Arthritis 1094

Systemic Sclerosis 1096Introduction 1096Pathogenesis 1096Clinical Manifestations and

Diagnosis 1096Pregnancy 1097

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Chapter 42 Collagen Vascular Diseases 1081

Several alterations in the human leukocyte antigen (HLA) system have been linked to the development of SLE, and homozygous carriers of mutations responsible for complement defi ciency disorders also appear to be pre-disposed to development of the disease.

Clinical Manifestations

DIAGNOSTIC CRITERIA

In 1971, the American Rheumatism Association devised criteria for SLE, primarily to facilitate clinical studies. These criteria were revised in 19825 and in 19976 (Table 42-2). An individual must have at least four of 11 clini-cal and laboratory criteria at one time or serially to be classifi ed as having SLE. These criteria are very sensitive and specifi c for SLE, but were never intended to be the only basis for the diagnosis of SLE. Frequently, individual patients will present with less than four clinical or labora-tory features of SLE, thus not meeting strict diagnostic criteria. Some experts use the terms such as probable lupus or lupus-like disease in reference to these cases. Indi-viduals with lupus-like disease may benefi t from therapies for SLE and require special care during pregnancy.

CLINICAL FEATURES

The most common presenting complaints in women diagnosed with SLE include fatigue, weight loss, arthral-gias, arthritis, and myalgias. Pleurisy and pericarditis are also seen. The joints most commonly involved are the proximal interphalangeal, knee, wrist, and metacarpo-phalangeal. Morning stiffness that improves as the day evolves is typical. The migratory nature of the joints involved can be striking. Deforming, erosive arthritis is uncommon.

Table 42-1. Approximate Frequency of Clinical Symptoms in SLE

SYMPTOMS PATIENTS (%)

Fatigue 80–100Fever 80–100Arthralgia, arthritis 95Myalgia 70Weight loss >60Skin butterfl y rash 50 photosensitivity 60 mucous membrane lesions 35Renal involvement 50Pulmonary Pleurisy 50 Effusion 25 Pneumonitis 5–10Cardiac (pericarditis) 10–50Lymphadenopathy 50CNS Seizures 15–20 Psychosis <25

CNS, central nervous system; SLE, systemic lupus erythematosus.

Table 42-2. Revised ARA Classifi cation Criteria for SLE (1982 and 1997)

CRITERION DEFINITION

Malar rash Fixed erythema, fl at or raised, over the malar eminences, tending to spare the nasolabial foldsDiscoid rash Erythematous raised patches with adherent keratotic scaling and follicular plugging; atrophic scarring may occur in older lesionsPhotosensitivity Skin rash as a result of unusual reaction to sunlight, by patient history or physician observationOral ulcers Oral or nasopharyngeal ulceration, usually painlessArthritis Nonerosive arthritis involving two or more peripheral joints, characterized by tenderness, swelling, or effusionSerositis a. Pleuritis—convincing history of pleuritic pain or rubbing heard by a physician or evidence of pleural

effusion b. Pericarditis documented by ECG or rub or evidence of effusionRenal a. Persistent proteinuria greater than 0.5 g/day or greater than 3+ if quantitation not performed b. Cellular casts—red cell, hemoglobin, granular, tubular, or mixedNeurologic a. Seizures—in the absence of offending drugs or known metabolic derangements; e.g., uremia,

ketoacidosis, or electrolyte imbalance b. Psychosis—in the absence of drugs or metabolic derangementsHematologic a. Hemolytic anemia–with reticulocytosis b. Leukopenia—less than 4,000/mm on two or more occasions c. Lymphopenia—less than 1,500/mm on two or more occasions d. Thrombocytopenia—less than 100,000/mm in absence of drugsImmunologic a. Anti-DNA: antibody to native DNA in abnormal titer b. Anti-Sm: presence of antibody to Sm nuclear antigen c. Positive fi nding of antiphospholipid antibodies based on (1) an abnormal serum level of IgG or IgM anticardiolipin antibodies, (2) a positive test result for lupus anticoagulant using a standard method, or (3) a false-positive serologic test for syphilis for 6 monthsAntinuclear An abnormal titer of antinuclear antibody by immunofl uorescence or an equivalent assay at any point in antibody time and in the absence of drugs known to be associated with drug-induced lupus syndrome

ARA, American Rheumatism Association; ECG, electrocardiogram.

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1082 Section VI Pregnancy and Coexisting Disease

The sun-sensitive, erythematous butterfl y rash along the malar eminences and across the upper nose occurs in about 50 percent of patients. Patients also may have a pruritic, maculopapular eruption, particularly in sun-exposed areas. Two distinct forms of cutaneous lupus are discoid and subacute. The lesions of discoid lupus mature to clearly outlined papules and plaques, with a central area eventually becoming atrophied and depressed. Scar-ring is the result. In contrast, subacute lesions appear as distinctly defi ned erythematous plaques that do not undergo central atrophy and scarring. Subacute lesions are usually more widespread than discoid lesions, with the latter tending to be confi ned to the face, neck, scalp, and upper arms or shoulders.

Clinically obvious renal disease eventually occurs in about 50 percent of patients with SLE. Lupus nephritis (LN) is likely a result of immune complex deposition leading to complement activation and infl ammatory tissue damage in the kidney. The most common presenting sign of renal involvement is proteinuria; about 40 percent of patients with SLE renal disease have hematuria or pyuria, and about a third have urinary casts.

Confi rming the diagnosis of LN requires a renal biopsy. This verifi cation is an important factor in determining prognosis and providing appropriate treatment. Renal biopsy fi ndings are used to group LN into four basic his-tologic and clinical categories. Of the four, diffuse prolif-erative glomerulonephritis (DPGN) is the most common (40 percent) and most severe. DPGN has a 10-year sur-vival rate of approximately 60 percent. Patients with DPGN typically present with hypertension, moderat e-to-heavy proteinuria and nephrotic syndrome, hematu-ria, pyuria, casts, hypocomplementemia and circulating immune complexes. Another category is focal prolifera-tive glomerulonephritis, which is usually associated with mild hypertension and proteinuria. Serious renal insuf-fi ciency with focal proliferative glomerulonephritis is uncommon. Membranous glomerulonephritis typically presents with moderate to heavy proteinuria but lacks the active urinary sediment and does not cause renal insuffi ciency. Mesangial glomerulonephritis appears to be the least clinically severe lesion and carries the best long-term prognosis.

LABORATORY TESTS

The diagnosis of SLE, suspected based upon the clinical presentation, is confi rmed by demonstrating the presence of pertinent circulating autoantibodies. Most clinicians initially test for autoantibodies directed against nuclear antigens, most commonly using immunofl uorescent assays for antinuclear antibodies (ANA). Positive test results are typically reported in terms of the antibody titer and the pattern of antibody binding. A homogeneous pattern is found most commonly in patients with SLE (65 percent), although its specifi city is low. A peripheral pattern is the most specifi c for SLE, but is not very sensitive. The speckled and nucleolar patterns are more specifi c for other autoimmune diseases.

Immunofl ourescent assays that identify specifi c nuclear antigen-antibody reactions are better for confi rming the diagnosis of SLE, monitoring disease activity, and guiding

immunotherapy. Particularly useful are anti–double-stranded DNA (anti-dsDNA) antibodies, present in 80 to 90 percent of patients with newly diagnosed SLE. When elevated, these antibodies have been associated with a symptomatic fl are in 80 percent of SLE patients followed prospectively.7,8 In pregnancy, anti-dsDNA antibodies correlate with fl are and preterm delivery.8,9 Antibodies to single-stranded DNA (ssDNA) are also found in a large proportion of untreated SLE patients but are less specifi c for SLE than anti-dsDNA. Patients with SLE may have antibodies to RNA-protein conjugates, often referred to as soluble or extractable antigens, because they can be separated from tissue extracts. These antigens include the Sm antigen, nuclear ribonucleoprotein, and the Ro/SSA and La/SSB antigens. The Sm and nuclear ribonucleo-protein antigens are nuclear in origin, and the presence of anti-Sm, found in about 30 to 40 percent of patients with SLE, is highly specifi c for the disease. Anti-Ro/SS-A and La/SS-B, found in the sera of both SLE patients and patients with Sjögren’s syndrome, are of particular importance to obstetricians because they are associated with neonatal lupus.

Systemic Lupus Erythematosus and Pregnancy

Preexisting SLE or onset during pregnancy carries important implications for the mother and the fetus. For the mother, the primary concerns are SLE exacerbation, nephritis and preeclampsia, possible need for preterm delivery, and an increased rate of cesarean delivery. Fetal-neonatal concerns include miscarriage and fetal death, preeclampsia, placental insuffi ciency and intrauterine growth restriction (IUGR), preterm birth (PTB) and com-plications thereof, and neonatal lupus.

THE RISK OF SYSTEMIC LUPUS ERYTHEMATOSUS EXACERBATION (FLARE)

Whether or not pregnancy is associated with a higher rate of SLE exacerbation is a matter of considerable debate. Early studies were hampered by poor study design and diffi culties differentiating between SLE and obstetric disorders, for example, severe hypertension due to preeclampsia. The small, retrospective series published during the 1960s and 1970s suggested that pregnancy in women with SLE was associated with substantial risk for severe maternal morbidity and mortality and that this risk was related to SLE activity.10 Given this concern, many practitioners held the opinion that patients with SLE should not become pregnant.

Studies since 1980 have done much to clarify the relationship of pregnancy to the rate and nature of SLE exacerbations. Overall, 15 to 60 percent of women with SLE have a fl are during pregnancy or the postpartum period.3,11–23 Several prospective studies deserve special consideration. Using a previously published scoring system to defi ne SLE exacerbations, Lockshin et al.11 matched non-pregnant SLE patients with 28 SLE patients under-taking 33 pregnancies. There was no difference in the fl are score between the cases and controls, and a similar

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number in either group required a change in their medica-tion. When only signs or symptoms specifi c for SLE were included, exacerbations occurred in only 13 percent of cases. Mintz et al.13 prospectively studied 92 pregnancies in women with SLE and used a similar group of nonpreg-nant SLE patients on oral contraceptives derived from a previous study as controls. Exacerbations were defi ned by criteria different from those used by Lockshin et al.11 As a matter of policy, all pregnant women were started on 10 mg prednisone daily, even if there was no evidence of SLE activity. The rate of SLE fl ares per month at risk was similar in both groups. Most of the exacerbations tended to be easily controlled with low to moderate doses of glucocorticoids, but seven patients (8 percent) had severe exacerbations requiring more aggressive therapies. Inter-estingly, the majority (54 percent) of the exacerbations occurred in the fi rst trimester. Urowitz et al.15 reported their experience comparing 79 pregnancies in patients with active SLE with a matched control group of 59 non-pregnant active SLE women. They also compared these women with 216 women with inactive disease. Using a previously defi ned SLE exacerbation score, they found no signifi cant difference in disease activity between the three groups. Georgiou et al.22 prospectively evaluated the frequency of SLE exacerbation during 59 pregnan-cies in 47 women with SLE and 59 nonpregnant women matched for parameters other than disease activity and duration. Using accepted clinical criteria, they reported an SLE exacerbation in 8 (13.5 percent) of the preg-nant patients compared with 13 (22 percent) of the non-pregnant group. More than half of the exacerbations in the pregnant women occurred during the fi rst trimes-ter; all exacerbations were mild and easily treated with glucocorticoids.

In contrast to the negative fi ndings discussed above, two prospective series suggest that pregnant women with SLE have higher rates of exacerbation. Petri et al.3 found SLE fl ares (fl ares per person years) to be more common among pregnant women than among controls. Fortunately, more than three quarters of the fl ares were mild to moderate in nature. Only inactive patients at the onset of pregnancy showed a signifi cant reduction in SLE activity (41 percent). Ruiz-Irastorza et al.16 analyzed the course of SLE in 78 pregnancies in 68 patients and a matched control group of 50 nonpregnant women. Sixty-fi ve percent of the patients experienced an exacer-bation of SLE during pregnancy, for a fl are rate of 0.082 per patient-month. In the control group, 42 percent of the patients fl ared, with a fl are rate of 0.039 per patient-month, representing a statistically signifi cant difference.

Without a doubt, preexisting disease activity, plays a large role in the risk of SLE fl are during pregnancy. Derksen et al.19 reported that SLE exacerbation occurred in fewer than 20 percent of women with sustained remission prior to pregnancy. More recently, Cortez-Hernandez and colleagues23 studied 60 women with 103 pregnancies and found that SLE exacerbations during pregnancy were more likely in women who discontinued maintenance therapy before pregnancy or had a history of more than three severe fl ares before pregnancy. The fi ndings of several other studies support the notion that women with active disease should postpone pregnancy until sustained remission can be achieved.20–22

Thus, from the available literature one can surmise that if pregnancy predisposes to a lupus fl are, it does so only modestly. A majority of studies of pregnant women with SLE indicate that most fl ares are mild to moderate in nature and easily treated with glucocorticoids.11,13,15,16,20–22 The routine or prophylactic use of glucocorticoids in all pregnant SLE patients, as suggested by some investi-gators, seems unnecessary in view of the excellent results achieved by others without the routine prophylactic immunosuppression.

To ensure timely and accurate detection of an SLE exacerbation, thorough and frequent clinical assessment remains essential. The criteria for measuring an SLE fl are during pregnancy have been recently tested and found valid.24 Commonly presenting symptoms of fl are during pregnancy are extreme fatigue, skin lesions (>90 percent), and arthritis/arthralgias (>80 percent).22,25

Serologic evaluation of SLE disease activity may be benefi cial in confi rming a fl are in confusing cases. As mentioned earlier, elevations in anti-dsDNA titers that precede or accompany a lupus fl are in more than 80 percent of patients are a specifi c indicator.7,8 In addition, some reports suggest that the serial serologic evaluation of complement components and activation products is benefi cial in predicting an SLE fl are during pregnancy. In two studies, Devoe and colleagues found that an SLE exacerbation was signaled by a decline of C3 and C4 into the subnormal range.26,27 Buyon et al.28 found that an SLE exacerbation was associated with an absence of the usual increase in C3 and C4 levels during normal pregnancies. However, the practical utility of serial deter-minations of complement components or their activation products during pregnancy remains unproven. Lockshin et al.29 reported that low-grade activation of the classic pathway may be attributed to pregnancy alone. Wong et al.30 prospectively studied 19 continuing pregnancies complicated by SLE and found that neither ANA nor C3 or C4 levels predicted which patients were going to have a fl are, whereas Nossent and Swaak31 observed that fewer than half of the pregnancies with decreased serum C3 levels were associated with a clinical SLE fl are. Last, although some have found that hypocomplementemia correlates with poor pregnancy outcomes,32–34 hypocom-plementemia may occur in pregnant patients without SLE or adverse pregnancy outcomes.35

LUPUS NEPHRITIS EXACERBATION

Women with LN face several challenges during preg-nancy. Pregnancy may worsen renal function. Moreover, underlying renal disease is associated with increased risks of maternal and fetal complications. Those with chronic renal disease are likely to experience worsening protein-uria during gestation as renal perfusion increases. In turn, this inevitably poses the diagnostic dilemma as to whether the increased proteinuria represents an exacerbation of underlying renal disease, preeclampsia, or both.

As with an SLE exacerbation in general, whether or not renal fl ares are more common in pregnant women with SLE remains controversial. Two studies have reported high frequencies of renal fl ares (43 to 46 percent) during pregnancy,25,30 but others have reported lower fi gures (9

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to 28 percent).13,16,31,36 Three studies assessed the patients’ status during pregnancy in regard to whether the SLE was active or in remission prior to conception.37–39 In all three, the rate of SLE exacerbation was lower in pregnancies in which the patient was in remission before conception.

Studies of pregnancy outcome in women with past or current LN are limited. This may be explained, in part, by (1) the reduced fertility associated with long-term cyclophosphamide or impaired renal function, or both, and (2) the traditional assumption that pregnancy should be discouraged in women with a history of LN. The earliest reports suggest that LN was a major con-tributor to serious maternal morbidity or death.40–42 More recent series suggest that the outlook of pregnancy for women with LN is usually favorable if the disease is well controlled and renal function preserved.43 Oviasu et al.44 reviewed eight studies (151 pregnancies) pub-lished between 1973 and 1991 to determine the effect of completed pregnancy on maternal renal function in established LN and reported transient deterioration of renal function in 17 percent and permanent deterioration in 8 percent of the pregnancies.44

Better outcomes were reported in three studies pub-lished in the 1990s.43–45 Out of 143 patients with LN, only one developed irreversible loss of renal function after pregnancy. It is important to note that the majority of women in these studies had normal renal function, mild proteinuria, and well-controlled hypertension before conception. Petri and colleagues at the Hopkins Lupus Pregnancy Center reported that only women who began pregnancy with nephrotic syndrome went on to renal failure after delivery.25 Hayslett and Lynn37 and Bobrie et al.39 found that the rate of renal deterioration was somewhat lower among pregnancies in which the patient was in remission before conception. In a recent study, Moroni and colleagues46 reported that renal fl are occurred in 5 percent (1/20) of pregnancies in women with inac-tive LN before conception compared with 39 percent (12/31) in women with active LN before conception. The sole predictors for renal fl are were a plasma creatinine greater than 1.2 mg/dL or proteinuria equal to 500 mg in 24-hour collection. Permanent deterioration occurred in two women with active LN before conception, one of whom eventually died.

A troublesome clinical situation is differentiating between renal exacerbation and preeclampsia, because both may present with proteinuria, hypertension, and evidence of multiorgan dysfunction. Some of the features that may prove helpful in the distinction between the two conditions are listed in Table 42-3. Preeclampsia is more likely in women with decreased levels of antithrom-bin III.47,48 Complement concentrations are not always helpful because activation may also occur in women with preeclampsia.49 In the most severe and confusing cases, the correct diagnosis is possible only by renal biopsy. In reality, situations involving either the more severe cases of SLE fl are or preeclampsia inevitably raise concerns about maternal and fetal well-being and often prompt delivery, thus rendering the distinction between the two clinically moot.

Women with active LN (especially DPGN), nephritic syndrome, and severe hypertension are at considerable

risk of preeclampsia and early delivery. Moderate renal insuffi ciency (creatinine 1.5 to 2.0 mg/dl) is a relative contraindication to pregnancy and advanced renal insuf-fi ciency (creatinine greater than 2.0 mg/dl) should be con-sidered an absolute contraindication to pregnancy.

PREGNANCY LOSS

In most retrospective studies, the rate of pregnancy loss appears to be higher in women with SLE than in the general obstetric population, ranging between 8 and 41 percent, with a median of 22 percent.10,12,37,38,50–55 A large case-controlled study compared obstetric outcomes in 481 pregnancies in 203 lupus patients with those of 566 pregnancies in 177 healthy relatives and 356 preg-nancies in 166 healthy unrelated women.55a The investi-gators found that pregnancy loss occurred signifi cantly more often in women with SLE (21 percent) than in either their healthy relatives (8 percent) or unrelated healthy controls (14 percent). However, the pregnancy loss rates observed in most prospective trials of lupus pregnancies have been better than those of their retrospective coun-terparts, possibly because of careful monitoring of SLE activity and routine antenatal surveillance. In the most recent, well-detailed, prospective trials, fetal deaths in the second or third trimester accounted for between 10 to 40 percent of the total losses.22,23

Control of disease activity appears to have a helpful effect on the rate of pregnancy loss,56 with one early study reporting live births in 64 percent of women with active disease within 6 months of conception, compared with 88 percent in women with quiescent disease.37 In a more

Table 42-3. Distinguishing Between Preeclampsia and SLE/LN Flare

TEST PREECLAMPSIA SLE

Serologic Decreased complement ++ +++ Elevated Ba or Bb fragments ± ++ with low CH50 Elevated anti-dsDNA − +++ Antithrombin III defi ciency ++ ±Hematologic Microangiopathic hemolytic ++ − anemia Coombs’ positive hemolytic − ++ anemia Thrombocytopenia ++ ++ Leukopenia − ++Renal Hematuria + +++ Cellular casts − +++ Elevated serum creatinine ± ++ Elevated ratio of serum blood urea ++ ± nitrogen/creatinine Hypocalciuria ++ ±Liver Transaminases ++ ±

+++, present; ++, occasionally present; ±, may or may not be present; −, not present; LN, lupus nephritis; SLE, systemic lupus erythematosus.

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recent, prospective study, pregnancy loss occurred in 75 percent of women with active disease compared with 14 percent of women with inactive disease.22 Not surpris-ingly, pregnancy loss is more likely if SLE is diagnosed during the index pregnancy.38,52,57

Preexisting renal disease appears to increase the rate of pregnancy loss in women with SLE, but loss rates vary widely among studies, likely because of variations in the degree of renal impairment of patients included. Also, the degree of renal impairment is a factor in the rate of pregnancy loss in women with LN. In a recent study of LN in pregnancy that included only women with inactive disease and normal renal function (serum creatinine less than 0.8 mg/dl), the overall fetal survival rate was greater 90 percent, after exclusion of embryonic losses (losses less than 10 weeks’ gestation).20 These results contrast markedly to those of another study in which the rate of fetal loss was 50 percent in pregnant women with LN and moderate-to-severe renal insuffi ciency (serum creati-nine = 1.5 mg/dl).37 In another study comparing obstetric outcomes according to the degree of renal impairment in women with LN, spontaneous abortion occurred in 26 percent of women with minimally impaired renal func-tion (serum creatinine less than 1 mg/dl, clearance greater than 80 ml/min, and proteinuria less than 1 g/day) and 36 percent in women with “mild” impairment (clearance 50 to 80 ml/min, proteinuria 1 to 3 g/day).50

Fetal death (greater than 10 weeks’ gestation) among SLE pregnancies is tied to the presence of antiphos-pholipid antibodies (aPL) (see the section on Antiphos-pholipid Syndrome). In several studies, the existence of aPL has been the single most sensitive predictor of fetal death,58 with a positive predictive value of more than 50 percent.59 For women with SLE and a prior fetal death, the predictive value is more than 85 percent.60 In the most recent prospective trial, the presence of any aPL was the single strongest predictor of subsequent pregnancy loss, even in women with active disease and underlying renal impairment.23

PREECLAMPSIA

It is diffi cult to estimate the exact incidence of preg-nancy-related hypertension associated with SLE. This is in large part due to inconsistencies in the defi nition and classifi cation of these disorders, as well as the inclusion of patients with LN in the various studies. Neverthe-less, it appears that between 20 to 30 percent of women with SLE develop either gestational hypertension (GH) or preeclampsia (GH with proteinuria) sometime during pregnancy.37,58,61–63 Women with LN are most suscep-tible, probably owing to the known association between preeclampsia and underlying renal disease of any origin. In one prospective series, preeclampsia occurred in 7 of 19 (37 percent) women with LN, compared with 15 of 106 (14 percent) without. Other factors that likely predispose SLE patients to GH or preeclampsia include chronic hypertension, secondary antiphospholipid syn-drome (APS), and chronic steroid use17,37,45,50,62,63a (see Table 42-3).

FETAL GROWTH RESTRICTION

Uteroplacental insuffi ciency resulting in IUGR and small-for-gestational-age neonates has been reported in between 12 and 40 percent of pregnancies complicated by SLE.16,21,23,45,56,64 It would seem likely that factors such as underlying renal insuffi ciency and chronic hypertension play a role.23,62,65 Medications, such as glucocorticoids, might also be related to IUGR. In a recent prospective trial Georgiou and colleagues reported no signifi cant dif-ferences in the rate of IUGR between SLE pregnancies and healthy controls.22 In this study, glucocorticoids were given only for symptomatic SLE fl are.

PRETERM BIRTH

PTB has been reported in as few as 3 percent and as many as 73 percent of pregnancies complicated by SLE.13,30,37,38,50,52,57,58,60,66,67 aPLs, chronic hypertension, and disease activity have all been reported to increase the likelihood of PTB in women with SLE.22,23 Only a few studies have included controls for comparison. PTB was more common in a group of women with SLE than in a group of matched controls (12 percent vs 4 percent) in one retrospective case-control study.55a In a recent prospective trial, PTB in women with SLE and healthy controls was statistically similar (8 percent versus 15 percent),22 although PTB was more common among women with active SLE compared with those with inac-tive disease (12.5 percent versus 4 percent).

A substantial proportion of PTB associated with SLE is without a doubt the result of iatrogenic delivery for obstet-ric and medical indications. Data from the few studies that provide suffi cient detail suggest that between 28 to 66 percent of preterm deliveries are indicated because of preeclampsia and another 12 to 33 percent because of suspected or confi rmed fetal compromise.23,52,55a,60,66 An association between SLE and preterm premature rupture of membranes (PPROM) has also been reported, occur-ring in 39 percent of pregnancies delivered at 24 to 36 weeks’ gestation.68

NEONATAL LUPUS ERYTHEMATOSUS

Neonatal lupus erythematosus (NLE) is an infrequent condition of the fetus and neonate, occurring in 1 of 15,000 of all live births and in a relatively small per-centage of lupus pregnancies. It is a result of passively acquired immunity in pregnant women with circulating antibodies directed against Ro/SSA and La/SSB ribo-nucleoprotein antigens.69–73 These antibodies can cross the placenta as early as 11 weeks’ gestation, and they are associated with congenital complete atrioventricular heart block (CCHB), a neonatal lupus rash, and hepatic and blood cell abnormalities.

Anti-Ro/SSA antibodies are found in 75 to 95 percent mothers who deliver babies with NLE.70,72,73 A smaller percentage has only anti-La/SSB. Dermatologic NLE has also been associated with anti-U1RNP without anti-Ro/SSA or anti-La/SSB.70,74 Fortunately, of mothers with SLE

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who are serologically positive for anti-Ro/SSA antibod-ies, no more than 15 percent to 20 percent deliver an infant affected with evidence of NLE. The most common manifestation is dermatologic NLE. Of all women with anti-Ro/SSA or anti-La/SSB, 1 to 5 percent deliver an infant with CCHB. It is important to note, however, that once a woman with SLE and anti-Ro/SSA antibod-ies delivers one infant with CCHB, the risk for recur-rence is at least two- to threefold higher than in women with anti-Ro/SSA-La/SSB antibodies who has never had an affected child.73 Recurrence of dermatologic NLE is approximately 25 percent.72,76

The skin lesions of NLE are erythematous, scaling annular, or elliptical plaques occurring on the face or scalp. They are analogous to the subacute cutaneous lesions in adults. They typically appear in the fi rst weeks of life, probably induced by exposure of the skin to ultraviolet light, and may last for up to 6 months.77 Hypopigmentation may persist for up to 2 years. Hema-tologic NLE is rare and may be manifest as autoimmune hemolytic anemia, leukopenia, thrombocytopenia and hepatosplenomegaly.

Cardiac NLE lesions include CCHB and the less fre-quently reported endocardial fi broelastosis. CCHB is due to disruption of the cardiac conduction system, especially in the area of the atrioventricular node. The diagnosis of CCHB is typically made around 23 weeks’ gestation73 when a fi xed bradycardia of 60 to 80 beats per minute is detected during a routine prenatal visit. Fetal echocar-diography reveals complete atrioventricular dissociation with a structurally normal heart. CCHB is irreversible, and greater than 65 percent of surviving infants will require a pacemaker, 50 percent of them at birth. In the more severely affected fetus, more widespread endo-myocardial damage leads to fi broelastosis and markedly diminished cardiac pump function, hydrops fetalis, and fetal death. In the largest series of prenatally diagnosed CCHB, the 3-year survival was 79 percent; the majority of deaths occurred before 90 days of life.73

Suspected cases of CCHB in utero should be evaluated by fetal echocardiography and maternal tests for anti-Ro/SSA and anti-La/SSB antibodies. If the diagnosis of CCHB due to NLE is made, some experts currently rec-ommend administration of a glucocorticoid that crosses the placenta to limit further damage to the fetal heart. Maternal plasmapheresis, to reduce the antibody load, or invasive fetal pacing to increase the fetal ventricular rate also have been used. None of these treatments have been shown to be effective.78 In addition, all of the aforemen-tioned maternal treatments have known potential and real side effects. The effi cacy of prenatal treatments is being examined in a registry of cases collected by Dr. J.P. Buyon, Hospital for Joint Disease, New York University, New York City ([email protected]).

Although of unproven effi cacy, many experts recom-mend screening fetuses of antibody-positive mothers who have previously delivered an infant with CCHB using echocardiographic-Doppler techniques to measure the mechanical PR interval79 from 16 weeks’ forward. Because of the grave nature of CCHB, the fi nding of any conduction disturbance would prompt attempts at

preventing further or ongoing damage using glucocorti-coids or intravenous immune globulin (IVIG). Again, this approach is of unproven effi cacy.

The apparent success of IVIG in the treatment of fetal-neonatal alloimmune thrombocytopenia has led to speculation that IVIG might be effective in preventing or treating autoantibody-mediated CCHB. An international, multicenter trial has been suggested.

OBSTETRIC MANAGEMENT

Women with SLE who are contemplating pregnancy should be counseled before conception about potential obstetric problems including pregnancy loss, gestational hypertensive disorders, IUGR, and PTB. They should also be informed of the risk of SLE fl are and special concerns related to APS and NLE. Laboratory evaluation before pregnancy should include an assessment for anemia and thrombocytopenia, underlying renal disease (urinalysis, serum creatinine and 24-hour urine for creatinine clear-ance and total protein), and aPL (lupus anticoagulant, anticardiolipin and anti-β2-glycoprotein I antibodies). Many experts routinely obtain anti-Ro/SSA and anti-La/SSB antibodies in patients with SLE; however, the cost-effectiveness of these tests is not proven.

Women with active SLE should be discouraged from becoming pregnant until they are in remission. Cyto-toxic drugs should be stopped before conception, and every effort should be made to reduce or eliminate long-term treatment with nonsteroidal anti-infl ammatory drug (NSAID). However, maintenance therapy with hydroxy-chloroquine or low doses of glucocorticoids need not be discontinued.

The prenatal care of the patient with SLE should be guided by the potential risks to the mother and fetus. Prenatal visits should occur every 1 to 2 weeks in the fi rst and second trimesters and every week thereafter. A primary goal of the antenatal visits after 20 weeks’ gestation is the detection of hypertension, proteinuria, or suspicion of IUGR. Because of the risk of uteroplacental insuffi ciency, fetal ultrasonography should be performed every 4 to 6 weeks starting at 18 to 20 weeks’ gestation. In the usual case, fetal surveillance (daily fetal move-ment counts and periodic nonstress tests and amniotic fl uid volume measurements) should be instituted at 30 to 32 weeks’ gestation. More frequent ultrasonography and fetal testing may be indicated in patients with SLE fl are, hypertension, proteinuria, clinical evidence of IUGR, or APS. Fetal surveillance as early as 24 to 25 weeks may be necessary in patients with APS.80

Management of SLE during labor and delivery is a continuation of antenatal care. Exacerbations of SLE can occur during labor and may require the acute adminis-tration of steroids. Regardless, stress doses of glucocor-ticoids should be given during labor or at the time of cesarean delivery to all patients who have been treated with chronic steroids within the year. Intravenous hydro-cortisone, given in doses of 100 mg every 9 hours for three doses, is an acceptable regimen. Obstetric com-plications, such as preeclampsia and IUGR, should be

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managed in the usual fashion, and not specifi cally altered because of the SLE. Neonatology support may be needed at delivery for problems associated with CCHB and other manifestations of NLE.

It is uncertain which patients, if any, are at risk for SLE fl are following delivery, and it probably best to maintain frequent contact with SLE patients in the post-partum period. Maintenance medications discontinued during labor and delivery should be restarted immedi-ately following delivery, at similar doses as during the pregnancy. Dose adjustments can be handled in the out-patient setting.

Treatment of Systemic Lupus Erythematosus in Pregnancy

GLUCOCORTICOIDS

Glucocorticoids are often used to treat SLE during pregnancy. These medications can be given as mainte-nance therapy or in “bursts” to treat SLE fl ares. The doses used in pregnancy are the same as those in non-pregnant patients. Tapering to the lowest dose required to manage the disease is prudent because glucocorticoids are associated with preeclampsia, gestational diabetes mellitus, and PPROM.

Some experts have recommended the use of prophylac-tic glucocorticoids during pregnancy.13,36,81 However, this practice is not evidence based, and comparable maternal and fetal outcomes have been documented in patients without prophylactic treatment in the presence of stable disease.82

Despite the fact that glucocorticoids have a low poten-tial for teratogenesis,83 they are not without risk during pregnancy. Patients requiring long-term therapy are best treated with prednisolone or methylprednisolone because of their conversion to relatively inactive forms by the abundant 11-β-ol dehydrogenase found in the human placenta. Glucocorticoids such as dexamethasone and betamethasone, with fl uorine at the 9-a position, are poorly metabolized by the placenta, and long-term use during pregnancy should be avoided. Recent analyses suggest a very slight increased risk of cleft lip and palate associated with glucocorticoid exposure in the early fi rst trimester.84–86 Maternal side effects may be signifi cant and include weight gain, striae, acne, hirsutism, immunosup-pression, osteonecrosis and gastrointestinal ulceration. Long-term glucocorticoid therapy during pregnancy has been associated with an increased risk of preeclamp-sia,58,87,88 PPROM, uteroplacental insuffi ciency, and IUGR.89 Because of the increased risk of glucose intoler-ance,87,88 women treated over the long term with glu-cocorticoids should be screened for gestational diabetes mellitus somewhat earlier and more than once, probably at 22 to 24, 28 to 30, and 32 to 34 weeks’ of gestation.

ANTIMALARIAL MEDICATIONSIn the past, many patients and their physicians have

discontinued antimalarials before or during pregnancy because of concerns about teratogenicity, specifi cally

otic90 and ocular damage.91 Considerable clinical experi-ence, in cases with malaria prophylaxis, failed to confi rm rare reports of these adverse fetal effects. And recent case series suggest hydroxychloroquine is relatively safe during pregnancy.92–95 The fi ndings of a recent case-controlled trial, which compared the effects of in utero exposure to hydroxychloroquine, were confi rmatory.96 No differences were noted between the 122 infants with in utero expo-sure to hydroxychloroquine and the 70 control infants regarding the number and type of defects identifi ed at birth. There was also no difference in the percentages of infants affected with visual, hearing, growth, or devel-opmental abnormalities at follow-up (median follow-up, 24 months).

Just as importantly, hydroxychloroquine may be emerging as the best overall agent for maintenance SLE therapy during pregnancy. In a recent randomized con-trolled trial, women who continued hydroxychloroquine during pregnancy experienced a signifi cant reduction in SLE disease activity compared with women who changed to glucocorticoid therapy.97 Many experts now recom-mend continuing hydroxychloroquine during pregnancy in patients being treated with this agent.

CYTOTOXIC AGENTS

Cytotoxic agents, including azathioprine, methotrex-ate, and cyclophosphamide, are used to treat only the most severely affected patients with SLE. Limited data suggest that azathioprine, a derivative of 6-mercaptopu-rine, is not teratogenic in humans but is associated with IUGR98,99 and impaired neonatal immunity.100 Thus, in women requiring chronic azathioprine, consideration of pregnancy demands that the patient and physician have carefully weighed potential fetal risks against the benefi ts of the medication.

Cyclophosphamide has been reported to be teratogenic in both animal101 and human studies102,103; it should be avoided during the fi rst trimester. Thereafter, cyclophos-phamide should be used only in special circumstances, such as in women with severe, progressive proliferative glomerulonephritis.104

Methotrexate is toxic to actively dividing trophoblast and causes miscarriage and early fetal death. Moreover, methotrexate is documented to cause malformations in up to 30 percent of surviving pregnancies when using doses greater than 10 mg per week in the fi rst trimes-ter. These malformations include cranial dysostosis with delayed ossifi cation, hypertelorism, wide nasal bridge, micrognathia, and ear anomalies.105 Case reports have also described cleft palate and deformities of the toes and fi ngers when methotrexate is used in early pregnancy.106 Principles underlying teratogenicity of a drug are dis-cussed in Chapter 8.

NONSTEROIDAL ANTI-INFLAMMATORY DRUGS

NSAIDs are the most common type of analgesics used in the treatment of SLE outside of pregnancy. Although

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effective, they readily cross the placenta and can block prostaglandin synthesis in a wide variety of fetal tissues. Maternal ingestion of normal adult doses of aspirin in the week before delivery has been associated with intra-cranial hemorrhage in preterm neonates.107,108 Although short-term (less than 72 hours) tocolytic therapy with indomethacin appears to be safe,109,110 long-term use has been associated with a number of untoward fetal effects. After 32 weeks’ gestation, indomethacin can cause con-striction or closure of the fetal ductus arteriosus.111 Long-term use of any NSAID has been associated with decreased fetal urinary output, oligohydramnios, and neonatal renal insuffi ciency.112 Given these risks, long-term use of adult dosages of aspirin and other NSAIDs should be avoided during pregnancy, especially after the fi rst trimester. Acetaminophen and narcotic-containing preparations are reasonable alternatives if analgesia is needed during pregnancy.

OTHER IMMUNOSUPPRESSIVE AGENTS

Several other treatments, including cyclosporin, high-dose IVIG, mycophenolate mofetil (MMF), and tha-lidomide, are sometimes used in SLE patients.104 Only IVIG has been used during pregnancy without reports of adverse fetal effects. MMF is a reversible inhibitor of inosine monophosphate dehydrogenase. It works by blocking de novo purine synthesis. MMF is an Food and Drug Administration (FDA) Category C drug, but terato-genic risks are a concern because experiments in animals revealed developmental toxicity, malformations, and intrauterine death at dosages that coincide with recom-mended clinical dosages.98 Given this information, there is a possibility of increased risk in humans, and therefore, MMF is contraindicated in pregnancy. Thalidomide is strictly contraindicated during pregnancy because of its known potent teratogenicity.

ANTIPHOSPHOLIPID SYNDROME

Introduction

aPL are a family of autoantibodies that bind to epi-topes associated with negatively charged phospholipids or proteins that bind to negatively charged phospholip-ids. Clinicians fi rst recognized that aPL were associated with hypercoagulability 50 years ago, and an association with pregnancy loss was established in the mid-1970s. The term APS was introduced in 1986 to formalize the association of aPL with these clinical features. Over a decade of subsequent international laboratory and clini-cal experience led to the development of an international consensus statement on preliminary criteria for defi nite APS, published in 1999 and revised in 2005 (Table 42-4).113,114 Clinicians should recognize that the diagnosis of APS rests fi rst and foremost on clinical features and is confi rmed by demonstrating repeatedly positive tests for aPL.

Epidemiology

The actual prevalence and incidence of APS is unknown. APS may exist as an isolated immunologic derangement (primary APS) or in combination with other autoimmune diseases (secondary APS), most commonly SLE. aPL are found in up to 5 percent of apparently healthy controls and in up to 35 percent of patients with SLE.115 The prospective risks associated with a positive test for aPL antibodies in otherwise healthy subjects are unknown (Table 42-5).

Pathophysiology

Whether aPL per se are the cause of adverse obstet-ric outcomes associated with the antibodies remains a

Table 42-4. Preliminary Classifi cation Criteria for APS*

Clinical criteria Vascular thrombosis a. One or more clinical episodes of arterial, venous, or small-vessel thrombosis in any tissue or organ, AND b. Thrombosis confi rmed by imaging or Doppler studies or histopathology, with the exception of superfi cial venous

thrombosis, AND c. For histopathologic confi rmation, thrombosis should be present without signifi cant evidence of infl ammation in the

vessel wall. Pregnancy morbidity a. One or more unexplained deaths of a morphologically normal fetus at or beyond the 10th week of gestation, with

normal fetal morphology documented by ultrasound or by direct examination of the fetus, OR b. One or more premature births of a morphologically normal neonate at or before the 34th week of gestation because

of severe preeclampsia or severe placental insuffi ciency, OR c. Three or more unexplained consecutive spontaneous abortions before the 10th week of gestation, with maternal

anatomic or hormonal abnormalities and paternal and maternal chromosomal causes excluded. Laboratory criteria a. Anticardiolipin antibody of IgG and/or IgM isotype in blood, present in medium or high titer, on at least 2 occasions

at least 6 weeks apart, measured by standard enzyme-linked immunosorbent assay for β2-glycoprotein I-dependent anticardiolipin antibodies, OR

b. Lupus anticoagulant present in plasma, on 2 or more occasions at least 6 weeks apart, detected according to the guidelines of the International Society on Thrombosis and Hemostasis.

*Defi nite antiphospholipid syndrome (APS) is considered to be present if at least 1 of the clinical and 1 of the laboratory criteria are met.

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subject of debate, although mounting evidence supports a direct antibody-mediated effect. Working with mice, some investigators found administration of human aPL results in clinical manifestations of APS, including fetal loss.116,117 Rodent venous thrombosis models have also been developed.118

A variety of mechanisms by which aPL may cause pregnancy loss (and thrombosis) have been suggested. Considerable work has focused on aPL interfering with the normal in vivo function of phospholipids or phospho-lipid-binding proteins crucial to the regulation of coag-ulation. Candidate molecules or pathways that might be adversely affected include β2-glycoprotein I (which has anticoagulant properties), prostacyclin, prothrombin, protein C, annexin V, and tissue factor. aPL may activate endothelial cells, as indicated by increased expression of adhesion molecules, secretion of cytokines, and pro-duction of arachidonic acid metabolites. Other evidence suggests that aPL cross-react with oxidized low-density lipoprotein and bind only to oxidized cardiolipin,119 implying that aPL may participate in oxidant-mediated injury of the vascular endothelium. These abnormalities may result in thrombosis during the development of the normal maternoplacental circulation, perhaps through interference with trophoblastic annexin V,120 which is abundant in the human placenta, or by impairing tropho-blastic hormone production or invasion.121

The in vivo targets of aPL remain uncertain. Normal living cells do not express phospholipids bound by aPL on their surface. The antibodies do, however, bind to phospholipids expressed by perturbed cells, such as acti-vated platelets or apoptotic cells. Recent work points to the complement system as having a primary role in APS-related pregnancy loss, showing that C3 activation is required for fetal loss in a mouse model.122 Moreover, the benefi cial effect of heparin seen in this model appears to be linked to heparin’s anticomplement, not anticoagu-lant activity. Anticoagulants other than heparin do not prevent fetal loss in this murine system,123 suggesting that thrombosis may not be the immediate cause of pregnancy morbidity and mortality in this syndrome.

Regardless of the primary mechanism, the negative effect of APS on human pregnancy appears to be tied to abnormal maternal-fetal circulation. Some investigators have found narrowing of the spiral arterioles, intimal thickening, acute atherosis, and fi brinoid necrosis in cases of fetal loss associated with APS. Others have found extensive placental necrosis, infarction, and thrombosis.

Diagnosis

CLINICAL MANIFESTATION

The International Consensus Statement provides sim-plifi ed criteria for the diagnosis of APS.113,124 Patients with bona fi de APS must manifest at least one of two clinical criteria (vascular thrombosis or pregnancy morbidity). Thrombosis may be either arterial or venous and must be confi rmed by an imaging or Doppler study or by his-topathology. Pregnancy morbidity is divided into three categories: (1) otherwise unexplained fetal death (10 weeks’ gestation or older), (2) PTB (less than 34 weeks’ gestation) for severe preeclampsia or placental insuffi -ciency, or (3) otherwise unexplained recurrent preembry-onic or embryonic pregnancy loss. Other clinical features, such as autoimmune thrombocytopenia, are associated with aPL but are not considered specifi c enough to be diagnostic criteria.

Obstetric features of APS, which include events of both the preembryonic-embryonic and the fetal-neonatal periods, are divided into three categories—one encom-passing early pregnancy loss, and the other two relat-ing primarily to complications in the second or third trimester (see Table 42-5). In the original description of APS, the single obstetric criterion for diagnosis was fetal loss.125,126 Recently, APS-related pregnancy loss has been extended to include women with early recurrent pregnancy loss [RPL] including those occurring in the preembryonic (less than 6 menstrual weeks of gestation) and embryonic periods (6 through 9 menstrual weeks of gestation).114 In serologic evaluation of women with RPL, 10 to 20 percent have detectable aPL.127–132

Complications occurring in the fetal-neonatal period of pregnancies affected by APS can be serious. At least 40 percent of pregnancy losses reported by women with lupus anticoagulant (LA) or medium-to-high posi-tive IgG aCL occur in the fetal period.133–137 For those pregnancies complicated by APS with fetal survival past 20 weeks’ gestation, the median rate of gestational hypertension-preeclampsia is 32 percent, ranging up to 50 percent.134–140 Indeed, preeclampsia may develop as early as 15 to 17 weeks’ gestation,134 and two groups of investigators have reported that women with early-onset, severe preeclampsia are more likely to test positive for aPL antibodies compared to healthy controls.141,142 Several investigators have relatively high rates of IUGR in association with aPL antibodies.134,138,141,143,144 Even

Table 42-5. Nonautoimmune Causes for Positive Antiphospholipid Antibody Tests

ASSAY TYPE ANTIBODY TYPE CAUSES

ELISA β2-glycoprotein independent Infection: syphilis, Lyme disease, leptospirosis, pinta, HIV β2-glycoprotein dependent Advanced age Drugs Either Lymphoproliferative disease Hyperimmunoglobulin MLupus anticoagulant — Infection; HIV, drugs

ELISA, enzyme-linked immunosorbent assay; HIV, human immunodefi ciency virus.

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with currently used treatment protocols, the rate of IUGR approaches 30 percent.134,138 Pregnancies compli-cated by APS are also more likely to exhibit nonreas-suring fetal heart rate patterns during antenatal tests of fetal well being and intrapartum monitoring.59,134,135 Not surprisingly, the rate of PTB in these series ranges from 32 to 65 percent.134,138,140

LABORATORY FEATURES

Laboratory testing for aPL is necessary to confi rm or refute the diagnosis of APS. As indicated in Table 42-5, a patient with APS should manifest at least one of three laboratory criteria: (1) presence of LA, or (2) medium-to-high titers of β2-glycoprotein I-dependent IgG or IgM isotype anticardiolipin antibodies, or (3) medium to high titers of IgG or IgM isotype anti-β2-glycoprotein I anti-bodies. Very importantly, positive tests must be confi rmed on two separate occasions, at least 12 weeks apart.

LA is identifi ed by in vitro coagulation assays and named as such because the antibodies present prolong clotting times. It is important that published labora-tory criteria for the diagnosis of LA be followed. Anti-cardiolipin antibodies are detected by a standardized enzyme-linked immunosorbent assay that measures β2-glycoprotein I-dependent IgG and IgM anticardiolipin antibodies. The standard anticardiolipin antibody assay detects β2-glycoprotein I-dependent anticardiolipin anti-bodies because β2-glycoprotein I is present in the diluted patient serum and in the bovine serum typically used in the assay buffer-diluent. There is the possibility that the use of bovine serum biases the standard anticardiolipin antibody assay to detect antibodies that react with both bovine and human β2-glycoprotein I and explains differ-ences in reactivity between anticardiolipin antibodies and anti-β2-glycoprotein I assays.

Recent work in the fi eld of aPL has emphasized assays that specifi cally detect the antibody that binds to β2-glycoprotein I itself. Most experts now believe that posi-tive tests for this antibody or group of antibodies, referred to as anti-β2-glycoprotein I, are relatively specifi c for APS. Thus, anti–β2-glycoprotein I antibodies are now included as one of three antibodies diagnostic of the condition.

Whereas LA is reported as being positive or negative, anticardiolipin and anti–β2-glycoprotein I antibodies are reported in terms of international units (designated GPL for IgG binding and MPL for IgM binding). In most laboratories, there is substantial concordance between LA activity and anticardiolipin and anti–β2-glycoprotein I antibodies, with approximately 70 percent of patients with defi nite APS having both LA and anticardiolipin or anti–β2-glycoprotein I antibodies. However, the antibod-ies detected in three assays are likely not to be identical. As a general rule, LA and IgG anti–β2-glycoprotein I antibodies are more specifi c for APS, and anticardio-lipin antibody detected in the standard enzyme-linked immunosorbent assay is the more sensitive test for APS. For both anticardiolipin and anti-β2-glycoprotein I anti-bodies, specifi city is highest for the IgG isotype and for medium-to-high titers. Low positive results should be viewed with suspicion because they may be found in up to 5 percent of normal individuals and should not be

used to make the diagnosis of APS. When they occur alone, IgM results are widely considered to have reduced specifi city for APS. In spite of well-intentioned efforts at standardization and the availability of positive standard sera, substantial interlaboratory variation when testing the same sera remains a serious problem for both anti-cardiolipin and anti–β2-glycoprotein I antibodies. This is due in part to the large number of commercial kits and homemade assays used worldwide.

Clinicians should recognize that the international con-sensus criteria were developed primarily for research pur-poses to ensure more uniform characterization, as well as subcategorization, of patients included in studies. This objective is crucial for credible investigative efforts and for appreciation of subtleties of treatment. The consen-sus criteria also serve to emphasize standardization of laboratory testing, an area of proven concern in aPL. As with other autoimmune conditions, such as SLE, there are individuals who present with one or more clinical or laboratory features suggestive of APS but in whom the diagnosis cannot be made by the relatively strict inter-national consensus criteria. In such cases, experienced clinical judgment is required for best care.

Pregnancy in Women with Antiphospholipid Syndrome

Even with treatment, the potential complications of pregnancy in women with APS include RPL (including fetal death), preeclampsia, placental insuffi ciency, mater-nal thrombosis (including stroke), and complications due to treatment. In women with SLE, the potential complica-tions also include lupus exacerbation.

It is perhaps obvious that pregnancy-related risks vary depending on the population in which the diagnosis of APS is made. Women diagnosed because of recurrent preembryonic or embryonic loss, who appear to be typi-cally healthy, are not at high risk for maternal thrombo-sis, fetal death, preeclampsia, or placenta insuffi ciency requiring PTB.14,145–149

These low-risk patients contrast with those patients that have a history of medical problems (see discussion under Clinical Manifestations earlier). In a case series of APS pregnancies that included women with SLE and prior thrombosis, the median rate of gestational hyper-tension–preeclampsia was 32 percent, ranging up to 50 percent.134,139–141,143,150 Placental insuffi ciency requiring delivery is also relatively frequent in some of these case series.134,139,143 In contrast to the high rate of preeclamp-sia observed in some case series of women previously diagnosed with APS, aPL are not found in a statistically signifi cant proportion of a general obstetric population presenting with preeclampsia151 or in women at moderate risk to develop preeclampsia because of conditions such as underlying chronic hypertension or preeclampsia in a prior pregnancy.152

Management

Given the array of potential complications in APS pregnancy, appropriate obstetric care calls for frequent

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prenatal visits, at least every 2 weeks before midgesta-tion and every week thereafter. The objectives are close observation for maternal thrombosis, hypertension, and other features of preeclampsia, periodic patient evalua-tion and obstetric ultrasound to assess fetal growth and amniotic fl uid volume, and appropriate fetal surveillance testing. The latter should begin at 32 weeks’ gestation, or earlier if the clinical situation is suspicious for placental insuffi ciency, and continue at least weekly until delivery. Frequent rheumatologic consultation every 2 to 4 weeks during pregnancy is recommended, especially in women with SLE.

The ideal treatment for APS during pregnancy would (1) improve maternal and fetal-neonatal outcome by preventing pregnancy loss, preeclampsia, placenta l insuffi ciency, and PTB; and (2) reduce or eliminate the maternal thrombotic risk of APS during pregnancy. Treatment of APS in pregnancy to improve fetal outcome has evolved considerably. Enthusiasm for glucocorticoids waned when a small, randomized trial found maternally administered heparin to be as effective as prednisone.153 Maternally administered heparin is widely considered the treatment of choice at present (Table 42-6), usually initi-ated in the early fi rst trimester after ultrasonographic dem-onstration of a live embryo. The dose of heparin required for safe and effective treatment is debated, however. In one trial of nearly 100 women, two thirds of whom had recurrent preembryonic and embryonic pregnancy loss and none of whom had a history of thromboembolic disease, a heparin dose of 5000 U twice daily was associ-ated with a 71-percent live-birth rate.148 Another study of women with aPL and predominantly preembryonic and embryonic pregnancy loss, none of whom had a history of thromboembolic disease, with heparin administered in a twice daily regimen and adjusted to keep the mid-interval activated partial thromboplastin time approxi-mately 1.5 times the control mean, was associated with an 80-percent live-birth rate.146 In most case series and trials, daily low-dose aspirin is included in the treatment

regimen. A paradigm for the management of APS in pregnancy is shown in Figure 42-1.

It is important that clinicians be aware that the heparin doses recommended for APS patients with prior throm-bosis are considerably higher than the 5000 U twice daily used by Rai and colleagues.148 Indeed, full anticoagula-tion is urged by some experts.154 The optimal dose of heparin for women with APS diagnosed because of prior fetal loss or neonatal death after delivery at less than 34 weeks’ gestation, for severe preeclampsia or placental insuffi ciency, but who do not have a history of throm-boembolism, is controversial. These women are at risk for thromboembolic disease,155 and it seems reasonable that these cases receive suffi cient thromboprophylaxis (see Table 42-6).

Low-molecular-weight heparins are an acceptable option for the treatment of APS pregnancy. Cost consid-erations limit the use of low-molecular-weight heparins in the United States, and there is little reason to suspect that one preparation would be better than the other if used in regimens that provide equivalent anticoagulant effects over 24 hours. A direct comparison of standard heparin versus low molecular-weight-heparin in pregnancy is lacking. The potential complications of heparin treatment during pregnancy include hemorrhage, osteoporosis with fracture, and heparin-induced thrombocytopenia. Fortu-nately, the reported rate of osteoporosis and associated fracture is low, although cases have occurred, even with low-molecular-weight heparin.139 However, it is likely that the risk is higher in women with underlying autoimmune disease who have required glucocorticosteroid treatment. Heparin-induced thrombocytopenia, which may be lethal, is also fortunately infrequent in pregnant women.156

Women with particularly serious thrombotic histories, such as recurrent thrombotic events or cerebral throm-botic events, are understandably viewed as being at very high risk for thrombosis during pregnancy. In selected such cases, we recommend the judicious use of warfarin anticoagulation rather than heparin.

Table 42-6. Subcutaneous Heparin Regimens Used in the Treatment of Antiphospholipid Syndrome During Pregnancy

Prophylactic Regimens

Recurrent Preembryonic and Embryonic Loss; No History of Thrombotic Events

Standard heparin 1. 5,000–7,500 U every 12 hours in the fi rst trimester, 5,000–10,000 U every 12 hours in the second and third trimesters

Low-molecular-weight heparin 1. Enoxaparin 40 mg once daily or dalteparin 5,000 U once daily, OR 2. Enoxaparin 30 mg every 12 hours or dalteparin 5,000 U every 12 hours

Prior Fetal Death or Early Delivery Because of Severe Preeclampsia or Severe Placental Insuffi ciency; No History of Thrombotic Events

Standard heparin 1. 7,500–10,000 U every 12 hours in the fi rst trimester, 10,000 U every 12 hours in the second and third trimesters

Low-molecular-weight heparin 1. Enoxaparin 40 mg once daily or dalteparin 5,000 U once daily, OR 2. Enoxaparin 30 mg every 12 hours or dalteparin 5,000 U every 12 hours

Anticoagulation Regimens—Recommended in Women with A History of Thrombotic Events

Standard heparin 1. 7,500 U every 8–12 hours adjusted to maintain the mid-interval heparin levels in the therapeutic range

Low-molecular-weight heparin 1. Weight-adjusted (e.g., enoxaparin 1 mg/kg every 12 hours or dalteparin 200 U/kg every 12 hours)

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IVIG has also been used during pregnancy, usually in conjunction with heparin and low-dose aspirin, especially in women with particularly poor histories or RPL during heparin treatment.157 However, a randomized, controlle d, pilot study of IVIG treatment during pregnancy in unselected APS cases found no benefi t to this expensive therapy relative to heparin and low-dose aspirin.158

Clinicians should realize that otherwise healthy women with RPL and low titers of aPL do not require treatment. The controlled trial of Pattison and colleagues159 included a majority of such women and found no difference in live-birth rates using either low-dose aspirin or a placebo.

Anticoagulant coverage of the postpartum period in women with APS and prior thrombosis is critical.160 We prefer switching the patient to warfarin thromboprophy-laxis as soon as she is clinically stable after delivery. In most cases, an international normalized ratio of 2.0 to 3.0 is desirable. There is no international consensus regarding the postpartum management of those women without prior thrombosis in whom APS is diagnosed because of a prior fetal loss, or neonatal death after delivery at or before 34 weeks’ gestation, or for severe preeclampsia or placental insuffi ciency, although all agree there is an increased risk of thrombosis. The recommendation in the United States is anticoagulant therapy for 6 weeks following delivery. The need for postpartum anticoagula-tion in women with APS diagnosed solely on the basis of recurrent preembryonic or embryonic losses is uncertain but may be unnecessary. Both heparin and warfarin are safe to use in patients who are breast-feeding.

RHEUMATOID ARTHRITIS

Introduction

Rheumatoid arthritis (RA) is a debilitating disease involving chronic symmetric infl ammatory arthritis of the synovial joints with an incidence of 2.5 to 7 per 10,000 per year and a prevalence of approximately 1 percent in the adult U.S. population. RA is usually diag-nosed between ages 40 and 50 years, but can appear at any age of life and the prevalence increases with age into the 60s or 70s in both women and men. Although found in virtually all populations, it is more common in some (Native American) and less common in others (Native African). As with most autoimmune conditions, RA is more common in women than in men, with a ratio of 2 to 3 female cases to one male.161

Juvenile rheumatoid arthritis (JRA) is diagnosed in children before age 16 years and can be clinically indis-tinguishable from RA at time of presentation. However, JRA tends to have a milder clinical course and typically resolves without serious disability in 70 to 90 percent of children diagnosed.

Pathophysiology

The histologic features of RA include symmetric infl am-matory synovitis marked by cellular hyperplasia, accu-mulation of infl ammatory leukocytes, and angiogenesis

Woman diagnosed with antiphospholipidsyndrome desires pregnancy

Preconception consultations withobstetrician and rheumatologist

Initiate low-dose aspirin

Transvaginal ultrasound to confirm liveembryo at 5.5–6.5 weeks of gestation

Initiate heparin treatment*

Clinical care Diagnostic tests

Prenatal visits every 2–4 weeks until 20–24weeks of gestation then every 1–2 weeks

Monitor for fetal death, preeclampsia, andintrauterine growth restriction

Rheumatologic visits every 2–4 weeks

Obstetric ultrasound every 3–4 weeksbeginning at 17–20 weeks of gestation

Assess fetal growth and amniotic fluidvolume†

Fetal surveillance testing at leastweekly beginning at 30–32 weeks of

gestation, or earlier if placentalinsufficiency is suspected

Figure 42-1. Suggested algorithm for the management of antiphospholipid syndrome in pregnancy. See Table 42-6 for dosing. In the United Kingdom, Doppler assessment of the uterine arteries is commonly used at 20–24 weeks’ gestation for the prediction of preeclampsia and placental insuf-fi ciency risks. This is not commonly done in the United States.

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Chapter 42 Collagen Vascular Diseases 1093

with membrane thickening, edema, and fi brin deposition as common early fi ndings. Infl ammatory damage at the synovium eventually leads to typical joint erosion involv-ing a locally invasive synovial tissue called pannus.

The infl ammatory damage in RA appears to be primar-ily mediated by CD4+ T cells. The CD4+ T cells recognize unknown endogenous or exogenous antigens, are acti-vated by these antigens, and stimulate monocytes, mac-rophages, and synovial fi broblasts to produce cytokines interleukin-1 (IL-1), IL-6, and tumor necrosis factor-α (TNF-α), which, in turn, are key contributors to infl am-mation in RA. CD4+ T cells also express osteoprotegerin ligands that stimulate osteoclastogenesis, as confi rmed in animal models of RA.162 Activated CD4+ T cells also stimulate B cells to produce immunoglobulins, one of which is rheumatoid factor (RF), the characteristic auto-antibody in patients with RA. RF is present in the periph-eral circulation and synovium of RA patients. Whether or not RF autoantibodies are substantially involved in tissue damage remains controversial. There is some evidence that RF autoantibodies form aggregates in synovial fl uid, resulting in complement activation and local infl amma-tion, and eventual joint erosion.

Concordance for RA is found in approximately 15 percent of monozygotic twins and 5 percent of dizygotic twins. It is estimated that heritable factors account for approximately 60 percent of the predisposition to RA.163 The HLA region (HLA class II gene locus DRB1, encoding HLA-DR), is of primary importance in RA susceptibility. Variant forms of DRB1 have been identifi ed in association with RA including DRB1*0401, *0404, *0405, *0101, *1402, and *1001. These alleles encode for similar amino acid sequences (so-called shared epitopes) that are sus-pected of bestowing susceptibility to RA. Other suspect HLA complex genes are located on chromosomes 1p and 1q, 9, 12 p, 16 cen, and 18q.164,165

Clinical Manifestations and Laboratory Findings

RA typically has an insidious onset over several months; less commonly, the disease onset is acute and somewhat rapid. Twice as many patients present during winter months compared with the summer months, and trauma (including surgery) may be a precursor. The most common initial features of RA are morning stiffness, pain, and swelling of peripheral joints. Fatigue, weak-ness, weight loss, and malaise can also be common fi nd-ings. The disease tends to involve primarily the joints of the wrists, knees, shoulders, and metacarpophalangeal joints in an erosive arthritis that usually follows a slowly progressive course marked by exacerbations and remis-sions. Eventually, joint deformities may occur; these are especially obvious at the metacarpophalangeal joint and proximal and distal interphalangeal joints of the hands.

Rheumatoid nodules, composed of a local prolifera-tion of small vessels, histiocytes, fi broblasts, and other cells, present in 20 to 30 percent of affected patients and are usually located in the subcutaneous tissues of the extensor surfaces of the forearm. Although uncom-mon, extra-articular tissues may also be affected. These extra-articular tissues include the lung (pleuritis, pleural effusions, interstitial fi brosis, pulmonary nodules, pneu-monitis, and airway disease) and heart (pericarditis, effu-sion, myocarditis, endocardial infl ammation, conduction defects, and arteritis leading to myocardial infarction).

The classifi cation criteria published by the American College of Rheumatology are shown in Table 42-7. Physi-cal examination should reveal evidence of joint infl amma-tion including joint tenderness, synovial thickening, joint effusion, erythema, and decreased range of motion. Sym-metric involvement should be noted. Radiographic evi-dence of RA includes joint space narrowing and erosion

Table 42-7. Classifi cation Criteria for the Diagnosis of Rheumatoid Arthritis (1987, ACR)

CRITERIA* DEFINITION

Morning stiffness Morning stiffness in and around the joints, lasting at least 1 hour before maximal improvementArthritis of three joint At least 3 joint areas simultaneously have had soft tissue swelling or fl uid (not bony areas overgrowth alone) observed by a physician. The 14 possible areas are right or left PIP, MCP, wrist, elbow, knee, ankle, and MTP jointsArthritis of hand joints At least 1 area swollen (as defi ned above) in a wrist, MCP, or PIP jointSymmetric arthritis Simultaneous involvement of the same joint areas (as defi ned in 2) on both sides of the body (bilateral involvement of PIPs, MCPs, or MTPs is acceptable without absolute symmetry)Rheumatoid nodules Subcutaneous nodules, over bony prominences, or extensor surfaces, or in juxtaarticular regions, observed by a physicianSerum rheumatoid Demonstration of abnormal amounts of serum rheumatoid factor by any method for which the result has been positive in less than 5% of normal control subjectsRadiographic changes Radiographic changes typical of rheumatoid arthritis on posteroanterior hand and wrist radiographs, which must include erosions or unequivocal bony decalcifi cation localized in or most marked adjacent to the involved joints (osteoarthritis changes alone do not qualify)

*For classifi cation purposes, a patient shall be said to have rheumatoid arthritis if he/she has satisfi ed at least four of these seven criteria. Criteria one through four must have been present for at least 6 weeks. Patients with two clinical diagnoses are not excluded. Designation as classic, defi nite, or probable rheumatoid arthritis is not to be made.

MCP, metacarpophalangeal joint; MTP, metatarsophalangeal joint; PIP, proximal interphalangeal joint.Arnett FC, Edworthy SM, Bloch DA, et al: The American Rheumatism Association 1987 revised criteria for the classifi cation of rheumatoid

arthritis. Arthritis Rheum 31:315, 1988.

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and, though too expensive for routine use, magnetic reso-nance imaging may detect synovial hypertrophy, edema, and early erosive changes.

Of those patients with clinical features of RA, 70 percent are also seropositive for RF. In addition, some of those who are initially seronegative eventually convert, leaving only 10 percent of patients with RA without a positive RF. Approximately 5 percent of people in the general population test positive for RF, as do many patients with viral infections, parasitic infections, chronic bac-terial infections, irradiation or chemotherapy, or other autoimmune conditions, for example, SLE, scleroderma, and mixed connective tissue disease.

Pregnancy and Rheumatoid Arthritis

CLINICAL COURSE OF RHEUMATOID ARTHRITIS DURING PREGNANCY

Numerous studies (Table 42-8) show that at least 50 percent, and maybe as much as 75 percent, of patients with RA demonstrate improvement in their disease in at least 50 percent of their pregnancies.166–173 For a major-ity of patients, the improvement in RA starts in the fi rst trimester heralded by a reduction in joint stiffness and pain.169 The peak improvement in symptoms generally occurs in the second or third trimester. Other aspects of the disease may also improve during pregnancy, including subcutaneous nodules associated with RA.171 In addition, Hazes and colleagues reported a protective effect of preg-nancy in development of RA.174

Even with the overall improvement in symptoms, the clinical course of RA during pregnancy is characterized by short-term fl uctuations in symptoms. Most but not all patients who experience an improvement in RA during pregnancy have a similar improvement in subsequent pregnancies. At present, there is no laboratory or clinical feature that predicts improvement of RA in pregnancy, and in a few patients, the disease worsens. Nearly three quarters of patients whose disease has improved during pregnancy will suffer a relapse in the fi rst several post-partum months.169,171 The level of disease during the fi rst year after delivery generally returns to that of a year before conception, but it may be worse.173 There are few studies of JRA, but one found that only one case in 20 had a worsening or reactivation of the disease associated with pregnancy.176

There are no data to suggest that RA in remission is likely to have a better course during pregnancy than active RA. The long-term prognosis for RA patients undertak-ing pregnancy appears to be similar to those that avoid pregnancy. Oka and Vainio173 compared 100 consecu-tive pregnant RA patients with age- and disease-matched controls, and found no signifi cant differences between the groups in terms of the severity of their disease.

The mechanisms by which pregnancy favorably affects RA is unknown. Plasma cortisol, which rises during preg-nancy to peak at term, was initially thought to be impor-tant in the amelioration of RA.166 However, there is no correlation between cortisol concentrations and disease state.176 Some studies suggest that estrogens or estrogens and progestagens favorably affect arthritis,177 but there are confl icting studies,178 and a double-blind crossover trial found that estrogen did not benefi t patients with RA.179 Sex hormones may interfere with immunoregulation and interactions with the cytokine system.180 Promising data suggest that certain proteins circulating in higher con-centrations during pregnancy or unique to pregnancy are associated with improvement of RA. These include preg-nancy-associated a2-glycoprotein181 and gamma globulins eluted from placenta.182 Other investigators believe that the placenta may modify RA by clearing immune com-plexes183 or that modifi cation of immune globulins during pregnancy alters their infl ammatory activity.184

In 1993, Nelson and coworkers185 reported that ame-lioration of RA during pregnancy is associated with a maternal-fetal disparity in HLA class II antigens. Maternal-fetal HLA class II disparity was noted in 26 of the 34 pregnancies (75 percent) described as having remis-sion or improvement in their arthritis, compared with only three of 12 whose condition remained unchanged or worsened. The authors suggested that the maternal immune response to paternal HLA antigens may have a role in pregnancy-induced remission of RA.185

OBSTETRIC COMPLICATIONS

About 15 to 25 percent of pregnancies in women with RA end in miscarriage,186,187 a fi gure that may or may not be slightly higher than in normal women. One con-trolled study found that women with RA have a sig-nifi cantly higher frequency of miscarriage than normal women, even before the onset of their disease (25 versus 17 percent before disease, 27 versus 17 percent after

Table 42-8. Improvement of Rheumatoid Arthritis in Pregnancy

AUTHOR PATIENTS PATIENTS WITH IMPROVEMENT (%) PREGNANCIES PREGNANCIES WITH IMPROVEMENT (%)

Hench161 22 20 (91) 37 33 (89)Oka168 93 73 (78) 114 88 (77)Betson164 21 13 (62) 21 13 (62)Ostensen171 10 8 (90) 10 9 (90)Ostensen175* 51 NA 76 35 (46)

*Study of patients with juvenile rheumatoid arthritis.

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Chapter 42 Collagen Vascular Diseases 1095

disease).186 However, another controlled study did not fi nd that women with RA have a higher proportion of miscarriage before the onset of disease,161 although the frequency of fetal death was higher in patients who later develop RA than in nonaffected relatives. There are scant data available, but women with RA do not appear to be at signifi cant risk for PTB, preeclampsia, fetal growth impairment, or stillbirth.

MANAGEMENT

Ideally, a woman with RA should have a preconception visit to discuss the present state of her disease to reduce and or change maintenance medications so as to avoid fetal risks (see later). Given that a majority of patients experience improvement in RA during pregnancy, routine prenatal care is usually suffi cient. Those patients with persistent symptoms may require more attention and care by a rheumatologist. Rest is an important part of the management of RA, and the patient should be coun-seled to plan adequately for this. Physical therapy can be helpful in patients whose disease does not improve with pregnancy. In an otherwise uncomplicated pregnancy, antepartum fetal testing, including serial ultrasound, non-stress testing, or use of the biophysical profi le, is not necessary in a patient with RA.

ANTIRHEUMATIC MEDICATIONS

Within the last decade, there have been dramatic advancements in the pharmacologic management of RA (Table 42-9). Whereas in the past, patients would fre-quently be maintained on glucocorticoids and NSAIDs, modern day treatment often involves new disease modify-

ing antirheumatic drugs (DMARDs) along with NSAIDs. Older agents, such as penicillamine and gold salts, are now rarely used and are not discussed. Use of glucocor-ticoids in pregnancy, including maternal and fetal risk, is discussed in the section covering SLE.

If at all possible, an attempt should be made to manage RA with acetaminophen, because it is a FDA pregnancy category A, and low-dose glucocorticoids (5 to 10 mg prednisone/day). However, because of changes in the pharmacotherapy used to treat RA, many patients present to their obstetrician having taken other medications. DMARDs are one such group. This classifi cation of medi-cations includes lefl unomide, an isoxazole derivative that competitively inhibits dihydroorotate dehydrogenase, the rate-limiting enzyme required for the de novo synthesis of pyrimidines. Activated lymphocytes are dependent on this pyrimidine synthesis pathway, and by instituting a blockade, antiproliferative effects are noted. Lefl unomide is teratogenic and is associated with fetal death. Thus, it is contraindicated in pregnancy. Importantly, this medica-tion has an extremely long half life of 15 to 18 days, such that merely discontinuing the medication before preg-nancy may not be suffi cient to spare a embryonic expo-sure. An elimination protocol using oral cholestyramine and measuring plasma levels of lefl unomide should be followed. Methotrexate is also included in the DMARDs group and is contraindicated in pregnancy or in those attempting to conceive.

TNF antagonists include medications like etanercept, infl iximab, and adalimumab. As the category implies, these drugs work by antagonizing TNF-α, a key infl am-matory cytokine in RA released by activated monocytes, macrophages, and T lymphocytes. The most common side effect seen is an increase in the number of serious bacterial infections seen in patients on these medications. The effect of TNF antagonists in pregnancy has been

Table 42-9. Drugs Used for Rheumatoid Arthritis

DRUG MECHANISM OF ACTION DOSAGE MONITORING REQUIRED

NSAIDs Anti-infl ammatory 600 mg–800 mg PO q 6–8 hours Gastrointestinal upsetGlucocorticoids Anti-infl ammatory/ Varies based on medication used immunosuppressiveAcetaminophen Analgesic 650 mg PO q 4–6 h, not to exceed None 3–4 g/dayDMARDs Lefl unomide Inhibits pyrimidine synthesis Loading dose of 100 mg daily for 3 Not for use in pregnancy. days, then 20 mg daily Extensive washout procedure recommended Methotrexate Inhibits dihydrofolate reductase 7.5–25 mg once a week CBC, ALT q monthTNF antagonists Etanercept Binds TNF-α and TNF-β 25 mg twice/week or 50 mg once/week Alert for infectious processes, 3 mg/kg of body weight at 0, 2, specifi cally TB, 6 wks then every 8 wk histoplasmosis Infl iximab Chimeric anti–TNF-α antibody 40 mg every second week Adalimumab Human anti–TNF-α antibody 20–40 mg once a weekAnakinra Interleukin-1 receptor antagonist 100 mg daily CBC monthly × 3 months then q 3 months

ALT, alanine transaminase; CBC, complete blood count; DMARDs, disease-modifying antirheumatic drugs; NSAIDs, nonsteroidal anti-infl ammatory drugs; TNF-α, tumor necrosis factor-α; TNF-β, tumor necrosis factor-β.

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evaluated by Katz et al.188 In this study, they followed 96 pregnancies in women taking infl iximab. Of those patients, 67 percent had a normal live birth, 15 percent ended in miscarriage, and 19 percent of the pregnan-cies were electively terminated. One of the infants had tetralogy of Fallot, another demonstrated an intestinal malrotation, and one twin had hypothyroidism. The authors concluded that outcomes were similar to that of the general population. It is too early, however, to suggest that TNF antagonists are safe in pregnancy. Anakinra, a relatively newly introduced DMARD, blocks the IL-1 receptor. The use of anakinra in pregnancy has not been evaluated and, therefore, is not recommended.

The use of NSAIDs in pregnancy, also covered in the section dealing with SLE, should be avoided ex-cept in specifi c instances and, if used, restricted to a limited time period. Chronic use of these medications is contraindicated.

SYSTEMIC SCLEROSIS

Introduction

Systemic sclerosis (SSc) is a multisystem disorder affect-ing the skin and internal organs. It is characterized histo-logically by a marked increase in collagen, mostly in the dermis with hyalinization and often obliteration of small blood vessels. The term scleroderma most specifi cally refers to the skin fi brosis most noticeable to the patient but is frequently used interchangeably with term systemic sclerosis. SSc is uncommon, occurring in no more than 10 to 15 individuals per million per year. The ratio of women to men is 10 : 1 in the 15- to 44-year age group. However, the mean age of onset is in the range from 30 to 50 years, a time when many affected women may potentially become pregnant.189

Pathogenesis

The pathophysiologic changes of SSc include vascular abnormalities, immunologic abnormalities, and disor-dered collagen synthesis. The initial event most likely occurs in small blood vessels, with early proliferation of intimal layer endothelial cells that produce cytokines, growth factors, adhesion proteins, vasoactive proteins, coagulation factors, and extracellular matrix. Aberrant production of substances such as von Willebrand’s factor may also occur. A hallmark feature of SSc is increased fi broblast activity with an accelerated rate of fi broblast collagen synthesis.

Early in the disease process, the dermis contains mono-nuclear cell infi ltrates and sometimes calcium, owing to the deposition of calcium hydroxyapatite. Thinning of the epidermis and loss of normal dermal appendages are other pathologic changes seen in SSc. Small arteries and arterioles exhibit characteristic endothelial cell prolifera-tion and intimal thickening, as well as increased amounts of fi brinogen and fi brin with lumina often occluded by fi brosis. Remaining vessels become dilated and are visible through the skin as telangiectasias.

Internal organs have similar histologic changes. Fibro-mucoid intimal thickening in the kidney results in nar-rowing and thinning of the lumen. Cortical glomerular involvement is typically focal in nature and includes endothelial cell proliferation and thickening of the base-ment membrane. In the lung, the most common fi nding is interstitial fi brosis with increased numbers of fi broblasts, capillary congestion, and thickening and occlusion of alveolar walls and arteriolar intima. Densely hyalinized fi brosis is found in the gastrointestinal tract and random focal fi brosis in the myocardium.

An association between an increase of HLA-DR11 (whites) and DR15 (Asians) in patients with SSc has been described. Associations have also been described with the SSc-associated autoantibodies, topo-isomerase I, and anticentromere antibody, although results have varied in ethnic and racial groups.190

A number of different non-HLA genes have recently been identifi ed with SSc. Genes encoding extracellular matrix proteins have been identifi ed, notably C0L1A1 and C0L1A2, genes encoding type I collagen. Analysis of a Native American population with a particularly high prevalence of SSc identifi ed a candidate gene near the fi brillin 1 gene on chromosome 15q. Polymorphisms in transforming growth factor-β (TGF-β) 1, 2, and 3 genes have also been identifi ed in association with SSc, as have polymorphisms in TNF-α, tumor necrosis factor-β (TNF-β), CXC chemokine receptor 2 (CXCR2), tissue inhibi-tor of metalloproteinase 1 (TIMP-1), and interleukin-4R (IL-4R) alpha.191

Clinical Manifestations and Diagnosis

CLASSIFICATION

The American College of Rheumatology has suggested preliminary criteria for the classifi cation of SSc based on clinical and laboratory assessments of patients192 (Table 42-10). The major criterion for classifi cation was sclero-dermatous skin change in any location proximal of the metacarpophalangeal joints. This feature had a sensitivity of 91 percent and a specifi city of greater than 99 percent in establishing the diagnosis. Minor criteria were also established and consisted of the presence of sclerodactyly, digital pitting scars on the fi ngertips, loss of digital fi nger pad substance, and bibasilar pulmonary fi brosis.

Within the diagnosis of SSc, there are several recog-nized subgroups. These subgroups have been established based on clinical features and have clinical and prognos-tic importance. Diffuse cutaneous scleroderma refers to skin thickening present on the trunk in addition to face and proximal and distal extremities. Limited cutaneous SSc refers to skin thickening limited to sites distal to the elbow and knee but also involving the face and neck. CREST syndrome, sometimes referred to as a form of limited cutaneous SSc, involves calcinosis of involved skin, Raynaud’s phenomenon, esophageal dysmotility, sclerodactyly and telangiectasias. Subgroup classifi cation also extends to include disease duration. Measured from the time of the fi rst symptom attributable to SSc, the clas-

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Chapter 42 Collagen Vascular Diseases 1097

Table 42-10. Classifi cation of Systemic Sclerosis

SKIN FEATURES SYSTEMIC FEATURES

Diffuse cutaneous Above the elbows or knees and/or on trunkLimited cutaneous Distal to the elbow, knees and above the claviclesCREST syndrome Subcutaneous calcinosis, Raynaud’s phenomenon, (3 of 5 present) Esophageal dysfunction sclerodactyly, telangiectasiaSystemic sclerosis sine No skin involvement Presence of internal organ manifestations, vascular and serologic abnormalitiesLocalized scleroderma Asymmetric plaques of fi brotic skin No systemic disease

CREST syndrome, calcinosis of involved skin, Raynaud’s phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasias.

sifi cation varies but one defi nition includes early as being less than 3 years’ duration and late as 6 or more years’ duration (Table 42-11).

Patients who develop early diffuse disease are more likely to present with arthritis, fi nger and hand swelling, and skin thickening. The skin thickening, which usually starts on the fi ngers and hands, may eventually involve the neck and face. Marked deformities of the hands and fi ngers may occur and is attributed to fi brosis of arterioles and small arteries. In these circumstances, the normal vasoconstrictor response to various stimuli, including cold, causes near-complete obliteration of the vessel, and as a result, digital ischemia may occur. Internal organ involvement and dysfunction is a common fi nding in early diffuse disease and probably results from the same vasculopathy seen in the extremities. Lower esophageal dysfunction is most common, but other portions of the gastrointestinal tract may be involved, producing malab-sorption, diarrhea, and constipation.

Patients with SSc develop a variety of pulmonary lesions, with the most common being progression inter-stitial fi brosis. Pulmonary hypertension, a problem of special interest to the obstetrician, may also occur in long-standing disease. Nearly half of the patients with well-established SSc have evidence of myocardial involve-ment, specifi cally dysrhythmias. Renal disease occurs to some extent in many patients and is a major cause of mortality among patients with SSc. Severely involved cases may present with proteinuria and renal insuffi -ciency, hypertension, or both. Sudden onset of severe hypertension and progressive renal insuffi ciency with microangiopathic hemolysis is known as scleroderma renal crisis. These crises usually occur in cold weather, suggesting that the pathophysiology is similar to that of Raynaud’s phenomenon.

DIAGNOSIS

The diagnosis of SSc is primarily clinical. ANA are present in most patients with SSc, but anti-DNA anti-bodies are not. About half of patients have serum cryo-globulins. Antibodies to centromere detected by indirect immunofl uorescence are common among patients with limited cutaneous SSc (CREST syndrome), but not among those with diffuse cutaneous disease. Up to 40 percent of patients have antibody to an extractable nuclear antigen designated ScI, although the biologic signifi cance of these autoantibodies is unclear.

Pregnancy

EFFECTS OF PREGNANCY ON SYSTEMIC SCLEROSIS

Whether or not pregnancy plays a causative role in the genesis of SSc is a subject of controversy. One recent report193 noted an increased risk of SSc related to nul-liparity and that the risk of developing SSc decreased with increasing number of births, an association possibly due to subfecundity. In contrast, a considerable litera-ture has grown around the concept that fetal microchi-merism is a cause of SSc, or at least contributes to the pathogenesis of SSc.193 Numerous studies have evaluated the effect of fetal cells on maternal disease. Bianchi et al.,194 in 1996, reported that fetal cells remain in maternal

Table 42-11. Subsets of Systemic Sclerosis

Diffuse Cutaneous SSc (dSSc)

Onset of Raynaud’s within 1 year of onset of skin changes Truncal and acral skin involvement Presence of tendon friction rubs Early and signifi cant incidence of interstitial lung

disease, oliguric renal failure, diffuse gastrointestinal disease, and myocardial involvement

Absence of anticentromere antibodies (ACA) Nailfold capillary dilantation and capillary destruction Antitopoisomerase antibodies (30% of patients)

Limited Cutaneous SSc (lSSc)

Raynaud’s phenomenon for years (occasionally decades) Skin involvement limited to hands, face, feet and

forearms (acral) or absent A signifi cant late incidence of pulmonary hypertension,

with or without interstitial lung disease, trigeminal neuralgia, skin calcifi cations, telangiectaisa

A high incidence of ACA (70–80%) Dilated nailfold capillary loops, usually without capillary

dropout

From LeRoy EC, Black C, Fleischmgjer R, et al: Scleroderma (systemic sclerosis): classifi cation, subsets and pathogenesis. J Rheumatol 15:202, 1988.

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circulation up to 27 years after childbirth, and Nelson et al.195 questioned whether microchimerism arising from pregnancy could imitate graft-versus-host disease. Using these studies as a basis, Nelson et al.195 evaluated the presence of fetal microchimerism in women with SSc compared with matched healthy controls. Semiquantita-tive PCR assays were used to detect Y chromosome–specifi c sequences in the maternal blood. Y—specifi c DNA was detected in 25 percent of the control patients and 59 percent of the SSC patients. In addition, the total cell number was signifi cantly increased in the SSc patients, with a mean number of male cell DNA equivalents among controls of 0.38 cells per 16 ml of whole blood and 11.1 among scleroderma patients.196 Another group of inves-tigators, however, did not fi nd increased Y chromosome DNA in skin biopsies of women with SSc, although they also found an increased number of male cells present in the patients with SSc when compared with healthy con-trols.197 Lambert et al.200 recently quantifi ed the maternal microchimeric HLA specifi c DNA in patients with SSc and controls using real-time PCR assays. Maternal micro-chimerism was present more often in women with SSc (72 percent) than in healthy controls (22 percent); however, the levels of microchimeric cells were not signifi cantly dif-ferent.193 Thus, these and several other studies198,199 have yielded contradictory results, possibly from using differ-ent detection methods or from quantitative variations.200 At this time, the impact of maternal microchimerism on SSC is not yet known.

The largest and most recent case series suggest that overall maternal outcomes in women with SSc are gener-ally good, with worsening of disease in pregnancy in no more than 20 percent of cases. In most pregnancies (60 to 80 percent), the disease remains clinically stable.189,201,202 Esophageal manifestations may worsen, which is most likely a result of a decreased tone in the lower esophageal sphincter.184

Pregnancy is probably safest in SSc patients without obvious renal, cardiac, or pulmonary disease. Although data are scant, women with SSc patients with moderat e-to-severe cardiac or pulmonary involvement likely face increased risks of substantial morbidity or mortality and should not undertake pregnancy. In addition, SSc patients with moderate to severe renal disease and hypertension probably face a substantial risk for preeclampsia, and perhaps for mortality due to renal crisis. Pregnancy should be discouraged in these women as well. Finally, there may be an increased risk of renal crisis in patients with early diffuse SSc,202 and it may be prudent to delay pregnancy in these patients.

Postpartum, about one third of women with SSc have exacerbations of Raynaud’s phenomenon, arthritis, and skin thickening.202

EFFECTS OF SYSTEMIC SCLEROSIS ON PREGNANCY

Pregnancy in women with SSc is uncommon, with no more than a few hundred cases reported in the pub-lished literature. Early reports that fertility was impaired in women with SSc may have been due to factors

such as maternal age or a desire to avoid pregnancy or children.189

FETAL OUTCOMESAs with many other autoimmune conditions, early case

reports and small series focused on poor pregnancy out-comes. In addition, one group of investigators found that a predisposition to miscarriage might predate the onset of SSC in some women. Of 154 patients who eventually developed SSc and 115 matched controls, a signifi cantly greater number of cases had a history of miscarriage (29 versus 17 percent).203

However, reports and case series of women with pre-existing SSc do not point to SSc being associated with pregnancy loss. For example, among the 29 pregnancies accumulated in case reports, there were two miscarriages (7 percent), two fetal deaths (7 percent), and one neona-tal death attributable to prematurity; two other infants died because of multiple anomalies. Among 103 pregnan-cies in several small series,204–207 there were 24 miscar-riages (23 percent), three fetal deaths (3 percent), and two neonatal deaths due to prematurity. Taken together, noncontrolled reports suggest that 72 to 83 percent of pregnancies among women with SSc are successful, excluding perinatal deaths due to anomalies.

Case-control studies provide a slightly different view. In the case-controlled study by Giordano et al.,208 80 SSc patients had 299 pregnancies. Of these, 50 ended in mis-carriage (17 percent), a rate signifi cantly higher than the rate of miscarriage in the matched controls (10 percent). There was no difference in the miscarriage rate between patients with diffuse cutaneous versus limited cutaneous SSc. The retrospective study of Steen et al.201 included 86 pregnancies after the onset of SSc. Of these, 15 percent ended in miscarriage and 2 percent in midtrimester fetal deaths, percentages similar to those in RA controls or neighborhood controls. A later prospective study found that 16 percent of 80 SSc pregnancies ended in miscar-riage compared with 14 percent in a control group.202 With these studies, the available data suggest that the rate of miscarriages and fetal deaths in patients with SSc might be slightly increased compared with controls. It is worth emphasizing that in the prospective study by Steen (1999) women with late, diffuse SSc demonstrated an increased risk for miscarriage, 42 percent compared with 13 percent for all other subjects.

Of ongoing pregnancies, about one third of SSc pregnan-cies are delivered preterm. In Steen’s202 series, 15 percent of pregnancies in women with SSc delivered early second-ary to preterm labor or PPROM. In other reports and case series, at least 25 percent of ongoing pregnancies in SSc patients were delivered prematurely.172,201,204–209 PTB is particularly prominent in women with early, diffuse cutaneous disease.202

Given the microvascular pathology of the condition and the relative frequency of renal involvement in SSc, one might speculate that preeclampsia and IUGR occur signifi cantly more often in SSc pregnancies. This is sup-ported by high rates of preeclampsia in case reports, although this is not so apparent in case series. In one case series, 10 percent of pregnancies were complicated

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by IUGR,201 but the same authors found a lower rate of IUGR in subsequent pregnancies.202

Neonatal manifestations of skin sclerosis, perhaps sec-ondary to SSc, have been reported in a few cases. The risks of this condition, as well as its relationship to SSc itself, however, remain unclear.

MANAGEMENT

Preconception counseling is important in patients with scleroderma. Those with early diffuse scleroderma or patients with signifi cant cardiopulmonary involvement or severe renal disease should be counseled regard-ing risks associated with pregnancy. Special attention should be given to the evaluation of possible renal or cardiopulmonary involvement. The option of preg-nancy termination should be entertained in patients with diffuse SSc, cardiopulmonary involvement or moderate-to-severe renal involvement.

Even in the nonpregnant state, there is no satisfactory therapy for SSc. Patients with limited cutaneous SSc are usually managed with vasodilators and anti-infl ammatory agents. As discussed earlier, use of NSAIDs should be limited or avoided if at all possible during pregnancy. Oral vasodilators for the prevention and treatment of Raynaud’s phenomenon may be continued, although defi nitive proof of fetal safely is lacking. Patients with early, diffuse cutane-ous SSc may be taking glucocorticoids. Other immunosup-pressive or cytotoxic agents should be avoided.

The use of angiotensin-converting enzyme inhibitors appears to be particularly effective in treating SSc-related hypertension and renal crises. However, the use of these drugs in pregnancy is associated with fetoneonatal renal insuffi ciency and, as a general rule, should be avoided. In the case of SSc-related hypertension, the practitioner must evaluate whether the benefi ts of these medications outweigh the risks of discontinuing them.210

Given the rarity of this illness, evidenced-based recom-mendations regarding prenatal care are lacking. It would seem reasonable that SSc patients with continuing preg-nancies should be seen by a physician every 1 to 2 weeks in the fi rst half of pregnancy and once weekly thereafter. Although serial laboratory testing is not necessary, labo-ratory assessment of unusual or suspicious symptoms or signs may be helpful. Pregnancies should be monitored for evidence of preeclampsia, because this complication may be more likely with scleroderma.202 The possible risk of IUGR and fetal death suggest that serial examination of the fetus by sonography might be benefi cial. Most experts would suggest fetal surveillance be instituted by 30 or 32 weeks’ gestation, or sooner if the clinical situ-ation demands.

In patients with mild-to-moderate disease, few addi-tional precautions are needed during the labor and deliv-ery process. Wound healing may be a problem in patients with advanced disease or those on steroids. In patients with signifi cant pulmonary, cardiac or renal impairment, intensive care management may be needed.

Postpartum resumption of prepregnancy management should be implemented. Most often, reinstitution of maintenance medication is all that is required.

KEY POINTS

❑ SLE is the most common serious autoimmune disease affecting women of reproductive age. The most common presenting complaints in women diag-nosed with SLE include fatigue, weight loss, arthral-gias, arthritis, and myalgias. SLE is associated with an increase in poor pregnancy outcomes including IUGR, stillbirth, and spontaneous abortion.

❑ Renal disease, LN, eventually occurs in about 50 percent of patients with SLE. Confi rmation of the diagnosis requires a renal biopsy. SLE complicated by active LN with advanced renal insuffi ciency (cre-atinine greater than 2.0 mg/dl) should be considered an absolute contraindication to pregnancy.

❑ Immunofl ourescent assays, such as the anti-dsDNA antibodies that identify specifi c nuclear antigen-antibody reactions are better for confi rming the diag-nosis of SLE, monitoring disease activity, and guiding immunotherapy.

❑ Overall, 15 to 60 percent of women with SLE have a fl are during pregnancy or the postpartum period. The level of preexisting disease activity plays a large role in the risk of SLE fl are during pregnancy. Women with active SLE should be discouraged from becoming pregnant until they are in remission. If pregnancy predisposes to a lupus fl are, it does so only modestly.

❑ Once a woman with SLE and anti-Ro/SSA anti-bodies delivers an infant with CCHB, the risk for recurrence is at least two- to threefold higher than in women with anti-Ro/SSa or anti-La/SSB antibodies who have never had an affected child.

❑ Hydroxychloroquine may be safely continued during pregnancy and is a highly effective agent for maintenance SLE therapy.

❑ aPL are found in up to 5 percent of apparently healthy controls and in up to 35 percent of patients with SLE. Patients with APS are at increased risk for RPL, hypertension complicating pregnancy, particu-larly with its onset early in gestation, IUGR, nonreas-suring fetal heart rate patterns, and PTB.

❑ Low-dose heparin and low-dose aspirin are the therapies of choice for patients with APS. Women with APS who have had a prior thrombosis will require doses of heparin that are considerably higher.

❑ RA tends to improve during pregnancy but may relapse in the postpartum period. RA does not appear to have a deleterious effect on pregnancy.

REFERENCES

1. Kotzin BL: Systemic lupus erythematosus. Cell 85:303, 1996. 2. Beeson PB: Age and sex associations of 40 autoimmune diseases.

Am J Med 96:457, 1994.

Ch042-F06930.indd 1099Ch042-F06930.indd 1099 4/17/2007 5:38:39 PM4/17/2007 5:38:39 PM

Page 21: sindrome antifosfolipido

1100 Section VI Pregnancy and Coexisting Disease

3. Petri M, Howard D, Repke J: Frequency of lupus fl are in preg-nancy: The Hopkins lupus pregnancy center experience. Arthritis Rhem 34:1538, 1991.

4. Hayslett JP: The effect of systemic lupus erythematosus on preg-nancy and pregnancy outcome. Am J Reprod Immunol 28:199, 1992.

5. Tan EM, Cohen AS, Fries JF, et al: The 1982 revised criteria for the classifi cation of systemic lupus erythematosus. Arthritis Rheum 25:1271, 1982.

6. Hochberg MC: Updating the American College of Rheumatology revised criteria for the classifi cation of systemic lupus erythema-tosus. Arthritis Rheum 40:1725, 1997.

7. Ter Borg EJ, Hurst G, Hummel EJ, et al: Measurements of increases in anti-double stranded DNA antibody levels as a pre-dictor of disease exacerbation in SLE: A long term, prospective study. Arthritis Rheum 33:634, 1990.

8. Bootsma H, Spronk PE, Derksen R, et al: Prevention of relapses in systemic lupus erythematosus. Lancet 345:1595, 1995.

9. Tomer Y, Viegas OAC, Swissa M, et al: Levels of lupus autoanti-bodies in pregnant SLE patients: correlations with disease activity and pregnancy outcome. Clin Exp Rheumatol 14:275, 1996.

10. Garenstein M, Pollach VE, Kark RM: Systemic lupus erythema-tosus and pregnancy. N Engl J Med 267:165, 1962.

11. Lockshin MD, Reinits E, Druzin ML, et al: Case-control prospec-tive study demonstrating absence of lupus exacerbation during or after pregnancy. Am J Med 77:893, 1984.

12. Meehan RT, Dorsey JK: Pregnancy among patients with systemic lupus erythematosus receiving immunosuppressive therapy. J Rheumatol 14:252, 1987.

13. Mintz R, Niz J, Gutierrez G, et al: Prospective study of pregnancy in systemic lupus erythematosus: Results of a multidisciplinary approach. J Rheumatol 13:732, 1986.

14. Lockshin MD: Pregnancy does not cause systemic lupus erythe-matosus to worsen. Arthritis Rheum 32:665, 1989.

15. Urowitz MB, Gladman DD, Farewell VT, et al: Lupus and preg-nancy studies. Arthritis Rheum 36:1392, 1993.

16. Ruiz-Irastorza G, Lima F, Alves J, et al: Increased rate of lupus fl are during pregnancy and the puerperium: a prospective study of 78 pregnancies. Br J Rheumatol 35:133, 1996.

17. Kleinman D, Katz VL, Kuller JA: Perinatal outcomes in women with systemic lupus erythematosus. J Perinatol 18:178, 1998.

18. Johns KR, Morand EF, Littlejohn GO: Pregnancy outcome in systemic lupus erythematosus (SLE): a review of 54 cases. Aust N Z J Med 28:18, 1998.

19. Derksen RH, Bruinse HW, de Groot PG, Kater L: Pregnancy in systemic lupus erythematosus: a prospective study. Lupus 3:149, 1994.

20. Huong DL, Wechsler B, Vauthier-Brouzes D, et al: Pregnancy in past or present lupus nephritis: a study of 32 pregnancies from a single centre. Ann Rheum Dis 60:599, 2001.

21. Aggarwal N, Sawhney H, Vasishta K, et al: Pregnancy in patients with systemic lupus erythematosus. Aust N Z J Obstet Gynaecol 39:28, 1999.

22. Georgiou PE, Politi EN, Katsimbri P, et al: Outcome of lupus pregnancy: a controlled study. Rheumatology 39:1014, 2000.

23. Cortes-Hernandez J, Ordi-Ros J, Labrador M, et al: Predictors of poor renal outcome in patients with lupus nephritis treated with combined pulses of cyclophosphamide and methylprednisolone. Lupus 12:287, 2003.

24. Ruiz-Irastorza G, Khamashta MA, Gordon C, et al: Measuring systemic lupus erythematosus activity during pregnancy: Vali-dation of the lupus activity index in pregnancy scale. Arthritis Rheum 51:78, 2004.

25. Petri, M: Hopkins Lupus Pregnancy Center: 1987 to 1996. Rheum Dis Clin North Am 23:1, 1997.

26. Devoe LD, Taylor RL: Systemic lupus erythematosus in preg-nancy. Am J Obstet Gynecol 135:473, 1979.

27. Devoe LD, Loy GL: Serum complement levels and perinatal outcome in pregnancies complicated by systemic lupus erythe-matosus. Obstetr Gynecol 63:796, 1984.

28. Buyon JP, Cronstein BN, Morris M, et al: Serum complement values (C3 and C4) to differentiate between systemic lupus activ-ity and preeclampsia. Am J Med 81:194, 1986.

29. Lockshin MD, Qamar T, Redecha P, Harpel PC: Hypocomple-mentemia with low C1s-C1 inhibitor complex in systemic lupus erythematosus. Arthritis Rheum 12:1467, 1986.

30. Wong KL, Chan FY, Lee CP: Outcome of pregnancy in patients with systemic lupus erythematosus. A prospective study. Arch Intern Med 151:269, 1991.

31. Nossent HC, Swaak TJ: Systemic lupus erythematosus. VI. Anal-ysis of the interrelationship with pregnancy. J Rheumatol 17:771, 1990.

32. Shibata S, Sasaki T, Hirabayashi Y, et al: Risk factors in the preg-nancy of patients with systemic lupus erythematosus: association of hypocomplementaemia with poor prognosis. Ann Rheum Dis 51:619, 1992.

33. Rubbert A, Pirner K, Wildt L, et al: Pregnancy course and com-plications in patients with systemic lupus erythematosus. Am J Reprod Immunol 28:205, 1992.

34. Girardi G, Salmon JB: The role of complement in pregnancy and fetal loss. Autoimmunity 36:19, 2003.

35. Adelsberg BR: The complement system in pregnancy. Am J Reprod Immunol 4:38, 1983.

36. Tincani A, Faden D, Tarantini M, et al: Systemic lupus erythema-tosus and pregnancy: a prospective study. Clin Exp Rheumatol 10:439, 1992.

37. Hayslett JP, Lynn RI: Effect of pregnancy in patients with lupus nephropathy. Kidney Int 18:207, 1980.

38. Jungers P, Dougados M, Pelissier C, et al: Lupus nephropathy and pregnancy. Arch Intern Med 142:771, 1982.

39. Bobrie G, Liote F, Houillier P, et al: Pregnancy in lupus nephritis and related disorders. Am J Kidney Dis 9:339, 1987.

40. Garenstein M, Pollach VE, Kark RM: Systemic lupus erythema-tosus and pregnancy. N Engl J Med 267:165, 1962

41. Estes D, Larson DL: Systemic lupus erythematosus and preg-nancy. Clin Obstet Gynecol 8:307, 1965.

42. Bear R: Pregnancy and lupus nephritis: A detailed report of six cases with a review of the literature. Obstet Gynecol 47:715, 1976.

43. Julkunen H: Pregnancy and lupus nephritis. Scand J Urol Nephrol 35:319, 2001.

44. Oviasu E, Hicks J, Cameron JS: The outcome of pregnancy in women with lupus nephritis. Lupus 1:19–25, 1999.

45. Packham DK, Lam SS, Nichols K, et al: Lupus nephritis and pregnancy. QJM 83:315, 1992.

46. Moroni G, Quaglini S, Banfi G, et al: Pregnancy in lupus nephri-tis. Am J Kidney Dis 40:713, 2002.

47. Weiner CP, Brandt J: Plasma antithrombin III activity: an aid in the diagnosis of preeclampsia-eclampsia. Am J Obstet Gynecol 142:275, 1982.

48. Weiner CP, Kwaan HC, Xu C, et al: Antithrombin III activity in women with hypertension during pregnancy. Obstet Gynecol 65:301, 1985.

49. Mellembakken JR, Hogasen K, Mollnes TE, et al: Increased systemic activation of neutrophils but not complement in pre-eclampsia. Obstet Gynecol 97:371, 2001.

50. Fine LG, Barnett EV, Danovitch GM, et al: Systemic lupus erythematosus in pregnancy. Arch Intern Med 94:667, 1981.

51. Fraga A, Mintz G, Orozco J, et al: Sterility and fertility rates, fetal wastage and maternal morbidity in systemic lupus erythe-matosus. J Rheumatol 1:293, 1974.

52. Gimovsky, ML, Montoro M, Paul RH: Pregnancy outcome in women with systemic lupus erythematosus. Obstet Gynecol 63:686, 1984.

53. McHugh NJ, Reilly PA, McHugh LA: Pregnancy outcome and autoantibodies in connective tissue disease. J Rheumatol 16:42, 1989.

54. Zulman Jl, Talal N, Hoffman GS, et al: Problems associated with the management of pregnancies in patients with systemic lupus erythematosus. J Rheumatol 7:37, 1979.

55. Siampoulou-Marridou A, Manoussakis MN, Mavridis AK, et al: Outcome of pregnancy in patients with autoimmune rheumatic disease before the disease onset. Ann Rheum Dis 47:982, 1988.

55a. Petri M, Albritton J: Fetal outcome of lupus pregnancy: a ret-rospective case-control study of the Hopkins Lupus Cohort. J Rheumatol 20:650, 1993.

56. Johns KR, Morand EF, Littlejohn GO: Pregnancy outcome in systemic lupus erythematosus (SLE): a review of 54 cases. Aust N Z J Med 28:18, 1998.

57. Imbasciati E, Surian M, Bottino W et al: Lupus nephropathy and pregnancy. Nephron 36:46, 1984.

Ch042-F06930.indd 1100Ch042-F06930.indd 1100 4/17/2007 5:38:39 PM4/17/2007 5:38:39 PM

Page 22: sindrome antifosfolipido

Chapter 42 Collagen Vascular Diseases 1101

58. Lockshin MD, Qamar T, Druzin ML: Hazards of lupus preg-nancy. J Rheumatol 14:214, 1987.

59. Lockshin MD, Druzin ML, Goei S, et al: Antibody to cardiolipin as a predictor of fetal distress or death in pregnant patients with systemic lupus erythematosus. N Engl J Med 313:152, 1985.

60. Englert HJ, Derue GM, Loizou S, et al: Pregnancy and lupus: Prognostic indicators and response to treatment. QJMed 66:125, 1988.

61. Nicklin JL: Systemic lupus erythematosus and pregnancy at the Royal Women’s Hospital, Brisbane 1979–1989. Aust N Z J Obstet Gynaecol 31:128, 1991.

62. Julkunen H, Kaaja R, Palosuo T, et al: Pregnancy in lupus nephropathy. Acta Obstet Gynecol Scand 72:258, 1993.

63. Kleinman D, Katz VL, Kuller JA: Perinatal outcomes in women with systemic lupus erythematosus. J Perinatol 18:178, 1998.

63a. Ramsey-Goldman R, Kutzer JE, Kuller LH, et al: Pregnancy outcome and anticardiolipin antibody in women with systemic lupus erythematosus. Am J Epidemiol 138:1057, 1993.

64. Yasmeen S, Wilkins EE, Field NT, et al: Pregnancy outcomes in women with systemic lupus erythematosus. J Matern Fetal Med 10:91, 2001.

65. Rahman P, Gladman DD, Urowitz MB: Clinical predictors of fetal outcome in systemic lupus erythematosus. J Rheumatol 25:1526, 1998.

66. Varner MW, Meehan RT, Syrop CH, et al: Pregnancy in patients with systemic lupus erythematosus. Am J Obstet Gynecol 145:1025, 1983.

67. Houser MT, Fish AJ, Tagatz GE, et al: Pregnancy and systemic lupus erythematosus. Am J Obstet Gynecol 138:409, 1980.

68. Johnson MJ, Petri M, Witter FR, et al: Evaluation of preterm delivery in a systemic lupus erythematosus pregnancy clinic. Obstet Gynecol 86:396, 1985.

69. Scott JS, Maddison PJ, Taylor MV, et al: Connective tissue disease, antibodies to ribonucleoprotein and congenital heart disease. N Engl J Med 309:209, 1983.

70. Lee LA: Neonatal lupus erythematosus. J Invest Dermatol 100:9S, 1993.

71. Reed BR, Lee LA, Harmon C, et al: Autoantibodies to SS-A/Ro in infants with congenital heart block. Pediatrics 103:889, 1983.

72. Buyon JP, Clancy RM: Neonatal lupus syndromes. Curr Opin Rheumatol 15:535, 2003.

73. Buyon JP, Hiebert R, Copel J, et al: Autoimmune-associated congenital heart block: demographics, mortality, morbidity and recurrence rates obtained from a national neonatal lupus registry. J Am Coll Cardiol 31:1658, 1998.

74. Provost TT, Watson R, Gaither KK, et al: The neonatal lupus erythematosus syndrome. J Rheumatol Suppl 14(Suppl 13):199, 1987.

75. Julkunen H, Kurki P, Kaaja R, et al: Isolated congenital heart block. Long-term outcome of mothers and characterization of the immune response to SS-A/Ro and to SS-B/La. Arthritis Rheum 36:1588, 1993.

76. Waltuck J, Buyon JP: Autoantibody associated complete heart block: Outcome in mothers and children. Ann Intern Med 120:544, 1994.

77. Neiman AR, Lee LA, Weston WL, Buyon JP: Cutaneous mani-festations of neonatal lupus without heart block: characteristics of mothers and children enrolled in a national registry. J Pediatr 137:674, 2000.

78. Breur JM, Visser GH, Kruize AA, et al: Treatment of fetal heart block with maternal steroid therapy: case report and review of the literature. Ultrasound Obstet Gynecol 24:467, 2004.

79. Glickstein JS, Buyon J, Friedman D: Pulsed Doppler echocardio-graphic assessment of the fetal PR interval. Am J Cardiol 86:236, 2000.

80. Druzin ML, Locksrun M, Edersheim TG, et al: Second trimester fetal monitoring and preterm delivery in pregnancies with sys-temic lupus erythematosus and/or circulating anticoagulant Am J Obstet Gynecol 157:1503, 1987.

81. Le Huong D, Wechsler B, Vauthier-Brouzes D, et al: Outcome of planned pregnancies in systemic lupus erythematosus: a pro spective study on 62 pregnancies. Br J Rheumatol 36:772, 1997.

82. Derksen RH, Bruinse HW, de Groot PG, Kater L: Pregnancy in systemic lupus erythematosus: a prospective study. Lupus 3:149, 1994.

83. Brooks PM, Needs CJ: Antirheumatic drugs in pregnancy and lactation. Baillieres Clin Rheumatol 4:157, 1990.

84. Kallen B, Rydhstraem H, Aberg A: Congenital malformations after the use of inhaled budesonide in early pregnancy. Obstet Gynecol 93:392, 1999.

85. Robert E, Vollset SE, Botto L, et al: Malformation surveillance and maternal drug exposure: the madre project. Int J Risk Safety Ed 6:75, 1994.

86. Carmichael SL, Shaw GM: Maternal corticosteroid use and risk of selected congenital anomalies. Am J Med Genet 86:242, 1999.

87. Laskin CA, Bombardier C, Hannah ME, et al: Prednisone and aspirin in women with autoantibodies and unexplained recurrent fetal loss. N Engl J Med 337:148, 1997.

88. Vaquero E, Lazzarin N, Valensise H, et al: Pregnancy outcome in recurrent spontaneous abortion associated with antiphospholipid antibodies: a comparative study of intravenous immunoglobulin versus prednisone plus low-dose aspirin. Am J Reprod Immunol 45:174, 2001.

89. Rahman P, Gladman DD, Urowitz MB: Clinical predictors of fetal outcome in systemic lupus erythematosus. J Rheumatol 25:1526, 1998.

90. Hart C, Naughton RF: The ototoxicity of chloroquine phos-phate. Arch Otolaryngol 80:407, 1964.

91. Nylander U: Ocular damage in chloroquine therapy. Acta Oph-thalmol 45(Suppl 92):5, 1967.

92. Buchanan NM, Toubi E, Khamashta MA, et al: Hydroxychloro-quine and lupus pregnancy: review of a series of 36 cases. Ann Rheum Dis 55:486, 1996.

93. Khamashta MA, Buchanan NM, Hughes GR: The use of hydroxychloroquine in lupus pregnancy: the British experience. Lupus 5:S65, 1996.

94. Klinger G, Morad Y, Westall CA, et al: Ocular toxicity and antenatal exposure to chloroquine or hydroxychloroquine for rheumatic diseases. Lancet 358:813, 2001.

95. Motta M, Tincani A, Faden D, et al: Antimalarial agents in pregnancy. Lancet 359:524, 2002.

96. Costedoat-Chalumeau N, Amoura Z, Duhaut P, et al: Safety of hydroxychloroquine in pregnant patients with connective tissue diseases: a study of one hundred thirty-three cases compared with a control group. Arthritis Rheum 48:3207, 2003.

97. Levy RA, Vilela VS, Cataldo MJ, et al: Hydroxychloroquine (HCQ) in lupus pregnancy: double-blind and placebo-controlled study. Lupus 10:401, 2001.

98. Armenti VT, Ahlswede KM, Ahlswede BA, et al: National trans-plantation pregnancy registry: outcomes of 154 pregnancies in cyclosporine-treated female kidney transplant recipients. Trans-plantation 57:502, 1994.

99. Armenti VT, Moritz MJ, Davison JM: Drug safety issues in pregnancy following transplantation and immunosuppression: effects and outcomes. Drug Saf 19:219, 1998.

100. Cote CJ, Meuwissen HJ, Pickering RJ: Effects on the neonate of prednisone and azathioprine administered to the mother during pregnancy. J Pediatr 85:324, 1974.

101. Ujhazy E, Balonova T, Durisova M, et al: Teratogenicity of cyclophosphamide in New Zealand white rabbits. Neoplasma 40:45, 1993.

102. Kirshon B, Wasserstrum N, Willis R, et al: Teratogenic effects of fi rst-trimester cyclophosphamide therapy. Obstet Gynecol 72:462, 1988.

103. Enns GM, Roeder E, Chan RT, et al: Apparent cyclophospha-mide (cytoxan) embryopathy: a distinct phenotype? Am J Med Genet 86:237, 1999.

104. Ruiz-Irastorza G, Khamashta MA, Castellino G, Hughes GR: Systemic lupus erythematosus. Lancet 357:1027, 2001.

105. Cardonick E, Moritz M, Armenti V: Pregnancy in patients with organ transplantation: a review. Obstet Gynecol Surv 59:214, 2004.

106. Granzow JW, Thaller SR, Panthaki Z: Cleft palate and toe mal-formations in a child with fetal methotrexate exposure. J Cra-niofac Surg 14:747, 2003.

107. Stuart JJ, Gross SJ, Elrad H, et al: Effects of acetylsalicylic acid ingestion on maternal and neonatal hemostasis. N Engl J Med 307:909, 1982.

108. Rumack CM, Guggenheim MA, Rumack BH, et al: Neonatal intracranial hemorrhage and maternal use of aspirin. Obstet Gynecol 58:52S, 1981.

Ch042-F06930.indd 1101Ch042-F06930.indd 1101 4/17/2007 5:38:39 PM4/17/2007 5:38:39 PM

Page 23: sindrome antifosfolipido

1102 Section VI Pregnancy and Coexisting Disease

109. Macones GA, Robinson CA: Is there justifi cation for using indo-methacin in preterm labor? An analysis of neonatal risks and benefi ts. Am J Obstet Gynecol 177:819, 1997.

110. Vermillion ST, Newman RB: Recent indomethacin tocolysis is not associated with neonatal complications in preterm infants. Am J Obstet Gynecol 181:1083, 1999.

111. Pryde PG, Besinger RE, Gianopoulos JG, Mittendorf R: Adverse and benefi cial effects of tocolytic therapy. Semin Perinatol 25:316, 2001.

112. Ostensen M, Villiger PM: Nonsteroidal anti-infl ammatory drugs in systemic lupus erythematosus. Lupus 10:135, 2001.

113. Sydney Criteria.114. Wilson WA, Gharavi AE, Koike T, et al: International consen-

sus statement on preliminary classifi cation criteria for defi nite antiphospholipid syndrome. Report of an international work-shop. Arthritis Rheum 42:1309, 1999.

115. Levine JS, Rauch J, Branch DW: Antiphospholipid syndrome. N Engl J Med 346:752, 2002.

116. Branch DW, Dudley DJ, Mitchell MD, et al: Immunoglobulin G fractions from patients with antiphospholipid antibodies cause fetal death in BALB/c mice: A model for autoimmune fetal loss. Am J Obstet Gynecol 163:210, 1990.

117. Blank M, Cohen J, Toder V, Shoenfeld Y: Induction of antiphos-pholipid syndrome in naive mice with mouse lupus monoclonal and human polyclonal anticardiolipin antibodies. Proc Natl Acad Sci U S A 88:3069, 1991.

118. Pierangeli SS, Gharavi AE, Harris EN: Experimental thrombosis and antiphospholipid antibodies: New insights. J Autoimmun 15:241, 2000.

119. Hörkkö S, Miller E, Dudl E, et al: Antiphospholipid antibodies are directed against epitopes of oxidized phospholipids: Recog-nition of cardiolipin by monoclonal antibodies to epitopes of oxidized low density lipoprotein. J Clin Invest 98:815, 1996.

120. Rand JH, Wu S, Andree HAM, et al: Pregnancy loss in the antiphospholipid antibody syndrome—a possible thrombogenic mechanism. N Engl J Med 337:154, 1997.

121. di Simone N, Meroni PL, Del Papa N, et al: Antiphospholipid antibodies affect trophoblast gonadotropin secretion and inva-siveness by binding directly and through adhered beta2-glycopro-tein I. Arthritis Rheum 43:140, 2000.

122. Holers VM, Girardi G, Mo L, et al: Complement C3 activation is required for antiphospholipid antibody-induced fetal loss. J Exp Med 195:211, 2002.

123. Girardi G, Salmon JB: The role of complement in pregnancy and fetal loss. Autoimmunity 36:19, 2003.

124. Wilson WA, Gharavi AE, Koike T, et al: International consen-sus statement on preliminary classifi cation criteria for defi nite antiphospholipid syndrome: report of an international work-shop. Arthritis Rheum 42:1309, 1999.

125. Harris EN: Syndrome of the black swan. Br J Rheumatol 26:324, 1987.

126. Asherson RA, Cervera R, de Groot PG, et al: Catastrophic Antiphospholipid Syndrome Registry Project Group. Cata-strophic antiphospholipid syndrome: international consensus statement on classifi cation criteria and treatment guidelines. Lupus 12:530, 2003.

127. Kutteh WH: Antiphospholipid antibody-associated recurrent pregnancy loss: treatment with heparin and low-dose aspirin is superior to low-dose aspirin alone. Am J Obstet Gynecol 174:1584, 1996.

128. Rai R, Cohen H, Dave M, Regan L: Randomised controlled trial of aspirin and aspirin plus heparin in pregnant women with recurrent miscarriage associated with phospholipid antibodies (or antiphospholipid antibodies). BMJ 314:253, 1997.

129. Pattison NS, Chamley LW, Birdsall M, et al: Does aspirin have a role in improving pregnancy outcome for women with the antiphospholipid syndrome? A randomized controlled trial. Am J Obstet Gynecol 183:1008, 2000.

130. Clifford K, Rai R, Watson H, Regan L: An informative protocol for the investigation of recurrent miscarriage: preliminary experi-ence of 500 consecutive cases. Hum Reprod 9:1328, 1994.

131. Yetman DL, Kutteh WH: Antiphospholipid antibody panels and recurrent pregnancy loss: prevalence of anticardiolipin antibodies compared with other antiphospholipid antibodies. Fertil Steril 66:540, 1996.

132. Branch DW, Silver R, Pierangeli S, et al: Antiphospholipid anti-bodies other than lupus anticoagulant and anticardiolipin anti-

bodies in women with recurrent pregnancy loss, fertile controls, and antiphospholipid syndrome. Obstet Gynecol 89:549, 1997.

133. Branch DW, Rote NS, Dostal DA, Scott JR: Association of lupus anticoagulant with antibody against phosphatidylserine. Clin Immunol Immunopathol 42:63, 1987.

134. Branch DW, Silver RM, Blackwell JL, et al: Outcome of treated pregnancies in women with antiphospholipid syndrome: An update of the Utah experience. Obstet Gynecol 80:614, 1992.

135. Oshiro BT, Silver RM, Scott JR, et al: Antiphospholipid antibod-ies and fetal death. Obstet Gynecol 87:489, 1996.

136. Lockwood CJ, Romero R, Feinberg RF, et al: The prevalence and biologic signifi cance of lupus anticoagulant and anticardio-lipin antibodies in a general obstetric population. Am J Obstet Gynecol 161:369, 1989.

137. Pattison NS, Charnley LW, McKay EJ, et al: Antiphospholipid antibodies in pregnancy: Prevalence and clinical associations. Br J Obstet Gynaecol 100:909, 1993.

138. Lima F, Khamashta MA, Buchanan NM, et al: A study of sixty pregnancies in patients with the antiphospholipid syndrome. Clin Exp Rheumatol 14:131, 1996.

129. Pauzner R, Dulitzki M, Langevitz P, et al: Low molecular weight heparin and warfarin the treatment of patients with antiphospho-lipid syndrome during pregnancy. Thromb Haemost 86:1379, 2001.

140. Huong DLT, Wechsler B, Bletry O, et al: A study of 75 pregnan-cies in patients with antiphospholipid syndrome. J Rheumatol 28:2025, 2001.

141. Branch DW, Dudley DJ, Mitchell MD, et al: Immunoglobulin G fractions from patients with antiphospholipid antibodies cause fetal death in BALB/c mice: A model for autoimmune fetal loss. Am J Obstet Gynecol 163:210, 1990.

142. Moodley J, Bhoola V, Duursma J, et al: The association of antiphospholipid antibodies with severe early onset preeclamp-sia. S Afr Med J 85:105, 1995.

143. Lockshin MD, Druzin ML, Qamar T: Prednisone does not prevent recurrent fetal death in women with antiphospholipid antibody. Am J Obstet Gynecol 160:439, 1989.

144. Polzin WJ, Kopelman IN, Robinson RD, et al: The association of antiphospholipid antibodies with pregnancy complicated by fetal growth restriction. Obstet Gynecol 78:1108, 1991.

145. Miyakis S, Lockshin MD, Atsumi T, et al: International con-sensus statement on an update of the classifi cation criteria for defi nite antiphospholipid syndrome (APS). J Thromb Haemost 4:295, 2006.

146. Kutteh WH: Antiphospholipid antibody-associated recurrent pregnancy loss: treatment with heparin and low-dose aspirin is superior to low-dose aspirin alone. Am J Obstet Gynecol 174:1584, 1996.

147. Silver RM, Porter TF, van Leeuwen I, et al: Anticardiolipin anti-bodies: Clinical consequences of “low titers.” Obstet Gynecol 87:494, 1996.

148. Rai R, Cohen H, Dave M, Regan L: Randomised controlled trial of aspirin and aspirin plus heparin in pregnant women with recurrent miscarriage associated with phospholipid antibodies (or antiphospholipid antibodies). BMJ 314:253, 1997.

149. Farquharson RG, Quenby S, Greaves M: Antiphospholipid syn-drome in pregnancy: a randomized, controlled trial of treatment. Obstet Gynecol 100:408, 2002.

150. Caruso A, de Carolis S, Ferrazzani S, et al: Pregnancy outcome in relation to uterine artery fl ow velocity waveforms and clini-cal characteristics in women with antiphospholipid syndrome. Obstet Gynecol 82:970, 1993.

151. Dreyfus M, Hedelin G, Kutnahorsky R, et al: Antiphospho-lipid antibodies and preeclampsia: A case-control study. Obstet Gynecol 97:29, 2001.

152. Branch DW, Porter TF, Rittenhouse L, et al: Antiphospholipid antibodies in women at risk for preeclampsia. Am J Obstet Gynecol 184:825, 2001.

153. Cowchock FS, Reece EA, Balaban D, et al: Repeated fetal losses associated with antiphospholipid antibodies: A collaborative randomized trial comparing prednisone with low-dose heparin treatment. Am J Obstet Gynecol 166:1318, 1992.

154. Ginsberg JS, Greer I, Hirsh J: Use of antithrombotic agents during pregnancy. Chest 119:122S, 2001.

155. Erkan D, Merrill JT, Yazici Y, et al: High thrombosis rate after fetal loss in antiphospholipid syndrome: Effective prophylaxis with aspirin. Arthritis Rheum 44:1466, 2001.

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156. Fausett MB, Vogtlander M, Lee RM, et al: Heparin-induced thrombocytopenia is rare in pregnancy. Am J Obstet Gynecol 185:148, 2001.

157. Clark AL, Branch DW, Silver RM, et al: Pregnancy complicated by the antiphospholipid syndrome: Outcomes with intravenous immunoglobulin therapy. Obstet Gynecol 93:437, 1999.

158. Branch DW, Peaceman AM, Druzin M, et al: A multicenter, placebo-controlled pilot study of intravenous immune globulin treatment of antiphospholipid syndrome during pregnancy. The Pregnancy Loss Study Group. Am J Obstet Gynecol 182:122, 2000.

159. Pattison NS, Chamley LW, Birdsall M, et al: Does aspirin have a role in improving pregnancy outcome for women with the antiphospholipid syndrome? A randomized controlled trial. Am J Obstet Gynecol 183:1008, 2000.

160. Ginsberg JS, Greer I, Hirsh J: Use of antithrombotic agents during pregnancy. Chest 119:122S, 2001.

161. Silman AJ, Hochberg MC (eds): Epidemiology of the Rheumatic Diseases, 2nd ed. Oxford University Press, 2001.

162. Kong YY, Yoshida H, Sarosi I, et al: OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature 397:315, 1999.

163. MacGregor AJ, Snieder H, Rigby AS, et al: Characterizing the quantitative genetic contribution to rheumatoid arthritis using data from twins. Arthritis Rheum 43:30, 2000.

164. Jawaheer D, Seldin JM, Anoms, CI, et al: Screening the genome for rheumatoid arthritis susceptibility genes. Arthritis Rheum 48:906, 2003.

165. Fisher SA, Lanchbury JS, Lewis CM: Meta-analysis of four rheumatoid arthritis genome-wide linkage studies: Confi rmation of a susceptibility locus on chromosome 16. Arthritis Rheum 48:1200, 2003.

166. Hench PS: The ameliorating effect of pregnancy on chronic atro-phic (infectious) rheumatoid arthritis, fi brositis, and intermittent hydrarthritis. Proc Mayo Clin 13:161, 1938.

167. Oka M: Activity of rheumatoid arthritis and plasma 17-hydroxy-corticosteroids during pregnancy and following parturition. Acta Rheumatol Scand 4:243, 1958.

168. Oka M: Effect of pregnancy on onset and course of rheumatoid arthritis. Ann Rheum Dis 12:227, 1953.

169. Persellini RH: The effect of pregnancy on rheumatoid arthritis. Bull Rheum Dis 27:922, 1977.

170. Betson JR, Dorn RV: Forty cases of arthritis and pregnancy. J Int Coll Surg 42:521, 1964.

171. Ostensen M, Husby G: A prospective clinical study of the effect of pregnancy on rheumatoid arthritis and ankylosing spondylitis. Arthritis Rheum 26:1155, 1983.

172. Silman AJ, Roman E, Beral V, Brown A: Adverse reproduc-tive outcomes in women who subsequently develop rheumatoid arthritis. Ann Rheum Dis 47:979, 1988.

173. Oka M, Vainio V: Effect of pregnancy on the prognosis and serology of rheumatoid arthritis. Acta Rheumatologica Scandi-navica 12:47, 1966.

174. Hazes JM, Dijkmans BAC, Vandenbroucke JP, et al: Pregnancy and the risk of developing rheumaoid arthritis. Arthritis Rheum 33:1770, 1990.

175. Ostensen M: Pregnancy in patients with a history of juvenile rheumatoid arthritis. Arthritis Rheum 34:881, 1991.

176. Ostensen M: Glucocorticosteroids in pregnant patients with rheumatoid arthritis. Z Rheumatol 59:II70, 2000.

177. Royal College of General Practitioners: Oral Contraceptives and Health: Interim Report. London, Pitman, 1974.

178. Gilbert M, Rotstein J, Cunningham C: Norethynodrel with mes-tranol in the treatment of rheumatoid arthritis. JAMA 190:235, 1964.

179. Bijlsma WJ, Huger-Bruning O, Thijssen JHH: Effect of estrogen treatment on clinical and laboratory manifestations of rheuma-toid arthritis. Ann Rheum Dis 46:777, 1987.

180. DaSilva JA, Hall GM: The effects of gender and sex hormones on outcome in rheumatoid arthritis. Bailliers Clin Rheumatol 6:196, 1992.

181. Kasukawa R, Ohara M, Yoshida H, Yoshida T: Pregnancy-associated a2-glycoprotein in rheumatoid arthritis. Intern Arch Allergy Applied Immunol 58:67, 1979.

182. Sany J, Clot J, Borneau M, Ardary M: Immunomodulating effect of human placenta-eluted gamma globulins in rheumatoid arthri-tis. Arthritis Rheum 25:17, 1982.

183. Klippel GL, Cerere FA: Rheumatoid arthritis and pregnancy. Rheum Dis Clin North Am 15:213, 1989.

184. Mannik M, Nardella FA: IgG rheumatoid factor and self-associa-tion of these antibodies. Clin Rheum Dis 11:551, 1985.

185. Nelson JL, Voigt LF, Koepsell TD, et al: Pregnancy outcome in women with rheumatoid arthritis before disease onset. J Rheu-matol 19:18, 1993.

186. Kaplan D: Fetal wastage in patients with rheumatoid arthritis. J Rheumatol 13:857, 1986.

187. Morris WIC: Pregnancy in rheumatoid arthritis and systemic lupus erythematosus. Aust N Z J Obstet Gynaecol 9:136, 1969.

188. Katz, JA, Antoni C, Keenan GF, et al: Outcome of pregnancy in women receiving infl iximab for the treatment of Crohn’s disease and rheumatoid arthritis. Am J Gastroenterol 99:2385, 2004.

189. Steen VD: Scleroderma and pregnancy. Rheum Dis Clin North Am 23:133, 1997.

190. Morrow J, Nelson JL, Watts R, Isenberg DA (eds): Autoimmune Rheumatic Diseases, 2nd ed. Oxford, UK, Oxford University Press, 1999.

191. Johnson RW, Tew MB, Arnett FC: The genetics of systemic sclerosis. Curr Rheumatol Reports 4:99, 2002.

192. LeRoy EC, Black C, Fleischmajer R, et al: Scleroderma (systemic sclerosis): classifi cation, subsets and pathogenesis. J Rheumatol 15:202, 1988.

193. Lambert NC: HLA-DQA1 as a risk factor for microchimerism: comment on the article by Artlett et al. Arthritis Rheum 50:2713, 2004.

194. Bianchi DW, Zickwolf GK, Weil GJ, et al: Male fetal progenitor cells persist in maternal blood for as long as 27 years postpartum. Proc Natl Acad Sci U S A 93:705, 1996.

195. Nelson JL: Maternal-fetal immunology and autoimmune disease: is some autoimmune disease auto-alloimmune or allo-autoim-mune? Arthritis Rheum 39:191, 1996.

196. Nelson JL: Microchimerism and the causation of scleroderma. Scand J Rheumatol Suppl 107:10, 1998.

197. Ohtsuka T, Miyamoto Y, Yamakage A, Yamazaki S: Quantita-tive analysis of microchimerism in systemic sclerosis skin tissue. Arch Dermatol Res 293:387, 2001.

198. Murata H, Nakauchi H, Sumida T: Microchimerism in Japanese women patients with systemic sclerosis. Lancet 354:220, 1999.

199. Selva-O’Callaghan A, Mijares-Boeckh-Behrens T, Prades EB, et al: Lack of evidence of foetal microchimerism in female Spanish patients with systemic sclerosis. Lupus 12:15, 2003.

200. Lambert NC, Stevens AM, Tylee TS, et al: From the simple detec-tion of microchimerism in patients with autoimmune diseases to its implication in pathogenesis. Ann N Y Acad Sci 945:164, 2001.

201. Steen VD, Conte C, Day N, et al: Pregnancy in women with systemic sclerosis. Arthritis Rheum 32:151, 1989.

202. Steen VD: Pregnancy in women with systemic sclerosis. Obstet Gynecol 94:15, 1999.

203. Silman AJ, Black C: Increased incidence of spontaneous abortion and infertility in women with scleroderma before disease onset: A controlled study. Ann Rheum Dis 47:441, 1988.

205. Black CM: Systemic sclerosis and pregnancy. Bailliere’s Clin Rheumatol 4:105, 1990.

206. Johnson TR, Banner EA, Winkelmann RK: Scleroderma and pregnancy. Obstet Gynecol 23:467, 1964.

206. Slate WG, Graham AR: Scleroderma and pregnancy. Am J Obstet Gynecol 101:335, 1968.

207. Weiner RS, Brinkman CR, Paulus HE: Scleroderma, CREST syndrome and pregnancy. Arthritis Rheum 29:51, 1986.

208. Giordano M, Valentini G, Lupoli S: Pregnancy and systemic sclerosis. Arthritis and Rheumatism 28:237, 1985.

209. Englert H, Brennan P, McNeil D, et al: Reproductive function prior to disease onset in women with scleroderma. J Rheumatol 19:1575, 1992.

210. Baethge BA, Wolf RE: Successful pregnancy with scleroderma renal disease and pulmonary hypertension in a patient using angiotensin converting enzyme inhibitors. Ann Rheum Dis 48:776, 1989.

Ch042-F06930.indd 1103Ch042-F06930.indd 1103 4/17/2007 5:38:39 PM4/17/2007 5:38:39 PM