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Clinical Reviews


Management of lupus flare

If disease is handled quickly, mother and fetus usually fare well, but loss of mother, fetus, or both is not always avoidable

May 2006 · Vol. 18, No. 5

IN THIS ARTICLE

It was not that long ago that systemic lupus erythematosus (SLE) was considered a contraindication to pregnancy. With improved understanding and improved treatment options, many women with SLE have successful pregnancies.

Still, lupus flare during pregnancy is a medical and obstetric emergency, and a persistent obstetric dilemma. The most difficult dilemma is how to differentiate a lupus flare from preeclampsia, as both may present with worsening blood pressure, proteinuria and deteriorating renal function, and edema.1

If anticipated and handled quickly, most outcomes will be good for mother and fetus, but occasional severe consequences of lupus flare resulting in loss of mother, fetus, or both, are not always avoidable.

90% of lupus cases are in reproductive-age women

SLE is an autoimmune disease that affects virtually all organ systems. Specific clinical and laboratory criteria must be met to establish the diagnosis. About 90% of all cases are in women in the reproductive age range, with an overrepresentation of African Americans. The overall prevalence of lupus is approximately 15 to 50 per 100,000 population (both sexes, all ages).

Counsel the patient, gauge the risks

The most important first step is the preconception visit. While early prenatal care is better than late presentation, the best option is a preconception visit so that the relative risks of pregnancy may be assessed and discussed, and alterations to medication regimens can be made prior to establishment of a pregnancy (TABLE 1).2

As lupus patients are at increased risk for early pregnancy loss, the preconception visit may also allow for identification of risk factors and risk assessment. A recent study3 proposed the acronym PATH to help identify high-risk patients:

Proteinuria
Antiphospholipid syndrome
Thrombocytopenia
Hypertension

TABLE 1

Factors that increase the likelihood of a good outcome

  • Disease quiescence for more than 6 months prior to conception
  • Normal renal function (creatinine less than 0.7 mg/dL, but not more than 1.2 mg/dL)
  • Normal preconception blood pressure, preferably without the need for antihypertensive medication
  • Minimal doses or no need for immunosuppressive therapy (prednisone less than or equal to 10 mg/day)
  • Absence of antiphospholipid antibodies/antiphospholipid syndrome
  • No history of adverse pregnancy outcome
  • No history of thrombosis (not a factor specific to lupus)

Disease quiescence is not an infallible sign

One of the better indicators of a favorable prognosis for pregnancy is disease quiescence for at least 6 months, and preferably more than 12 months, prior to conception. A number of factors go into the definition of “disease quiescence” including blood pressure control, need for immunosuppressive medication, renal function, and overall physician global assessment, to name but a few, and these factors will be briefly reviewed.

Renal disease and hypertension

Nephritis

Patients with SLE not infrequently have hypertension secondary to renal involvement, specifically lupus nephritis. Nephritis is generally the most serious of lupus manifestations, and if not aggressively treated can lead to nephrotic syndrome, edema and end-stage renal disease in more than 50% of patients within 2 to 3 years.4 Patients with this complication, especially in the setting of proliferative glomerulonephritis, have a poorer prognosis for pregnancy.

Accelerated atherosclerotic vascular disease may also affect these patients—in addition to nephritis—and may herald poor placental function and fetal growth.

Hypertension

When there is coexisting hypertension, antihypertensive agents that are safe for use in pregnancy are preferred, such as beta-blockers, calcium channel blockers, and alpha methyldopa. Angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers should be avoided during the second and third trimester due to adverse effects on fetal renal function.

Diagnosis of antiphospholipid syndrome

Patients with SLE may have associated antiphospholipid antibodies. Screening tests such as antinuclear antibodies (ANA) and activated partial thromboplastin times (aPTT) are not very reliable and have relatively poor positive predictive value, although in the case of ANA, when the diagnosis of lupus is suspected, repetitive negative ANA titers make SLE unlikely. Anti-double stranded DNA is quite specific to SLE, and elevations in the Anti-ds-DNA titers correlate well with SLE disease activity, and can be helpful in making the diagnosis of a lupus flare.

Other antibodies such as Anti-Ro (SS-A) and Anti-La (SS-B) may be useful for predicting and managing for neonatal lupus syndromes, but are not very useful in maternal management.

Additional tests for anticardiolipin, lupus anticoagulant (Russell viper venom test), and beta-2-glycoprotein are also of use.

Diagnosis of APLS requires positive serologies (at least twice, separated by a minimum of 2 weeks), thrombosis, and/or recurrent early pregnancy loss.

Does pregnancy bring on lupus flare?

Whether or not pregnancy increases the incidence of lupus flare is a continuing controversy, stemming from variable definitions of “flare.” Universally accepted criteria have been lacking in published studies.5 Consensus indicates, however, that lupus flares are more common in pregnancy than in nonpregnant controls.

Some studies suggest that SLE flares are more common in the second and third trimesters, but the data are not clear on this point.6 This variability is due in part to differences in disease activity of the patients when they entered the studies.

One may conclude that for any given patient it is impossible to accurately predict whether she will experience a lupus flare, and if she does, when it will occur, and to what level of severity it will rise.

The mainstay of management: is to aggressively treat the lupus flare before irreparable maternal harm occurs

Nephritis is the most serious of lupus manifestations, and if not aggressively treated, can lead to nephrotic syndrome, edema, and end-stage renal disease in more than 50% of patients within 2 to 3 years

Potential adverse outcomes

Predicting who will have a lupus flare and its degree of severity may be difficult if not impossible, but there is little doubt that a significant percentage of women with SLE will experience a flare of some degree. How a lupus flare will affect the pregnancy is uncertain, as well. SLE activity in pregnancy has been linked to adverse outcomes ranging from increased risk of miscarriage to preterm delivery.

Diagnosis and initial management

Preventive treatments

Steroids. SLE flares being somewhat more common in pregnancy than in the nonpregnant patient has led to the belief in some centers that prophylactic administration of steroids to prevent flares would have beneficial pregnancy effects. To date, however, no conclusive evidence supports this approach. In fact, steroid use in particular has been associated in some series with higher rates of premature rupture of membranes (both term and preterm), preeclampsia, and gestational diabetes.

Hydroxychloroquine. It has been suggested that SLE patients whose disease has been controlled with hydroxychloroquine need not discontinue this therapy due to the pregnancy.

The risks of this agent in pregnancy—which are not thought to be significant—are far outweighed by the potential maternal and fetal benefits of averting a lupus flare.

The differential diagnosis

It is imperative, before starting a management strategy, to determine if in fact a lupus flare is the correct diagnosis. Many features of a lupus flare can be confused with features of normal pregnancy, or pregnancy associated complications such as preeclampsia (TABLE 2). The differential diagnosis includes most commonly preeclampsia, but diagnoses such as immune thrombocytopenia, poststreptococcal glomerulonephritis, and hemolyticuremic syndrome must also be considered.

TABLE 2

Clinical features of preeclampsia vs lupus flare*

FEATURE

PREECLAMPSIA

LUPUS FLARE

Hypertension

Present

Present

Proteinuria

Present

Present

Edema

Present

Present

Malar rash

Absent

Present

Arthritis

Absent

Present

Photophobia

Absent

Present

Oral ulcers

Absent

Present

Serositis

Absent

Present

Seizures

Present

Present

*Denoting presence or absence does not suggest absolute presence or absence, but rather, the likely compatibility with the diagnosis.

Is it lupus flare or preeclampsia?

The most frequent cause for uncertainty is whether the diagnosis is lupus flare or preeclampsia. It is important to find their distinguishing features, because therapy for these 2 conditions is radically different.

A few easy tests can help (TABLE 3), but the most important are:

  • positive ANA screen,
  • active urinary sediment,
  • hypocomplementemia (C3, C4, or CH 50—the latter is an assay of total serum hemolytic complement), and
  • high titers of anti-ds-DNA.

Additional tests for anticardiolipin antibody, anti-Ro and anti-La, and lupus anticoagulant may be of some prognostic importance, but do not help differentiate a lupus flare from other similar entities.7

TABLE 3

Tests that help tell lupus flare from preeclampsia

TEST

PREECLAMPSIA

LUPUS FLARE

PTT

Usually normal

May be abnormal

Platelet count

Normal or reduced

Normal or reduced

Urinalysis

Normal sediment

Active sediment

ANA

Usually negative

Usually positive

Anti-ds-DNA

Usually negative

Usually positive

AST

May be abnormal

May be abnormal

ALT

May be abnormal

May be abnormal

Lupus anticoagulant

Negative

May be positive

Hemolysis

May be present

Usually absent

Complement levels

Usually normal

Usually reduced

WBC

Increased

Decreased

SFlt-1*

Increased

Normal

*Investigational and not widely available for clinical use.

Aggressive drug therapy is imperative

Management of lupus flare depends on aggressive drug therapy. The choice of therapy is determined by whether the patient is currently on an immunosuppressive regimen, and if so, the types and doses of medications, and whether this is her first flare during the pregnancy.

The usual initial therapy is glucocorticoids, or the so-called steroid “pulses,” typically consisting of very high doses of steroids administered either orally or intravenously over a 3-day period. This strategy has had some success in ameliorating lupus flares, particularly lupus nephritis.

Dosage. Methylprednisolone, 1,000 mg/day intravenously, for 3 days followed by oral prednisone, 0.5 to 1.0 mg/kg per day, provides better survival than lower steroid doses in patients with diffuse proliferative glomerulonephritis.

The intravenous route is preferred because of its rapid response, though long-term outcome is probably not altered.

Without warning, a catastrophe

Even a healthy lupus patient who fulfills all the accepted criteria for a safe pregnancy can take a disastrous turn

A 28-year-old G0 with SLE since age 11 presented for preconception consultation. She was on no medications, with normal blood pressure and no evidence of disease activity for more than 2 years. Physical examination and laboratory findings were normal, including serum creatinine 0.7 mg/dL; less than 30 mg protein in a 24-hour urine collection; creatinine clearance 110 mL/min; and lupus anticoagulant, anti-cardiolipin antibodies, anti-Ro, and anti-La were negative.

Green light

One year later, she returned for follow-up and to inform her obstetrician that she was getting married and wished to conceive. She had no SLE activity since her last visit. Repeat laboratory studies were unchanged. She was given medical clearance to attempt conception, and told that she met all the criteria that would make her a suitable candidate for pregnancy.

7 weeks All findings normal

Three months later, a single intrauterine gestation of approximately 7 weeks was confirmed. Laboratory studies and physical examination were normal, and she reported no SLE-related symptoms.

11 weeks Lupus flare

Four weeks later, at her next prenatal visit, a 3+ proteinuria and blood pressure of 140/90 mm Hg were noted. Her rheumatologist made a diagnosis of lupus flare with probable nephritis. Oral prednisone was begun, with rapid taper. Clinical response was good. She remained on prednisone, 10 mg/day.

14 weeks Recurrence

A recurrence of lupus flare with probable nephritis was diagnosed and her oral prednisone dose was increased. One week later the patient seemed to worsen. She was admitted for steroid pulse therapy. Initially, she improved, but then continued to worsen.

16 weeks Cyclophosphamide therapy

After counseling, she was begun on cyclophosphamide, but her condition continued to deteriorate. Renal function worsened and the patient, now with nephrotic proteinuria, was profoundly edematous and hypoalbuminemic with a rising serum creatinine.

18 weeks Dilatation and evacuation

Ultrasound evaluation of the fetus revealed evidence of early growth restriction. After much discussion, the patient underwent dilatation and evacuation.

Cerebral infarct and anticoagulation

Continued...
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