Management Of Systemic Lupus ... Health Article

The most important cause of fetal loss in mothers with SLE is the presence of active disease during pregnancy. ¹⁰⁰ It is essential to suppress disease during this period, and many experts recommend administration of glucocorticoids (using preparations such as prednisone or prednisolone that do not cross the placenta in active forms, while avoiding hydrocortisone, betamethasone, and dexamethasone, which do cross the placenta in active forms and, thus, expose the fetus ¹⁰¹) in doses required to maintain suppression of serious disease activity. There is debate regarding whether or not betamethasone or dexamethsone given antenatally are associated with low birth weights, reduced brain weights, and later maturational abnormalities of brain development in human fetuses; ¹⁰² these become issues when the goal is to treat the fetus with neonatal lupus myocarditis or prematurity. In general, systemic treatment with fluorinated glucocorticoids such as betamethasone and dexamethasone should be avoided in treatment of pregnant women with SLE. Some women (with or without SLE) experience fetal loss in the presence of antiphospholipid antibodies, especially if the antibodies are high-titer IgG anticardiolipin or the lupus anticoagulant. There are several therapeutic choices in these women. First, if there have been no previous fetal losses, the physician can choose not to intervene; many pregnancies go well. The higher the number of previous fetal losses (especially if there are no live births), the lower the chance that subsequent pregnancies will have a good outcome. ¹⁰³

Several studies have addressed the benefits of different interventions. The administration of aspirin alone has had mixed results, with some studies suggesting a higher birth rate of live infants, and others suggesting no positive effects. ^{103, 104, 105} Similarly, the use of glucocorticoids along with aspirin has had advocates, but the majority of data suggest that moderate to high doses of glucocorticoids do not improve fetal survival and are associated with considerable maternal toxicity, including hypertension and diabetes. ^{105, 106, 107} There is general agreement that anticoagulation with heparin or low-molecular-weight heparin are effective in improving live birth rates. ^{103, 104, 106} Both treatments probably are associated with loss of maternal bone mass, sometimes leading to vertebral fractures. A recent clinical trial showed that 5000 units of heparin daily was not better than aspirin alone ¹⁰⁸ ; studies using 5000 units of heparin twice daily have shown benefits, and that is the dose I recommend. Dicumarol (Coumadin) is teratogenic when administered in the first trimester and should be avoided during that time. In general, with use of heparin (usually given with aspirin) or low-molecular-weight heparin, the rate of live births is 70 to 90 percent. ^{103, 104, 105, 106} Frequent fetal and maternal monitoring is critical to good outcomes with any of these interventions: These high-risk pregnancies often require early delivery in response to clinical evidence of fetal distress.

Several lupus syndromes can occur in neonates, ^{109, 110, 111, 112} usually associated with maternal antibodies to Ro. Manifestations can include rash (the most frequent), congenital heart block, cardiomyopathy, hepatobiliary disease, and thrombocytopenia (the last of which is more strongly associated with maternal thrombocytopenia than anti-Ro). The rash consists of plaques of slightly raised erythema that clear spontaneously over several weeks as maternal IgG is metabolized. Congenital heart block can be fatal; in children who survive neonatal cardiac lupus, subsequent cardiomyopathy or total heart block are common. ¹¹¹ Therefore, patients with SLE who are pregnant should be screened for anti-Ro, and fetal heart rates should be closely monitored in women with anti-Ro so that early delivery and cardiac pacing can be offered if heart block occurs. Treatment of antibody-positive women with prior fetuses with congenital heart block, or evidence of cardiac distress in a current fetus, has been reported. Glucocortoids (dexamethasone or betamethasone), IV gamma globulin, or plasmapheresis have been administered in an attempt to prevent congenital heart block. ^{109, 110, 111, 112} It is likely that the therapies are effective in suppressing fetal myocarditis as well as fetal pleural effusions, ascites, and hydrops, but chances of reversing heart block, once established, are probably poor. ^{111, 112}

Thrombocytopenia can occur in newborns, probably from maternal antiplatelet antibodies crossing the placenta. The mother may or may not have thrombocytopenia. It is short-lived in the newborn but may be associated with bleeding. Treatment of maternal thrombocytopenia with glucocorticoids is recommended.

Although a minority of patients experience severe disease flares or worsening during pregnancy, most women do well ¹⁰⁰. Patients at high risk for adverse effects include those with active renal, cardiac, pulmonary, or CNS lupus. Patients should be examined at frequent intervals during pregnancy. Signs of increasing disease activity or impending preeclampsia include rising liver enzymes (preeclampsia or HELLP [hemolysis, elevated liver enzymes, low platelets] syndrome), hypertension (either SLE or preeclampsia), new or increasing proteinuria (either SLE or preeclampsia), thrombocytopenia (lupus), and falling levels of serum complement (lupus). These signs indicate a need for aggressive intervention to treat both mother and fetus.

Patients with the thrombocytopenia of SLE may benefit from several therapies in addition to immunosuppression. Most authorities recommend high-dose glucocorticoids (60 to 100 mg prednisone daily) as the initial intervention in adults. Platelet counts begin to rise 3 to 10 days after introduction of glucocorticoids; the increase is usually sustained. Administration of IV gamma globulin (0.4 g/kg on each of 2 to 5 days) for 4 to 7 days is usually followed by rapid increase in platelet counts, which is usually transient. A study that compared prednisone alone to IV gamma globulin alone to combination therapy in idiopathic immune thrombocytopenia showed response appearing in a median of 5 days for each single-drug therapy and in 3 days for combination therapy. ¹¹³ Relapse rates and the percentage of patients that required subsequent splenectomy were similar in the three groups.

Splenectomy ^{114, 115} should be considered whenever glucocorticoid or IV gamma globulin therapy is ineffective, either initially or when tapered or discontinued. The objective of therapy is to maintain adequate levels of platelets (50,000/mm ³ or higher). The efficacy of splenectomy in lupus cytopenias is somewhat controversial. If the criterion of permanently sustained normal counts in the absence of any maintenance therapies is used, the response rate may be as low as 15 percent. ¹¹⁶ If the criterion of adequate platelet counts with or without requirement for additional maintenance therapies is used, about 90 percent of patients have good initial responses and 65 to 70 percent have good sustained responses. ^{114, 115} Asplenic patients are at increased risk for infection with encapsulated microorganisms, particularly Pneumococcus ; patients should receive pneumococcal vaccine before splenectomy if possible.

Danazol, an anabolic steroid, may be useful in some cases of SLE thrombocytopenia. ^{117, 118} Administration of danazol, 400 to 800 mg daily, may increase platelet counts to acceptable levels over 2 to 12 weeks. Danazol has been effective in some patients who failed on glucocorticoid therapy, splenectomy, and cytotoxic drugs. Side effects of danazol include weight gain, lethargy, myalgia, mild virilization, menopausal symptoms, rash, pruritus, hepatic tumors, hepatitis, and pancreatitis. ^{117, 118, 119}

Cyclosporine (Neoral) is also useful in some patients with thrombocytopenia. ^{70, 71} Doses of 3 to 5 mg/kg/day should be initiated; platelet counts usually increase in 2 to 3 weeks, and the dose can be slowly tapered to maintain the response. Use of cyclosporine has been discussed previously.

Cytotoxic drugs, including cyclophosphamide (daily or intermittent IV pulses), azathioprine, and vinca alkaloids are sometimes effective in patients with thrombocytopenia who are steroid and splenectomy resistant. See previous discussion for dosage and administration recommendations.

A recent French retrospective review of patients with SLE and "severe" thrombocytopenia (defined as platelet counts less than 50 × 10 ⁹ per liter) ¹¹⁴ concluded that glucocorticoids plus another intervention result in better long-term control than glucocorticoids alone. Initial response to glucocorticoid therapy (1 mg/kg per day) resulted in improvement in 80 percent, but the improvement was sustained in only 22 percent. In contrast, combinations of prednisone and hydroxychloroquine or danazol or splenectomy increased long-term responses to 50 to 65 percent. Responses to glucocorticoids plus cytotoxic agents were not sustained as well; however, the numbers of patients in each of the subgroups studied was too small to be confident that these data are applicable to all SLE patients. Because some patients have only one major episode of severe thrombocytopenia, I recommend beginning with glucocorticoids alone. Additional strategies can be introduced if the problem recurs. In most patients with stable platelet counts at or above 40,000/liter, I do not recommend treatment unless the counts are steadily falling, bleeding is or has occurred during episodes of moderate thrombocytopenia, there is additional risk for bleeding, or some other manifestation of SLE requires intervention. Hemolytic anemia of SLE, if severe, should also be treated initially with high-dose glucocorticoids. Splenectomy, danazol, cyclosporine, and cytotoxic drugs are useful in some steroid-resistant individuals.

The leukopenia (usually lymphopenia) of SLE is rarely associated with important clinical sequelae. Rare patients with granulocytopenia, however, experience recurrent bacterial infections that may resolve after the granulocyte count is increased by treatment with glucocorticoid therapy, cyclosporine, splenectomy, or G-CSF. Treatment with G-CSF has been successful in lupus granulocytopenia if doses are kept at the minimum required to maintain absolute neutrophil counts above 1000/mm ³. ¹²⁰ High doses run the risk of activating SLE. ^{120, 121} Use of G-CSF to manage granulocytopenia secondary to cyclophosphamide or other cytotoxic therapies in patients with SLE is reasonable, provided the risk of infection is greater than the risk of flaring the SLE.