Neonatal lupus erythematosus (NLE) is a rare disorder caused by the transplacental passage of maternal autoantibodies. Most mothers are healthy when they give birth to their baby, but some mothers have defined or undifferentiated autoimmune disorders. Overall, only 1% of infants with positive maternal autoantibodies develop NLE. The most common clinical manifestations of NLE are cardiac, dermatologic and hepatic in nature. 

While the features designated above may be considered essential to guide the clinician toward thinking about who gets lupus and how it commonly presents, eight organ systems may be involved in SLE. A number of validated measures have been developed for clinicians to use in scoring the degree of disease activity a patient with lupus has across these various domains. 

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The earliest signs and symptoms of lupus are often fatigue, hair loss (especially around the face), a sun-sensitive facial rash, and arthralgias. It is not unusual, however, to have a patient present with one very dramatic feature, such as nephritis or a pleural/pericardial effusion, in the setting of a significantly positive ANA titer. When the manifestations of disease are so dramatic, diagnosis should not wait for criteria. Such patients require prompt and well-coordinated subspecialty care.

Therapies for many of these complications are usually immunosuppressive and managed by the clinicians who prescribe them. However, follow-up is often left in the hands of primary-care providers. 

Role of primary care in persons with SLE

Primary-care providers monitoring lupus patients often find it challenging to identify which new events or complications are lupus-related. Not only do lupus symptoms vary widely, they come and go. Worsening symptoms signify a flare, while symptoms that are under control signify a remission.

Many lupus patients require lifelong community-based symptom and laboratory monitoring for their therapies. Such care requires coordination. Communication among the patient, the primary-care provider and the subspecialist is crucial.

Patients and clinicians can be encouraged by the fact that the 10-year survival of persons with SLE has vastly improved in recent decades. Safer and more successful treatment with immunosuppression — especially for severe disease, such as nephritis — along with the development of such renal-protective drugs as ACE inhibitors has made a critical difference. 

Many SLE patients with low disease activity are treated with sun protection, long-term hydroxychloroquine (Plaquenil), and such simple arthritis therapies as nonsteroidal anti-inflammatory drugs or acetaminophen.

Hydroxychloroquine is an antimalarial drug used in many patients with lupus. It modifies cell signaling and, as a result, reduces the activation of dendritic cells that mitigate the inflammatory process. Yearly ophthalmologic exams for those on hydroxychloroquine are necessary to screen for toxicity related to that drug. Two distinct areas of the eye — the cornea and the macula — may be affected. Many patients are on this medication indefinitely, as hydroxy­chloroquine is used for maintenance therapy as well as treatment. Encouraging patients to remain on the medication and get the requisite eye exams is important.

Persons who have concomitant lupus and cardiovascular disease will experience acceleration of their cardiovascular disease, especially if they have been treated with glucocorticosteroids. Aggressive modification of cardiovascular risk factors usually falls to the primary-care provider and should be started early. Many patients will require a statin. 

Some persons with SLE have the antiphospholipid syndrome and a prothrombotic state and may be on anticoagulation. In some communities, monitoring the antiphospholipid syndrome falls to the primary-care provider. The needed specific form of anticoagulation and duration of treatment is highly individualized to the patient and requires good clinician coordination to avoid overtreatment or undertreatment.

Fetal loss related to several factors may be higher in lupus patients. Women with SLE should try to plan their pregnancies for times of low disease activity and should be followed by clinicians specializing in high-risk pregnancy. 

Because lupus is seen primarily in women of childbearing age, birth-control issues are very important. Effective contraception and proper understanding of contraceptive options are important, as unwanted pregnancy can result in health risks to the mother and fetus.

Overall, OCs have a number of positive health effects. However, estrogen-containing OCs increase the risk of clotting events and need to be used carefully in patients with an underlying clotting disorder, such as those who have antiphospholipid antibodies. The well-known association between lupus and estrogen has added to the hesitancy to prescribe OCs to patients with lupus. Older confirmatory studies reported disease flares when women with lupus received a combination birth-control pill containing both estrogen and a progestin.

However, recent studies have shown that OC use does not increase the risk of lupus flare, time to first flare or global disease activity in women with mild lupus. Low-dose OCs are probably safe in women with mild lupus but should be avoided in women at increased risk of clotting or in those with moderate to severe disease. This includes women with antiphospholipid antibodies, the antiphospholipid syndrome or the nephrotic syndrome (i.e., renal lupus, which is characterized by marked protein in the urine). Progestin-only OCs are better choices if tolerated. 

The kidney is the visceral organ most commonly involved in SLE. Although only an estimated 50% of patients with SLE develop clinically evident renal disease, biopsy studies demonstrate some degree of renal involvement in almost all patients with moderate to severe disease. Kidney failure is a leading cause of death.

Sometimes the renal status of a lupus patient with treated renal disease deteriorates slowly, but it can also deteriorate precipitously. BP control and renal-protective therapy are lifelong and require monitoring. At all office visits, analysis for proteinuria should be performed and often quantified.

Screening for the complications of corticosteroid use often falls to the primary-care provider as well. Dual-energy x-ray absorptiometry scanning, calcium supplementation, monitoring of vitamin D levels, screening for cataracts and recommending the use of polarized sunglasses are essential. 

Fatigue, depression and fibromyalgia are quite common in the lupus patient. These symptoms do not improve with immunosuppression or when severe disease goes into remission. Approximately 10% of SLE patients will develop hypothyroidism. Dry mouth and eyes are common. All these health problems will come under the purview of the primary-care provider.

Self-care. One of the more important steps SLE patients can take is to protect themselves from the sun. Photosensitivity occurs in approximately 75% of SLE patients, and sun protection is the cornerstone of the management of cutaneous lupus.

A number of good strategies are available, from sunblocks to protective clothing to timed exposure. Patients who practice good sun protection will usually require vitamin D supplementation. Smoking not only drives hypertension, it also interferes with the benefit of hydroxychloroquine and seems to worsen skin disease in and of itself. Regular exercise helps prevent fatigue and joint stiffness.

Biologic therapies 

The age of biologics has arrived. Biologics are injected or infused agents rarely used by primary-care providers. While that is best practice, primary-care providers must be aware of these medications and their potential adverse events. 

Most currently used therapies for lupus are borrowed from other diseases and conditions and are often used off label. Belimumab (Benlysta), approved by the FDA in early 2011, is the first drug to have been developed specifically to treat lupus. Belimumab is a novel biologic agent that targets B-cell maturation and survival.

A human monoclonal antibody, belimumab is infused monthly and binds to B-cell surface molecules called “BLyS” (bliss). These cell-surface molecules are drivers of intercellular signaling. By binding to BLyS, the inhibitor blunts the survival of B-cells, including autoreactive B-cells and reduces the differentiation of B-cells into antibody-producing plasma cells. 

Patients with mild lupus may not ever need immunosuppressive or biologic treatment. They may be able to keep their symptoms under control with the relatively safe anti-malaria drugs, such as hydroxychloroquine. Patients with the most severe disease, including lupus affecting the kidneys or brain, benefit from more aggressive treatments.

In some ways, patients in the middle category are more challenging to treat. Most of the benefit of belimumab seems to come from improvement of skin rash and ulcers in the nose and mouth as well as diminished corticosteroid use. Skin symptoms can be prominent drivers of patient disability and prominent factors in ongoing corticosteroid use.

Primary-care providers need to be aware that live vaccines should not be given for 30 days before use of belimumab or any other biologic concurrently, because the biologic may blunt the response to immunizations. Persons being considered for belimumab are also typically prescreened for tuberculosis, hepatitis B and hepatitis C.

As with many biologic agents, serious infections are the greatest risk. These agents are not stopped for routine low-grade infections, such as colds, or for other minor infections or minor surgeries, such as dental work or skin biopsies. Do not decide whether to hold therapy without consulting the prescriber. Infectious complications related to active SLE and immunosuppressive treatment are still the most common cause of death in early active SLE.

Based on experience with such other biologic agents as the anti-tumor necrosis factor inhibitors, persons on biologics may be less likely to develop life-threatening infections than are patients on aggressive immunosuppression with corticosteroids or cytotoxic agents, such as those used to treat nephritis or vasculitis. 

The future is here

These so-called targeted therapies have long been in development. Derived from basic science elucidation of cell-signaling mechanisms, some are cell-surface-based, like the biologic abatacept (Orencia), which affects T-cell receptors; B-cell-based, like belimumab and rituximab (Rituxan); or in-development agents, like Janus tyrosine kinase modifiers, which approach the cell signaling pathways from within the cell rather than on the cell surface.

More easily tolerated pulse immunosuppressive approaches now include the use of rituximab and mycophenolate (Cellcept) for severe manifestations. These are far better-tolerated approaches. Such newer, less-difficult-to-manage anticoagulants as dabigatran (Pradaxa) for long-term anticoagulation may also help SLE patients feel that the treatments are not worse than the disease. Finally, broad-spectrum sunblock and effective sun-protective clothing are available and affordable.

Both the basic science and clinical-care pipelines for SLE are exciting. Hopefully, they will shift the risk/benefit ratio of treatment and improve the lives of patients over the entire clinical spectrum of SLE.

Joan McTigue, MS, PA-C, practices in the division of rheumatology and Byron Croker, PhD, MD, is a professor in the department of pathology, immunology and laboratory medicine at the University of Florida College of Medicine and the VA Medical Center, both in Gainesville. The authors have no relationships to disclose relating to the content of this article.

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All electronic documents accessed January 9, 2011.

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